When the Student Has Finished This Module, the Student Will Be Able To

DIABETES

OBJECTIVES

When the student has finished this module, the student will be able to:

1. Explain the role of insulin in the body.

2. Identify the process by which hyperglycemia damages tissues.

3. Explain the process that is the cause of type I diabetes.

4. Identify two risk factors for developing type II diabetes.

5. Identify three signs of diabetes.

6. Identify six complications of diabetes.

7. Identify three classes of medications that are used to treat diabetes.

INTRODUCTION

Diabetes mellitus is a metabolic disease characterized by a high blood glucose level that is caused by defects in insulin secretion, insulin action, or both. Diabetes is one of the most serious health problems in the world today. Estimates vary, but at least one source notes that there are approximately 170 million diabetics worldwide,1 that number is expected to increase to 300 million by 2025,2 and the number of diabetics in the United States and the amount of morbidity the disease causes are staggering.3

• Approximately 20.8 million people in the United States have diabetes.
• There are approximately 6.2 million people with diabetes that are undiagnosed.
• The number of new cases of diabetes is increasing each year. From 1980 to 2005, the number of adults newly diagnosed with diabetes almost tripled, from 493,000 in 1980 to 1.4 million in2005.
• From 1980 to 2005, the number of Americans with diabetes increased from 5.6 million to 15.8 million.
• Diabetes was the 6th leading cause of death in the United Sates in 2002.
• Adults with diabetes have rates of heart disease that are 2 to 4 times higher than adults without the disease.
• Diabetics are 2 to 4 times more likely to have a stroke than people without diabetes.
• Diabetes is the leading cause of blindness in adults 20 to 74 years old.
• Approximately 73% of all adults with diabetes have hypertension and use prescription anti-hypertensives.
• More than 60% of all non-traumatic lower limb amputations are caused by diabetes.
• Diabetes that is not well controlled in the first trimester of pregnancy can cause major birth defects.
• Diabetics are more likely to develop other illnesses and when they acquire these illnesses, their prognosis is worse.
• The total cost for diabetes in the United States in 2002 was estimated at 132 billion dollars.
• Lost productive time in the workplace is approximately 18% higher for diabetics than for non-diabetics.

INSULIN AND GLUCOSE

Carbohydrates are an important source of energy for the body. When carbohydrates are ingested, the final products of that process are glucose, fructose, and galactose, with glucose representing the majority. Glucose is a major source of energy, as is converted to adenosine triphosphate (ATP) by the glycolytic pathway.

But for glucose to be utilized it must be carried into the cells; the glucose molecule is too large to diffuse through the pores of the cell membrane, and the transport of glucose is done by insulin. Insulin is a large polypeptide that is secreted by the β cells in the islets of Langerhans in the pancreas, and it helps promote the transport of glucose into the liver (where it is stored as glycogen), or into the muscle cells, where it is also stored as glycogen, or used as an energy source. The process by which insulin promotes glucose entry into the cells is called facilitated diffusion, and it is not completely understood. However, it is thought that when insulin binds to an insulin receptor on a cell membrane, it increases the membrane concentration of a glucose transporter, Glut4.4

In the normal person, blood glucose is maintained within a narrow range of 80 to 90 mg/dL, and fasting glucose for adults should be < 110 mg/dL. Close control of blood glucose is important, as glucose is the only nutrient that can be used by the brain, retina, and germinal epithelium of the gonads. As well, prolonged hyperglycemia leads to the pathophysiologic changes characteristic of diabetes. When blood glucose rises (e.g., after a meal), the secretion of insulin rises dramatically, both in amount and the speed in which this rise occurs, as glucose enters the pancreatic β cells and stimulates insulin release.

HYPERGLYCEMIA AND ITS PATHOGENIC EFFECTS

It is clear that both the level and duration of hyperglycemia are associated with an increased risk of developing diabetic complications: the higher the blood sugar and the longer that elevation lasts, the greater the risk. In recent years there has been much research on the mechanisms by which elevated blood sugar damages tissues, and the current thinking is that there are four processes involved.5

• The polyol pathway: Aldose reductase reduces toxic aldehydes in the cell to inactive alcohols. However, when the glucose concentration inside the cell becomes too high, the glucose is also reduced to sorbitol and during this reduction process the NADPH cofactor is consumed. NADPH is also an essential cofactor for regenerating reduced glutathione which is a vital intracellular antioxidant, so as a result of the elevated glucose, the cell is exposed to oxidative stress and subsequent structural and functional damage.

• AGE precursors: Advanced glycation end products (AGEs) are reactive, unstable sugar-derived substances produced from the nonenzymatic reaction of reducing sugars with free amino groups of proteins, nucleic acids, and lipids. The production of AGEs is increased under the condition of increased oxidative stress caused by diabetes. An excess of AGEs has several harmful effects: they modify proteins involved in gene transcription, they cause a generalized cellular dysfunction by interfering with intracellular signaling mechanisms, and they increase the production of inflammatory cytokines and growth factors that damage the vasculature.
• PKC activation: Protein kinase-C (PKC) is an intracellular enzyme that modifies proteins by adding phosphate groups to them, thus regulating the transmission of signals within the cell. Hyperglycemia activates PKC and changes gene expression, decreasing the expression of activities that are essential for normal function and increasing the expression of activities that are harmful for normal expression.
• Increased hexosamine pathway activity: The hexosamine pathway is an additional pathway of glucose metabolism.During glycolysis, some of the byproducts of that process are diverted out of that pathway into a signaling pathway that produces compounds that change genetic expressions, and this harmful process is increased under conditions of hyperglycemia.

Obviously, when blood sugar is high, all the cells of the body are exposed, but the capillary endothelial cells in the retina, mesangial cells in the glomerulus, and neurons and Schwann cells in the peripheral nerves are critically affected. The end result of all of the above processes is the overproduction of reactive oxygen species(particularly superoxide) and oxidative stress, and that is though to be the mechanism by which hyperglycemia damages cells.

PATHOGENESIS OF TYPE I DIABETES

Type I diabetes is characterized by destruction of the pancreatic β cells by CD4+ and CD8+ T cells and macrophages that infiltrate the islets, and a subsequent lack of insulin production.6Approximately 10% of all people with diabetes have type I diabetes. It is thought to be caused by an autoimmune process in genetically susceptible people that is, at times, triggered by an infectious or environmental factor.7 Autoimmunity is a process by which immunocompetent cells attack tissues in their own body, and there is ample evidence that type I diabetes is an autoimmune process: the presence of immunopathologic T cells in the damaged islets, the presence of antibodies that react to the islets cells in the serum of diabetic patients, the effectiveness of immunosuppression in delaying the onset type I diabetes, the evidence that type I diabetes can be transferred from a diabetic to a non-diabetic via a bone marrow transplant, and the linkage to the disease with certain alleles at HLA class II loci.8 The exact contribution of these three factors – autoimmunity, infection, environmental – is not completely known. There are definitely susceptible genotypes but, given the relatively recent rise in type I diabetes among young adults (a rise to0 rapid to be caused by changes in the gene pool), it is also clear that environmental factors are important.9 The most commonly suspected environmental “triggers” that cause type I diabetes are viruses, specifically enteroviruses, rotavirus, and rubella. However, there is no conclusive evidence linking these viruses to the development of type I diabetes, perhaps because the infection can precede the disease by several years.10 People who will develop type I diabetes are born with a normal number of β cells, and the process of destruction of the β cells is, for most people, a slow process and takes many years. Type I diabetes occurs when 80% of the β cells are destroyed. The onset of type I diabetes is usually in children 4 years of age or older, and the peak time of onset is at the ages of 11 through 13.

PATHOGENESIS OF TYPE II DIABETES

Type I diabetes is caused by the auto-immunologic destruction of pancreatic β cells, but the pathogenesis of type II diabetes is much more complicated and involves genetic and environmental factors that cause impaired β cell function and insulin resistance.11

Although there appears to be little doubt about the genetic component of type II diabetes, there is little direct evidence of this. It is far clearer that the development of type II diabetes has a genetic component when family and ethnic factors are considered.

It is well known that type II diabetes is an inherited condition, as is shown by the 100% concordance rate of diabetes seen in identical twins, the tendency of type II diabetes to "run in the family," and the high rates of the disease that are seen in certain racial and ethnic groups.12 It was also shown in the Framingham Offspring Study that the risk of developing type II diabetes if a single parent had the disease was 3.5 times greater, and if both parents had the disease, the risk was 6 times greater. There were no differences noted in maternal versus paternal transmission.

As regards impaired β cell function, the current thinking is that insulin resistance is the primary mechanism responsible for the development of type II diabetes, not impaired insulin secretion.13 Insulin resistance occurs when there is a defect in the ability of insulin to transport glucose into the cell. It appears to be caused by genetics, obesity, age, and a sedentary lifestyle.14

Who develops type II diabetes? There are many risk factors. The usual onset of the disease is in adults over the age of 40. Old age is a risk factor fordiabetes: 18.4% of adults 65 years of age and older have type II diabetes. More alarmingly, in the past 8 years, the incidence of type II diabetes in adults between the ages of 30-39 has risen 70%.15Racial and ethnic factors are also important.African-Americans and Hispanic Americans are at a greater risk for developing type II diabetes than white Americans. The problem of type II diabetes is particularly serious among African-American females aged 55 years or older. The incidence of type II diabetes is also higher among Native Americans. Obesity and a sedentary lifestyle are probably the two most important factors for developing type II diabetes.16

SIGNS AND SYMPTOMS OF DIABETES

Diabetes usually presents with the classic triad of polyuria, polydipsia, and polyphagia, weight loss, and a fasting glucose > 200mg/dL. The American Diabetes Association suggests that a diagnosis of diabetes can be made if the above physical findings are present, the fasting blood glucose is > 126 mg/dL, and the fasting plasma glucose two hours after a 75 gram glucose load is ≥ 200 mg/dL and this is confirmed by a repeat test. Glycosated hemoglobin (HbA1c) indicates the average blood glucose during the 120 days prior to the test and is used for long-term monitoring of glycemic control.

PREVENTION OF DIABETES

Type I diabetes can be a devastating disease. Currently, the only available effective treatment is insulin therapy. Unfortunately, insulin therapy must be continued forever, and although insulin therapy, along with good preventive care and close attention can help reduce or delay the onset of complications, it cannot eliminate them entirely.17 Prevention would be far preferable.

One approach to prevention has been the efforts to spare the β cells from destruction before the process starts. However, although there have been intensive work directed towards prevention, there has not been much success. The first problem is identifying people at risk, and although there are strong genetic and familial factors associated with the development of the disease, at this point, they cannot be consistently used to determine with complete accuracy who is at risk and needs intervention.18

Another approach to prevention has been the use of immunosuppressive drugs. There was much interest in this in the 1980s and there was some initial enthusiasm. But it was subsequently found out that although some patients had a dramatic response to the therapy, not all did, and the response in the successful cases was not sustained. There were also serious side effects such as renal damage and infections.19

Large scale attempts for prevention have also been made by using both of these approaches, identifying at risk and using drug therapy. The Diabetes Prevention Trial – Type 1 was a large clinical trial conducted by several medical associations. Study subjects who were determined to be at risk for developing type 1 diabetes (e.g., family history, presence of islet cell antibodies) were given low dose insulin injections or oral insulin. Unfortunately, neither approach was successful.20

A more promising method of prevention has been transplantation, either islet cell transplantation or whole pancreas transplantation.21 Many patients who receive islet transplantation are insulin independent for a year after the operation, and the 5 year rate of partial islet function is very high. But islet function decay over time is common, the patients must accept the need for lifelong use of immunosuppressive drugs, and this approach is currently limited to patients with recurrent severe hypoglycemia and severe labile diabetes: whole pancreas transplantation is far superior.

There has been far more success is in preventing type II diabetes. Although it is clear that type II diabetes is caused by a subtle interplay between genetic and environmental factors, there is a large body of evidence from the epidemiology literature that strongly suggests that the increase in the incidence of the disease is due to diet and lifestyle factors.22 In particular, obesity and a sedentary lifestyle are implicated in the development of the disease. Prevention of the development of diabetes and diabetic complications, however, is possible.

• Obesity: Both the Nurse’s Health Study23 and the Women’s Health Study24 clearly showed that obesity dramatically increased the risk of developing type II diabetes, and several studies have clearly shown that change in diet and weight loss can prevent development of the disease.25,26
• Physical activity: Certainly, exercise can lead to weight loss which reduces the risk of developing type II diabetes. However, there is evidence that physical activity has an independent effect on decreasing the risk;27,28 this may be due to increasing insulin sensitivity.
• Smoking: Prospective studies have shown that cigarette smoking is associated with an increased risk of developing diabetes.29,30 Again, this effect may be due to an increase in insulin sensitivity.
• Alcohol: Alcohol in moderation has been shown to be associated with a decreased risk of developing diabetes compared with abstinence or occasional drinking. Heavy alcohol consumption increases the risk.31
• Diet: There have been many attempts to determine the effect of specific dietary patterns on the development of diabetes. However, research that has attempted to determine the association between nutrients (e.g., fats, carbohydrates, micronutrients) and the development of diabetes has been inconclusive.32
• Control of hypertension: Even modest reductions in diastolic blood pressure can reduce the incidence of death, stroke, and microvascular complications.33
• Drug therapy: Metformin and troglitazone have both been shown to significantly reduce the risk of developing type II diabetes, but less so when compared to changes in diet and lifestyle.34 Other drugs hat have shown some promise in preventing type II diabetes are the angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, pravastatin, orlistat, and bezafibrate.35

However, only the peroxisome proliferator-activated receptor-gamma agonists

and incretin-mimetic drugs (e.g., exenatide) appear to favorably affect β cell

volume and morphology.36

Prevention of the complications of diabetes, in particular the cardiovascular and cerebrovascular complications, has also received attention, and although the incidence of cardiovascular and cerebrovascular events can be decreased, achieving this requires a multifaceted approach. Glucose control alone does not appear to reduce the cardiovascular risk associated with type II diabetes, although it may be useful for patients with type I diabetes.37 A recent study showed that aggressive treatment with aspirin, tight glucose control, lipid lowering agents, and renin-angiotensin system blockers can decrease the risk of vascular complications and deaths from cardiovascular causes.38 The statin drugs have been shown to reduce the incidence of major cardiac events in diabetic patients and good control of hypertension is also beneficial.

COMPLICATIONS OF DIABETES

Cardiovascular Complications of Diabetes

Cardiovascular complications are very common among diabetics. Approximately 80% of all patients with diabetes die from a cardiovascular event;39 the risk of acute myocardial infarction (MI) is increased 2 to 4 times for diabetic patients.40 Also, many diabetic patients may have an acute MI without chest pain. Hypertension is twice as common among diabetics as among non-diabetics.41

The pathogenesis of cardiovascular complications in diabetes appears to be caused by a number of factors that injure the vascular endothelial wall such as high cholesterol, C-reactive protein, hyperglycemia, and hyperinsulinemia that cause capillary hypertension.42,43

Diabetic Retinopathy

Diabetic retinopathy is one of the more serious complications of diabetes, and the longer someone has diabetes, the greater the chance of developing it. It is the leading cause of blindness in adults 20 to 74 years of age, but it can be prevented with early detection and treatment. It is more prevalent among people with type I diabetes than type II. It affects the microcirculation of the eyes: capillary wall weakness causes aneurysms and fluid leakage from the capillaries, eventually leading to ischemia and infarction44 and the optic disc, venules and arterioles can also be affected. Hyperglycemia is strongly associated with diabetic retinopathy, and good control of blood sugar can greatly reduce the incidence of this complication.45 As well, good control of blood pressure may decrease the onset of diabetic retinopathy. Treatment can include laser photocoagulation and vitrectomy.46