Review
Contributions of Insulin-Resistance and Insulin-Secretory Defects to the Pathogenesis of Type 2 Diabetes Mellitus

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Controlled clinical trials have shown that optimal glycemic control can prevent the microvascular complications of type 2 diabetes mellitus; considerable epidemiological data suggest that this may also be true for macrovascular complications. However, this is frequently not achieved. Consequently, research efforts have been undertaken to better understand the pathophysiology of this disorder. It is now well recognized that 2 factors are involved: impaired β-cell function and insulin resistance. Prospective studies of high-risk populations have shown insulin-resistance and/ or insulin-secretory defects before the onset of impaired glucose tolerance. Thus, there has been a long-standing debate whether an alteration in insulin sensitivity or in insulin secretion is the primary genetic factor. Most of the available evidence favors the view that type 2 diabetes is a heterogeneous disorder in which the major genetic factor is impaired β-cell function and insulin resistance is the major acquired factor. Superimposition of insulin resistance on a β cell that cannot appropriately compensate leads to deterioration in glucose tolerance. Therefore, clinicians managing type 2 diabetes must reduce insulin resistance and augment and/or replace β-cell function.

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TYPE 2 DIABETES MELLITUS AS AN INSULIN-RESISTANT CONDITION

Insulin resistance is associated with a cluster of metabolic abnormalities known collectively as the insulin resistance syndrome, the metabolic syndrome, or syndrome X.36, 37, 38, 39, 40 Recently, the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) published criteria to identify the syndrome according to the following major components: abdominal obesity, hypertension,

ROLE OF IMPAIRED INSULIN SECRETION IN TYPE 2 DIABETES MELLITUS

The vast majority of patients with type 2 diabetes exhibit some degree of insulin resistance, but type 2 diabetes can occur in the absence of insulin resistance.20, 22, 65, 88, 89, 90, 91, 92 Furthermore, most obese individuals who are insulin resistant do not develop type 2 diabetes.12, 93 These individuals remain normoglycemic because they compensate for the reduction in insulin sensitivity by increasing their insulin secretion.24, 93, 94, 95 Therefore, insulin resistance per se is an

TYPE 2 DIABETES MELLITUS AS A HETEROGENEOUS DISORDER: IMPLICATIONS FOR TREATMENT

Although impaired insulin secretion and insulin resistance have both been proposed as the primary pathophysiologic defect in type 2 diabetes, at the present time the body of literature suggests that these 2 phenomena should be considered interrelated elements rather than competing explanations. Both defects are logical therapeutic targets. Therefore, optimal management of type 2 diabetes demands an individualized approach to treatment that considers the heterogeneous nature of this disorder and

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