The prevalence of diabetes is increasing in epidemic proportions on a worldwide basis. In the United States alone, it has been estimated that there are approximately 16 million patients with diabetes, representing about 6% of the population. In addition, an estimated 5.4 million people are undiagnosed. On a more alarming note, it has been estimated that approximately 20 million people have impaired glucose tolerance, a clinical state felt to be representative of pre-diabetes. The projected increase in new cases of diabetes is also expected to increase the prevalence of complications associated with the disease, i.e., retinopathy, neuropathy, nephropathy, and cardiovascular disease. In addition to the morbidity and mortality resulting from these complications, die financial cost is staggering. It has been estimated that the total cost to care for diabetes and its related complications in the United States alone was over $98 billion for the year 1997. Thus, the current and evolving emphasis in diabetes management is to 1) evaluate strategies for the prevention of the disease and 2) implement clinical treatment regimens, as outlined in subsequent chapters, with the goal of reducing or delaying the progression of these devastating complications.
There have been significant advances in the understanding of the etiology and pathogenesis of both type 1 and type 2 diabetes. Whereas type 1 diabetes has been established to be an autoimmune process associated with pancreatic destruction, resulting in an absolute insulin-deficient state, type 2 diabetes is associated with insulin resistance, increased hepatic glucose production, and, in all cases, a "relative" deficiency of insulin. As such, despite laboratory studies suggesting a normal or elevated insulin level in subjects with type 2 diabetes compared with nondiabetic subjects, the insulin level is not sufficient to completely compensate for the increased insulin resistance of the peripheral tissues—i.e., muscle and fat—required to maintain glycemia. The failure of adequate insulin secretory compensation ultimately results in hyperglycemia and the diagnosis of type 2 diabetes.
Despite differences in the etiology of type 1 and type 2 diabetes, the common biochemical manifestation is hyperglycemia. Chronic hyperglycemia is considered a major factor in the development of microvascular complications in both type 1 and type 2 diabetes and contributes greatly to the pathogenesis of macro-vascular disease. As such, diabetes remains a major cause of premature death and disability in the United States: It remains the leading cause of new cases of blindness in adults, and it is responsible for over 50% of nontraumatic lower-extremity amputations and approximately 50% of new cases of end-stage renal disease. It has also been established that the presence of diabetes causes a two-to fourfold increase in cardiovascular risk. Because of the accelerated cardiovascular risk, the most recent National Cholesterol Education Program (NCEP) guidelines suggest that diabetes represents a "risk equivalent" for cardiovascular disease and warrants treatment to lipid goals comparable to that for patients with pre-existing cardiovascular disease. It is hard to imagine that at one time the contribution of hyperglycemia to development of these complications was questioned. Yet the studies reported over the past 10 years leave little doubt that hyperglycemia is indeed a major causative factor in the development of complications. The precise mechanism(s) by which chronic hyperglycemia promotes tissue complications, however, is still an area of great debate and research interest.
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