THE NATURAL HISTORY OF TYPE 2 DIABETES: Implications for Clinical Practice

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PATHOGENESIS OF IMPAIRED GLUCOSE TOLERANCE AND TYPE 2 DIABETES MELLITUS

Type 2 diabetes mellitus is a heterogeneous disorder; three basic metabolic defects characterize the disease: insulin resistance, an insulin secretory defect that is not autoimmune mediated, and an increase in glucose production by the liver. The cause of these metabolic defects, and therefore the cause of type 2 diabetes, largely is unknown. Clearly, type 2 diabetes has a strong genetic component and is found more frequently in certain families and ethnic minority groups such as Hispanics,

PROGRESSION OF IMPAIRED GLUCOSE TOLERANCE TO MILD TYPE 2 DIABETES

The metabolic sequences that eventually lead to type 2 diabetes precede the development of hyperglycemia by years or even decades. As shown in Figure 2, studies have shown that 20% of type 2 diabetics have retinopathy at the time of diagnosis, a percentage that increases linearly with the duration of diabetes. Epidemiologists have extrapolated this data to estimate that the onset of detectable retinopathy probably occurs an average of 6.5 years before the clinical diagnosis of diabetes.

PROGRESSION OF MILD TYPE 2 DIABETES MELLITUS TO INSULIN-REQUIRING TYPE 2 DIABETES MELLITUS

Insulin resistance is the primary pathogenic insult underlying type 2 diabetes and remains a factor throughout the natural history of the disease, yet it is the changes in β-cell function that determines both the onset of frank diabetes and the progression of the disease once established. As outlined above, the transition from normal glucose tolerance to IGT is marked by hyperinsulinemia that reflects a quantitatively appropriate response on the part of the β-cell to insulin resistance and

ROLE OF OBESITY IN INSULIN RESISTANCE AND TYPE 2 DIABETES

Obesity has a profound impact on the progression of the diabetic state and on the patient's response to any particular form of treatment. For example, lean type 2 diabetics characteristically have a less severe insulin resistance and a more profound insulin secretory defect. These individuals typically respond better to exogenous insulin and medications that stimulate insulin secretion (“insulin secretagogues”). In contrast, obese diabetics have a more profound degree of insulin resistance and

RELATIVE PREVALENCE OF TYPE 2 DIABETES MELLITUS, IMPAIRED GLUCOSE TOLERANCE, AND INSULIN RESISTANCE: IMPLICATIONS FOR INTERVENTION

The incidence of IGT and type 2 diabetes is rising annually because many of the major risk factors for these conditions are becoming more prevalent (e.g., obesity, an increase in the mean age of the population, more sedentary lifestyles). Based on data from the National Health and Nutrition Examination Surveys (NHANES II and III), type 2 diabetes is on its way to becoming the most common chronic disease in the United States. An estimated 16 million Americans have type 2 diabetes, representing

MACROVASCULAR DISEASE AND IMPAIRED GLUCOSE TOLERANCE

Current research efforts in the prevention of type 2 diabetes reflect a growing interest in also addressing the pathologic consequences of the prediabetic state, IGT. Few clinicians doubt that type 2 diabetics have a threefold increased risk of coronary artery disease, but too few clinicians realize that IGT is associated with at least a twofold increased risk. The NHANES II documented an increased prevalence of several cardiovascular findings in IGT subjects when compared with rates found in

INTERVENTIONS TO ALTER THE NATURAL HISTORY OF TYPE 2 DIABETES

As interest grows to investigate and promote clinical interventions to prevent the onset of type 2 diabetes and its vascular complications, some argue that IGT is not just a risk factor for type 2 diabetes but may also be a disease in itself, with associated complications of macrovascular disease. Impaired glucose tolerance, therefore, should be treated as a disease that is worthy of clinical screening and intervention.7 Furthermore, studies have shown that patients can move in and out of IGT.

PREVENTION OF TYPE 2 DIABETES WITH DIET AND EXERCISE

Sedentary lifestyle and poor physical fitness are risk factors for the progression of IGT to type 2 diabetes.10 Although these factors are interrelated, both are potential targets for preventative intervention. The same comments also apply to obesity, a risk factor that has been identified unequivocally in all clinical trials addressing the issue. Several clinical trials have prospectively studied the use of diet or exercise with or without specific weight loss goals in the prevention of type 2

PREVENTION OF TYPE 2 DIABETES WITH PHARMACOLOGIC AGENTS

Several classes of oral antidiabetic agents are available for the treatment of type 2 diabetes. Not all, however, may be appropriate as agents to prevent or delay the progression of IGT to diabetes. All forms of antidiabetic therapy, including sulfonylureas, can potentiate a partial reversal of insulin resistance caused by improvement of the hyperglycemia-induced component of insulin resistance (peripheral glucose toxicity). For example, the improvement in insulin resistance that has been

THE DIABETES PREVENTION PROGRAM

An ongoing, multicenter, prospective, clinical trial in the United States initiated by the National Institutes of Health is attempting to prevent or delay the progression of IGT to frank diabetes. The trial is referred to as the Diabetes Prevention Program (DPP). Subjects at high risk for diabetes, that is, those with IGT, have been randomized to either lifestyle modifications or metformin. To keep the focus of the study on high risk populations, recruitment of participants emphasized the

SUMMARY

Type 2 diabetes is at one end of the continuum represented by the fully compensated insulin resistant state to IGT to frank type 2 diabetes. A triad of metabolic defects characterize type 2 diabetes: insulin resistance, nonautoimmune β-cell dysfunction, and inappropriately increased hepatic glucose production. The natural history of type 2 diabetes directly reflects the interrelationships between these three defects (see Fig. 3). The primary and earliest pathogenic lesion is insulin resistance,

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    Address reprint requests to Steven V. Edelman, MD, Division of Endocrinology and Metabolism, 3350 La Jolla Village Drive (111G), San Diego, CA 92161, e-mail: [email protected]

    This work was supported by a Career Development Grant from the Veterans Administration, San Diego, California, awarded to Barbara A. Ramlo-Halsted, MD.

    *

    Division of Endocrinology and Metabolism, University of California, San Diego; and the Veterans Affairs Medical Center, San Diego, California

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