Diabetes, Vol 39, Issue 6 647-652, Copyright © 1990 by American Diabetes Association

ARTICLES

Glucokinase as glucose sensor and metabolic signal generator in pancreatic beta-cells and hepatocytes

FM Matschinsky
Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia 19104-6015.

This article reviews evidence for a pivotal role of glucokinase as glucose sensor of the pancreatic beta-cells. Glucokinase explains the capacity, hexose specificity, affinities, sigmoidicity, and anomeric preference of pancreatic islet glycolysis, and because stimulation of glucose metabolism is a prerequisite of glucose stimulation of insulin release, glucokinase also explains many characteristics of this beta-cell function. Glucokinase of the beta-cell is induced or activated by glucose in contrast to liver glucokinase, which is regulated by insulin. Tissue-specific regulation corresponds with observations that liver and pancreatic beta-cell glucokinase are structurally distinct. Glucokinase could play a glucose-sensor role in hepatocytes as well, and certain forms of diabetes mellitus might be due to glucokinase deficiencies in pancreatic beta-cells, hepatocytes, or both.
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				L. M. de Vargas, J. Sobolewski, R. Siegel, and L. G. Moss Individual beta  Cells within the Intact Islet Differentially Respond to Glucose J. Biol. Chem., October 17, 1997; 272(42): 26573 - 26577. [Abstract] [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, C. Postic, T. L. Jetton, B. D. Bennett, D. W. Piston, S. Efrat, and M. A. Magnuson Cell-specific Expression and Regulation of a Glucokinase Gene Locus Transgene J. Biol. Chem., September 5, 1997; 272(36): 22564 - 22569. [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]

				Z. Ma, M. Landt, A. Bohrer, S. Ramanadham, D. M. Kipnis, and J. Turk Interleukin-1 Reduces the Glycolytic Utilization of Glucose by Pancreatic Islets and Reduces Glucokinase mRNA Content and Protein Synthesis by a Nitric Oxide-dependent Mechanism J. Biol. Chem., July 11, 1997; 272(28): 17827 - 17835. [Abstract] [Full Text] [PDF]

				R. J. Konrad, R. M. Dean, R. A. Young, P. C. Billings, and B. A. Wolf Glucose-induced Tyrosine Phosphorylation of p125 in Beta Cells and Pancreatic Islets. A NOVEL PROXIMAL SIGNAL IN INSULIN SECRETION J. Biol. Chem., September 27, 1996; 271(39): 24179 - 24186. [Abstract] [Full Text] [PDF]

				B. D. Bennett, T. L. Jetton, G. Ying, M. A. Magnuson, and D. W. Piston Quantitative Subcellular Imaging of Glucose Metabolism within Intact Pancreatic Islets J. Biol. Chem., February 16, 1996; 271(7): 3647 - 3651. [Abstract] [Full Text] [PDF]

				H. Odagiri, J. Wang, and M. S. German Function of the Human Insulin Promoter in Primary Cultured Islet Cells J. Biol. Chem., January 26, 1996; 271(4): 1909 - 1915. [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]

				R. J. Konrad, R. A. Young, R. D. Record, R. M. Smith, P. Butkerait, D. Manning, L. Jarett, and B. A. Wolf The Heterotrimeric G-protein G[IMAGE] Is Localized to the Insulin Secretory Granules of [IMAGE]-Cells and Is Involved in Insulin Exocytosis J. Biol. Chem., May 26, 1995; 270(21): 12869 - 12876. [Abstract] [Full Text] [PDF]

				P. Froguel, H. Zouali, N. Vionnet, G. Velho, M. Vaxillaire, F. Sun, S. Lesage, M. Stoffel, J. Takeda, P. Passa, et al. Familial Hyperglycemia Due to Mutations in Glucokinase -- Definition of a Subtype of Diabetes Mellitus N. Engl. J. Med., March 11, 1993; 328(10): 697 - 702. [Abstract] [Full Text]

				G. C. Weir A Defective Beta-Cell Glucose Sensor as a Cause of Diabetes N. Engl. J. Med., March 11, 1993; 328(10): 729 - 731. [Full Text]

				R. Unger Diabetic hyperglycemia: link to impaired glucose transport in pancreatic beta cells Science, March 8, 1991; 251(4998): 1200 - 1205. [Abstract] [PDF]

				A. Shiraishi, Y. Yamada, Y. Tsuura, S. Fijimoto, K. Tsukiyama, E. Mukai, Y. Toyoda, I. Miwa, and Y. Seino A Novel Glucokinase Regulator in Pancreatic beta Cells. PRECURSOR OF PROPIONYL-CoA CARBOXYLASE beta SUBUNIT INTERACTS WITH GLUCOKINASE AND AUGMENTS ITS ACTIVITY J. Biol. Chem., January 19, 2001; 276(4): 2325 - 2328. [Abstract] [Full Text] [PDF]