The effect of glipizide treatment on diabetic control and on in vivo insulin secretion and action was studied in 20 patients with non-insulin-dependent diabetes mellitus (NIDDM). Patients were examined before and after a minimum of 3 mo treatment. Mean (± SEM) fasting plasma glucose level fell from 264 ± 12 mg/dl to 172 ± 10 mg/dl (P < 0.001) after glipizide treatment, and this was associated with a fall in total plasma glucose response to a test meal of approximately 35﹪. Mean (±SEM) fasting plasma insulin levels increased slightly from 15 ± 2 μU/ml to 18 ± 2 μU/ml following sulfonylurea treatment, and the total plasma insulin response to the test meal increased by 63﹪. However, there was no correlation (r = −0.20) between the increase in plasma insulin response and the fall in plasma glucose levels that occurred as the result of sulfonylurea therapy. Glipizide treatment also led to enhanced in vivo insulin action, whether measured by the insulin clamp technique (P < 0.001) or the insulin suppression test (P < 0.02). Furthermore, in this instance there was a significant correlation (r = 0.69, P < 0.001) between the enhanced insulin action and the improvement on diabetes control. Thus, chronic therapy with glipizide, a new sulfonylurea agent, led to increased in vivo insulin secretion and insulin action. These results lend direct support to the assumption that sulfonylurea compounds have a substantial extrapancreatic effect on glucose homeostasis, and suggest that this effect contributes to the therapeutic efficacy of these drugs.

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