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From Clinicogenetic Studies of Maturity-Onset Diabetes of the Young to Unraveling Complex Mechanisms of Glucokinase Regulation

¹ Section for Pediatrics, Department of Clinical Medicine, University of Bergen, Bergen, Norway
² Department of Biochemistry and Biophysics and Diabetes Research Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
³ Section for Medical Genetics and Molecular Medicine, Department of Clinical Medicine, University of Bergen, Bergen, Norway
⁴ Division of Endocrinology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
⁵ Department of Pediatrics, Ullevål University Hospital, Oslo, Norway
⁶ Pediatric Department, Centre Hospitalier de Luxembourg, Luxembourg
⁷ Departments of Medicine and Human Genetics, University of Chicago, Chicago, Illinois
⁸ Department of Metabolic Diseases, Hoffmann-La Roche, Nutley, New Jersey
⁹ Section for Pathology, The Gade Institute, University of Bergen, Bergen, Norway
¹⁰ Department of Pediatrics, Haukeland University Hospital, Bergen, Norway

Address correspondence and reprint requests to Dr. Pål R. Njølstad, Section for Pediatrics, Department of Clinical Medicine, University of Bergen, Haukeland University Hospital, N-5021 Bergen, Norway. E-mail: pal.njolstad{at}uib.no

Abbreviations: GKA, glucokinase activator; GKRP, glucokinase regulatory protein; GSIR, glucose-stimulated insulin release; GST, glutathionyl S-transferase; MODY2, maturity-onset diabetes of the young, type 2; PEOE, partial equalization of orbital electronegativities; PNDM, permanent neonatal diabetes mellitus

Glucokinase functions as a glucose sensor in pancreatic ß-cells and regulates hepatic glucose metabolism. A total of 83 probands were referred for a diagnostic screening of mutations in the glucokinase (GCK) gene. We found 11 different mutations (V62A, G72R, L146R, A208T, M210K, Y215X, S263P, E339G, R377C, S453L, and IVS5 + 1G>C) in 14 probands. Functional characterization of recombinant glutathionyl S-transferase–G72R glucokinase showed slightly increased activity, whereas S263P and G264S had near-normal activity. The other point mutations were inactivating. S263P showed marked thermal instability, whereas the stability of G72R and G264S differed only slightly from that of wild type. G72R and M210K did not respond to an allosteric glucokinase activator (GKA) or the hepatic glucokinase regulatory protein (GKRP). Mutation analysis of the role of glycine at position 72 by substituting E, F, K, M, S, or Q showed that G is unique since all these mutants had very low or no activity and were refractory to GKRP and GKA. Structural analysis provided plausible explanations for the drug resistance of G72R and M210K. Our study provides further evidence that protein instability in combination with loss of control by a putative endogenous activator and GKRP could be involved in the development of hyperglycemia in maturity-onset diabetes of the young, type 2. Furthermore, based on data obtained on G264S, we propose that other and still unknown mechanisms participate in the regulation of glucokinase.

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