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Importance of Early Phase Insulin Secretion to Intravenous Glucose Tolerance in Subjects with Type 2 Diabetes Mellitus

Department of Medicine (S.E.K., B.M., W.H.), Division of Metabolism, Endocrinology, and Nutrition, VA Puget Sound Health Care System and University of Washington, Seattle, Washington 98108; and Novartis Pharmaceuticals Corp. (M.L.-S., C.-H.H., D.D., J.F.M., A.H., J.E.F.), East Hanover, New Jersey 07936

Address all correspondence and requests for reprints to: Steven E. Kahn, M.B., Ch.B., VA Puget Sound Health Care System (151), 1660 South Columbian Way, Seattle, Washington 98108. E-mail: skahn{at}u.washington.edu

Abstract

Insulin secretion is impaired in type 2 diabetes with the early response being essentially absent. The loss of this early insulin secretion is hypothesized to be important in the deterioration of glucose tolerance. To determine whether enhancement of the early-phase insulin response can enhance glucose tolerance, we administered 1) 120 mg nateglinide, an insulinotropic agent that enhances early insulin secretion; 2) 10 mg glyburide, which enhances the later phases of insulin secretion; or 3) placebo in random order to 21 subjects with type 2 diabetes (14 males and 7 females; aged 59.2 ± 2.1 yr, x ± SEM; body mass index 29.7 ± 1.0 kg/m²; fasting plasma glucose 8.1 ± 0.1 mM). ß-Cell function was quantified as the incremental area under the curve for different time periods for the 5 h following iv glucose administration and glucose tolerance as the glucose disappearance constant (Kg) from 10 to 60 min. Insulin release commenced immediately after nateglinide administration, even before glucose injection, but this was not observed with glyburide. Both nateglinide and glyburide enhanced glucose-induced insulin release, compared with placebo (area under the curve -15–300 min: nateglinide 23,595 ± 11,212 pM/min, glyburide 54,556 ± 15,253 pM/min, placebo 10,242 ± 2,414 pM/min). The profiles of insulin release demonstrated significant enhancement of release between -15 and 30 min for nateglinide, compared with glyburide and between 60 and 300 min for glyburide over nateglinide. Kg increased by 15% with nateglinide (0.87 ± 0.04%/min), but it did not increase significantly with glyburide (0.79 ± 0.04%/min), compared with placebo (0.76 ± 0.04%/min). The enhancement of insulin release by glyburide resulted in a lower minimal glucose concentration with glyburide (3.8 ± 0.2 mM), compared with nateglinide (5.0 ± 0.2 mM) and placebo (5.9 ± 0.2 mM). Thus, enhancement of the early phase of insulin secretion improves iv glucose tolerance, whereas delaying it by 30 min results in a slower rate of glucose disappearance for the first 2 h after iv glucose administration. Further, the differences in the kinetics of nateglinide and glyburide action results in continued insulin release with glyburide despite the fact that glucose levels have returned to basal, thus resulting in a further reduction in glucose levels and a lower nadir.

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