Introduction

I. OVERVIEW

The prevalence of diabetes mellitus has been difficult to quantitate because of the wide varying differences in various groups in the United States. There are differences in diabetes mellitus in various economic groups (poor have a greater prevalence rate), ethnic groups (Pima Indians having the highest rate of approximately 35% while Eskimos have the lowest rate, 1%), and age groups (50-65 years of age having the highest prevalence rate). Diabetes is most common in adults over 45 years of age; in people who are overweight or physically inactive; in individuals who have an immediate family member with diabetes and more women than men have been diagnosed with the disease. The impact of diabetes mellitus cannot be underestimated: 5000 new cases of blindness per year, 80,000 new cases of end stage renal disease per year, 25,000 amputations per year, 55% of all diabetes have some form of coronary artery disease.

Pathophysiology

Insulin has a short half life (4-8 minutes) as it interacts with its target tissue. By binding to the cell insulin alters glucose metabolism along with the modulation of carbohydrate homeostasis; insulin sets-off a cascade of second messengers that alter the cell's behavior. By stimulating peripheral glucose disposal and inhibiting hepatic glucose production, insulin is able to regulate carbohydrate metabolism. Glucagon, on the other hand, counteracts insulin's effect. Glucagon is released by low glucose levels and it binds to the liver cells wherein it stimulates glycogenolysis, gluconeogensis and ketogenesis. Therefore glucagon alters hepatic glucose production and in Type II diabetes glucagon levels are generally increased.

A wide variety of abnormalities in insulin secretion, action and biosynthesis can lead to diabetes. Secretion of insulin is not normal in the Type II diabetic. Some of these patients do not secrete a proper amount of insulin in response to a glucose load. It has been proposed that the defect is a response of the b pancreatic cells (that release insulin) to glucose recognition. Amyloid-like proteinaceous deposits are often found in the pancreatic islets of these patients. This peptide has been coined IAPP (islet amyloid polypeptide) and is shown to be cosecreted with insulin from the beta cells. IAPP may have a deleterious effect on the beta cells and be responsible for the defective release over the long run in Type II diabetes.

While defects in secretion of insulin do occur in Type II diabetes leading to deficiency, a great many of the patients have insulin resistance. Insulin binds to the cells and sets off binding and post binding events. Binding defects are lack of receptors (diminished number) while the more common defect, post binding, is an alteration in cellular signaling events that lead to modulation of glucose transport and diminished glycogen synthase activity. By lacking the normal response to insulin, the cell is unable to adequately metabolize glucose and hyperglycemia is one end event, the hallmark of Type II diabetes.

Finally, while deficiency in insulin amount and increased resistance are the major factors in producing hyperglycemia, hepatic glucose production rates are also enhanced. This response is in part, related to insulin's normal restraining effect on liver glucose production in addition to excess glucagon levels. Therefore deficiency, resistance and accelerated hepatic glucose production all exist in the Type II diabetic contributing to the overall hyperglycemic state.

Genetics

Most recently, researchers found that a variation of a gene called Caplain-10, which is not involved in glucose metabolism, is associated with the development of Type II diabetes. One form of this gene produces a small amount of protein, and researchers are studying how this decrease in protein increases a person's risk for diabetes. Other genetic studies indicate that certain genes cause a variation of Type II diabetes called maturity onset diabetes of the young (MODY), that develops in people under the age of 25. Although scientists do not yet understand how these genes cause MODY, the genes are known to be active in the liver, intestine, kidney, and pancreas. Researchers attribute most cases of Type II diabetes to obesity. Studies show that the risk for developing Type II diabetes increases by 4 percent for every pound of excess weight a person carries. Researchers are investigating the exact role that extra weight plays in preventing the proper utilization of insulin and why some overweight people develop the disease while others do not.

Finally, research also focuses on transplanting a healthy pancreas or its insulin-producing beta cells into a person with Type 1 diabetes to provide a natural source of insulin. Some patients who have received pancreas transplants have experienced considerable improvements in their health, but positive, long-term results with beta-cell transplants have not yet occurred. In both types of transplants recipients must take drugs that suppress their immune systems so the body will not reject the new pancreas or cells. These drugs can cause life-threatening side effects because the patient's body can no longer protect itself from other harmful substances and to date Type II diabetics have not been studied. In most people with diabetes, these drugs pose a greater risk to health than living with diabetes. Scientists are also studying the development of an artificial pancreas and ways to genetically manipulate non-insulin-producing cells into making insulin.

II. PATIENT EVALUATION

A. HISTORY

Perhaps the most important aspect of the history is defining the patient's family history of diabetes and other endocrine disorders. Type II diabetes mellitus is genetically transmitted, the risk of developing diabetes mellitus increases by 35% if a sibling develops diabetes. The health care provider (HCP) should take a careful social history as lifestyle information, including cultural, psychosocial, educational, and economic factors may influence management of the disease. Diet, exercise, alcohol, and smoking history all impact on the severity of the disease. In particular lack of poor dietary restraint leading to an increase in weight with little or no exercise increase the risk that the predisposed patient will develop diabetes mellitus. One should also review symptoms for end-organ damage, especially cardiovascular, ocular, neurologic, renal, and dermatologic. Quite often the patient upon diagnosis of diabetes mellitus (type II) will have already developed some form of end-organ damage such as visual difficulties and/or coronary artery disease. These issues are discussed below in detail. However before making the definitive diagnosis one needs to first rule out medications that may impair glucose tolerance (see Table I).

B. PHYSICAL EXAM

                Table I

                 Drugs That May Impair Glucose Tolerance

C. BASELINE LABORATORY TESTS

                                                    Table 2

                                    CRITERIA FOR THE DIAGNOSIS OF DM

                                                    Table 3

                                    OTHER TYPES OF GLUCOSE INTOLERANCE

In addition, initial screening laboratory values should include a fasting lipid profile in addition to serum electrolytes, BUN/ creatinine, and urinalysis for glucose, ketones, and protein (and culture if abnormal or symptomatic). If proteinuria is absent, test for microalbuminuria (timed or 24-hour collection, or the albumin to creatinine ratio in a random, spot collection). Another test being developed for Type 1 diabetes looks for specific antibodies (proteins of the immune system that attack foreign substances) present only in persons with diabetes. This test may detect Type 1 diabetes at an early stage, reducing the risk of complications from the disease.

There are a subgroup of individuals that should be screened for potential NIDDM. These patients are high risk for the development of diabetes and should be closely monitored. These individuals are summarized in Table 4 and most importantly specific ethnic groups such as Native American Indians should be closely evaluated.

                                                    Table 4

                        CANDIDATES FOR SCREENING (repeat testing every 3 years)