When insulin resistance is present, fasting and postprandial blood glucose con- §
centrations are maintained in the normal range by a compensatory increase in insulin secretion and the development of hyperinsulinemia. As long as the pancre- Ja atic beta cell is able to compensate adequately, glucose tolerance remains normal. J
However, if beta-cell function is inadequate, impaired glucose tolerance (IGT)
& u may develop. This is characterized by the maintenance of a normal fasting blood glucose concentration but a value that is intermediate between normal and the diabetic range 2 h after a 75-g oral glucose load. With further impairment of beta-cell function, both fasting and postprandial blood glucose concentrations increase and overt diabetes mellitus develops. This sequence of events has been demonstrated in prospective studies of insulin resistance and beta-cell function in several populations, including studies of Pima Indians who have either progressed sequentially from normal glucose tolerance to IGT and then to diabetes or who have maintained normal glucose tolerance (NGT) over several years (6). In those who progressed to diabetes, there was only a modest increase in insulin resistance over time, whereas a marked decrease in beta-cell function occurred. In contrast, those who did not progress maintained adequate beta-cell function to compensate for their worsening insulin resistance.
It is now clear from the United Kingdom Prospective Diabetes Study (UKPDS) that once type 2 diabetes is established, it becomes progressively more difficult to control over time, often requiring combinations of oral antidiabetic agents and/or insulin therapy (7,8). This is due largely to a progressive loss of beta-cell function, which is insufficient to overcome the underlying insulin resistance. Thus, insulin resistance is a fundamental underpinning of an entire spectrum of glucose intolerance from NGT with compensatory hyperinsulinemia, to IGT or full-blown type 2 diabetes with progressive loss of pancreatic beta-cell function.
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