Insulin Resistance In The Natural History Of Type 2 Diabetes

Reduced insulin-dependent glucose transport is frequently found in nondiabetic relatives and offspring of patients with type 2 diabetes (5). This observation, as demonstrated in families and populations with a high incidence of type 2 diabetes, suggests that insulin resistance may be a primary factor in the development of type 2 diabetes and the early development of accelerated atherosclerosis. As such, the natural history of type 2 diabetes suggests that patients may be euglycemic and have normal insulin levels for many years before the development of the disease. In the presence of obesity and a family history of diabetes, insulin resistance typically is present and the individual will need to increase insulin secretion, particularly after meals, to compensate for the insulin resistance (1-4). Eugly-cemia is maintained, therefore, as long as the individual continues to sustain the compensatory hyperinsulinemia required to overcome the resistance (1-4). As recently reviewed from the Consensus Development Conference on Insulin Resistance, plasma insulin levels, whether measured fasting or postprandially, appear to be predictive for development of type 2 diabetes, and this risk appears indepen- |

dent of obesity or waist circumference (5). In addition, this risk is particularly £

strong for individuals with a known family history of type 2 diabetes. However, as pancreatic beta-cell dysfunction becomes apparent, leading to a relative decrease in secretion of insulin, the individual is unable to compensate for the insulin resistance (3). Increased hepatic gluconeogenesis occurs and fasting blood J glucose begins to rise such that the clinician can now make the diagnosis of

& u type 2 diabetes. Results from both cross-sectional and longitudinal studies have supported this concept that the natural history of type 2 diabetes begins with insulin resistance and, subsequently, a decreasing insulin secretion resulting in fasting hyperglycemia (11,12). Specifically, a longitudinal study in the Pima Indians demonstrated that the transition from normal to impaired glucose tolerance was associated with insulin resistance and a decline in the acute insulin secretory response (11). The progression of the disease from impaired glucose tolerance to clinically overt type 2 diabetes was associated with further worsening of the insulin resistance and a markedly diminished pancreatic insulin secretion (11).

The period in the patient's life associated with insulin resistance and impaired glucose tolerance is felt to represent the prediabetic phase, as insulin resistance appears highly predictive of development of type 2 diabetes (2-5). It is at this prediabetic stage in the natural history of type 2 diabetes where prevention trials are currently evaluating interventions that improve insulin sensitivity by both pharmacological and nonpharmacological means, in the hope that type 2 diabetes can be prevented or delayed (13). It is also at this stage that the clustering of clinical risk factors (e.g., syndrome X, cardiovascular dysmetabolic syndrome, ''deadly quartet'') is observed (7-10). Therefore, we now recognize that insulin resistance occurs early in the development of type 2 diabetes and may be present many years before the diagnosis of type 2 diabetes is made. Further, insulin resistance is associated with a clustering of risk factors that predisposes a patient to accelerated atherosclerosis (7-10,14-20). A schematic representing the natural history of type 2 diabetes (i.e., insulin resistance and compensatory hyperinsuli-nemia, associated risk factors, and when a diagnosis of type 2 diabetes is likely to be made) is outlined in Figure 2 [adapted from the results of the Paris Prospective Study (15)].

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