Beneficial metabolic effects of chronic glipizide in obese african americans with impaired glucose tolerance: implications for primary prevention of type 2 diabetes

Abstract

We examined the long-term metabolic effects of glipizide gastrointestinal therapeutic system (GITS), a potent sulfonylurea (SU), in impaired glucose-tolerant (IGT), first-degree relatives of African American patients with type 2 diabetes. To this end, we assessed glucose homeostasis, beta-cell function, insulin sensitivity (Si), and glucose effectiveness (Sg) in patients with IGT before and at yearly intervals for 24 months of GITS or an identical placebo in a randomized, double-blind manner. Eighteen IGT patients were randomized to receive either glipizide GITS (GITS, 5 mg/d, n = 9; mean age, 43.3 ± 8.7 years; mean body mass index [BMI], 32.9 ± 6.3 kg/m 2) or identical placebo (PLAC, n = 9; mean age, 41.5 ± 5.7 years; mean BMI, 39 ± 4.2 kg/m 2) for 24 months. Each of the subjects underwent oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIGT) at baseline and yearly intervals for 2 years. Si and Sg were determined by Bergman’s minimal model method. The ability of beta cell to compensate for peripheral insulin resistance was calculated as the disposition index (DI). Chronic administration of glipizide GITS attenuated serum glucose responses to oral glucose challenge at 12 and 24 months when compared to baseline (0 months). In contrast, serum glucose levels at fasting and during OGTT tended to increase in the IGT/PLAC group at 12 and 24 months when compared to baseline. Serum insulin ( P < .05 to 0.01) and serum C-peptide levels progressively increased in the GITS group at 12 and 24 months versus 0 months. In contrast, serum insulin and C-peptide responses remained unchanged in the IGT/PLAC group. During FSIGT, chronic GITS was associated with significant improvement in the blunted acute first insulin release in the IGT patients at 12 and 24 months. These parameters remained blunted in the IGT/PLAC group. We found that Si increased in the IGT/GITS group at 12 months ( P < .01) and 24 months( P < .05) versus baseline, but deteriorated in the IGT/PLAC group. Similarly, the DIs significantly ( P < .01) increased following GITS therapy at 12 and 24 months when compared to baseline. In contrast, DI did not change from baseline values in the IGT/PLAC group throughout the study period. Chronic GITS partially restored the ability of beta cells to compensate for peripheral insulin resistance (as assessed by DIs). GITS was well tolerated without any symptoms suggestive of either hypoglycemia or significant weight gain. In summary, long-term chronic glipizde GITS administration improved glucose homeostasis by increasing beta-cell responsiveness to glucose, improving Si, as well as significantly improved DI, but not Sg, in high-risk, obese African Americans with IGT. Our study demonstrated that GITS appears to prime beta cells to intravenous glucose stimulation resulting in restoration of physiologic acute first- and second-phase insulin secretion in African Americans with IGT. We conclude that GITS might be considered as a useful agent in the primary prevention of type 2 diabetes in high-risk, obese African American patients with IGT.