Diabetes, Vol 48, Issue 1 99-105, Copyright © 1999 by American Diabetes Association

ARTICLES

Restoration of early rise in plasma insulin levels improves the glucose tolerance of type 2 diabetic patients

D Bruttomesso, A Pianta, A Mari, A Valerio, MC Marescotti, A Avogaro, A Tiengo and S Del Prato
Cattedra di Malattie del Metabolismo, University of Padova, National Research Council, Italy.

The loss of first-phase insulin secretion is a characteristic feature of type 2 diabetic patients. The fast-acting insulin analog lispro provides a therapeutic tool for assessing the metabolic outcome of restoration of an early rise in plasma insulin levels after the ingestion of an oral glucose load. We studied eight type 2 diabetic patients on two different occasions when they received an oral glucose load (50 g) preceded by either human regular insulin or insulin analog lispro (both 0.075 U/kg lean body mass). Tritiated glucose was infused throughout the studies, and the oral glucose was labeled with [13C6]glucose for monitoring systemic and oral glucose kinetics, respectively. Basal plasma glucose (8.2 +/- 0.9 vs. 7.5 +/- 0.8 mmol/l), insulin (224 +/- 21 vs. 203 +/- 21 pmol/l), and endogenous glucose production (10.4 +/- 1.0 vs. 11.1 +/- 1.1 micromol x kg(-1) x min(-1)) were similar on both occasions. In spite of comparable incremental areas under the curve, the time course of plasma insulin concentration was much different. After injection of regular insulin, plasma insulin peaked at 120 min (368 +/- 42 pmol/l), while with lispro, the peak occurred at 60 min (481 +/- 42 pmol/l). Plasma insulin concentration during the last 3 h of the study, however, was lower with lispro compared with regular insulin. The incremental area under the curve of plasma C-peptide was lower with lispro (0.05 +/- 0.01 vs. 0.13 +/- 0.04 micromol/300 min; P < 0.01). After the ingestion of the oral glucose load, plasma glucose concentration increased by 78% at 80-100 min with regular insulin and by 62% with lispro (P < 0.05) and remained lower for the ensuing 3 h. The incremental area under the curve was 46% lower with lispro (715 +/- 109 vs. 389 +/- 109 pmol/300 min; P < 0.01). There was no difference in the two studies in the rate of appearance of the ingested glucose and in the overall rate of glucose disposal. During the initial 90 min, however, the rate of endogenous glucose production was suppressed in a prompter and more profound manner when lispro was administered (1.39 +/- 0.10 vs. 5.00 +/- 1.22 micromol x kg(-1) x min(-1); P < 0.05), while there was no difference in the late prandial phase. These results show that an early rise in plasma insulin levels after the ingestion of a glucose load is associated with a significant improvement in glucose tolerance due to a prompter, though short-lived, suppression of endogenous glucose production. This amelioration in plasma glucose profile prevents late hyperglycemia and hyperinsulinemia. Therefore, restoration of a more physiologic profile of prandial plasma insulin profile represents a rational approach for treatment of type 2 diabetic patients.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				D. F. Kruger, C. L. Martin, and C. E. Sadler New insights into glucose regulation. The Diabetes Educator, March 1, 2006; 32(2): 221 - 228. [Abstract] [Full Text] [PDF]

				L. S. Cozma, S. D. Luzio, G. J. Dunseath, P. M. Underwood, and D. R. Owens {beta}-Cell Response During a Meal Test: A comparative study of incremental doses of repaglinide in type 2 diabetic patients Diabetes Care, May 1, 2005; 28(5): 1001 - 1007. [Abstract] [Full Text] [PDF]

				A. Mari, A. Gastaldelli, J. E. Foley, R. E. Pratley, and E. Ferrannini {beta}-Cell Function in Mild Type 2 Diabetic Patients: Effects of 6-month glucose lowering with nateglinide Diabetes Care, May 1, 2005; 28(5): 1132 - 1138. [Abstract] [Full Text] [PDF]

				J. Rossi, P. Santamaki, M. S. Airaksinen, and K.-H. Herzig Parasympathetic Innervation and Function of Endocrine Pancreas Requires the Glial Cell Line-Derived Factor Family Receptor {alpha}2 (GFR{alpha}2) Diabetes, May 1, 2005; 54(5): 1324 - 1330. [Abstract] [Full Text] [PDF]

				E. Wajcberg, Y. Miyazaki, C. Triplitt, E. Cersosimo, and R. A. DeFronzo Dose-Response Effect of a Single Administration of Oral Hexyl-Insulin Monoconjugate 2 in Healthy Nondiabetic Subjects Diabetes Care, December 1, 2004; 27(12): 2868 - 2873. [Abstract] [Full Text] [PDF]

				S. L. Aronoff, K. Berkowitz, B. Shreiner, and L. Want Glucose Metabolism and Regulation: Beyond Insulin and Glucagon Diabetes Spectr, July 1, 2004; 17(3): 183 - 190. [Abstract] [Full Text] [PDF]

				M. F. Carroll, A. Gutierrez, M. Castro, D. Tsewang, and D. S. Schade Targeting Postprandial Hyperglycemia: A Comparative Study of Insulinotropic Agents in Type 2 Diabetes J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5248 - 5254. [Abstract] [Full Text] [PDF]

				O. Torffvit Hyperglycaemia in diabetes: impact on nephropathy and cardiac risk Nephrol. Dial. Transplant., September 1, 2003; 18(9): 1711 - 1715. [Full Text] [PDF]

				P. Ruggenenti, C. Flores, C. Aros, B. Ene-Iordache, R. Trevisan, C. Ottomano, and G. Remuzzi Renal and Metabolic Effects of Insulin Lispro in Type 2 Diabetic Subjects With Overt Nephropathy Diabetes Care, February 1, 2003; 26(2): 502 - 509. [Abstract] [Full Text] [PDF]

				N. Ogihara, S. Ebihara, W. Kawamura, M. Okamoto, T. Sakai, K. Takiguchi, T. Morita, R. Uchida, Y. Matsuyama, Y. Hayashi, et al. Characterization of the portal signal in a nonsteady hyperglycemic state in conscious dogs Am J Physiol Endocrinol Metab, January 1, 2003; 284(1): E148 - E155. [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]

				B. Ahren and G. Pacini Insufficient islet compensation to insulin resistance vs. reduced glucose effectiveness in glucose-intolerant mice Am J Physiol Endocrinol Metab, October 1, 2002; 283(4): E738 - E744. [Abstract] [Full Text] [PDF]

				C. Saloranta, K. Hershon, M. Ball, S. Dickinson, and D. Holmes Efficacy and Safety of Nateglinide in Type 2 Diabetic Patients with Modest Fasting Hyperglycemia J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4171 - 4176. [Abstract] [Full Text] [PDF]

				L. S. Cozma, S. D. Luzio, G. J. Dunseath, K. W. Langendorg, T. Pieber, and D. R. Owens Comparison of the Effects of Three Insulinotropic Drugs on Plasma Insulin Levels After a Standard Meal Diabetes Care, August 1, 2002; 25(8): 1271 - 1276. [Abstract] [Full Text] [PDF]

				C. C. Jensen, M. Cnop, R. L. Hull, W. Y. Fujimoto, S. E. Kahn, and the American Diabetes Association GENNID Study Gro {beta}-Cell Function Is a Major Contributor to Oral Glucose Tolerance in High-Risk Relatives of Four Ethnic Groups in the U.S. Diabetes, July 1, 2002; 51(7): 2170 - 2178. [Abstract] [Full Text] [PDF]

				S. Del Prato, P. Marchetti, and R. C. Bonadonna Phasic Insulin Release and Metabolic Regulation in Type 2 Diabetes Diabetes, February 1, 2002; 51(90001): S109 - 116. [Abstract] [Full Text] [PDF]

				S. E. Kahn, B. Montgomery, W. Howell, M. Ligueros-Saylan, C.-H. Hsu, D. Devineni, J. F. McLeod, A. Horowitz, and J. E. Foley Importance of Early Phase Insulin Secretion to Intravenous Glucose Tolerance in Subjects with Type 2 Diabetes Mellitus J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5824 - 5829. [Abstract] [Full Text] [PDF]

				S. D. Luzio, D. M. Anderson, and D. R. Owens Effects of Timing of Administration and Meal Composition on the Pharmacokinetic and Pharmacodynamic Characteristics of the Short-Acting Oral Hypoglycemic Agent Nateglinide in Healthy Subjects J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 4874 - 4880. [Abstract] [Full Text] [PDF]

				P. A. Halban, S. E. Kahn, A. Lernmark, and C. J. Rhodes Gene and Cell-Replacement Therapy in the Treatment of Type 1 Diabetes: How High Must the Standards Be Set? Diabetes, October 1, 2001; 50(10): 2181 - 2191. [Abstract] [Full Text]

				P. N. Båvenholm, J. Pigon, C.-G. Östenson, and S. Efendic Insulin Sensitivity of Suppression of Endogenous Glucose Production Is the Single Most Important Determinant of Glucose Tolerance Diabetes, June 1, 2001; 50(6): 1449 - 1454. [Abstract] [Full Text]

				B. Ahrén and J. J. Holst The Cephalic Insulin Response to Meal Ingestion in Humans Is Dependent on Both Cholinergic and Noncholinergic Mechanisms and Is Important for Postprandial Glycemia Diabetes, May 1, 2001; 50(5): 1030 - 1038. [Abstract] [Full Text]

				J. B. Kalbag, Y. H. Walter, J. R. Nedelman, and J. F. McLeod Mealtime Glucose Regulation With Nateglinide in Healthy Volunteers: Comparison with repaglinide and placebo Diabetes Care, January 1, 2001; 24(1): 73 - 77. [Abstract] [Full Text]