Non-insulin Dependent Diabetes Mellitus develops in individuals who have peripheral tissue resistance to the action of insulin. These individuals often make normal or increased amounts of insulin but are unable to maintain physiologic blood glucose concentrations because of this defect. Women who develop gestational diabetes mellitus manifest this peripheral insulin resistance and 30% go on to develop non-insulin dependent diabetes within five years of the diagnosis of gestational diabetes mellitus. Women with increased risk for developing NIDDM will be identified as high risk at the Genesis Obstetrical Center in Tampa. These women will be evaluated after pregnancy and divided into two categories based upon fasting plasma glucose values. The first will be those women with fasting plasma glucose values less than 110 mg/ dl. The second will be women with fasting plasma glucose equal to or greater than 110 mg/ dl but less than 140 mg/dl. These individuals will have serum islet cell antibodies, insulin autoantibodies, tested to determine that they do not have autoimmune diabetes mellitus. They will then have an oral glucose tolerance test to determine whether they have normal or impaired glucose tolerance or diabetes mellitus as defined by the National Diabetes Data Group. These individuals will then be randomized into four intervention groups. Each individual will have - peripheral insulin sensitivity determined with a glucose clamp experiment. The first group will be placed on a calorically restricted diet (1600-1800 Kcal/day) and started on an aerobic exercise program designed to reduce body mass index. The next group will receive one of a number of oral agents (sulfonylureas, thiozolidinolione, or magnesium chloride) with potential for reducing peripheral insulin resistance will be evaluated. The third group will have intensified insulin therapy provided 5 days annually since this has been shown in insulin dependent diabetes to reduce peripheral insulin resistance. The fourth group will receive an oral placebo and serve as controls. Each of these individuals will be seen on a quarterly basis to measure their height, weight, blood pressure, fasting plasma glucose levels, glycosylated hemoglobin, sex hormone binding protein, serum insulin and urinary C-peptide levels. Each of these individuals will have a glucose clamp experiment performed to determine the degree of insulin resistance and oral glucose tolerance test as an indicator of glucose homeostasis on an annual basis. This protocol will require two years to enroll the study subjects and 5-6 years of follow-up to determine the role of peripheral insulin resistance and the above interventions for the delay or prevention of NIDDM.
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