This Article Full Text Full Text (PDF) Supplemental Data Alert me when this article is cited 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 Google Scholar Google Scholar Articles by Nakamura, A. Articles by Koike, T. Search for Related Content PubMed PubMed Citation Articles by Nakamura, A. Articles by Koike, T.

Impact of Small-Molecule Glucokinase Activator on Glucose Metabolism and β-Cell Mass

Department of Endocrinology and Metabolism (A.N., Y.T.), Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; Tsukuba Research Institute (S.O., J.K., H.S., T.N., J.E.), Banyu Pharmaceutical Co., Ltd., Tsukuba 300-2611, Japan; Department of Metabolic Diseases (I.T., N.K., T.K.), Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan; and Department of Medicine II (A.N., N.Y., T.K.), Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan

Address all correspondence and requests for reprints to: Yasuo Terauchi, M.D., Ph.D., Professor, Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. E-mail: terauchi-tky{at}umin.ac.jp.

We investigated the effect of glucokinase activator (GKA) on glucose metabolism and β-cell mass. We analyzed four mouse groups: wild-type mice and β-cell-specific haploinsufficiency of glucokinase gene (Gck^+/–) mice on a high-fat (HF) diet. Each genotype was also treated with GKA mixed in the HF diet. Rodent insulinoma cells and isolated islets were used to evaluate β-cell proliferation by GKA. After 20 wk on the above diets, there were no differences in body weight, lipid profiles, and liver triglyceride content among the four groups. Glucose tolerance was improved shortly after the GKA treatment in both genotypes of mice. β-Cell mass increased in wild-type mice compared with Gck^+/– mice, but a further increase was not observed after the administration of GKA in both genotypes. Interestingly, GKA was able to up-regulate insulin receptor substrate-2 (Irs-2) expression in insulinoma cells and isolated islets. The administration of GKA increased 5-bromo-2-deoxyuridine (BrdU) incorporation in insulinoma cells, and 3 d administration of GKA markedly increased BrdU incorporation in mice treated with GKA in both genotypes, compared with those without GKA. In conclusion, GKA was able to chronically improve glucose metabolism for mice on the HF diet. Although chronic GKA administration failed to cause a further increase in β-cell mass in vivo, GKA was able to increase beta cell proliferation in vitro and with a 3-d administration in vivo. This apparent discrepancy can be explained by a chronic reduction in ambient blood glucose levels by GKA treatment.