Diabetes, Vol 43, Issue 5 718-723, Copyright © 1994 by American Diabetes Association

ARTICLES

Compensation in pancreatic beta-cell function in subjects with glucokinase mutations

J Sturis, IJ Kurland, MM Byrne, E Mosekilde, P Froguel, SJ Pilkis, GI Bell and KS Polonsky
Department of Medicine, University of Chicago, IL 60637.

The relationship between the in vivo insulin secretory responsiveness of the pancreatic beta-cell to glucose and the flux of glucose through the enzyme glucokinase was investigated in six subjects with heterozygous glucokinase mutations and in six matched control subjects. This was done by combining data published previously on the in vivo dose-response relationships between glucose and insulin secretion and on the in vitro enzymatic properties of wild-type and mutant forms of glucokinase. The flux of glucose through glucokinase (GK flux) in these subjects was estimated using a model based on the approximate Michaelis-Menten kinetics of wild-type and mutant forms of the enzyme. In two subjects with glucokinase mutations, which resulted in only a small reduction in enzymatic activity, the decrease in insulin secretion was directly proportional to the decrease in GK flux predicted using a Michaelis-Menten model for both mutant and wild-type glucokinase. However, in four subjects with glucokinase mutations, which resulted in severe reductions in enzymatic activity, insulin secretion was reduced compared with control subjects but less than predicted. This latter result implies the existence of a compensatory change in the beta-cells of such subjects, which results in a relative increase in insulin secretory response. We propose modifications to the simple model relating glucose concentration and GK flux, including glucose-induced overexpression of the normal allele and a role of glucokinase regulatory protein. The modifications take into account the possibility that the degree of compensation may be directly related to the severity of the mutation.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. T. Hattersley and E. R. Pearson Minireview: Pharmacogenetics and Beyond: The Interaction of Therapeutic Response, {beta}-Cell Physiology, and Genetics in Diabetes Endocrinology, June 1, 2006; 147(6): 2657 - 2663. [Abstract] [Full Text] [PDF]

				A. L. Gloyn, K. Noordam, M. A.A.P. Willemsen, S. Ellard, W. W.K. Lam, I. W. Campbell, P. Midgley, C. Shiota, C. Buettger, M. A. Magnuson, et al. Insights Into the Biochemical and Genetic Basis of Glucokinase Activation From Naturally Occurring Hypoglycemia Mutations Diabetes, September 1, 2003; 52(9): 2433 - 2440. [Abstract] [Full Text] [PDF]

				M. I. McCarthy and P. Froguel Genetic approaches to the molecular understanding of type 2 diabetes Am J Physiol Endocrinol Metab, August 1, 2002; 283(2): E217 - E225. [Abstract] [Full Text] [PDF]

				S. S. Fajans, G. I. Bell, and K. S. Polonsky Molecular Mechanisms and Clinical Pathophysiology of Maturity-Onset Diabetes of the Young N. Engl. J. Med., September 27, 2001; 345(13): 971 - 980. [Full Text] [PDF]

				L. Rossetti, W. Chen, M. Hu, M. Hawkins, N. Barzilai, and S. Efrat Abnormal regulation of HGP by hyperglycemia in mice with a disrupted glucokinase allele Am J Physiol Endocrinol Metab, October 1, 1997; 273(4): E743 - E750. [Abstract] [Full Text] [PDF]

				K. D. Niswender, M. Shiota, C. Postic, A. D. Cherrington, and M. A. Magnuson Effects of Increased Glucokinase Gene Copy Number on Glucose Homeostasis and Hepatic Glucose Metabolism J. Biol. Chem., September 5, 1997; 272(36): 22570 - 22575. [Abstract] [Full Text] [PDF]

				D. Bali, A. Svetlanov, H.-W. Lee, D. Fusco-DeMane, M. Leiser, B. Li, N. Barzilai, M. Surana, H. Hou, N. Fleischer, et al. Animal Model for Maturity-onset Diabetes of the Young Generated by Disruption of the Mouse Glucokinase Gene J. Biol. Chem., September 15, 1995; 270(37): 21464 - 21467. [Abstract] [Full Text] [PDF]