This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kahn, S. E. Articles by Foley, J. E. Search for Related Content PubMed PubMed Citation Articles by Kahn, S. E. Articles by Foley, J. E.

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.

This article has been cited by other articles:

				K. L. Teff Visceral Nerves: Vagal and Sympathetic Innervation JPEN J Parenter Enteral Nutr, September 1, 2008; 32(5): 569 - 571. [Abstract] [Full Text] [PDF]

				N. Gustavsson, Y. Lao, A. Maximov, J.-C. Chuang, E. Kostromina, J. J. Repa, C. Li, G. K. Radda, T. C. Sudhof, and W. Han Impaired insulin secretion and glucose intolerance in synaptotagmin-7 null mutant mice PNAS, March 11, 2008; 105(10): 3992 - 3997. [Abstract] [Full Text] [PDF]

				T. Tuomi, E. H. Honkanen, B. Isomaa, L. Sarelin, and L. C. Groop Improved Prandial Glucose Control With Lower Risk of Hypoglycemia With Nateglinide Than With Glibenclamide in Patients With Maturity-Onset Diabetes of the Young Type 3 Diabetes Care, February 1, 2006; 29(2): 189 - 194. [Abstract] [Full Text] [PDF]

				C. Abletshauser, P. Brunel, K.-H. Usadel, and M. Hanefeld Effect of nateglinide and glimepiride in reducing postprandial hyperglycaemia in patients with type 2 diabetes mellitus The British Journal of Diabetes & Vascular Disease, March 1, 2005; 5(2): 93 - 99. [Abstract] [PDF]

				M. E. Doyle and J. M. Egan Pharmacological Agents That Directly Modulate Insulin Secretion Pharmacol. Rev., March 1, 2003; 55(1): 105 - 131. [Abstract] [Full Text] [PDF]

				F. Ferreira, E. Filiputti, V. C. Arantes, L. F. Stoppiglia, E. P. Araujo, V. Delghingaro-Augusto, M. Q. Latorraca, M. H. Toyama, A. C. Boschero, and E. M. Carneiro Decreased Cholinergic Stimulation of Insulin Secretion by Islets from Rats Fed a Low Protein Diet Is Associated with Reduced Protein Kinase C{alpha} Expression J. Nutr., March 1, 2003; 133(3): 695 - 699. [Abstract] [Full Text] [PDF]

				S. W Limesand and W. W Hay Jr Adaptation of ovine fetal pancreatic insulin secretion to chronic hypoglycaemia and euglycaemic correction J. Physiol., February 15, 2003; 547(1): 95 - 105. [Abstract] [Full Text] [PDF]

				M. F. Carroll, A. Izard, K. Riboni, M. R. Burge, and D. S. Schade Control of Postprandial Hyperglycemia: Optimal use of short-acting insulin secretagogues Diabetes Care, December 1, 2002; 25(12): 2147 - 2152. [Abstract] [Full Text] [PDF]

				J. Rosenstock, S. G. Shen, M. R. Gatlin, and J. E. Foley Combination Therapy With Nateglinide and a Thiazolidinedione Improves Glycemic Control in Type 2 Diabetes Diabetes Care, September 1, 2002; 25(9): 1529 - 1533. [Abstract] [Full Text] [PDF]

				R. M. Cohen and B. A. Ramlo-Halsted How Do the New Insulin Secretagogues Compare? Diabetes Care, August 1, 2002; 25(8): 1472 - 1473. [Full Text] [PDF]