The pathogenesis of NIDDM in Mexican-Americans is poorly understood. Prospective data from other ethnic groups suggest a two-step process in which resistance to insulin-mediated glucose uptake is an early defect that is compensated by enhanced insulin release from the pancreas. Later, a subset of people develop B-cell failure and overt diabetes. Thus, it has been suggested that the pathogenesis of NIDDM in at least some ethnic groups involves late failure of B-cell compensation for primary, pathological insulin resistance. Late pregnancy normally is characterized by severe, physiological insulin resistance. The insulin resistance is compensated by enhanced insulin release in women who maintain normal glucose tolerance during pregnancy. Our preliminary data indicate that most women who develop mild to moderate gestational diabetes mellitus (GDM) have defective B-cell compensation for the normal insulin resistance of late pregnancy. However, a subset of women with GDM maintain appropriate B-cell function for their degree of insulin resistance. After pregnancy, most women with prior GDM (approximately 50-70%) will eventually develop NIDDM. However, a minority may never develop non-gestational diabetes. Based on these findings, we hypothesize that limited capacity of pancreatic B-cells to compensate for insulin resistance is an early defect that becomes manifest during pregnancy in the subset of Mexican American women with GDM who are at highest risk for NIDDM. To test that hypothesis, we will measure insulin sensitivity (euglycemic clamp and minimal model techniques) and pancreatic B-cell function (first phase insulin response to intravenous glucose) in Mexican-American women with GDM during pregnancy, when physiological insulin resistance is severe. We then will measure glucose tolerance in those women at 15, 30 and 45 months after pregnancy to test whether impaired B-cell function during pregnancy is associated with a high rate of development of NIDDM after pregnancy. We also will measure insulin action and B-cell function serially during follow-up to identify metabolic abnormalities that may contribute to the eventual development of overt NIDDM. Finally, we will measure B-cell function and insulin action in non-diabetic Mexican-American women during and after pregnancy to establish normal insulin sensitivity-secretion relationships against which insulin action and B-cell function in gestational diabetic women can be assessed. Our results should identify early metabolic defects in Mexican-American women who are at high risk for NIDDM. In future studies, those defects can be targeted for interventions aimed at delaying or preventing the onset of NIDDM.
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