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To determine whether the abnormal glucagon and amylin secretions in NIDDM are secondary to hyperglycemia and relative hypoinsulinemia.A total of 13 patients with NIDDM were studied before and after treatment with glipizide gastrointestinal therapeutic system (GITS) in a randomized double-blind placebo-controlled fashion. Of the 13 subjects, 9 were randomized to the glipizide GITS arm and 4 were randomized to the placebo arm of the study. Serum glucose, insulin, C-peptide, plasma glucagon, and plasma amylin concentrations were measured under fasting and postprandial (post-Sustacal ingestion) conditions. The Sustacal challenge was performed at baseline and after 12 weeks of treatment with either glipizide GITS or placebo.Glipizide GITS treatment resulted in a significant reduction in hyperglycemia and increases in insulin and C-peptide secretion. Hyperglucagonemia was not ameliorated, and amylin secretion was not altered after glipizide GITS treatment. Placebo-treated patients did not show significant changes in any of the parameters measured.Glipizide GITS treatment failed to ameliorate the hyperglucagonemia of NIDDM and did not alter amylin secretion even though it increased insulin secretion and significantly ameliorated the hyperglycemia. These observations suggest that NIDDM related abnormalities in some of the islet cell hormonal responses are the result of changes inherent in the islet cells and may be independent of hyperglycemia and relative hypoinsulinemia.