Manual of Diabetes mellitus

Diabetes mellitus (contents)

2009-02-01T01:49:00.000-08:00

General information

Type 1 Diabetes mellitus

Type 2 Diabetes mellitus

Diabetes and pregnancy

Investigations

Management

Oral antidiabetic drugs

Insulin

Diabetic emergencies

Complications of diabetes

Diabetes insipidus

Diabetes insipidus

Erectile dysfunction and diabetes

Diabetes and other conditions

New developments

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What is diabetes mellitus?

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Diabetes mellitus is a metabolic disorder. patients with diabetes mellitus have a high blood sugar (glucose) due to the lack of insulin or due to increased resistance to insulin. Diabetes mellitus is the new world pandemic. Now diabetes is considered as a part of metabolic syndrome.

There are four types of diabetes;

Type 1 diabetes mellitus ( due to lack of insulin)
Type 2 diabetes mellitus (due to increased resistence to insulin)
Type 3 diabetes mellitus ( secondary to other illness)
Type 4 diabetes mellitus (diabets mellitus during pregnancy)

Universal blue circle symbol for diabetes

clinical features, management and different aspects of diabetes mellitus depend on the type of diabetes mellitus.

Clinical presentation of diabetes mellitus

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There are four ways of presentations;

asymptomatic( incidental finding)
presentation with acute symptoms
subacute presentation
presentation with complications

Asymptomatic presentation

This is the commonest presentation and it is an incidental finding during routine examination or medical examination for insurance/ license/ employment

There is no evidence of ill health

Elevated blood sugar level could be a finding at those routine examinations. There can be glucose in the urine as well, even though it is a clue of hyperglycemia, not diagnostic

Further investigations should be done

Acute presentation

Usually these patients present with classic triad of symptoms;

polyuria
polydipsia
weight loss

They have a brief history (2-6 weeks)

Usually patients with type 2 diabetes present like this

Subacute presentation

These patients have symptoms over a period of months or years. Common symptoms are polyuria, polydipsia, and weight loss.

They can also present with non-specific symptoms such as:

lack of energy
visual blurring
pruritus vulvae
balanitis

This is the usual presentation of type 2 diabetes mellitus.

Presentation with complications

Types of complications are;

1. microvascular
2. macrovascular
3. others

Microvascular complications;

1. nephropathy
2. neuropathy
3. retinopathy

Macrovascular complications;

1. Ischemic heart disease
2. stroke
3. peripheral vascular disease

Others;

1. staphylococcal skin infections (furuncles, carbuncles, abscesses)
2. wound infections

3. fungal infections

What are the types of diabetes mellitus?

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DEFINITION

Diabetes is a metabolic disease characterized by hyperglycemia resulting from defects in insulin secretion or insulin action or both.

TYPES OF DIABETES

There are four types of diabetes.

1. Type 1 diabetes.
2. Type 2 diabetes.
3. Diabetes secondary to other diseases
4. Diabetes during pregnancy.

Type 1 diabetes

This is due to the lack of insulin. Insulin deficiency is due to the beta cell destruction by an autoimmune process. There are two types of type 1 diabetes according to the presence of immunological markers.

Type 1A diabetes is a condition resulting from autoimmune destruction of beta cells in which immunological markers can be detected whereas in Type 2B immunological markers cannot be detected.
Type 1 diabetes is common among younger people especially children. But it can affect any age group.
Latent Autoimmune Diabetes of Adults (LADA) is a variant of type 1 diabetes but it is difficult to distinguish from type 2 diabetes mellitus.

Type 2 diabetes

This is the commonest form of diabetes and it carries a significant risk of morbidities and mortalities. 90-95% of patients with diabetes belong to this category. This condition is due to the resistance to insulin. But sometime it can be due to the lack of insulin or both. Majority of patients are middle or older age group.

Diabetes secondary to other diseases

1-2% of diabetes patients belong to this group. This condition can be cured if the underlying cause is identified. This can be due to liver disorders, pancreatic disorders, other endocrinopathies or drug induced.

Diabetes during pregnancy (gestational diabetes mellitus).

This is a special category and it occurs during pregnancy and disappears after the delivery. But it is a real burden for the patient and doctors as it can be difficult to control. Obesity, family history of diabetes and past history of gestational diabetes are some risk factors.

What is pre-diabetes?

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Introduction

Pre-diabetes is a condition that comes before type 2 diabetes. Blood glucose (sugar) levels are higher than normal but aren’t high enough to be called diabetes. Pre-diabetes is a silent disease, meaning you can have it but not know it. By reducing the calorie intake, being physically active and loosing weight can delay the type 2 diabetes mellitus.

Prevention of type 2 diabetes mellitus

People with risk factors should be identified and they should be educated on how to reduce those risk factors.

Cut down calorie intake
Stop smoking
Exercise about 30 minutes per day
Loosing weight

People who are at risks;

You’re at risk for diabetes if you

are overweight
are physically inactive
have a parent, brother, or sister with diabetes
are African American, Native American, Asian American, Pacific Islander, or Hispanic American
have had a baby weighing more than 9 pounds or have had gestational diabetes
have high blood pressure (over 140/90 mmHg)
have low HDL cholesterol (35 mg/dl or lower)
or high triglycerides (250 mg/dl or higher)

Investigations

It does not have any symptoms therefore people with risk factors should undergo investigations.

1. fasting blood glucose

Pre-diabetes is diagnosed when fasting glucose levels are between 100 and 125 mg/dl. A fasting plasma glucose of 126 mg/dl or higher means diabetes.

2. oral glucose tolerance test

Pre-diabetes is diagnosed when blood glucose is between 140 and 199 mg/dl 2 hours after drinking glucose drink. These glucose levels are above normal but not high enough to be called diabetes. A 2-hour blood glucose of 200 mg/dl or higher means diabetes.

Treatment

There are no drugs to be effective in this condition. Only measures that patient should take is reduction of risk factors and undergoing regular assessments.

Maturity onset Diabetes of the Young (MODY)

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Introduction

Diabetes is a metabolic disease characterized by hyperglycemia resulting from defects in insulin secretion or insulin action or both. Several types of diabetes mellitus were described. Maturity onset diabetes of the young is a special type. The different MODY genotypes are associated with different clinical phenotypes. MODY should be considered in young people presenting with a typical family history (diabetes affecting a parent and 50% expression of the disease in the family) plus a form of early-onset diabetes which appears easy to control.

Maturity onset diabetes of the young (MODY) is a subtype of DM. It is characterized by autosomal dominant inheritance, early onset of hyperglycemia, and impairment in insulin secretion. Several monogenic forms of DM have been identified.

1. MODY 1

2. MODY 2

3. MODY 3

4. MODY 4

5. MODY 5

6. MODY 6

The glucokinase gene is intimately involved in the glucose-sensing mechanism within the pancreatic beta-cell. The hepatic nuclear factor (HNF) genes and the insulin promoter factor-1 (IPF-1) gene control nuclear transcription in the beta-cell where they regulate its development and function. Abnormal nuclear transcription genes may cause pancreatic agenesis or more subtle progressive pancreatic damage

MODY 1

This is caused by mutations in the hepatocyte nuclear transcription factors (HNF) 4a.

Chromosomal location	20q
Proportion of all MODY cases	5%
Onset	Teens to thirties
Progression	Progressive hyperglycemia
Microvascular complications	Frequent
Other features	None

MODY 2

MODY 2 is the result of mutations in the glucokinase gene that lead to mild-to-moderate hyperglycemia. Glucokinase catalyzes the formation of glucose-6-phosphate from glucose.

Chromosomal location	7q
Proportion of all MODY cases	15%
Onset	Present from birth
Progression	Little deterioration with age
Microvascular complications	Rare
Other features	Reduced birthweight

MODY 3

This is caused by mutations in the hepatocyte nuclear transcription factors (HNF) 1a.

Chromosomal location	12q
Proportion of all MODY cases	12q
Onset	teens/twenties
Progression	Progressive hyperglycemia
Microvascular complications	frequent
Other features	sensitive to sulphonylurea

MODY 4

This is a rare variant caused by mutations in the insulin promoter factor (IPF) 1, which is a transcription factor that regulates pancreatic development and insulin gene transcription.

Chromosomal location	13q
Proportion of all MODY cases	<1%
Onset	teens to thirties
Progression	Progression unclear
Microvascular complications	few data
Other features	Pancreatic agenesis in homozygotes

MODY 5

This is caused by mutations in the hepatocyte nuclear transcription factors (HNF) 1b.

Chromosomal location	17q
Proportion of all MODY cases	2%
Onset	Teens/twenties
Progression	Progression unclear
Microvascular complications	Frequent
Other features	Renal cysts, Proteinuria, Renal failure

MODY 6

This is due to the mutation in the neurogenic differention factor1 (NeuroD1)

Chromosomal location	2q
Proportion of all MODY cases	<7%
Onset
Progression
Microvascular complications
Other features

Epidemiology of Diabetes

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Type 1 diabetes

The acute onset of type 1 diabetes and the fact that almost all cases rapidly reach medical attention means that registers of new cases can be relatively easily established. Provided ascertainment can be verified, these data can be combined with population denominator data to give age-specific and sex-specific rates.

1. Geographical variation

There is a marked geographical variation in the incidence of type 1 diabetes.In Finland, the age-standardized incidence in children aged 14 years and under is 36.8/100,000/year. A high rate is also observed in Sardinia (36.5/100,000/year) that is notably discordant with the incidence in Italy as a whole. These two countries have incidences 350-fold greater than those in Zunyi, China and Caracas, Venezuela, where the incidence is 0.1/100,000/year. In general, countries in Europe and North America have either high or intermediate incidences. The incidence in Africa is generally intermediate, and that in
Asia is low. Variation in incidence by age and sex – in the UK, wellestablished registers with high ascertainment (98.6%) (e.g. in Scotland) show an incidence of 15.3/100,000/year in children aged 0–4 years, rising to 24.4/100,000/year at 5–9 years and 31.9/100,000/year at 10–14 years. Overall, the incidence is slightly higher in boys than in girls (ratio 1.08:1). The peak incidence in boys is at 12–13 years,whereas in girls the peak occurs at 9–12 years.

2. Temporal variation

In the Scottish register, a steady increase in the incidence of type 1 diabetes of about 2% per annum was described during the period 1984–1993. This increase is seen in other studies worldwide in both low incidence and high-incidence areas. The overall pooled increase in 37 countries was 3.0% per year; the increase was relatively greater in populations with the lowest incidence. The incidence of type 1 diabetes also varies with season, being highest in autumn and winter.

3. Aetiological factors

genetic susceptibility is necessary but not sufficient as a cause of type 1 diabetes. The nature of the environmental factors that impact on this genetic predisposition are unclear. Studies have concentrated on the ecological correlation between incidence and geographical variation in environmental factors. These have includedsocial factors such as population density, household overcrowding and population mixing. These studies are ecological because the data on the risk of outcome (diabetes) is not collected from the same individuals as that on exposure (social factors). Inferences about causality from such data are weaker than evidence from studies based on the association between individual exposure and risk. However, prospective cohort studies are difficult to conduct in type 1 diabetes because of the relatively low incidence – many individuals would have to be recruited and assessed and only a few would progress to disease.The case-control approach is efficient, but is subject to recall bias because exposure is assessed by proxy from parents after the diagnosis has been made. Case-control studies havedemonstrated associations with early social mixing, viral infections, toxins and dietary factors such as exclusive breastfeeding and delayed introduction of cows’ milk.

Type 2 diabetes

1. geographical variation

The slow onset of type 2 diabetes, and its presentation without the acute metabolic disturbance seen in type 1 diabetes, means that the true time of onset is difficult to determine. Thus, the distinction between abnormality and normality is more blurred, there is a long pre-detection period, and as many as one-half of cases in the population at any one time are undiagnosed. Data on the prevalence of clinically detected type 2 diabetes provide information that is useful for health service planning, but cannot provide any insight into the true prevalence unless the prevalence of undetected diabetes is also known. Because the ratio of detected to undetected cases may vary over time and between places, epidemiological research aimed at defining the true prevalence of type 2 diabetes has had to rely on special studies in which the presence and absence of disease is defined by the oral glucose tolerance test (OGTT). However, the distinction between normality and abnormality is unclear, and debate continues about how it should be defined. The WHO currently recommends use of the 75-g OGTT, with diabetes defined by fasting glucose 7.0 mmol/litre or more and/or 2-hour post-challenge glucose 11.1 mmol/litre or more. Geographical variation – Figure 2 shows the agestandardized and sex-standardized prevalence of type 2 diabetes and impaired glucose tolerance as defined by the 75-g OGTT in various countries. As in type 1 diabetes, there is marked geographical variation, but the pattern is different. The prevalence is lowest in rural areas of developing countries, is generally intermediate in developed countries, and is highest in certain ethnic groups who have adopted Western lifestyle patterns. The populations with the highest prevalences (Pima Indians in Arizona and Nauruans in Micronesia) have a high prevalence of obesity. It is hypothesized that genetic susceptibility to obesity in these populations would be disadvantageous in times of food abundance, but would be advantageous when food is scarce, giving rise to maintenance of the gene by natural selection. This ‘thrifty genotype’ hypothesis is supported by evidence of gene–environment interaction – individuals who migrate from low prevalence areas (e.g. Japan) to the West are at increased risk of type 2 diabetes.

In the UK, the prevalence of known diabetes is about 2% and the age-standardized prevalence of undiagnosed diabetes is 2% in the over-40s. The true incidence of the disease is difficult to determine because this requires repeated glucose tolerance testing. However, such studies have been undertaken and the incidence found to be about 6/1000 personyears of follow-up. The incidence in individuals known to have impaired glucose tolerance is about eight times greater than in those with normal glucose tolerance; the absolute cumulative incidence is 10% over 5 years in Caucasians, but may be higher in high-risk populations. The risk of future progression to diabetes is also greater in those with other hyperglycaemic states, including gestational diabetes mellitus.

2. Temporal variation

data from studies such as the National Health and Nutrition Examination Survey (NHANES III) demonstrate that the prevalence of type 2 diabetes in the USA increased by 33%, from 4.9% in 1990 to 6.5% in 1998. This increase mirrors the increasing prevalence of obesity. Repeated surveys in developing countries show even more marked increases, particularly in areas where populations are rapidly adopting Western lifestyles . The increase in the prevalence of obesity in childhood has led to the appearance of type 2 diabetes in children and young adults, particularly those in highly susceptible ethnic groups.

3. Aetiological factors

Prospective population-based cohort studies suggest that the main pathophysiological defects leading to type 2 diabetes are insulin resistance and a relative insulin secretory defect. The main aetiological risk factors for type 2 diabetes are age, obesity, family history, physical inactivity and dietary factors such as a high proportion of energy consumed as saturated fat and low intake of fruit and vegetables. The observation of an association between low birth weight and risk of diabetes in later life has led to the development of an alternative to the thrifty genotype hypothesis. In this ‘thrifty phenotype’ hypothesis, the risk of diabetes and other adult disorders is programmed by fetal nutrition and the pattern of early growth. The causal nature of these associations is strengthened by data from studies in which the incidence of diabetes is reduced by interventions aimed at reducing weight, increasing activity and improving diet.

Type 1 diabetes mellitus

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Introduction

Diabetes mellitus is a multisystem. Consequences are in the form of biochemical and anatomical. Disturbances in the metabolism of carbohydrates, protein and fat are the biochemical consequences whereas macrovascular and microvascular complications are the anatomical derangements. Absence or deficiency of insulin is the cause which result all the consequences of the type 1 DM. This is a disease of young individuals, not always.

How does it happen (Pathophysiology)?

Type 1 DM is a catabolic disorder in which circulating insulin is very low or absent. This is due to the failure of pancreatic beta cells to respond to all insulin-secretory stimuli. Therefore patients require exogenous insulin to reverse this catabolic condition, prevent ketosis, and normalize lipid and protein metabolism.

This is an autoimmune disease. There are histological evidence of immunological involvement such as lymphocytic infiltration and destruction of insulin-secreting cells of the islets of Langerhans, causing insulin deficiency. Approximately 85% of patients have circulating islet cell antibodies, and the majority also has detectable anti-insulin antibodies before receiving insulin therapy. Most islet cell antibodies are directed against glutamic acid decarboxylase (GAD) within pancreatic B cells.

There is another school of thought and it says that pancreatic beta cell destruction is due to an infectious or environmental agent. It triggers the immune system in a genetically susceptible individual to develop an autoimmune response against altered pancreatic beta cell antigens or molecules in beta cells that resemble a viral protein. Environmental agents that have been hypothesized to induce an attack on beta cell function include viruses (eg, mumps, rubella, Coxsackie B4), toxic chemicals, and exposure to cow's milk in infancy, and cytotoxins.

Recent evidence suggests a role for vitamin D in the pathogenesis and prevention of diabetes mellitus as well.

Epidemiology

This is the commonest metabolic disorder of childhood. Scandinavia has the highest prevalence rates for type 1 DM (ie, approximately 20% of the total number of people with DM), while China and Japan have the lowest prevalence rates, with less than 1% of all people with diabetes. Some of these differences may relate to definitional issues and the completeness of reporting.

Type 1 DM is more common in men than in women.

Type 1 DM usually starts in children aged 4 years or older, with the peak incidence of onset at 11-13 years of age, coinciding with early adolescence and puberty.

Type 1 DM is more common among non-Hispanic whites, followed by African Americans and Hispanic Americans. It is comparatively uncommon among Asians

Type 1 DM is associated with a high morbidity and premature mortality due to complications.

Clinical features of type 1diabetes mellitus

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In clinical practice, history, examination and investigations are important to diagnose the disease. History and examinations are the fundamental things and they give evidence of the condition.

History

Polyuria (increased frequency of urination), polydipsia (thirst), and polyphagia (Increased appetite) are the cardinal features of type 1 diabetes. Patients can have other features like lassitude, nausea and blurred vision as well. These symptoms are due to the hyperglycemic state. Usually the onset is sudden. Disease maybe diagnosed following an infection. Usually patients are lean and present with features of ketoacidosis. History may reveal following features;

Polyuria: this is due to osmotic diuresis secondary to hyperglycemia.
Thirst is due to the hyperosmolar state and dehydration.
Polyphagia with weight loss: The weight loss with a normal or increased appetite is due to depletion of water and a catabolic state with reduced glycogen, proteins, and triglycerides.
Fatigue and weakness: This may be due to muscle wasting from the catabolic state of insulin deficiency, hypovolemia, and hypokalemia.
Muscle cramps: This is due to electrolyte imbalance.
Nocturnal enuresis: Severe enuresis secondary to polyuria can be an indication of onset of diabetes in young children.
Blurred vision: This also is due to the effect of the hyperosmolar state on the lens and vitreous humor. Glucose and its metabolites cause dilation of the lens, altering its normal focal length.
Gastrointestinal symptoms: Nausea, abdominal discomfort or pain, and change in bowel movements may accompany acute DKA. Acute fatty liver may lead to distention of the hepatic capsule, causing right upper quadrant pain. Persistent abdominal pain may indicate another serious abdominal cause of DKA, eg, pancreatitis. Chronic gastrointestinal symptoms in the later stage of diabetes are due to visceral autonomic neuropathy.
Patients may maintain their normal weight or exhibit wasting, depending on the interval between the onset of the disease and initiation of treatment.
Peripheral neuropathy: It presents as numbness and tingling in both hands and feet, in a glove and stocking pattern. It is bilateral, symmetric, and ascending neuropathy, which results from many factors, including the accumulation of sorbitol in peripheral sensory nerves due to sustained hyperglycemia.
Symptoms at the time of the first clinical presentation usually can be traced back several days to several weeks; however, beta cell destruction may have started months, or even years, before the onset of clinical symptoms.

Examination findings

Usually physical examination is normal. If the patient present with diabetes ketoacidosis, signs of Kussmaul respiration, dehydration, hypotension will be there.
In established cases, patients should be examined every 3 months for macrovascular and microvascular complications. They should have funduscopic examination for retinopathy and monofilament testing for peripheral neuropathy.

Investigations for type1 diabetes mellitus

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Investigations are important to diagnose the diabetes and to identify the type of the diabetes as well. Types of investigations are;

1. hematological
2. genetic studies

Hematological investigations (Blood tests)

Blood glucose: This is the mainstay of test to diagnose. Results are interpreted according to the
Serum electrolytes: to identify the renal involvement.
Urinalysis for glucose, ketones, and protein: these are important to detect renal involvement and diabetes ketoacidosis.
White blood cell count and blood and urine cultures to rule out infections.
Glycosylated hemoglobin (Hb)/Hb A1c ; this is a good test to recognize the glycemic control
Oral glucose tolerance test with insulin levels: Although this test usually is considered unnecessary to make the diagnosis in type 1 DM, with the dramatic increase of type 2 diabetes in the young population, assessment of insulin secretion may become more important.
To determine whether the individual has type 1 rather than type 2 DM, an insulin and/or C-peptide level below 5 µU/mL, or 0.6 ng/mL, suggests type 1. C-peptide is formed during conversion of proinsulin to insulin. A high positive titre of glutamic acid decarboxylase antibodies also suggests type 1 DM. An exception is the individual with type 2 DM who presents with a very high glucose, eg, above 300 mg/dL, who temporarily has a low insulin and/or C-peptide level but who will recover insulin production once normal glucose is restored.
Islet cell antibodies
Thyroxine (T4) and thyroid antibodies

Genetic studies

HLA typing may be considered.

Overview of management of type 1 diabetes mellitus

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Treatment of this disease requires a multidisciplinary approach by physician, nurse, and dietitian.

Medical Care

Type 1 DM patients require insulin therapy to control initial hyperglycemia and maintain serum electrolytes and hydration. At times, the first incidence of ketoacidosis is followed by a symptom-free period where patients do not need treatment. This "honeymoon period" follows the initial treatment, in which the disease remits and the patient requires little or no insulin. This remission is due to a partial return of endogenous insulin, which may last for several weeks or months (and sometimes 1-2 y). Ultimately, however, the disease recurs, and patients require insulin therapy.

Multiple subcutaneous insulin injections are administered to control hyperglycemia after meals and to maintain normal plasma glucose levels throughout the day. This may increase the risks of hypoglycemia. Therefore, patients should be well educated about their disease and about self-monitoring of plasma glucose levels.

Surgical Care

Pancreatic transplantation is a possibility in some referral centers and is performed most commonly with simultaneous kidney transplantation for end-stage renal disease.

Consultations

These patients should be referred to an endocrinologist for multidisciplinary management.
These patients should have a complete retinal examination by an ophthalmologist at least once a year.The patients with significant proteinuria or a reduced creatinine clearance should be referred to a nephrologist.

Diet

One of the first steps in managing type 1 DM is diet control. Diet recommendations should be made in view of the patient's eating habits and lifestyle.Diet management includes education about the timing, size, frequency, or composition of meals to avoid hypoglycemia or postprandial hyperglycemia. All patients on insulin should receive a comprehensive diet plan that includes a daily caloric intake prescription; recommendations for amounts of dietary carbohydrate, fat, and protein; and how to divide calories between meals and snacks. A professional dietitian should be involved to create the individual diet plan.

Activity

Exercise is an important aspect of diabetes management. Patients should be encouraged to exercise regularly. Educate the patients about the effects of exercise on the blood glucose level. If patients are planning to participate in rigorous exercise for more than 30 minutes, they may develop hypoglycemia. To prevent hypoglycemia, they either can decrease the insulin by 10-20% or can have an extra snack. These patients must maintain their hydration status during exercise

Medication for type 1diabetes mellitus

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Subcutaneous insulin is the mainstay of treatment for the type 1 diabetes mellitus. But there are different types of insulin available depending on their onset of action and the duration of the action. These types of insulins are as follows:

1. short acting insulin
2. intermediate acting insulin
3. long acting insulin
4. mixtures

Short acting insulin

Rapid- and short-acting insulins have the most rapid onsets of action and are used whenever quick glucose utilization is needed
There are two types;

1. soluble insulin
2. rapid acting insulin analogue

Soluble insulin

Human insulin currently is the best species of insulin available, and it is less antigenic than previously used animal-derived varieties. It can be given subcutaneous, intravenous and intramuscular routes.

Rapid acting insulin analogue

Rapid-acting insulins include regular insulin, lispro, and aspart insulin. Regular insulin is a preparation of zinc insulin crystals in solution. Its onset of action is 0.5-1 h, it peaks at 2.5-5 h, and duration of action is 6-8 h. Lispro insulin is a form of regular insulin that is genetically engineered with the reversal of the amino acids lysine and proline in the B chain. Aspart insulin has aspartic acid substituted for proline in position 28 of the B chain. Both of these insulins are absorbed more quickly and have a rapid onset (5-10 min), peak (1 h), and duration (4 h) of action. Therefore, they have the advantage that they may be administered shortly before eating. Semilente insulin is like regular insulin and is slightly slower rapid-acting insulin. It contains zinc insulin microcrystals in an acetate buffer and is not readily available.

Intermediate acting insulin

Intermediate-acting insulins have slower onsets of action and longer durations of action and are usually administered in combination with faster-acting insulins to maximize benefits of a single injection.

Intermediate-acting insulins include neutral protamine Hagedorn (NPH) insulin, which contains a mixture of regular, and protamine zinc insulin, and lente insulin, which contain 30% semilente insulin and 70% ultralente insulin in an acetate buffer.

Long acting insulin

These insulins offer a very long duration of action and, when combined with faster-acting insulins, offer better glucose control for some patients.

Long-acting insulins include ultralente insulin, containing large zinc insulin crystals in an acetate buffer, and glargine insulin, newer long-acting insulin that has no peak and produces a relatively stable level lasting more than 24 hours. Both insulins can supply basal 24-hour insulin with a single daily injection.

Mixtures

Mixtures of insulin preparations with different onsets and durations of action frequently are administered in a single injection by drawing measured doses of 2 preparations into the same syringe immediately before use. The exception is glargine insulin, which should not be mixed with any other form of insulin. Preparations that contain a mixture of 70% NPH and 30% regular human insulin (ie, Novolin 70/30, Humulin 70/30) are available, as is Humulin 50/50, but the fixed ratios of intermediate-acting to rapid-acting insulin may restrict their use. In addition, a 25/75 mixture of NPH and lispro insulin is available.

Follow up plan for type 1diabetes mellitus

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After diagnosis of the diabetes, the Clinician and the patient should discuss to set a follow up plan. The aim of the follow up plan is to ensure that the patient is compliance with treatments and at the same time the patient should have a normal life as well.

Points are as follows;

1. Stick to treatment regimes
2. care during surgical procedures
3. regular assessment
4. foot care
5. patient education

Stick to treatment regime

Patients with type 1diabetes require lifetime insulin in order to have a normal life. This is a huge burden for the patients but the importance of continuation should be emphasized. This is important to have a good blood sugar control.

Regular insulin doses may cause hypoglycemia if the patient becomes anorectic or has another cause for reduced food intake, has gastroparesis, or is vomiting. Therefore insulin dose should be changed to tally the requirement.

The insulin coverage, with a sliding scale for insulin administration, should not be the only intervention because it is reactive, rather than proactive, in correcting hyperglycemia. Also, insulin may be used inappropriately when hyperglycemia reflects hepatic gluconeogenesis in response to previously uncorrected hypoglycemia.

Care during surgical procedures

Surgical procedures, inclusive of pre-surgery emotional stress, the effects of general anesthesia, and the trauma of the procedure, can markedly increase plasma glucose levels and induce DKA in patients with type 1 DM. In patients who normally take 1-2 daily injections of insulin, a third to a half of the usual morning dose can be administered in the morning before the operation and an IV infusion of 5% glucose in either 0.9% sodium chloride solution or water administered at a rate of 1 L (50 g glucose) over 6-8 hours.

Some physicians prefer to withhold subcutaneous insulin on the day of the operation and to add 6-10 units of regular insulin to 1 L of 5% glucose in 0.9% sodium chloride solution or water infused initially at 150 mL/h on the morning of the operation, depending on the plasma glucose level. The infusion is continued through recovery, with insulin adjustments depending on the plasma glucose levels obtained in the recovery room and at 2- to 4-hour intervals thereafter. The use of an intravenous insulin infusion in the postoperative period after major surgical procedures now is considered the standard of care in most hospitals.

Regular assessment

This is very important to ensure the good blood sugar control. Clinical examination should be carried out to detect complications. Several investigations should be done regularly;

1. Fasting blood sugar
2. Lipid profile

Foot care

This is a special topic. Read more

Patient education

Education is the most important aspect of diabetes management. The physician or the health care provider should educate the patient and, in the case of children, the parents about the disease process, management, goals, and long-term complications. They should be made aware of the signs and symptoms of hypoglycemia and ways to manage it.

A dietitian should provide specific diet control education to the patient and family.

A nurse should educate the patient about self–insulin injection and performing finger sticks for blood glucose level monitoring.

Type 2 diabetes mellitus

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Introduction
This is a group of disorders characterized by hyperglycemia and associated with microvascular, macrovascular complications. Unlike type 1 diabetes mellitus, the patients are not absolutely dependent upon insulin for life, even though many of these patients ultimately are treated with insulin.
How does it happen (Pathophysiology)?
Muscles, fat and liver are the major sites where insulin acts. But in type 2 DM these sites offer a resistance to insulin therefore metabolism of carbohydrates, fat and protein become abnormal. This pathophysiologic abnormality results in decreased glucose transport in muscle, elevated hepatic glucose production, and increased breakdown of fat. Therefore hyperglycemia will result.
The genetic aspects of this condition is very complex and not completely understood, but presumably this disease is related to multiple genes (with the exception of maturity-onset diabetes of the young [MODY]). Evidence supports inherited components for both pancreatic beta cell failure and insulin resistance.
Recent work has suggested that elevated free fatty acids may be the driving force behind insulin resistance and perhaps even beta cell dysfunction. If this defect is more proximal than defects specifically related to glycemia, then therapies aimed at correcting this phenomenon would be highly beneficial.
Hyperglycemia appears to be the determinant of microvascular and metabolic complications. However, glycemia is much less related to macrovascular disease. Insulin resistance with concomitant lipid (ie, small dense low-density lipoprotein [LDL] particles, low high-density lipoprotein-cholesterol [HDL-C] levels, elevated triglyceride-rich remnant lipoproteins) and thrombotic (ie, elevated type-1 plasminogen activator inhibitor [PAI-1], elevated fibrinogen) abnormalities, as well as conventional atherosclerotic risk factors (eg, family history, smoking, hypertension, elevated low-density lipoprotein-cholesterol [LDL-C], low HDL-C), determine cardiovascular risk.
Epidemiology
Type 2 diabetes mellitus is less common in non-Western countries where the diet contains fewer calories and caloric expenditure on a daily basis is higher. However, as people in these countries adopt Western lifestyles, weight gain and type 2 diabetes mellitus are becoming virtually epidemic.
The prevalence of type 2 diabetes mellitus varies widely among various racial and ethnic groups Type 2 diabetes mellitus is becoming virtually pandemic in some groups of Native Americans and Hispanic people. Recent work suggests more retinopathy and nephropathy in blacks, Native Americans, and Hispanic groups.
Type 2 diabetes mellitus is slightly more common in older women than men.
While type 2 diabetes mellitus traditionally has been thought to affect individuals older than 40 years, it is being recognized increasingly in younger persons, particularly in highly susceptible racial and ethnic groups.

Type 2 diabetes mellitus is slightly more common in older women than men.
Diabetes mellitus is one of the leading causes of morbidity and mortality because of its role in the development of optic, renal, neuropathic, and cardiovascular disease. These complications, particularly cardiovascular disease (~50-75% of medical expenditures), are the major sources of expenses for patients with diabetes mellitus.

Clinical features of type 2 diabetes mellitus

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In clinical practice, history, examination and investigations are important to diagnose the disease. History and examinations are the fundamental things and they give evidence of the condition.

History
Most patients with type 2 diabetes mellitus are asymptomatic for years. Classic symptoms are polyuria, polydipsia, polyphagia and weight loss. Other symptoms that might suggest hyperglycemia include blurred vision, lower extremity paresthesias, or yeast infections, particularly balanitis in men.

The possible presence of diabetes mellitus should be considered in patients with risk factors;
1. obese
2. patients with a first-degree relative with type 2 diabetes mellitus
3. members of high-risk ethnic groups ( black, Hispanic, Native American, Asian American, Pacific Islander) women with a previous delivery of a large infant (>9 lb)
4. a history of gestational diabetes mellitus
5. patients with hypertension
6. Patients with high triglycerides (>250 mg/dL) or low HDL-C (<35 mg/dL).
7. Evidence of polycystic ovary disease

Examination findings
Usually patients with type 2diabetes mellitus present with macrovascular and microvascular complications. Therefore there can be examination findings as well.
1. Evidence of infections (abscesses)
2. skin colour changes
3. parasthesea
4. high blood pressure
5. retinal changes
6. diabetic foot changes

Investigations for type 2 diabetes mellitus

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Investigations are important to diagnose the diabetes and to identify the type of the diabetes as well. Aims of investigations are;
1. to confirm the disease
2. to detect the glycemic control over a period
3. to detect complications
4. to assess the severity of the disease
5. to detect associated conditions

Tests to confirm the disease

1. Fasting blood sugar; this is the basic and the simplest method of diagnosing diabetes.
2. Random blood sugar

the diagnosis is made when the health care provider discovers either fasting plasma glucose (FPG) greater than or equal to 126 mg/dL on 2 occasions or random glucose greater than or equal to 200 mg/dL and classic symptoms of diabetes mellitus (ie, polyuria, polydipsia, polyphagia, weight loss).

Tests to detect glycemic control

Glycosylated hemoglobin (GHb) measurement is the popular method which is used to determine the glycemic control over a period of 3 months.

Tests to detect complications

1. ECG and Echocardiogram
2. urine micro albumin
3. serum electrolyte and blood urea
4. funduscopy

Tests to assess the severity

1. blood sugar level
2. HbA1C

Tests to detect associated conditions

1. Lipid profile
2. thyroxin level

Overview of management of type 2 diabetes mellitus

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Treatment of this disease requires a multidisciplinary approach by physician, nurse, and dietitian.

Medical Care
The goals in caring for patients with diabetes mellitus include the elimination of symptoms; microvascular risk reduction through control of glycemia and blood pressure; macrovascular risk reduction through control of lipids and hypertension, smoking cessation, and utilizing aspirin therapy; and metabolic risk reduction through control of glycemia. Such care requires appropriate goal setting, regular complications monitoring, dietary and exercise modifications, medications, appropriate self-monitoring of blood glucose (SMBG), and laboratory assessment. Focus on glucose alone does not provide adequate treatment for patients with diabetes mellitus. Treatment involves multiple goals
Complications monitoring: The American Diabetes Association recommends initiation of complications monitoring at the time of diagnosis of diabetes mellitus. This regimen should include yearly dilated eye examinations, yearly microalbumin checks, and foot examinations at each visit.
Laboratory monitoring: Because diabetes mellitus is a multisystem disease, focusing solely on blood sugar is inadequate.
Intercurrent medical illness: Patients with intercurrent illness become more insulin resistant because of the effects of increased counter-regulatory (ie, anti-insulin) hormones. Therefore, despite decreased nutritional intake, glycemia may worsen. Patients on oral agents may need transient therapy with insulin to achieve adequate glycemic control. In patients requiring insulin, scheduled doses of insulin, as opposed to sliding scale insulin, are far more effective in achieving glycemic control.
Surgical Care
Bariatric surgery has been shown to improve diabetes control and, in some situations, normalize glucose tolerance in morbidly obese patients. It is certainly a reasonable alternative in carefully selected patients if an experienced team (providing appropriate preoperative evaluation as well as technical surgical expertise) is available.
Consultations
Primary care physicians can care for patients with type 2 diabetes mellitus adequately. The multiple facets of disease treatment (eg, nutrition, exercise, smoking cessation, medications, complications monitoring) and data management (eg, glucose levels, BP, lipids, complications monitoring) must be continually noted. Inability to achieve adequate glycemic (or BP or lipid) control usually should be a clear indication to consult a diabetes specialist. When a patient has developed advanced complications, a diabetes specialist cannot be expected to be able to lessen the burden of these complications.
Diet
For most patients, the best diet is of what they are currently eating. Time honored attachments to a precise macronutrient composition of the diet to control diabetes are generally not supported by the research. Caloric restriction is of first importance. After that, individual preference is reasonable. Modest restriction of saturated fats and simple sugars is reasonable. However, some patients have remarkable short-term success with high-fat low-carbohydrate diets of various sorts. Therefore, the author always stresses weight management in general and is flexible regarding the actual diet that the patient consumes. Also, the practitioner should advocate a diet using foods that are within the financial reach and cultural milieu of the patient.
Activity
In general, most patients with type 2 diabetes mellitus can benefit from increased activity. Aerobic exercise improves insulin sensitivity and may improve glycemia markedly in some patients.
• The patient should choose an activity that she or he is likely to continue. Walking is accessible to most patients in terms of time and financial expenditure.
• A previously sedentary patient should start activities slowly.
• Older patients, patients with long-standing disease, patients with multiple risk factors, and patients with previous evidence of atherosclerotic disease should have a cardiovascular evaluation, probably including an imaging study, prior to beginning a significant exercise regime.

Medication for type 2 diabetes mellitus

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Pharmacologic therapy has changed dramatically in the last 10 years. New drug classes and new drugs effectively treat type 2 diabetes mellitus, allowing glycemic control previously beyond the reach of medical therapy.
Treatment options;
1. Oral hypoglycemic agents
2. Insulin

Oral hypoglycemic agents
1. Sulfonylureas are time-honored insulin secretagogues (and probably have the greatest efficacy for glycemic lowering of any of the oral agents.

2. Meglitinides are much more short-acting insulin secretagogues than sulfonylureas, with preprandial dosing potentially achieving more physiologic insulin release and less risk for hypoglycemia.

3. Biguanides are old agents that reduce hepatic glucose production and may have a minor effect on glucose utilization in the periphery (ie, antihyperglycemics, hepatic insulin sensitizers). Insulin must be present for biguanides to work.

4. Alpha-glucosidase inhibitors prolong the absorption of carbohydrates. Their induction of flatulence greatly limits their use. These agents should be titrated slowly to reduce gastrointestinal intolerance.

5. Thiazolidinediones (glitazones) are a new class of drugs that reduce insulin resistance in the periphery (ie, sensitize muscle and fat to the actions of insulin) and perhaps to a small degree in the liver (ie, insulin sensitizers, antihyperglycemics). They activate peroxisome proliferator–activated receptor (PPAR) gamma, a nuclear transcription factor that is important in fat cell differentiation and fatty acid metabolism.
Insulin
Ultimately, many patients with type 2 diabetes mellitus become markedly insulinopenic. The only therapy that corrects this defect is insulin. Because most patients are insulin resistant, small changes in insulin dosage may make no difference in glycemia in some patients. Furthermore, because insulin resistance is variable from patient to patient, therapy must be individualized in each patient.
Types of isulins available are as follows;
1. short acting insulin
2. intermediate acting insulin
3. long acting insulin
4. mixtures

Follow up plan for type 2 diabetes mellitus

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Diabetes and pregnancy

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INTRODUCTION

Diabetes is a metabolic disease characterized by hyperglycemia resulting from defects in insulin secretion or insulin action or both.
About 3-10% of pregnant mothers are suffering from diabetes. Depending Recent studies suggest that the prevalence of diabetes among women of childbearing age is increasing in the world. This increase is believed to be attributable to
1. more sedentary lifestyles,
2. changes in diet,
3. the virtual epidemic of childhood and adolescent obesity

Although 80% or more of this glucose intolerance during pregnancy occurs in women with gestational diabetes mellitus (GDM), the associated fetal and newborn morbidity rates are disproportionate.
Infants of mothers with preexisting diabetes experience double the risk of serious injury at birth, triple the likelihood of cesarean delivery, and quadruple the incidence of newborn intensive care unit admission. Recent studies indicate that the risk of these morbidities in individual cases is proportional to the degree of maternal hyperglycemia. For this reason, the excessive fetal and neonatal morbidity attributable to diabetes in pregnancy should be considered preventable.
The prevalence of gestational diabetes is strongly related to the patient's race and culture.
• Typically, only 1.5-2% of white persons from the mid western United States develop GDM, while American Indians from the southwestern United States may have rates as high as 15%.
• In Hispanic, African American, and Asian populations, the rate is 5-8%.

PATHOPHYSIOLOGY (HOW DOES IT HAPPENS)
Normal metabolism during pregnancy
The goal of metabolism during pregnancy is to ensure that an ample, but not excessive, supply of glucose is available to the mother and fetus. To achieve this goal with each feeding, the pregnant woman undergoes a complex series of maternal hormonal actions:
1. a rise in blood glucose,and
2. the secondary secretion of pancreatic insulin, glucagon, somatomedins, and adrenal catecholamines.
The key features of this complex interaction include the following:
• A pregnant woman has a tendency to develop low sugar level (hypoglycemia) between meals and during sleep than that of nonpregnant woman because the fetus continues to draw glucose across the placenta from the maternal bloodstream, even during periods of fasting.
• The mean insulin level is 50% higher during last trimester than that of nonpregnant. This due to the high levels of placental steroid and peptide hormones (eg, estrogens, progesterone, chorionic somatomammotropin). These hormones increase the tissue resistance to insulin therefore insulin secretion is increased
• If insulin secretion is inadequate, both the mother and fetus develop high sugar levels (hyperglycemia). This can lead to accelerated fetal growth, which can bring many fetal and maternal complications
During a healthy pregnancy, mean fasting blood sugar levels decline progressively to a remarkably low value of 74 ± 2.7 (standard deviation) mg/dL. On the other hand, peak postprandial blood sugar values rarely exceed 120 mg/dL. Meticulous replication of the normal glycemic profile during pregnancy has been demonstrated to reduce the rate of macrosomia (large fetus). Specifically, when 2-hour postprandial glucose levels are maintained at less than 120 mg/dL, approximately 20% of fetuses demonstrate macrosomia. Conversely, if postprandial levels range up to 160 mg/dL, macrosomia rates rise to 35%.

Fetal abnormalities with diabetes during pregnancy

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Diabetes during pregnancy is a leading cause which can results many fetal abnormalities/problems
1. Miscarriages
2. Birth defects
3. Growth restriction
4. Growth acceleration
5. Fetal obesity
6. Central obesity
Miscarriages
There is a strong association between the degree of blood sugar control prior to pregnancy and the miscarriage rate. Poor blood sugar control may double the miscarriage rates. Patients with long-standing diabetes (glycohemoglobin,HbAc , exceeding 11%) have been shown to have miscarriage rates of up to 44%. Conversely, recent reports demonstrate a normalization of the miscarriage rate with excellent glycemic control.

Birth defects

The occurrence of birth defects in normal population is 1-2%. But the likelihood of structural abnormalities in fetus of diabetic mothers is increased 4-8 folds. Most lesions involve the central nervous and cardiovascular systems. The periconceptional glycemic control is the main factor in the genesis of diabetes-associated birth defects.

1. cardiac malformations(ASD, PDA, VSD)
2. Neural tube defects
3. sacral agenesis
4. hypoplastic left colon

Growth restriction

Usually fetuses with diabetic mothers are macrosomic but there is a risk of Intra Uterine Growth restriction (IUGR) as well. The risk is three fold as compared to fetuses of non diabetic mothers. The risk is higher when the diabetes is preexisting.
The most import predictor of fetal growth restriction is underlying maternal vascular disease. Specifically, pregnant patients with diabetes-associated retinal or renal vasculopathies and/or chronic hypertension are most at risk for growth restriction.
Growth acceleration
Excessive body fat stores, stimulated by excessive glucose delivery during diabetic pregnancy, often extend into childhood and adult life. The adverse downstream effects of deranged maternal metabolism have been documented well into puberty. Glucose intolerance and higher serum insulin levels are more frequent in offspring of diabetic mothers compared with normal controls. By age 10-16 years, offspring of diabetic mothers have a 19.3% rate of impaired glucose intolerance.
Fetal obesity

Macrosomia is typically defined as a birth weight above the 90th percentile for gestational age or greater than 4000 g. In pregnant diabetic women, macrosomia occurs in 15-45% of cases, a 3-fold increase from normoglycemic controls. The infants of diabetic mothers (IDMs) had 5-fold higher rates of severe hypoglycemia, a 4-fold increase in macrosomia, and a doubled increase in neonatal jaundice. Birth injury, including shoulder dystocia and brachial plexus trauma, is more common among IDMs, and macrosomic fetuses are at the highest risk.

Central obesity

The macrosomic fetus develops a unique pattern of overgrowth, involving central deposition of subcutaneous fat in the abdominal and interscapular areas. Skeletal growth is largely unaffected. Neonates of diabetic mothers have a larger shoulder and extremity circumference, a decreased head-to-shoulder ratio, significantly higher body fat, and thicker upper extremity skin folds compared with nondiabetic control infants of similar weights.

Maternal problems (morbidity) associated with diabetes during pregnancy

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Diabetes is a condition which can affect any system. Therefore monitoring of functions of all the systems is important to detect the problems. But common maternal problems are as follows;
1. Diabetic retinopathy
2. Deterioration of renal functions
3. Chronic hypertension
4. Preeclampsia

Diabetic retinopathy

This is one of the major causes of blindness in women in reproductive age group. Degree of retinal damage depends on the type of diabetes, duration of diabetes and glycemic control. Patients with preexisting diabetes have a higher risk than that of patients with gestational diabetes. A prospective study showed that while half the patients with preexisting retinopathy experienced deterioration during pregnancy, all the patients had partial regression following delivery and returned to their prepregnant state by 6 months postpartum. However, when the total effect of pregnancy on ophthalmologic status was considered, pregnant women had a slower progression of retinopathy than nonpregnant women.

Deterioration of renal function

Degree of renal damage depends on the type of diabetes, duration of diabetes and glycemic control. Patients with preexisting diabetes have a higher risk than that of patients with gestational diabetes. If there is preexisting renal damage, patient will have varying degree of deterioration of renal function during pregnancy as renal blood flow and the glomerular filtration rate increase 30-50% during pregnancy, the degree of proteinuria also increases. The most recent studies indicate that pregnancy does not measurably alter the time course of diabetic renal disease and it does not increase the likelihood of progression to end-stage renal disease.
Perinatal complications are greatly increased in patients with diabetic nephropathy. Preterm birth, intrauterine growth restriction, and preeclampsia are all significantly more common in women with diabetic nephropathy during pregnancy.

Chronic hypertension
About 10% of diabetic pregnancies are complicated with chronic hypertension. . Patients with underlying renal or retinal vascular disease are at a substantially higher risk. The risk of Intra Uterine growth Restriction (IUGR), preeclampsia, placental abruption and maternal stroke are high when the diabetes and chronic hypertension co-exist.
Preeclampsia
Preeclampsia is a clinical syndrome (collection of signs and symptoms). Abrupt elevation in blood pressure, significant proteinuria, and elevated uric acids level, evidence of hemolysis, elevated liver enzymes and low platelet count are the features of preeclampsia. The frequency of preeclampsia is higher when the pregnancy is complicated with diabetes.

Investigations of diabetes during pregnancy

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Investigations play a major role during pregnancy. Types of investigations are laboratory investigations, imaging studies and other investigations. Type of the investigation required is determined by the trimester of the pregnancy.
Goals of investigations are;
1. To ensure the maternal wellbeing.
2. To ensure the fetal wellbeing.
Lab Studies
First trimester (in addition to normal prenatal laboratory tests)
1. Hemoglobin A1C
2. Blood urea nitrogen and creatinine
3. Thyrotropin
4. Free thyroxine
5. Twenty-four–hour urine collection for protein and creatinine
6. Blood sugar levels from a capillary device 4-7 times daily

Second trimester

1. Repeat 24-hour urine studies in women with elevated creatinine value in first trimester or 24-hour protein or creatinine clearance less than 100 mL/min
2. Repeat HbA1C
3. Blood sugar levels from capillary device 4-7 times daily in all women with diabetes
If preeclampsia is suggested

1. Repeat 24-hour urine studies
2. Blood urea nitrogen and creatinine
3. Liver function tests
4. Uric acid
5. CBC count with platelets
6. Assessment of fetal well-being with nonstress test, amniotic fluid index, fetal growth, and Doppler examination of the umbilical cord and middle cerebral artery

Imaging Studies
First trimester
1. Ultrasonogram (crown-rump length) for dating and viability

Second trimester

2. Detailed anatomy ultrasonogram at 18-20 weeks' gestation
3. Fetal echocardiogram if HbA1C value was elevated in first trimester
Third trimester

1. Growth ultrasonogram to assess fetal size every 4-6 weeks from 26-36 weeks' gestation in women with overt preexisting diabetes
2. Growth ultrasonogram for fetal size at least once at 36-37 weeks' gestation for women with GDM (Consider performing this study more frequently if macrosomia is suggested.)
Other Tests
• First trimester - Ophthalmologic evaluation
Procedures
• Third trimester - Amniocentesis for fetal lung profile if delivery is contemplated prior to 39 weeks' gestation

problems associated with pregnancies complicated with diabetes

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Perinatal morbidity and birth injuries will be high if the mother is diabetic during the pregnancy. Apart from these two conditions, other perinatal conditions associated with gestational diabetes are;
1. Perinatal mortality
2. Polycythemia
3. Hypoglycemia
4. Neonatal hypocalcemia
5. Postnatal hyperbilirubinemia
6. Respiratory problems
7. Hypertrophic cardiomyopathy

Perinatal mortality

Perinatal mortality is higher among the fetuses of diabetic mothers than that of nondiabetic mothers. The current perinatal mortality rates among diabetic women remain approximately twice those observed in the nondiabetic population.
Congenital malformations, respiratory distress syndrome (RDS) and extreme prematurity are the leading causes of most perinatal deaths in the context of diabetes during pregnancy. Because of intensive obstetrics and infant care, the perinatal mortality rate is going down. But this provides a major contribution to infant mortality in developing countries.
Birth injury

The factors which increase the birth injuries are macrosomia, prematurity, etc. These conditions are more prevalent among fetuses/infants of diabetic mothers. Common birth injuries associated with diabetes are brachial plexus trauma, facial nerve injury, cephalohematoma and shoulder dystocia.
Polycythemia

A central venous hemoglobin concentration greater than 20 g/dl or a hematocrit value greater than 65% (polycythemia) is not uncommon in infants of diabetic mothers (IDMs) and is related to glycemic control. Treatment with partial exchange transfusion to reduce the hematocrit may be required.

Hypoglycemia

Transient hypoglycemia is common during the first day of life from fetal hyperinsulism, but often be prevented by early feeding .The infant’s blood glucose should be closely monitored during first 24 hours and hypoglycemia treated. Unrecognized postnatal hypoglycemia may lead to neonatal seizures, coma, and brain damage.

Neonatal hypocalcemia

Up to 50% of IDMs have low levels of serum calcium (<7 mg/100 mL). With improved management of diabetes in pregnancy, this rate has been reduced. These changes in calcium appear to be attributable to a functional hypoparathyroidism, although the exact pathophysiology is not well understood.

Postnatal hyperbilirubinemia

Hyperbilirubinemia occurs in approximately 25% of IDMs, a rate approximately double that in a normal population. The causes of hyperbilirubinemia in IDMs are multiple, but prematurity and polycythemia are the primary contributing factors. Increased destruction of red blood cells contributes to the risk of jaundice and kernicterus.
The treatment of this complication is usually phototherapy, but exchange transfusions may be necessary if bilirubin levels are markedly elevated.

Respiratory problems
Neonatal respiratory distress syndrome (RDS) is one of the dreaded complications of gestational diabetes. This is due to the delayed lung maturation.

Diagnosis of diabetes during pregnancy

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Diagnosis of diabetes during pregnancy is a difficult task as pregnant mothers can be suffered from all four types of diabetes. Recognition of the exact type is essential for the definitive management.
WHO diagnostic criteria;
1. One abnormal sugar level (fasting blood sugar/random blood sugar) in symptomatic patients or two abnormal values (taken two weeks apart) are needed to diagnose diabetes.
A) Fasting Blood Sugar(FBS) > 7mmol/l (126mg/dl)
B) Random Blood Sugar(RBS)> 11.1mmol/l(200mg/dl)

2. Glucose Tolerance Test (GTT)needed for borderline cases and for GDM
A) Method for adults; 75g glucose in 300 ml water should be given. Then blood sugar level should be measured 2 hours after the ingestion of glucose.
B) Method for children; 1.75g/kg body weight given and blood sugar measured after 2 hours.

• If the 2 hour sugar level is greater than 11.1mmol/l, patient can be labeled as diabetes.
• This test can be used to diagnose the gestational diabetes as well. This is the diagnostic test during 24-28 weeks of pregnancy.

Diagnosis of type 1 diabetes
Usually these patients know that they are diabetic before they become pregnant. They are typically diagnosed during an episode of hyperglycemia, ketosis and dehydration. Type 1 diabetes is diagnosed only rarely during pregnancy and is most often accompanied by unexpected coma because early pregnancy may provoke diet and glycemic control instability in patients with occult diabetes. Therefore as a precaution, a pregnancy test should be performed in all reproductive-aged women admitted to the hospital for blood sugar management.
Diagnosis of type 2 diabetes

This is very difficult to diagnose as severe form of gestational diabetes mimic type 2 diabetes. If the first trimester HbA1C value of 8% is highly suggestive of preexisting type 2 diabetes, definitive diagnosis of type 2 diabetes must be made after pregnancy using the 75-g, 2-hour glucose tolerance test.

Diagnosis of gestational diabetes

Gestational diabetes (GDM) is a state of carbohydrate intolerance of varying degrees and it is first recognized during pregnancy with a probable resolution after the end of pregnancy. Diabetes, glucose intolerance or insulin resistance may have existed before the pregnancy. GDM is not the same as Type 1 or Type 2 Diabetes. Glucose Tolerance test is used to diagnose this condition

Peripartal management of patients and fetuses with diabetes

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Peripartal period is the period just prior to delivery and soon after the delivery. During his period, patient should be prepared for the delivery. Timing of the delivery and the mode of the delivery is usually decided during this period.
Prenatal obstetric management
The goals of management of third-trimester pregnancies in women with diabetes are to prevent stillbirth and asphyxia while minimizing maternal and fetal morbidity associated with delivery.
Monitoring fetal growth is essential to select the proper timing and route of delivery. This is accomplished by frequent testing for fetal well-being and serial ultrasound examinations for trending of fetal size.

Periodic fetal biophysical testing

Various fetal biophysical tests are available to the clinician to ensure that the fetus is well oxygenated, including fetal heart rate testing, fetal movement assessment, ultrasound biophysical scoring, and fetal umbilical Doppler studies. If applied properly, most of these can be used with confidence to provide assurance of fetal well-being while awaiting fetal maturity. Initiate testing early enough to avoid significant stillbirth but not so early that a high rate of false-positive test results is encountered. In patients with poor glycemic control or significant hypertension, begin formal biophysical testing as early as 28 weeks' gestation. In patients who are at lower risk, most centers begin formal fetal testing by 34 weeks' gestation. Fetal movement counting is performed in all pregnancies from 28 weeks onward.

Assessing fetal growth

Monitoring fetal growth continues to be a challenging and imprecise process. Although the tools available now (eg, serial plotting of fetal growth parameters) are superior to those used previously for clinical estimations, accuracy is still only plus or minus 15%.
Despite problems with accuracy, ultrasound-based estimations of fetal size have become the standard of care. Estimate fetal size once or twice at least 3 weeks apart in order to establish a trend. Time the last examination to be at 36-37 weeks' gestation or as close to the planned delivery date as possible.

Pregnancy management of women with gestational diabetes (GDM)

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Gestational diabetes (GDM) is a state of carbohydrate intolerance of varying degrees and it is first recognized during pregnancy with a probable resolution after the end of pregnancy. Since this condition is present for a limited time period, patients may not understand the importance of glycemic control to reduce the potential risk to their fetuses. Therefore patient education is important and it should be done early as possible. Followings are key points that should be considered in the management of GDM.
1. Dietary therapy
2. Glucose monitoring
3. Insulin therapy
4. Oral hypoglycemic agents

Dietary therapy
It is very difficult to manipulate diet during pregnancy. During the first trimester patient may experience nausea and vomiting therefore food intake can be low. Metabolic management of a patient with GDM is focused on dietary control, regular home glucose monitoring, and judicious use of insulin therapy.
Most patients with GDM diagnosed in the third trimester can maintain 1-hour postprandial blood glucose levels less than 130 mg/dl via diet manipulation alone (ie, multiple, small, nonglycemic meals and increased exercise).

Glucose monitoring
This is an essential part in the management of GDM. Patient should be educated how to monitor blood glucose level and to adjust the insulin amount according to the blood glucose level. A home glucose monitor is also essential to assist the patient in choosing the types and timing of food ingestion.
Once the patient has demonstrated success in controlling postprandial glucose with diet, the occurrence of abnormal fasting levels is exceedingly rare and the morning checks can be discontinued. Fasting checks are reinstituted if any postprandial glucose levels are abnormal.

Insulin therapy

Insulin therapy is the mainstay of treatment for GDM. Determine the insulin regimen based on the patient's individual glucose profile. Typically, one to several postprandial glucose levels become consistently above target because the patient's ability to compensate for rising insulin resistance with diet becomes inadequate. When more than 20% of postprandial blood sugar values exceed 130 mg/dl, administering rapid-acting lispro or aspart insulin injections (4-8 U to start) before meals is usually successful in controlling glucose overshoots. If more than 10 U of short-acting insulin is needed prior to the noon meal, adding an 6-12 U dose of neutral protamine Hagedorn (NPH) insulin prior to breakfast helps achieve smoother control. When more than 10% of fasting glucose levels rise above 95 mg/dL, a starting dose of 6-8 U of NPH insulin at bedtime can be used.
The doses are scaled up as necessary once or twice weekly to keep glucose levels on target.
Insulin pumps can be used to administrate insulin. This is more convenience for the patients but it is expensive when compare with insulin syringes.

Oral hypoglycemic agents
This is a controversial topic as the most of oral drugs are teratogenic, but there are some drugs with safe profile
Glyburide is a second generation sulfonylurea. It has a safe profile as it does not cross the placenta. Therefore this drug can be used in management of GDM.

Pregnancy management of women with preexisting diabetes

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Aspects that should be considered in the management of preexisting diabetes are same as for the management of GDM but there are differences as well. Therefore recognition of the exact type of diabetes is the fact which matters the management. Followings are key points that should be considered in the management of GDM.
1. Dietary therapy
2. Glucose monitoring
3. Insulin therapy

Dietary therapy

The goal of dietary therapy is to avoid single large meals and foods with a large percentage of simple carbohydrates. A total of 6 feedings per day is preferred, with 3 major meals and 3 snacks to limit the amount of energy intake presented to the bloodstream at any interval. Examples include foods with complex carbohydrates and cellulose, such as whole grain breads and legumes. Carbohydrates should account for no more than 50% of the diet, with protein and fats equally accounting for the remainder. For women who are obese (BMI >30 kg/m2), a 30-33% energy restriction ([25 kcal/kg/d] actual weight) has been shown to reduce hyperglycemia and plasma triglyceride levels with no increase in ketonuria.

Glucose monitoring

The availability of capillary, glucose, and chemical test strips has revolutionized the management of diabetes, and these should now be considered the standard of care for pregnancy monitoring. The discipline of measuring and recording blood glucose levels prior to and after meals clearly has a positive effect on improving glycemic control.

Individualize the frequency and timing of home glucose monitoring. A typical schedule involves capillary glucose checks upon awakening in the morning, 1 hour after breakfast, before and after lunch, before dinner, and at bedtime. Place emphasis on gaining and sustaining compliance with the target glucose levels mentioned above. Meticulous glycemic control requires attention to both pre-prandial and postprandial glucose levels.

Insulin therapy

The goal of insulin therapy during pregnancy is to achieve glucose profiles similar to those of nondiabetic pregnant women. Given that healthy pregnant women maintain their postprandial blood sugar excursions within a relatively narrow range (70-120 mg/dl), the task of reproducing this profile requires meticulous daily attention by both the patient and physician.

Insulin therapy in management of diabetes during pregnancy

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Insulin is the mainstay of treatment for the pregnant mothers who are suffering from diabetes as all the other oral hypoglycemic agents are teratogenic. Research suggests that early intervention with insulin is superior to diet therapy alone.
Determine the choice of insulin and regimen based on the patient's individual glucose profile. Postprandial glucose levels become consistently above the target with diet therapy. When more than 20% of postprandial blood glucose levels exceed 130 mg/dl, administer lispro insulin (4-8 U SC initially) before meals. If more than 10 U of regular insulin is needed before the noon meal, adding 8-12 U of NPH insulin before breakfast helps achieve control. When more than 10% of fasting glucose levels exceeds 95 mg/dl, initiate 6-8 U NPH insulin.
Insulins
Insulin is essential in regulating carbohydrate, protein, and fat metabolism. Primarily affect carbohydrate homoeostasis by binding to specific cell-surface receptors on insulin-sensitive tissues (eg, liver, muscles, adipose tissue).When starting insulin consider following things;
1. Dose of the insulin: 0.5-1 U/kg/d SC in divided doses; base dose on IBW; titrate dose to maintain a premeal and bedtime glucose level of 80-110 mg/dl; combine short- and longer-acting insulin to maintain blood glucose within target.

2. Contraindications: Documented hypersensitivity; hypoglycemia

3. Interactions: Since most of the drugs are contraindicated during pregnancy, interactions are not a big problem. Medications that may decrease hypoglycemic effects include acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid estrogens. Medications that may increase hypoglycemic effects include calcium, ACE inhibitors, alcohol, tetracyclines, beta-blockers, lithium carbonate.

Medical Care for pregnancies complicated with diabetes.

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This is the utmost important part of the management of pregnancies complicated with diabetes. Ideally this should be started preconceptionally. If a reduction in diabetes-associated neonatal morbidity is to be achieved, counsel the patient before conception and perform a medical risk assessment in all women with overt diabetes and those with a history of GDM during a previous pregnancy.

Followings are the key points which should be addressed in management of pregnancies complicated with diabetes.

1. Complete assessment of cardiovascular, renal and ophthalmologic status of the patient.

2. Frequent and regular monitoring of both pre-prandial and post-prandial capillary glucose level.

3. Following blood sugar levels should be achieved in order to have a safe pregnancy period and outcome.

I. Fasting blood glucose < 105 mg/dl (5.8mmol/l)
II. One-hour postprandial plasma glucose less than 155 mg/dl (8.6mmol/L)

4. The insulin regimen should result a smooth glycemic profile without any hypoglycemic attacks.

5. Patients should take a prenatal vitamin containing at least 1 mg/d folic acid for at least 3 months prior to conception to minimize the risk of neural tube defects in the fetus.

6. Urge nonpregnant patients to continue avoidance of pregnancy until their HbA1C value is in within the reference range (<6.5%).

Timing and route of delivery for pregnancies with diabetes.

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This decision should be taken by both the clinician and the patient. The decision depends on the maternal and fetal factors.
Maternal factors
1. Period of gestation
2. Cervical maturity
3. Other cormobidities
Fetal factors
1. Maturity of the fetus
2. Weight of the fetus
3. Other biophysical factors

Select the timing of delivery to minimize morbidity for the mother and fetus. Delaying delivery to as near as possible to the expected date of confinement helps maximize cervical maturity and improves the chances of spontaneous labor and vaginal delivery. However, the risks of advancing fetal macrosomia, birth injury, and in utero demise increase as the due date approaches
Although delivery as early as 37 weeks' gestation might reduce the risk of shoulder dystocia, a coinciding increase in the incidence of failed labor inductions and poor neonatal pulmonary status would also occur. Because fetal growth from 37 weeks' gestation onward may be 100-150 g/wk, the reduction in net fetal weight and the risk of shoulder dystocia by inducing labor 2 weeks early may theoretically improve outcome
If the fetus is not macrosomic and results from biophysical testing are reassuring, the obstetrician can await spontaneous labor. In patients with GDM and superb glycemic control, continued fetal testing and expectant management can be considered until 41 weeks' gestation. In a fetus with an abdominal circumference measurably larger than the head circumference or with an estimated fetal weight of greater than 4000 g, consider induction. After 40 or more weeks' gestation, the benefits of continued conservative management are likely to be less than the danger of fetal compromise. Induction of labor before 41 weeks' gestation in pregnant women with diabetes, regardless of the readiness of the cervix, is prudent
Thus, an optimal time for delivery of most diabetic pregnancies is typically on or after the 39th week. Only deliver a patient with diabetes before 39 weeks' gestation without documented fetal lung maturity for compelling maternal or fetal indications. For elective induction, fetal lung maturity should be verified via amniocentesis.
Because the risk of shoulder dystocia and fetal injury in labor is increased 3-fold in diabetic pregnancy, elective cesarean delivery should be considered if the fetus is suspected to be significantly obese. The American College of Obstetricians and Gynecologists recommends offering diabetic patients cesarean delivery if the fetal weight is estimated to be 4500 g or more.

Screening for diabetes during pregnancy

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Screening is important for the early detection of the diabetes thereby quality of life can be improved. Following should be considered in the screening;
1. Who Should Be Screened
2. Routing screening tests
3. How to diagnose
Who should be screened?

Screen patients with any of the following risk factors for GDM at the first prenatal visit.

1. Maternal age older than 35 years
2. Women who are obese (>90 kg)
3. Women with a Strong immediate family history of type 2 diabetes mellitus or GDM

4. Women of ethnic/racial high risk groups
5. Women who have had a >9 # baby
6. Previous infant weighing more than 4000 g
7. Previous unexplained fetal demise
8. Previous pregnancy with GDM
9. Fasting glucose value greater than 140 mg/dl (7.8mmol/L) or random glucose value greater than 200 mg/dl (11.1mmol/L)

Routing screening test
1. Oral Glucose Tolerance Test;
A) A 50-g, 1-hour screening test is administered to all pregnant women at 26-28 weeks', followed by a 100-g, 3-hour OGTT for those with an abnormal screening result or,
B) A 1-step, 75-g, 2-hour test can be administered.
OGTT prerequisites for gestational diabetes are as follows:
a. One-hour, 50-g glucose challenge result greater than 135 mg/dL
b. Overnight fast of 8-14 hours
c. Carbohydrate loading for 3 days (>150 g carbohydrates)
d. Seated and not smoking during the test
e. Two or more values met or exceeded
f. Either a 2-hour (75 g of glucose) or 3-hour (100 g of glucose) test
How to diagnose
Plasma glucose criteria for gestational diabetes are as follows:
1. Fasting test
I. With glucose load of 100 g, result of 95 mg/dL (5.3 mmol/L)
II. With glucose load of 75 g, result of 95 mg/dL (5.3 mmol/L)

2. one-hour test
I. With glucose load of 100 g, result of 180 mg/dL (10 mmol/L)
II. With glucose load of 75 g, result of 180 mg/dL (10 mmol/L)

3. two-hour test
I. With glucose load of 100 g, result of 155 mg/dL (8.6 mmol/L)
II. With glucose load of 75 g, result of 155 mg/dL (8.6 mmol/L)

4. Three-hour test –
I. With glucose load of 100 g, result of 140 mg/dL (7.8 mmol/L)

Follow up of diabetes mothers following delivery

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This is very important as many complications may occur following the delivery. If the type of diabetes is not diagnosed, further investigations should be carried out in order to diagnose the type of diabetes. Following points should be addressed in follow up;

1. Further inpatient care

A) Avoiding shoulder dystocia
B) Intrapartum glycemic management
C) Treatment of neonates

2. Prevention
3. Patient education

Further Inpatient Care
Avoiding shoulder dystocia
Mainstay for assessing risk in pregnancy complicated with diabetes is ultrasound scan. But its sensitivity is 65% in the detection of macrosomia whereas the specificity is 50-60% therefore rate of false positive is 30-50%. In this context normal vaginal delivery could be done for macrosomic fetuses on the basis of ultrasound scan results. These infants should be closely monitored in order to detect birth injuries as early as possible. When taking the decision for mode of delivery, risk of birth injuries associated with vaginal deliveries and risk of caesarian section should be considered.

Intrapartum glycemic management
Maintenance of intrapartum metabolic homeostasis optimizes postnatal infant transition by reducing neonatal hyperinsulinemia and subsequent hypoglycemia.
The use of a combined insulin and glucose infusion during labor to maintain maternal blood sugars in a narrow range (80-110 mg/dl) during labor is a common and clinically efficient practice. Typical infusion rates are 5% dextrose in Ringer lactate solution at 100 mL/h and regular insulin at 0.5-1.0 U/h. Capillary blood sugar levels are monitored hourly in these patients.

Treatment of the neonate
The most critical metabolic problem affecting IDMs is hypoglycemia. Unmonitored and uncorrected hypoglycemia can lead to neonatal seizures, brain damage, and death. The strongest predictor of neonatal hypoglycemia is the maternal mean blood glucose level during labor. IDMs also appear to have disorders of both catecholamine and glucagon metabolism and have a diminished capability to mount normal compensatory responses to hypoglycemia. Therefore continuous monitoring of the neonate is essential to detect hypoglycemia and to prompt treatment.
Prevention

Prevention of gestational diabetes is an attractive concept, but no progress has been made, despite attempts in smaller studies. Because body fat and diet contribute to the risk of GDM, patients who lose weight prior to pregnancy and follow an appropriate diet may lower their risk of GDM. However, the pregnancy hormones impose such a high degree of insulin resistance that in very susceptible individuals, even marked weight loss and attention to diet are not likely to be successful.
Patient Education

Education is the cornerstone of effective metabolic management of the patient with diabetes during pregnancy. Patients should be educated on importance of dietary control, compliance and attendance of clinics regularly. However, specially trained and certified nurses and dietitians (ie, certified diabetes educators) are the most effective in this regard. Most large programs treating women with diabetes during pregnancy assist the patient with a staff that includes a registered nurse, a certified diabetes educator, a dietitian knowledgeable about pregnancy, and a social worker. Successful management of diabetic pregnancy is optimized when this type of team care is available.

Medicolegal Pitfalls and diabetes in pregnancies

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Two main issues present medicolegal pitfalls for the clinician treating patients with diabetes in pregnancy.
1. Congenital malformations
2. Birth injuries

Congenital malformations
The occurrence of a severe, debilitating congenital anomaly in the infant of a mother with diabetes is serious burden for the mother as well as for the family. Clinicians must take necessary actions to prevent congenital malformations. Ideally this should be started preconceptionally.
If the patient is diabetic prior to pregnancy, The patient should be advised to use a reliable method of contraception until she has achieved a preconceptional HbA1C level within the reference range. This counseling should be recorded in the patient's medical record.
Structural defects occur in 3-8% of offspring of diabetic pregnancy, but this rate drops 3- to 4-fold if excellent glycemic control is maintained during the period of embryogenesis.
Birth injuries
Birth injuries include perinatal asphyxia, clavicle or humerus fracture, brachial plexus disruption, or, less commonly, direct cerebral or cervical spine trauma, shoulder dystocia.
Permanent palsy of the arm and hand after a difficult delivery of an obese fetus usually leads to litigation and, in some cases, large judgments. Although current scientific data establishing the foreseeability and preventability of these injuries remain inadequate, defending obviously high-risk cases can be difficult.
The obstetrician managing the patient's third-trimester prenatal care and labor may be judged at fault should an injury occur during delivery if an ultrasound suggests that fetal weight exceeds 10 lb, labor proceeds slowly, or a difficult forceps or vacuum procedure is necessary to deliver the fetal head. Thus, obtaining an ultrasound-based estimation of fetal weight in the last 2-3 weeks prior to delivery and offering cesarean delivery to a patient with an estimated fetal weight of more than 4500 g or a labor course that is protracted such that she is unable to expel the fetal head spontaneously after 2-3 hours of pushing effort are prudent.

Laboratory tests for Screening and Diagnosis of diabetes mellitus

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• Fasting plasma glucose (FPG)
• Random plasma glucose (RPG)
• 2hr plasma glucose of an OGTT (2hr PG)
• Capillary blood Glucose (CBG)
• Urinary glucose (UG)

Screening:

• Screening is recommended for all individuals with one or more major risk factors for
developing diabetes mellitus
• FPG is the laboratory test recommended for screening of individuals for diabetes mellitus
• RPG is an alternative test for screening.
• When facilities to do FPG or RPG are not available, CBG and UG are alternatives
screening for patients with classical symptoms of DM.

Diagnosis:

• The term diagnosis refers to confirmation of diabetes in people who have symptoms, or who have had a positive screening test.
• Either FPG or RPG can be used for the confirmation of diagnosis In symptomatic individuals one abnormal plasma glucose measurement in the diabetic range confirms the diagnosis.
• Asymptomatic individuals with a positive screening test (FPG or RPG) need another abnormal plasma glucose measurement on another day for the confirmation of the diagnosis.
• OGTT is not recommended for routine use as a confirmatory test.

Criteria for the diagnosis of Diabetes Mellitus:

• FPG ≥7.0 mmol/l (126 mg/dl). Fasting is defined as no caloric intake for at least 8 h. or
• Symptoms of diabetes plus random plasma glucose concentration ≥11.1 mmol/l (200 mg/dl). Random is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss or
• 2-h postload glucose ≥ 11.1 mmol/l (200 mg/dl) during an OGTT

Baseline laboratory tests in a newlydiagnosed patient with diabetes mellitus

Patients with type 2 DM could have had the disease for 5 – 7 years prior to the diagnosis.
Therefore the following biochemical tests are recommended for all newly diagnosed patients with DM to detect other associated metabolic and microvascular
complications. Baseline biochemical tests for newly diagnosed patients with DM

• Serum electrolytes
• Serum creatinine and estimated GFR (eGFR)
• Lipid profile (preferred) or serum cholesterol
• Urinary protein
• Urinary microalbumin (patients with negative
proteinuria)
• 24 hr urinary protein (patients with overt proteinuria)

Laboratory tests for the follow up of patients with IFG, IGT and DM (impaired glucose regulation and diabetes):

• All patients with IFG alone should be followed up with FPG annually
• All patients with IGT should be followed up with an OGTT annually. Patients diagnosed with DM should be monitored with FPG monthly.
• Glycosylated Haemoglobin (HbA1C) is recommended for follow up once in three months until satisfactory glycaemic control is achieved.
• HbA1C is recommended at least once in six months in patients who have achieved optimal control.
• Annual microalbumin (patients with negative proteinuria) and lipid profile testing are recommended for patients with DM.

Laboratory tests in the management of patients with metabolic complications of diabetes mellitus

Metabolic complications of DM

• Diabetic ketoacidotic coma
• Hyperosmolar nonketotic coma
• Hypoglaycaemia

Recommended laboratory tests in patients with metabolic complications
• Capillary Blood glucose
• Random plasma glucose (If CBG is abnormal)
• Urinary glucose
• Urinary ketone bodies
• Serum electrolytes
• Blood urea
• Serum creatinine
• Arterial blood gas analysis

Laboratory tests for Screening, Diagnosis and Management of
Gestational DM:

Selective screening is recommended for women with risk factors for developing GDM.
Risk factors for GDM

• Glycosuria in the 1st trimester
• Glycosuria on two occasions in either the second or third trimester
• Polyhydroamnios, macrosomia, large for gestational age in the current pregnancy
• Previous unexplained stillbirth
• Family history in a first degree relative
• Obesity (BMI>25Kg/m2) at the booking visit
• Age > 35 years
• Previous GDM
• Recurrent miscarriages
• Previous macrosomic baby

2hr postprandial plasma glucose (2hr PPG) following a standard meal at antenatal booking is recommended for screening for GDM.

• All abnormal screening tests should be followed up with an OGTT for confirmation of GDM.
• Pregnant mothers with a negative screening test should be evaluated at 24 -28 weeks of gestation with an OGTT.
• Protocol for OGTT is the same as for non pregnant adults and should be interpreted by an Obstetrician.

Glucose tolerance test

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A glucose tolerance test in medical practice is the administration of glucose to determine how quickly it is cleared from the blood. The test is usually used to test for diabetes, insulin resistance, and sometimes reactive hypoglycemia. The glucose is most often given orally so the common test is technically an oral glucose tolerance test (OGTT). The test may be performed as part of a panel of tests, such as the comprehensive metabolic panel.

Indications for OGTT:

In non pregnant adults an OGTT is recommended,

• For all patients with impaired fasting glucose.
• When results of the recommended diagnostic tests (FPG and RPG) fail to determine the diagnosis in an individual patient (E.g. equivocal or borderline results).

Protocol for the OGTT

1. Preparation of the patient:

• Three days unrestricted, carbohydrate rich diet and activity.
• No medication on the day of the test.
• 8 to 14 h fasting
• for paediatric patients: Children > 6 years: 8 -10 hr fast,Children <> 6.1 & <7.0>7.8 >7.0 >11.1
(mg/dl) <110>110 & <126>140 >126 >200

Variations
A standard 2 hour OGTT is sufficient to diagnose or exclude all forms of diabetes mellitus at all but the earliest stages of development. Longer tests have been used for a variety of other purposes, such as detecting reactive hypoglycemia or defining subsets of hypothalamic obesity. Insulin levels are sometimes measured to detect insulin resistance or deficiency.
The OGTT is of limited value in the diagnosis of reactive hypoglycemia, since (1) normal levels do not preclude the diagnosis, (2) abnormal levels do not prove that the patient's other symptoms are related to a demonstrated atypical OGTT, and (3) many people without symptoms of reactive hypoglycemia may have the late low glucoses that are said to be characteristic. Using a glucose tolerance in this context resembles use of a Rorschach test in that it is often used to support a diagnosis that the patient and doctor are already reaching agreement on based on other evidence, but it is inadequate by itself to confirm or refute the diagnosis (unlike its use for diabetes).
When the glucose is given intravenously it is termed an intravenous glucose tolerance test (IVGTT). This has been used in the investigation of early insulin secretion abnormalities in prediabetic states.

Glycosylated Hemoglobin (HbA1C)

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Introduction

Glycosylated hemoglobin is the combination of hemoglobin and glucose. When the blood sugar level is higher than normal for long period, hemoglobin is glycosylated. Glycosylation of hemoglobin occurs as a two-step reaction, resulting in the formation of a covalent bond between the glucose molecule and the terminal valine of the β chain of the hemoglobin molecule. The rate at which this reaction occurs is related to the prevailing glucose concentration.

Glycosylated haemoglobin is expressed as a percentage of the normal haemoglobin (standardized range 4-6.5%). This test provides an index of the average blood glucose concentration over the life of the haemoglobin molecule (approximately 6 weeks). The figure will be misleading if the life-span of the red cell is reduced or if an abnormal haemoglobin or thalassaemia is present. There are considerable inter-individual variations in HbA1c levels, even in normal people. Although the glycosylated haemoglobin test provides a rapid assessment of the level of glycaemic control in a given patient, blood glucose testing is needed before the clinician can know what to do about it.

Important HbA1C values are;

HbA1c <6.5% Good glycemic control

HbA1C 6.5-8.5% Moderate glycemic control

HbA1C >8.5% Bad glycemic control

Assessment of Long-Term Glycemic Control

Measurement of glycated hemoglobin is the standard method for assessing long-term glycemic control. When plasma glucose is consistently elevated, there is an increase in nonenzymatic glycation of hemoglobin; this alteration reflects the glycemic history over the previous 2 to 3 months, since erythrocytes have an average life span of 120 days.

Glycated hemoglobin or A1C should be measured in all individuals with DM during their initial evaluation and as part of their comprehensive diabetes care. As the primary predictor of long-term complications of DM, the A1C should mirror, to a certain extent, the short term measurements.

In standardized assays, the A1C approximates the following mean plasma glucose values:

1. HbA1C of 6% is 7.5 mmol/L (135 mg/ dL),
2. HbA1C of 7% is 9.5 mmol/L (170 mg/dL),
3. HbA1C of 8% is 11.5 mmol/L (205 mg/dL),
4. A 1% rise in the A1C translates into a 2.0-mmol/L (35 mg/dL) increase in the mean glucose

ESTABLISHMENT OF A TARGET LEVEL OF GLYCEMIC CONTROL

Because the complications of DM are related to glycemic control, normoglycemia or near normoglycemia is the desired, but often elusive, goal for most patients. However, normalization of the plasma glucose for long periods of time is extremely difficult. Regardless of the level of hyperglycemia, improvement in glycemiccontrol will lower the risk of diabetes complications In general; the target A1C should be 7.0%.

Overview of management

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Nutrition and diabetes mellitus

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Nutrition in diabetes mellitus is an important part of alongandhealthy life. The newest concept is the medical nutrition therapy

What is medical nutrition therapy (MNT)?

Medical nutrition therapy (MNT) is a term used to describe the optimal coordination of caloric intake with other aspects of diabetes therapy (insulin, exercise, weight loss). For example, MNT now includes foods with sucrose and seeks to modify other risk factors such as hyperlipidemia and hypertension rather than focusing exclusively on weight loss in individuals with type 2 DM. Like other aspects of DM therapy, MNT must be adjusted to meet the goals of the individual patient. Main aims of MNT are prevention of short term and long term complications.

Nutrition and Type1 Diabetes mellitus

The goal of MNT in the individual with type 1 DM is to coordinate and match the caloric intake, both temporally and quantitatively, with the appropriate amount of insulin. MNT in type 1 DM and self-monitoring of blood glucose must be integrated to define the optimal insulin regimen. MNT must be flexible enough to allow for exercise, and the insulin regimen must allow for deviations in caloric intake. An important component of MNT in type 1 DM is to minimize the weight gain often associated with intensive diabetes management.

Nutrition and Type2 Diabetes mellitus

The goals of MNT in type 2 DM are slightly different and address the greatly increased prevalence of cardiovascular risk factors (hypertension, dyslipidemia, obesity) and disease in this population. The majority of these individuals are obese, and weight loss is strongly encouraged and should remain an important goal. Hypocaloric diets and modest weight loss often result in rapid and dramatic glucose lowering in individuals with new-onset type 2 DM. Current MNT for type 2 DM should emphasize modest caloric reduction, reduced fat intake, increased physical activity, and reduction of hyperlipidemia and hypertension. Increased consumption of soluble, dietary fiber may improve glycemic control in individuals with type 2 DM.

Dietary constituents and Diabetes mellitus

1. Carbohydrates

• 50-55% of calorie should be provided by carbohydrates
• consume unrefined carbohydrates (parboiled rice) rather than simple sugars (glucose)
• foods with low glycemic index aids the metabolic control
• high fiber diets are considered as foods with low glycemic index

2. Protein

• 10-20% of calorie should come from protein
• protein should be cut down if nephropathy is present

3. Fat

• Fat should provide 30% of the caloric need

10% unsaturated fat
10% poly saturated fat
10% monosaturated fat

• if the patient is hyperlipedimic, fat should be cut down

4. Alcohol

• Alcohol consumption is same as for the general public

2drinks/day for male
1drink/day for female

• Patients on insulin therapy should avoid alcohol as it can precipitate hypoglycemic attacks.

Life style modifications

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Oral glucose lowering agents (oral hypoglycemic agents)

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Introduction

Oral antidiabetic drugs are used for the treatment of type 2 diabetes mellitus. They should be prescribed only if the patient fails to respond adequately to at least 3 months restriction of energy and carbohydrates intake and an increase in physical activity. They should be used to augment the effect of diet and exercise, and not to replace them.
Advances in the therapy of type 2 DM have generated considerable enthusiasm for oral glucose-lowering agents that target different pathophysiologic processes in type 2 DM. Based on their mechanisms of action, oral glucose-lowering agents are subdivided into agents that;

1. increase insulin secretion,
2. reduce glucose production, or
3. increase insulin sensitivity .

Agents that increase insulin secretion (INSULIN SECRETAGOGUES)

Insulin secretagogues stimulate insulin secretion by interacting with the ATP-sensitive potassium channel on the beta cell. These drugs are most effective in individuals with type 2 DM of relatively recent onset, who tend to be obese and have residual endogenous insulin production. At maximum doses, first-generation sulfonylureas are similar in potency to second-generation agents but have a longer half-life, a greater incidence of hypoglycemia, and more frequent drug interactions. Thus, second-generation sulfonylureas are generally preferred.

Agents that reduce glucose production

Glucosidase inhibitors (acarbose and miglitol) reduce postprandial hyperglycemia by delaying glucose absorption; they do not affect glucose utilization or insulin secretion. Postprandial hyperglycemia, secondary to impaired hepatic and peripheral glucose disposal, contributes significantly to the hyperglycemic state in type 2 DM. These drugs, taken just before each meal, reduce glucose absorption by inhibiting the enzyme that cleaves oligosaccharides into simple sugars in the intestinal lumen. Therapy should be initiated at a low dose.
Metformin is representative of this class of agents. It reduces hepatic glucose production through an undefined mechanism and improves peripheral glucose utilization slightly

Agents that increase insulin sensitivity or reduce resistance

Thiazolidinediones reduce insulin resistance. These drugs bind to the PPAR (peroxisome proliferator-activated receptor) nuclear receptor. The PPAR-_ receptor is found at highest levels in adipocytes but is expressed at lower levels in many other tissues.

Classes of drugs
Read more

1. Sulphonylureas
2. Biguanides
3. Thiazolidinediones (Glitazones)
4. Alpha-Glucosidase inhibitors
5. Meglitinides

Sulphonylureas

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Introduction

The Sulphonylureas act mainly by augmenting insulin secretion and consequently are effective only when some residual pancreatic beta cells activity is present; during long term administration they also have extra-pancreatic actions. All may cause hypoglycemia but this is uncommon and usually indicates excessive dose. Followings are the common drugs;

1. Tolbutamide
2. Chlorprapamide
3. Glibenclamide
4. Glipizide

Mechanism of action

They bind with potassium channels on the cell membrane of beta cells and reduce the potassium permeability. Therefore cell membrane becomes depolarized. Thus calcium will influx to the cell. This will result insulin secretion.

Mode of actions

1. increase insulin secretion
2. increase peripheral sensitivity for insulin
3. extra-pancreatic functions are;

I. reduce hepatic glucose production
II. reverse post receptor defect in insulin action
III. increase number of insulin receptors

Pharmacokinetics

Oral absorption is good and it achieves peak plasma concentration within 2-4 hours after the ingestion. Sulphonylureas bind strongly with albumin therefore they implicate with other drugs which have an affinity towards albumin such as salicylate and sulfonamide. These drugs are excreted via urine therefore extra precautions should be taken when prescribing for a patient with renal failure. Sulphonylureas are contraindicated during pregnancy as they cross the placenta (except glibenclamide).

Adverse drug reactions

1. They cause hypoglycemia. This effect is highest with chlorprapamide and glibenclamide and lowest with tolbutamide.
2. They increase appetite therefore increases the weight gain.
3. 3% of patients experience gastrointestinal disturbances.
4. They can cause allergic skin reaction
5. Bone marrow suppression is a dreaded drawback of these drugs but it occurs rarely.

Drug interaction

1. following drugs can augment the hypoglycemic effect of Sulphonylureas by replacing them from albumin

I. Non-steroidal anti-inflammatory drugs(Diclofenac sodium)
II. Uricosuric drugs(Sulfinpyrazone)
III. Alcohol
IV. Mono Amine Oxidase inhibitors (Phenalzine)
V. Antibacterial agents (sulfonamide, trimethoprime, chloramphenicol)
VI. Antifungal agents (imidazole)

2. Following drugs reduce the effects of Sulphonylureas

I. Thiazide diuretics (HCT)
II. Corticosteroids

Clinical uses

1. Useful in early stages of type 2 diabetes mellitus
2. They can be combined with Metformin or Glitazones.
3. Sulphonylureas are given ½ hour prior to the meal
4. Glibenclamide should not be given to elderly patients and patients with renal failure.

Metformin (Biguanides)

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Introduction

Metformin is the only available drug in this class and it has a different mode of action from the Sulphonylureas, and it is not interchangeable with them. Metformin is the drug of first choice in overweight patients in whom strict dieting has failed to control diabetes.

Mechanism of action

This is very complex and incompletely understood

Mode of actions

1. it increases the peripheral sensitivity for insulin by;

I. increasing glucose uptake and utilization by skeleton muscles
II. reducing insulin resistance

2. it reduces LDL and VLDL level
3. It increase HDL level

Pharmacokinetics

Oral bio-availability is 50-60%.The half life of metformin is about 3 hours. It is excreted via urine as it is.

Adverse drug reactions

1. Dose related gastrointestinal disturbances(anorexia, diarrhea, nausea)
2. It can cause lactic acidosis. Even though this is rare it can be fatal. Therefore Metformin should not be given to patients with renal/ hepatic disease, hypoxic pulmonary disease, heart failure or shock.
3. Long term use may interfere with vitamin B12 absorption.
4. teratogenic

Clinical uses

1. Start with smaller doses and gradually increase the dose to over come the adverse effects.
2. given immediately after the meal
3. Drug of choice for patients with type2 DM and obesity.
4. can be combined with Sulphonylureas, Glitazones or insulin
5. does not cause hypoglycemia
6. preserved for middle and old age patients

Glitazones (Thiazolidinediones)

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Introduction

The thiazolidnediones reduce peripheral insulin resistance, leading to a reduction of blood glucose concentration. Either drug may be used alone or in combination with metformin or with a Sulphonylurea. Following are the examples for thiazolidnediones;

1. Rosiglitazones
2. Pioglitazones
3. Ciglitazones (not in use due to the hepatotoxicity)
4. Troglitazones (not in use due to the hepatotoxicity)

Mechanism of actions

Glitazones bind with a nuclear receptor called Peroxisomal Proliferator-Activated Receptor Gamma (PPARγ), which is complexed with retinoid X-receptor (RXR). This binding will cause a conformational change in the PPARγ-RXR complex. Thus, this complex binds with DNA and promotes transcription of several genes. Therefore following proteins result. These are important in insulin signaling.

Lipoprotein lipase
Fatty acid transporter protein
Adipocytes fatty acid binding protein
Glut 4 receptors
Phophoenolpyruvate carboxykinase

PPARγ is mainly found adipose tissue, muscles and liver. It mediates differentiation of adipocytes, increase lipogenesis and enhances uptake of fatty acid and glucose.

Effects of Glitazones

1. reduce hepatic glucose out put
2. increase glucose uptake into muscles
3. enhances the effectiveness of endogenous insulin
4. reduce the amount of exogenous insulin needed to maintain a given blood sugar level by 30%
5. reduce circulating insulin and fatty acids
6. reduce small density LDL, which is more atherogenic
7. increase weight gain
8. cause fluid retention
9. increase extravascular fluids
10. increase deposition of subcutaneous fat.

Pharmacokinetics

Oral absorption is rapid and complete. They achieve peak plasma concentration within 2 hours. They are highly bound to plasma protein. They undergo hepatic metabolism. Half life is less than 7 hours for parent drug but the half life of rosiglitazone is 150hous whereas the half life of pioglitazone is 24 hours. Rosiglitazone is excretd via urine whereas pioglitazone is excreted via bile.

Side effects

1. hepatotoxicity ( uncommon with newer drugs)
2. weight gaining and fluid retention
3. headache
4. fatigue
5. gastrointestinal disturbances
6. may resume ovulation in women who are anovulatory. This is due to the reduction insulin resistance. Therefore precautions should be taken
7. teratogenic

Drug interaction

1. additive with other oral hypoglycemic agents
2. increase the risk of heart failure with insulin

Clinical uses

1. useful in type 2 diabetes mellitus
2. good for patient who cannot tolerate metformin
3. can be combined with other oral hypoglycemic agents
4. monotherapy or polytherapy is possible

Alpha-Glucosidase inhibitors(Arcabose)

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Introduction

Alpha-Glucosidase is an enzyme found in the intestinal brush border. It involves with carbohydrates metabolism.

Arcabose is the available Alpha-Glucosidase inhibitor. It has a small but significant effect in lowering blood glucose and is used either on its own or as an adjunct to metformin or Sulphonylureas when they prove inadequate.

Mechanism of actions

Acarbose is a competitive inhibitor of Alpha-Glucosidase enzyme. Thereby it reduces the carbohydrate breakdown and it will slow down the glucose absorption. The ultimate result is reduction of postprandial blood glucose level.

Pharmacokinetics

It is given orally. Small amount of the drug is absorbed into the circulation.

Side effects

1. Abdominal discomfort, flatulence and diarrhea due to the fermentation of undigested carbohydrates.
2. If it is absorbed into the circulation in large dose, it can cause liver dysfunction

Clinical uses

1. Useful for patients with type 2 diabetes mellitus whose blood sugar control is inadequate with diet and other oral hypoglycemic drugs.
2. good for obese patients
3. It can be used to reduce the post-prandial blood sugar in patients with type1 diabetes mellitus.

Meglitinides

2009-01-31T22:19:00.000-08:00

Introduction

This is a newer class of insulin secretagogues. Meglitinide is the non-sulphonylurea moiety of glibenclamide. This drug stimulates the insulin secretion. Followings are the examples for Meglitinides;

1. Nateglinide
2. Repaglinide

Mechanism of action

Meglitinides close the potassium channel in the cell membrane of pancreatic beta cell. It causes depolarization of the cell membrane thus calcium will influx to the beta cell. This will result in secretion of insulin. This mechanism is different from Sulphonylureas.

Effects

1. Increase insulin secretion
2. risk of hypoglycemia between meal is less

Pharmacokinetics

Onset of action is quicker and duration of action is shorter than that of Sulphonylureas.

Side effects

1. hypersensitivity reactions
2. hypoglycemia

Clinical uses

1. useful in type 2 diabetes mellitus
2. can be given with metformin

PHYSIOLOGY OF INSULIN

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What is insulin?

Insulin is a hormone which is secreted by the pancreatic beta cells. It is a protein. This hormone is essential for the metabolism of carbohydrates, protein and fat.

Biosynthesize

Insulin is produced in the beta cells of the pancreatic islets. It is initially synthesized as a single-chain 86-amino-acid precursor polypeptide, preproinsulin. Subsequent proteolytic processing removes the aminoterminal signal peptide, giving rise to proinsulin. Proinsulin is structurally related to insulin-like growth factors I and II, which bind weakly to the insulin receptor. Cleavage of an internal 31-residue fragment from proinsulin generates the C peptide and the A (21 amino acids) and B (30 amino acids) chains of insulin, which are connected by disulfide bonds.

The mature insulin molecule and C peptide are stored together and cosecreted from secretory granules in the beta cells. Because the C peptide is less susceptible than insulin to hepatic degradation, it is a useful marker of insulin secretion

Secretion

Glucose enters to the beta cells via GLUT 2 receptors

Metabolized by the Glucokinase

Produce ATP

ATP inhibits potassium channel

Depolarization of the cell membrane

Opening of voltage dependant calcium channel

calcium influx

Insulin secretion

Action

Insulin acts on almost all the tissues but liver, muscles and adipose tissues are the main sites. Overall effect is to conserve fuel by facilitating the uptake and storage of glucose , amino acids and fatty acids following a meal.

Insulin binding to its receptor stimulates intrinsic tyrosine kinase activity, leading to receptor autophosphorylation and the recruitment of intracellular signaling molecules, such as insulin receptor substrates (IRS). These and other adaptor proteins initiate a complex cascade of phosphorylation and dephosphorylation reactions, resulting in
the widespread metabolic and mitogenic effects of insulin.

Structure

Insulin consists of two amino acids; A chain (21 amino acids): B chain (30 amino acids).
These two amino acids chains are combined with two sulphide bonds.

TYPES OF INSULIN

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1. Short acting insulin

I. Soluble insulin
II. Rapid acting insulin analogues

2. Intermediate acting insulin
3. Long acting insulin
4. Mixed insulin

Soluble insulin

Soluble insulin is a short acting insulin. This is the most appropriate form of insulin for use in diabetic emergencies and at the time of surgery. There are two types of soluble insulins;

1. Soluble human insulin (Product of DNA recombinant technique)
2. Soluble animal insulin (Bovine and porcine)

Soluble insulin is injected 15-30 minutes prior to a meal. It reaches peak concentration within 60-90 minutes and duration of action is about 8 hours. It can be administrate in intravenous, intramuscular and subcutaneous routes.

Rapid acting insulin analogue

The structure of the insulin molecule is modified as to change its pharmacokinetics without altering the biological effects

The human insulin analogues have a faster onset and shorter duration of action; as a result, compared to soluble insulin, fasting and pre-prandial blood glucose concentration is a little lower, and hypoglycemia occurs slightly less likely. Route of administration is subcutaneous. There are two types of analogues available;

1. Insulin lispro
2. Insulin aspart

Intermediate acting insulin

When they are given in subcutaneous route, the onset of action is 1-2 hours and duration of action is about 18-24 hours. There are two types of intermediate acting insulin;

1. Isophane insulin (NPH: Neutral Protamine Hagedorn);

This is prepared by adding protamine into soluble insulin. It has a cloudy appearance. This can be pre-mixed with soluble insulin or can be combined with insulin analogues as well

2. Insulin Zn suspension (Crystalline/ lente insulin);

Prepared by adding Zn into soluble insulin
Duration of action is longer than that of NPH
Cannot be pre-mixed with soluble insulin, but can be mixed just prior to inject.

Long acting insulin

Onset of action is 4-6 hours and duration of action is 24-36 hours when given subcutaneously. There are mainly two types;

1. Insulin gargling

This is an insulin analogue. It has a prolonged duration of action and it is given once a daily basis.

2. Protamine Zn insulin (ultralente)

Given once a daily basis
Usually given with soluble insulin
Rarely used.

Mixed insulin

This is the commonest way of giving insulin. Preparations are made to suit the patients’ need. There are several preparations available;

1. Biphasic insulin aspart

This is the mixture of insulin aspart(30%) and isophane insulin(70%).

2. Biphasic insulin lispro

This is the mixture of insulin lispro and isophane insulin. Percentages can be varying.

Eg; Biphasic insulin lispro 25 (25% insulin lispro and 75% isophane insulin)
Biphasic insulin lispro 50 (50% insulin lispro and 50% isophane insulin)

3. Biphasic isophane insulin

This is the mixture of soluble insulin and isophane insulin. Percentages can be varying.

Eg; Biphasic isophane insulin30/70(30% soluble insulin and 70% isophane insulin)
Biphasic isophane insulin10 (10% soluble insulin and 90% isophane insulin)
Biphasic isophane insulin20 (20% soluble insulin and 80% isophane insulin)
Biphasic isophane insulin40 (40% soluble insulin and 60% isophane insulin)

Insulin injection technique

2009-01-31T22:16:00.002-08:00

Introduction

Diabetes is one of the most common and serious chronic diseases. A third of its victims remain unaware that they have it. Each year, approximately 800,000 people are diagnosed with diabetes, its prevalence increasing steadily over the last half of this century. Incidence is expected to continue rising with the aging.

When talking about insulin injection techniques, followings should be considered.

1. Syringes
2. Insulin pen
3. other insulin aids
4. site selection
5. mixing of insulin
6. injection technique

SYRINGES

Insulin syringes are in the four basic capacities;
1. 1 cc (100 units)
2. 1/2 cc (50 units)
3. 3/10 cc (30 units)
4. 200-unit syringes (used in rare cases where patients require doses in excess of 100 units)
The unit scale or graduations on the barrel of the syringe may differ depending on the size of the syringe and the manufacturer;
1. 1 cc syringes usually marked in 2-unit intervals
2. 1/2 cc and 3/10 cc syringes in 1-unit intervals
The barrels of the smaller-capacity syringes are narrower to allow expansion of scales and easier reading, so patients should generally be counseled to use syringes with the smallest capacity that will accommodate the required dose.

Insulin syringes are also fitted with different needle gauges and lengths ranging from 28G, 29G and 30G. As with other needles, the higher the number of the needle gauge, the smaller the diameter of the needle. In general, patients prefer the thinner needles, associating thinner needles with greater comfort. Patients should be warned that with the thinner gauge needle also comes increased needle flexibility.

Insulin syringe needles are available in;
1. The standard 1/2-inch (12.7mm)
2. A shorter 5/16-inch (8 mm)
A patient changing needle lengths may experience a change in glycemic control, as absorption from a different subcutaneous depth can affect rate and extent of insulin absorption.
Insulin Pens

Insulin pens have become especially convenient for active people or those who have difficulty drawing insulin from a vial. They are compact, easy to carry and store, and discreet to use; and they eliminate the need to carry vials of insulin. Insulin is stored in a cartridge inside the pen, and the delivered dose is selected by turning a dial prior to activation of the device.
Other Injection Aids
Injecting insulin may become more difficult for patients with compromised dexterity or eyesight, so various injection aids have been designed to help overcome these difficulties. A magnifier fits around the syringe to enable the user with compromised visual acuity to read syringe measurements more accurately.
Automatic injector devices facilitate ease of administration, some delivering needle and insulin simultaneously and others requiring the user to push a syringe plunger after the needle has pierced the skin. Such a device may be helpful for people who have a fear of needles or of self-injection, as the injection is not directly observable.

Site Selection

Insulin is injected into the fatty tissue under the skin from which it is absorbed into the blood stream at rates that vary with the site of injection, so blood glucose values may also vary with injection site.

Common sites are;

1. Abdomen
2. Arms
3. Hip
4. Buttocks
5. Thigh

Absorption is most rapid from sites in the abdomen, somewhat slower from the arms, slower still from the legs, and slowest from the hip or buttock area.

Patients may choose one area over others because of comfort, or how quickly or slowly insulin is absorbed. Rotating injection sites within one area is generally recommended over rotating to a different area due to the variable absorption between the different sites. Increasing exercise of the injection site increases the rate of insulin absorption by enhancing blood flow to the area. Preferred sites for insulin injections include the upper arm, the anterior and lateral aspects of the thigh, the buttocks, and the abdomen (stomach area).

Mixing Insulins

Certain short-acting and long-acting insulins can be mixed in the same syringe to minimize the number of injections. The short-acting (clear) insulin should be drawn up first, followed by the long-acting insulin, as follows.

Hands should be cleaned with soap and water before mixixng
Mixing should be done gently by rolling the vial between the palms of the hands, or gently turning the bottle from end to end a few times. Do NOT shake!

Injection Technique

Detailed information regarding insulin injection technique should provided to the patient.

All the equipment should be ready. Then select the site.
Wash hands with warm, soapy water prior to the procedure.
After choosing an injection site, clean the area with an alcohol swab.
Pick up the syringe and uncap if previously recapped. “Pinch” the area of skin to be injected, and quickly push the needle through the skin at a 90° angle. Inject the insulin by pushing down on the plunger, release the pinched skin, and pull the needle straight out of the site. Press gently over the area injected with a finger or alcohol swab, but do not rub the area.
Dispose of used needles and syringes safely.

How do you minimize the pain?
1. Inject insulin at room temperature.
2. Remove all air bubbles from the syringe before injection.
3. Wait until topical alcohol has evaporated before injecting.
4. Keep muscles in the injection area relaxed during injection.
5. Penetrate the skin quickly.
6. Avoid changing direction of the needle during insertion or removal.
7. Do not reuse disposable needles.

Insulin Resistance

2009-01-31T22:16:00.001-08:00

Introduction

Insulin resistance is a condition that increases your chances of developing type 2 diabetes and heart disease. When you have insulin resistance, your body has problems responding to insulin. Eventually, your blood glucose (sugar) levels rise above normal. The good news is that cutting calories, adding physical activity to your daily routine, and losing weight can reverse insulin resistance and lessen your chances of getting type 2 diabetes and heart disease.

Risk factors for insulin resistance

You’re more likely to have insulin resistance if you

• are overweight
• are physically inactive
• are a woman with a waist measurement at your belly button over 35 inches or a man with a waist measure over 40 inches
• have a parent, brother, or sister with type 2 diabetes
• have polycystic ovary syndrome
• are over age 45
• have a blood pressure over 140/90 mmHg
• have low HDL (good) cholesterol levels (35 mg/dl or lower)
• have high levels of a fat called triglycerides in the blood (250 mg/dl or higher)

All of these risk factors put you at risk for heart disease as well.

How is insulin resistance diagnosed?

At this time, there is no commonly used test to diagnose insulin resistance. People with insulin resistance usually have no symptoms. Your doctor can review your risk factors and then consider whether you’re likely to be insulin resistant. If you have a risk factor for insulin resistance, your doctor should check your fasting blood glucose levels to see whether you have pre-diabetes or even diabetes.

How can I prevent or reverse insulin resistance?

You can cut calories and be physically active. If you do, it’s more likely you’ll lose weight. Remember, you don’t have to lose a lot; even a loss of 10 pounds can help.

C-peptide

2009-01-31T22:15:00.000-08:00

C-peptide is a peptide which is made when proinsulin is split into insulin and C-peptide. They split before proinsulin is released from endocytic vesicles within the pancreas -- one C-peptide for each insulin molecule.
C-peptide is the abbreviation for "connecting peptide", although its name was probably also inspired by the fact that insulin is also composed of an "A" chain and a "B" chain. C-peptide was discovered in 1967. It should not to be confused with c-reactive protein or Protein C. The first documented use of the C-peptide test was in 1972.

Function
Cellular effects of C-peptide: C-peptide binds to a receptor at the cell surface and activates signal transduction pathways that result in stimulation of Na+,K+ATPase and endothelial nitric oxide synthase (eNOS), both of which are enzymes with reduced activitities in type I diabetes.
C-peptide functions in repair of the muscular layer of the arteries.
C-peptide also exerts beneficial therapeutic effects on many complications associated with diabetes mellitus,[2] such as diabetic neuropathy[3] and other diabetes-induced ailments. In the kidneys, C-peptide prevents diabetic nephropathy,[4][5] and in the heart blood flow is improved in diabetic patients.[6]
In spite of these physiological functions, C-peptide is not present in pharmaceutical preparations of insulin sold by drug companies that are in wide-scale clinical usage today, a practice seen as unethical in light of more research suggesting the peptide's utility.
Ironically, back in 1997, insulin manufacturer Eli Lilly and Company jointly funded research into C-Peptide as a possible therapeutic. In the research undertaken by researchers at Washington University School of Medicine in St. Louis, they determined that C-Peptide may effectively prevent and even reverse cardiovascular disease and nerve damage in people with diabetes, although their studies were only on rodent models of the disease.[7][8] However, the company never pursued commercialization of the product. But in a 2007 letter to the Indianapolis Star, company executive John C. Lechleiter did indicate that the company was pursuing development of drugs to treat diabetes-induced complications.
Uses
• Newly diagnosed diabetes patients often get their C-peptide levels measured as a means of distinguishing type 1 diabetes and type 2 diabetes. C-peptide levels are measured instead of insulin levels because insulin concentration in the portal vein ranges from two to ten times higher than in the peripheral circulation. The liver extracts about half the insulin reaching it in the plasma, but this varies with the nutritional state. The pancreas of patients with type 1 diabetes is unable to produce insulin and therefore they will usually have a decreased level of C-peptide, whereas C-peptide levels in type 2 patients are normal or higher than normal. Measuring C-peptide in patients injecting insulin can help to determine how much of their own natural insulin these patients are still producing. C-peptide is easily detected because antibodies that are sensitive to it are readily available, whereas antibodies to insulin are much more difficult to obtain.
• C-peptide is also used for determining the possibility of gastrinomas associated with Multiple Endocrine Neoplasm syndromes (MEN 1). Since a significant amount of gastrinomas also include MEN which include pancreatic, parathyroid, and pituitary adenomas, higher levels of C-peptide together with the presence of a gastrinoma suggest that organs besides the stomach may harbor neoplasms.
• Can be used for identifying malingering: hypoglycemia with low C-peptide level may indicate abuse of insulin.
• C-peptide levels are checked in women with Polycystic Ovarian Syndrome (PCOS) to determine degree of insulin resistance.
Both excess body weight and a high plasma concentration of C-peptide predispose men with a subsequent diagnosis of prostate cancer to an increased likelihood of dying of the disease, according to the results of a long-term survival analysis reported in the October 6, 2008 Online First issue of Lancet Oncology.
[edit] Therapeutics
C-peptide has been administered experimentally to improve neuropathy and other symptoms of diabetes.[9] [10] [11] [12] [13] [2] [14] [15] [16].
A company based in Stockholm, Sweden called Creative Peptides has secured manufacturing and other patents in a number of countries for C-peptide, and aims to commercialize it as a therapeutic. It is now undergoing human clinical trials. However since C-Peptide was discovered in 1967, patenting the peptide itself is not possible, only the processes to create it. This makes it very difficult to obtain research dollars from pharmaceutical companies to conduct research. Creative Pepides solution is to patent processes to create C-Peptide, thus making the product more profitable to invest in for pharmaceutical companies.
After delays due to lack of funding, Creative Peptides has now obtain funding based on a process that will make it possible to inject C-peptide once a week instead of daily. Stage 3 Clinical Trials are set for late 2009.

Diabetic ketoacidosis (DKA)

2009-01-31T22:14:00.000-08:00

Introduction

Diabetes ketoacidosis is an acute complication of diabetes as hyperglycemic hyperosmolar state (HHS).It was formerly considered a hallmark of type 1 DM, but it also occurs in individuals with type 2 diabetes mellitus as well. This is associated with potentially serious complications if not promptly diagnosed and treated.

Clinical Features

The symptoms and physical signs of DKA are listed below and usually develop over 24 hours. DKA may be the initial presentation of type 1 DM, but more frequently it occurs in individuals with established diabetes. Nausea and vomiting are often prominent,

1. Symptoms

Nausea
Vomiting
Thirst
Polyuria
Abdominal pain
Shortness of breath

2. Physical findings

Tachycardia
Dry mucous membranes
Reduced skin turgor
Dehydration
Hypotension
Tachypnea
Kussmaul respirations
Respiratory distress
Abdominal tenderness (may resemble acute pancreatitis or surgical abdomen)
Lethargy
Obtundation
Cerebral
Edema
Possibly coma

3. Precipitating events

Inadequate insulin administration
Infection (pneumonia/UTI/gastroenteritis/sepsis)
Infarction (cerebral, coronary, mesenteric, peripheral)
Drugs (cocaine)
Pregnancy

Pathophysiology

DKA results from relative or absolute insulin deficiency combined with counterregulatory hormone excess (glucagon, catecholamines, cortisol, and growth hormone). Both insulin deficiency and glucagon excess, in particular, are necessary for DKA to develop. The decreased ratio of insulin to glucagon promotes gluconeogenesis, glycogenolysis, and ketone body formation in the liver, as well as increases in substrate delivery from fat and muscle (free fatty acids, amino acids) to the liver.

Laboratory Abnormalities and Diagnosis

The timely diagnosis of DKA is crucial and allows for prompt initiation of therapy. DKA is characterized by hyperglycemia, ketosis, and metabolic acidosis (increased anion gap) along with a number of secondary metabolic derangements;

Glucose 13.9–33.3 mmol/L (250–600 mg/dL)
Sodium 125–135 meq/L
Potassium Normal to higher
Magnesium Normal to higher
Chloride Normal
Phosphate Normal
Creatinine Slightly high
Osmolality 300–320 mOsm/mL
Plasma ketones ++++
Serum bicarbonate >15 meq/L
Arterial pH 6.8–7.3
Arterial PCO 20–30mmHg
Anion gap [Na-(Cl+HCO3)] higher

Treatment

1) Confirm diagnosis
2) Admit to hospital; intensive-care setting
3) Assess: Serum
4) Replace fluids
5) Administer regular insulin
6) Assess patient: What precipitated the
7) Measure capillary glucose every 1–2 h
8) Monitor blood pressure, pulse, respirations, mental status, fluid intake and output every 1–4 h.
9) Replace potassium
10) Continue above until patient is stable
11) Administer intermediate or long-acting insulin as soon as patient is eating. Allow for overlap in insulin infusion and subcutaneous insulin injection.

Hyperglycemic hyperosmolar state (HHS)

2009-01-31T22:13:00.002-08:00

Introduction

Hyperglycemic hyperosmolar state (HHS) is an acute complication of diabetes as DKA. HHS is primarily seen in individuals with type 2 DM.

Clinical Features

The prototypical patient with HHS is an elderly individual with type 2 DM, with a several week history of polyuria, weight loss, and diminished oral intake that culminates in mental confusion, lethargy, or coma.

The physical examination reflects profound dehydration and hyperosmolality and reveals hypotension, tachycardia, and altered mental status.

Notably absent are symptoms of nausea, vomiting, and abdominal pain and the Kussmaul respirations characteristic of DKA. HHS is often precipitated by a serious, concurrent illness such as myocardial infarction or stroke. Sepsis, pneumonia, and other serious infections are frequent precipitants and should be sought.

Pathophysiology

Relative insulin deficiency and inadequate fluid intake are the underlying causes of HHS. Insulin deficiency increases hepatic glucose production (through glycogenolysis and gluconeogenesis) and impairs glucose utilization in skeletal muscle (see above discussion of DKA). Hyperglycemia induces an osmotic diuresis that leads to intravascular volume depletion, which is exacerbated by inadequate fluid replacement. The absence of ketosis in HHS is not completely understood.

Laboratory Abnormalities and Diagnosis

The laboratory features in HHS are summarized as follows;

Glucose 33.3–66.6 (mmol/L (600-1200 mg/dL)
Sodium 135–145 meq/L
Potassium Normal
Magnesium Normal
Chloride Normal
Phosphate Normal
Creatinine Moderately high
Osmolality 330–380 mOsm/mL
Plasma ketones +/-
Serum bicarbonate Normal to slightly low
Arterial pH >7.3
Arterial PCO Normal
Anion gap [Na-(Cl+HCO3)] Normal to slightly higher

Treatment

Volume depletion and hyperglycemia are prominent features of both HHS and DKA. In both disorders, careful monitoring of the patient’s fluid status, laboratory values, and insulin infusion rate is crucial. Underlying or precipitating problems should be aggressively sought and treated. In HHS, fluid losses and dehydration are usually more pronounced than in DKA due to the longer duration of the illness. The patient with HHS is usually older, more likely to have mental status changes, and more likely to have a life-threatening precipitating event with accompanying comorbidities. Even with proper treatment, HHS has a substantially higher mortality than DKA (up to 15% in some clinical series).

Complications of diabetes mellitus

2009-01-31T22:13:00.001-08:00

There are mainly two types of complications associatedwith diabetes

Acute complications

1. Diabetic ketoacidosis (DKA)
2. Hyperglycemic hyperosmolar state (HHS)

Chronic complications

1. Microvascular

I. Eye disease; Retinopathy (nonproliferative/proliferative): Macular edema

II. Neuropathy; Sensory: motor (mono- and polyneuropathy):Autonomic

III. Nephropathy

2. Macrovascular

I. Coronary artery disease

II. Peripheral vascular disease

III. Cerebrovascular disease

3. Other

I. Gastrointestinal (gastroparesis, diarrhea)

II. Genitourinary (uropathy/sexual dysfunction)

III. Dermatologic

IV. Infectious

V. Cataracts

VI. Glaucoma

VII. Psychological problems

Diabetic Nephropathy

2009-01-31T22:12:00.001-08:00

Introduction

Diabetic nephropathy is one of the leading causes of ESRD and it is also a leading cause of DM-related morbidity and mortality. Proteinuria in individuals with DM is associated with markedly reduced survival and increased risk of cardiovascular disease. Individuals with diabetic nephropathy almost always have diabetic retinopathy.

Pathogenesis

Chronic hyperglycemia is the fundamental cause of diabetic nephropathy as in other microvascular complications. The mechanisms by which chronic hyperglycemia leads to end stage renal disease, though incompletely defined, involve the effects of soluble factors (growth factors, angiotensin II, endothelin, AGEs), hemodynamic alterations in the renal microcirculation (glomerular hyperfiltration or hyperperfusion, increased glomerular capillary pressure), and structural changes in the glomerulus (increased extracellular matrix, basement membrane thickening, mesangial expansion, fibrosis). Some of these effects may be mediated through angiotensin II receptors.

Clinical course

It is important to note that diabetic nephropathy is a multistage condition that takes several years to become clinically overt.

Microalbuminuria: the definition of diabetic nephropathy used to be dictated by the lower limit of detection of the assays for urinary albumin available at the time. Microalbuminuria is the first indication of diabetic nephropathy, and is defined as a persistent increase in urinary albumin excretion rate to 20–200 μg/minute (30–300 mg/ day).

Persistent albuminuria: an increase in albumin excretion to persistently more than 200 μg/minute (> 300 mg/day) marks the onset of clinically defined overt diabetic nephropathy.

Uraemia: persistent albuminuria is accompanied by a gradual decline in GFR. If untreated, this eventually leads to uraemia and death after an average of 7–10 years.

Diagnosis

Normally, there is little urinary albumin; normal ranges are:
1. urine albumin concentration < 20 mg/litre
2. albumin:creatinine ratio < 2.5 mg/mmol in men and < 3.5 mg/mmol in women
3. albumin excretion rate < 20 μg/minute.

Treatment

The optimal therapy for diabetic nephropathy is prevention. As part of comprehensive diabetes care, microalbuminuria should be detected at an early stage when effective therapies can be instituted. Interventions effective in slowing progression from Microalbuminuria to overt nephropathy include:

(1) Near normalization of glycemia,
(2) Strict blood pressure control, and
(3) Administration of ACE inhibitors or ARBs, and
(4) Treatment of dyslipidemia.

Diabetic neuropathy

2009-01-31T22:11:00.002-08:00

Introduction

Diabetic neuropathy occurs in approximately 50% of individuals with long-standing type 1 and type 2 DM. There are two types of neuropathies; Microvascular and macrovascular

1. Microvascular
I. Hyperglycemic neuropathy
II. Acute painful sensory neuropathy
III. Sensory motor polyneuropathy
IV. Mononeuropathy
V. Diabetic truncal neuropathy
VI. Proximal diabetic neuropathy
VII. Autonomic neuropathy

2. Macrovascular
I. TIA & Strokes

Hyperglycemic neuropathy

This is common among newly diagnosed or poorly controlled diabetic patients. This is a very uncomfortable dysasthesiae affecting feet and lower legs. This condition is rapidly resolved with the establishment of euglycemia.

Acute painful sensory neuropathy

This condition is common among diabetic male whose glycemic control is poor. The patient will experience burning and aching pain. There is a widespread Cutaneous contact hyperesthesia. This is associated with depression and impotence. Proper control of blood sugar is the treatment.

Mononeuropathy

This is a dysfunction of isolated cranial or peripheral Nerves and it is less common than polyneuropathy in DM and presents with pain and motor weakness in the distribution of a single nerve. A vascular etiology has been suggested, but the pathogenesis is unknown. Involvement of the third cranial nerve is most common and is heralded by diplopia.

Diabetic truncal neuropathy

This occurs in thoracic nerve roots and it could be unilateral. Patient may have symptoms of chest pain or abdominal pain. This is commonly associated with Sensory motor and autonomic neuropathy

Proximal diabetic neuropathy/ proximal amyotrophy

• Involvement of lumbo - sacral nerves
• Metabolic in origin
• Middle aged or elderly
• Symptoms unilaterally or bilaterally
• Clinical features
• Prognosis - Good

Autonomic neuropathy

• Prevalence increases with poor control of DM and longer duration
• Poor prognostic indicator
• Symptoms
– Gustatory sweating
– Postural hypotension
– Diarrhoea alternating constipation
– Anhidrosis of limbs
– Small pupil
– Dysphagia and vomiting due to gastroparesis
– Impotence

TIA & Strokes

• Commonest brain disorder responsible for deaths and disability of adults.
• What are the risk factors?
• What are the clinical features?
• Characteristic feature is sudden onset of symptoms with maximum disability in the acute stage

Treatment

• Near normal glycaemic control
– DCCT -Reduced clinical neuropathy by 60% in Type I
– UKPDS - Reduced micro vascular complications by 25% in Type II
• Prevention of foot damage
– Screening
• Drugs
– Amitriptyline - Side effects
– Imipramine
– Carbemazepine
– Phenytoin
– GLA

Diabetic Retinopathy

2009-01-31T22:11:00.001-08:00

Introduction

Diabetes is the leading cause of blindness between the ages of 20 and 74 years.
Individuals with DM are 25 times more likely to become legally blind than individuals without DM. Blindness is primarily the result of progressive diabetic retinopathy and clinically significant macular edema.

Pathogenesis

Diabetic retinopathy is a microvascular disease that leads to capillary occlusion. It affects the retinal precapillary, arterioles, capillaries and venules. Early pathological features include thickening of the basement membrane, loss of pericytes and the development of microaneurysms. Persistent hyperglycemia is considered to be the primary cause of changes in the vascular endothelium. The end result is an ischaemic retina, which releases cytokines that promote the growth of new blood vessels, particularly vascular endothelial growth factor, which is also involved in the early stages of increased vascular permeability.

Risk factors

1. Duration of diabetes
2. Poor control
3. Pregnancy
4. Hypertension
5. Hyperlipidaemia
6. Nephropathy
7. Cataract surgery

Classification

Diabetic retinopathy is classified into two stages:
1. Nonproliferative
2. Proliferative.

1. Nonproliferative diabetic retinopathy

This usually appears late in the first decade or early in the second decade of the disease and is marked by retinal vascular microaneurysms, blot hemorrhages, and cotton wool spots. Mild nonproliferative retinopathy progresses to more extensive disease, characterized by changes in venous vessel caliber, intraretinal microvascular abnormalities, and more numerous microaneurysms and hemorrhages.

2. proliferative diabetic retinopathy

The appearance of neovascularization in response to retinal hypoxia is the hallmark of proliferative diabetic retinopathy. These newly formed vessels appear near the optic nerve and/or macula and rupture easily, leading to vitreous hemorrhage, fibrosis, and ultimately retinal detachment.

Management

1. Control of risk factors delays the onset of retinopathy and can slow progression of the disease
2. Laser treatment is the only known means of stopping the progression of diabetic eye disease.

Screening

It is important to screen all patients with diabetes for eye disease. It can prevent blindness and has been shown to be cost-effective. The GP, the optometrist or the diabetologist may undertake this, depending on local policy.

DIABETIC FOOT

2009-01-31T22:10:00.001-08:00

Introduction

This is a serious burden for both the patient and physician. Once it occurs, it is very difficult to treat. Therefore prevention is the best option.

Prevalence and prognosis

1. 5-15% of Diabetics develop foot ulcers
2. 70% of healed Diabetic ulcer are likely to recur within 5 years
3. 85% of non traumatic lower limb amputations follow diabetic foot ulcers

Why do Diabetics sustain trauma to feet?

There are two main factors which make the diabetic patient more susceptible for trauma

1. Extrinsic
I. Poor vision
II. Falls due to joint immobility
III. strokes
IV. Edema due to Cardiac causes

2. Intrinsic
I. Neuropathy
II. Arterial Disease
III. Abnormal tissue response to trauma and sepsis

I) Neuropathy

a. Sensory – loss of pressure, pain, temperature and joint sense. i.e. removes warning signals
b. Motor – weakness and atrophy of intrinsic muscles of foot, hence altered foot structure and leading to deformity and altered biomechanics
c. Autonomic – AV shunting affects maintenance of skin integrity and vascular tone. i.e. warm, dry, fissured foot

What is Charcot foot?

This is the extreme end of diabetic foot disease. This occurs due to the long standing neuropathy. Other factors that contribute to charcot foot are as follows;

a) Long duration Diabetic neuropathy
b) Hyperaemic response
c) Osteopenia
d) Local fractures
e) Inflammatory response
f) Proprioception – Deformity
g) 0.2% of Diabetics

II) Arterial Disease

There are two types;

A. Macrovascular
B. Microvascular

A) Macrovascular Disease

Atherosclerosis is the main form of macrovascular disease affecting the foot and it increases the risk 4 to 20 times than in non-diabetics. In atherosclerosis;

 Systemic disease Coronaries, Cerebrals
 Calcification Unreliable AB index
 Collateral disease Poor reserve
 Angiography often foot vessels preserved

B) Microvascular Disease
1. Early onset of micro-vascular dysfunction
2. Affects arterioles an capillaries of several organs
3. Basement membrane thickening may impair oxygen diffusion
4. Reduced tissue response to sepsis

Wound healing is affected by...

 Growth factors deficiency
 Impaired fibroblast response
 Abnormalities of Extracellular matrix
 Neuroinflammatory response
 Hyperaemic response
 Thermoregulatory response

Diabetic foot Infections
 Cell mediated immunity depressed
 Phagocytic function of multinuclear leukocytes affected
 Leucocyte migration at microcirculatory level is affected
 Hyperglycaemia associated with mycotic infections could contribute
Painless collection of pus
 Tracking of pus along tendon sheaths
 Staphylococcus aureus is common
 Foot compartments

CLINICAL ASSESSMENT OF A DIABETIC FOOT

A) General

 Glycaemic control
 Smoking
 Renal disease
 Poor social circumstance

B) Extent of Neuropathy

 Vibration sense – using tuning fork
 Discriminating touch – 10g monofilament Nylon
 Ankle jerks

C) Extent of Ischaemia
 Pulse examination – Aortoiliac and FemPop bruits
 Skin color, Temperature
 ABPI
 X ray medial calcinosis

D) Extent of Neuroischaemia and sepsis

Wargner 1-5 a Global Severity Score

1: Superficial ulceration limited to dermis
2: Ulceration down to fascia or bone without abscess or osteomyelitis
3: Deep ulcers with abscess or osteomyelitis
4: Localized gangrene confined to the toes or forefoot
5: Gangrene requiring immediate major (above ankle) amputation

Extent of Infection Is Due to..

 Walking on pus
 Tracking of pus along tendons
 Foot compartments
 Septicaemia

Management of diabetic foot diseases

2009-01-31T22:06:00.000-08:00

Diabetes insipidus

2009-01-31T22:05:00.000-08:00

Clinical Characteristics

Decreased secretion or action of AVP usually manifests as DI, a syndrome characterized by the production of abnormally large volumes of dilute urine. The 24-h urine volume is >50 mL/kg body weight and the osmolarity is <300 mosmol/L. The polyuria produces symptoms of urinary frequency, enuresis, and/or nocturia, which may disturb sleep and cause mild daytime fatigue or somnolence. It is also associated with thirst and a commensurate increase in fluid intake (polydipsia). Clinical signs of dehydration are uncommon unless fluid intake is impaired.

Etiology

Deficient secretion of AVP can be primary or secondary. The primary form usually results from agenesis or irreversible destruction of the neurohypophysis and is variously referred to as neurohypophyseal DI, pituitary DI, or central DI.

Pathophysiology

When the secretion or action of AVP is reduced to <80>

Male Erectile Failure and Diabetes

2009-01-31T22:04:00.000-08:00

Erectile failure is particularly common in men with diabetes;
it affects up to 30%, and the prevalence increases further
with age, duration of diabetes, and the presence of microvascular
and macrovascular complications. It can be distressing
for both the man and his partner. There is now increasing
awareness of the importance of the problem, and the increased
effi cacy and availability of treatment makes it correctable
in more than 80% of cases.

Why is erectile dysfunction so common in men
with diabetes?

Normal erectile function is physiologically complex. It depends
on:
• normal psychological and endocrine status for libido and
arousal
• neural integrity
• normally responsive corpora cavernosal smooth muscle
• adequate arterial infl ow
• adequate veno-occlusive mechanisms.
These factors are all vulnerable in diabetes and its complications.
• Diabetes may cause psychological problems, and concomitant
endocrine and other disorders can also reduce libido and
arousal.
• Poor metabolic control, autonomic neuropathy, peripheral
vascular disease and cardiovascular risk factors such as
smoking and dyslipidaemia may all contribute.
• Hypertension is common in type 2 diabetes and, together
with increasingly intensive antihypertensive drug regimens,
may disturb erectile function.
• Corpora cavernosal smooth muscle may be directly affected
by microvascular disease and impaired endothelial cellmediated
relaxation.
• Other primary penile problems (e.g. balanitis, phimosis,
Peyronie’s disease) may be associated with diabetes.

Awareness, assessment and investigation

Diabetes service providers should screen high-risk men, or
should at least have posters on display and information leafl ets
available, to make men aware of the fact that the team is
cognizant of erectile dysfunction and can offer help.

History and examination

History and examination are essential. Clinicians should
ascertain the extent and likely causes of the problem, to enable
them to give an informed explanation and constructive
advice to patients, and to determine the appropriate treatment.
The history and examination (which must include the genitalia)
should determine the patient’s general health, degree of
metabolic control and complication status, and the relevance
of associated conditions.
The sexual history should aim to answer the following
questions.
• What exactly is the problem?
• Why is it a problem?
• What is the partner’s attitude?
• What does the patient and/or partner want to be done about
the problem?

Investigations

Investigations are necessary only when the history or examination
suggests a specifi c cause (e.g. endocrine) or further
assessment of associated conditions (particularly cardiovascular
disease and risk factors) is required. Many possible penile
investigations are listed in the literature (e.g. nocturnal tumescence
tests, cavernosography), but their results do not influence
initial medical treatment and they can be reserved
for research or further assessment before surgical corrective
treatment.

Management of erectile dysfunction in diabetic patients

2009-01-31T22:03:00.000-08:00

Management
Some men are satisfied with just an explanation of their
erectile failure, but many want treatment to correct the problem.
Some men regain normal function after regular physical
treatments.

Counselling
General counselling is an important adjunct to all treatments,
to help the patient overcome anxiety and understand any
relationship problems. It is helpful if the patient’s partner is
present at the discussion.
Partner communication and performance anxiety may
be helped by discussing the modifi ed Masters and Johnson
‘sensate focusing’ technique.
Psychosexual therapy
In most men with diabetes, erectile dysfunction has an organic
basis and psychosexual therapy alone has little place in
treatment. However, it should be considered essential in men
with general psychological or relationship problems of which
erectile dysfunction is just a part. (Physical treatments can be
of major benefit in men with predominantly psychological
causes of erectile dysfunction.)
Viagra (sildenafi l citrate)
Until recently, results of treatment with tablets and/or topical
creams have been disappointing. Treatment has been revolutionized
by the availability of Viagra, which is successful in
more than 60% of men with type 1 or type 2 diabetes and is
now the usual treatment of choice. Sildenafi l is a phosphodiesterase
5 inhibitor that relatively specifically increases
cyclic GMP activity and thereby smooth muscle relaxation
in the corpora cavernosa. It requires sexual arousal, and
thus activation of the nitric oxide pathway, to be effective.
Men should start with a dose of 50 mg, but most require
100 mg tablets. Side-effects of dyspepsia, fl ushing or dizziness
are usually minimal. Concomitant use of nitrates is
an absolute contraindication, but in some men discontinuing
or replacing them can be considered. The presence of
cardiovascular disease or multiple risk factors is not a
contraindication to use of Viagra. Viagra should be tried on
at least six occasions before it is abandoned as ineffective.
Other agents
Other oral and topical agents, including newer agents such
as apomorphine, remain disappointing in diabetes-related
erectile dysfunction. Newer phosphodiesterase inhibitors are
under development.

Intracorporeal self-injection therapy
Intracorporeal self-injection therapy (Figures 1 and 2) continues
to be a useful and effective second-line treatment. It
is well tolerated, and is easy and painless to administer. Men
should be carefully taught the technique and advised to use
only the lowest effective dose, to prevent a prolonged erection
(> 6 hours) that may require emergency aspiration detumescence.
Complications include bruising, fi brosis (uncommon)
and discomfort in the erect penis. Alprostadil remains the
preferred drug, and is available as Caverject and Viridal.
Both are available in dual-chamber injector devices; Caverject
Dual Chamber is the simplest preparation to use. Other drugs
and combinations, including papaverine, phentolamine and
vasoactive intestinal peptide, can be considered, but are not
currently licensed.
Medicated urethral system for erection (MUSE)
MUSE was developed as an alternative to injection therapy. A
high-dose alprostadil pellet (500 or 100 ｵg) is placed into
the urethra using a special introducer, and diffuses into the
corpora cavernosa. This treatment is not very effective in
men with diabetes, and discomfort and lack of effi cacy limit
its usefulness.
Vacuum tumescence devices
Vacuum tumescence devices (Figure 3) are effective and well
tolerated. A cylinder with an attached vacuum pump is placed
over the penis and used to create an ‘erectile state’. A retention
band is then slipped off the cylinder and onto the base
of the penis to maintain the erection.
Surgical treatment
Surgical referral for the insertion of a penile prosthesis can
be considered, but this is now usually reserved for men who
have failed to respond to medical treatments or who have
structural penile abnormalities requiring such treatment. Prostheses
may be semi-rigid or infl atable.
Microvascular revascularization techniques remain largely
experimental.

Diabetes and Hypertension

2009-01-31T22:02:00.000-08:00

Hypertension occurs more often in patients with diabetes
than in individuals without diabetes. This 1.5–2-fold excess
of hypertension can be accounted for by several clinical and
pathophysiological factors including diabetic nephropathy,
altered neuroendocrine and sodium-volume determinants of
blood pressure, disturbed vascular tone and altered blood
pressure regulation (Figure 1). Hypertension is also a major
cause of diabetic nephropathy. The prevalence of hypertension
in type 2 diabetes has been reported to be 30–80%.
In type 1 diabetes, the prevalence is up to 25%, and hypertension
is usually seen in association with nephropathy.
Importance of hypertension in diabetes
Hypertension is important in diabetes mellitus because it accelerates
both macrovascular (ischaemic heart disease, stroke,
peripheral arterial disease, heart failure) and microvascular
complications. The presence of proteinuria (i.e. diabetic
nephropathy) is associated with a marked increase in overall
mortality from cardiovascular disease and end-stage renal
failure. Most diabetic complications occur in association with
hypertension. Cardiovascular complications account for up
to 75% of mortality in patients with type 2 diabetes.
What level of blood pressure requires treatment?
The most recent guidelines (Figure 2) have incorporated findings
from the major hypertension intervention trials that have
data specific for patients with diabetes (Figure 3).
In the UK Prospective Diabetes Study (UKPDS), patients
with type 2 diabetes (mean age 56 years) were treated for
8.4 years with either a β-blocker or an angiotensin-converting
enzyme (ACE) inhibitor-based regimen to achieve ‘tight’ blood
pressure control (mean 144/82 mm Hg). Compared with less
tight control (mean 154/87 mm Hg), there were significant
reductions in diabetes-related deaths (32%), stroke (44%),
heart failure (56%) and progression of retinopathy (37%), despite
drug side-effects and compliance problems. This study
showed that the clinical benefit of reducing blood pressure by
10/5 mm Hg was greater than that of intensive glucose lowering.
The lower blood pressure required mainly combination
therapy and not any specific single-drug treatment, there
was no threshold or ‘J-shaped’ effect of treatment, and the
benefits of treatment exceeded the benefits expected from
epidemiological data.
The Hypertension Optimal Treatment (HOT) study con-
firmed a reduction in cardiovascular events with combination
treatment, based on a calcium channel blocker (felodipine)
regimen. Treatment targets were diastolic blood pressure less
than 80 mm Hg, less than 85 mm Hg and less than 90 mm Hg.
The 4 mm Hg difference between the less than 80 mm Hg and
less than 90 mm Hg target groups was associated with a 51%
reduction in major cardiovascular events and a 67% reduction
in cardiovascular mortality. New findings were the additional
cardiovascular benefit of the addition of aspirin,
75 mg, and the safety of calcium channel blocker therapy.
Management
Non-drug treatment (Figure 4)
In combination with maximal diabetic control and attention
to other cardiovascular risk factors, non-drug treatments
(weight loss for obesity-related hypertension and aerobic
exercise) confer benefit. Reduction in dietary sodium intake
significantly reduces both systolic and diastolic blood
pressure.

Surgery in Patients with Diabetes

2009-01-31T22:01:00.000-08:00

Diabetes presents several special problems during surgery.
Fasting causes particular problems in type 1 diabetes. Such
patients need basal insulin to prevent ketosis, and develop
hypoglycaemia without additional carbohydrate intake. Fasting
is of little signifi cance in type 2 diabetes, unless the patient
has received oral hypoglycaemic agents.
Metabolic changes include the following.
• Increases in circulating adrenaline, adrenocorticotrophic
hormone, cortisol and growth hormone aggravate insulin
defi ciency and insulin resistance. These changes are a normal
response to surgery and proportional to the severity of
the operation. They antagonize the actions of insulin and its
secretion, resulting in catabolism with increased glycogenolysis,
gluconeogenesis, proteolysis and lipolysis. In diabetes,
the effects are compounded by insulin defi ciency.
• Gluconeogenesis from precursors such as lactate, pyruvate,
alanine and glutamine is increased in the liver and kidney,
and muscle and adipose tissue take up less glucose. The resultant
hyperglycaemia is more pronounced in patients with
diabetes than in non-diabetic patients.
• Without insulin, lipolysis is stimulated and leads to ketogenesis.
Plasma levels of free fatty acids, glycerol and ketone
bodies increase, and metabolic acidosis may develop even in
the presence of near-normal plasma glucose.
All these changes are aggravated by some types of anaesthesia,
particularly high doses of opiates or regional blockade.
They increase insulin requirements in patients with type 1
diabetes, and may cause those with type 2 diabetes to become
temporarily insulin-requiring.
Recognizing hypoglycaemia may be difficult in unconscious
patients.
Subcutaneous insulin absorption is poor or unpredictable
when peripheral vessels are constricted.

Principles of management

The fundamental principle of surgical management in diabetes
is that capillary blood glucose is measured regularly and
accurately, and that these results are recorded and acted on.
Most problems occur because staff have forgotten to measure
blood glucose, or because very low values have been ignored
or wrongly attributed to faulty meters.
Target glucose – during surgery, blood glucose should be
7–11 mmol/litre. At normal levels, patients are too close to
hypoglycaemia. At levels above 11 mmol/litre, urine output
increases and dehydration may ensue.
Fluids – any other fl uids given during the surgical period
should not contain glucose. Use of Hartmann’s solution
(Ringer lactate) in patients with diabetes remains controversial.
The lactate contained in this crystalloid is used for
gluconeogenesis, particularly in starved or catabolic patients.
In patients with type 2 diabetes, an infusion of Hartmann’s
solution may cause blood glucose levels to rise signifi cantly.
If fluids have to be restricted, glucose may be given as a
20% or 50% solution. This must be administered via a central
venous catheter, to avoid venous thrombosis.
Electrolytes – potassium levels should be monitored regularly
perioperatively. Serum potassium varies according to:
• the effects of insulin, which promotes potassium uptake
by muscle, liver and adipose tissue
• dehydration, which may cause a shift in potassium from
the intracellular to the extracellular space
• acidosis, which leads to hydrogen and potassium exchange
in the kidneys, potassium retention and hyperkalaemia.
Most patients with normal renal function require 20 mmol
potassium/litre fl uid given, but the requirement is often higher
in patients with diabetes.
Analgesia – in the past, there was a view among anaesthetists
that regional blockade (including spinal and epidural)
was undesirable in diabetes. This originated from fear
of aggravating (possibly latent) neuropathy, of uncontrolled
hypotension in those with signifi cant autonomic neuropathy,
or of causing infection at the site of the block. This view is no
longer valid. The advantages of regional blockade, which provides
excellent analgesia and blunting of the stress response,
outweigh any disadvantages in most patients with diabetes.

Psychological Aspects of Diabetes Management

2009-01-31T22:00:00.000-08:00

Diabetes mellitus is a largely self-managed disease. If the patient
is unwilling or unable to self-manage his or her diabetes
on a day-to-day basis, the outcome will be poor, regardless
of how advanced the treatment technology is. As Glasgow
et al. recently noted: ‘Diabetes is at heart a behavioural issue’.
Psychological and social factors have a vital role in diabetes
management.

Coping with diabetes

Treatment of diabetes is complex and demanding, and has
a major impact on the psychosocial functioning of patients
and their family, yet most patients, both children and adults,
seem to cope reasonably well with the strains of the disease.
The diagnosis of diabetes may come as a shock, and can
induce serious emotional distress in both patient and family.
Research indicates that emotional equilibrium is restored
within several months to 1 year after diagnosis in most patients,
and that they learn to integrate diabetes into their
daily lives. The onset of diabetes-related complications can be
significantly delayed by maintaining strict glycaemic control,
but many patients develop them at some time. Complications
such as eyesight problems or amputation can induce profound
psychological reactions, ranging from anger and guilt to
apathy and depression. At this stage, patients may be inclined
to stop their self-care activities.
Patients with diabetes need to come to terms with the fact
that they have a chronic disease and must ‘learn to live with
it’. However, to prevent diabetes-related complications, active,
problem-focused coping behaviour is required – patients
must take responsibility for daily management of the disease,
in different situations and over a long period of time.
Performing self-care tasks (particularly daily self-injections
of insulin and finger-pricks) and always having to think about
what can or cannot be eaten are generally found burdensome.
Adherence to the treatment regimen is complicated
by the fact that it often does not ‘pay off’ – that is, patients
receive little or no positive feedback in the short term to
help reinforce their daily efforts. This can be demotivating,
particularly in younger patients, who are more concerned
with the ‘here and now’ than the distant future. Also, ‘good’
behaviour does not always translate into good results, and
this is a major cause of frustration that can ultimately lead to
‘diabetes burnout’ (see below). It is not surprising that many
patients find it difficult to adhere to the treatment regimen
all the time. Even in the Diabetes Control and Complications
Trial, in which patients were self-selected and highly motivated,
less than one-half reached the target HbA1c level, and
only 5% maintained that level of control throughout the study.

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2009-01-30T23:15:00.000-08:00

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