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Diabetologia
Published in: Diabetologia 6/2012

01-06-2012 | Article

Control of beta cell function and proliferation in mice stimulated by small-molecule glucokinase activator under various conditions

Authors: A. Nakamura, Y. Togashi, K. Orime, K. Sato, J. Shirakawa, M. Ohsugi, N. Kubota, T. Kadowaki, Y. Terauchi

Published in: Diabetologia | Issue 6/2012

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Abstract

Aims/hypothesis

We investigated changes in the expression of genes involved in beta cell function and proliferation in mouse islets stimulated with glucokinase activator (GKA) in order to elucidate the mechanisms by which GKA stimulates beta cell function and proliferation.

Methods

Islets isolated from mice were used to investigate changes in the expression of genes related to beta cell function and proliferation stimulated by GKA. In addition, Irs2 knockout (Irs2 −/−) mice on a high-fat diet or a high-fat diet containing GKA were used to investigate the effects of GKA on beta cell proliferation in vivo.

Results

In wild-type mice, Irs2 and Pdx1 expression was increased by GKA. In Irs2 −/− mice, GKA administration increased the glucose-stimulated secretion of insulin and Pdx1 expression, but not beta cell proliferation. It was particularly noteworthy that oxidative stress inhibited the upregulation of the Irs2 and Pdx1 genes induced by GKA. Moreover, whereas neither GKA alone nor exendin-4 alone upregulated the expression of Irs2 and Pdx1 in the islets of db/db mice, prior administration of exendin-4 to the mice caused GKA to increase the expression of these genes.

Conclusions/interpretation

GKA-stimulated IRS2 production affected beta cell proliferation but not beta cell function. Oxidative stress diminished the effects of GKA on the changes in expression of genes involved in beta cell function and proliferation. A combination of GKA and an incretin-related agent might therefore be effective in therapy.
Literature
1.
Matschinsky FM (1996) Banting Lecture 1995. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes 45:223–241PubMedCrossRef
2.
Matschinsky FM, Glaser B, Magnuson MA (1998) Pancreatic beta-cell glucokinase: closing the gap between theoretical concepts and experimental realities. Diabetes 47:307–315PubMedCrossRef
3.
Terauchi Y, Takamoto I, Kubota N et al (2007) Glucokinase and IRS-2 are required for compensatory beta cell hyperplasia in response to high-fat diet-induced insulin resistance. J Clin Invest 117:246–257PubMedCrossRef
4.
Kassem S, Bhandari S, Rodríguez-Bada P et al (2010) Large islets, beta-cell proliferation, and a glucokinase mutation. N Engl J Med 362:1348–1350PubMedCrossRef
5.
Grimsby J, Sarabu R, Corbett WL et al (2003) Allosteric activators of glucokinase: potential role in diabetes therapy. Science 301:370–373PubMedCrossRef
6.
Efanov AM, Barrett DG, Brenner MB et al (2005) A novel glucokinase activator modulates pancreatic islet and hepatocyte function. Endocrinology 146:3696–3701PubMedCrossRef
7.
Futamura M, Hosaka H, Kadotani A et al (2006) An allosteric activator of glucokinase impairs the interaction of glucokinase and glucokinase regulatory protein and regulates glucose metabolism. J Biol Chem 281:37668–37674PubMedCrossRef
8.
Fyfe MC, White JR, Taylor A et al (2007) Glucokinase activator PSN-GK1 displays enhanced antihyperglycaemic and insulinotropic actions. Diabetologia 50:1277–1287PubMedCrossRef
9.
Coope GJ, Atkinson AM, Allott C et al (2006) Predictive blood glucose lowering efficacy by glucokinase activators in high fat fed female Zucker rats. Br J Pharmacol 149:328–335PubMedCrossRef
10.
Gorman T, Hope DC, Brownlie R et al (2008) Effect of high-fat diet on glucose homeostasis and gene expression in glucokinase knockout mice. Diabetes Obes Metab 10:885–897PubMedCrossRef
11.
Nakamura A, Terauchi Y, Ohyama S et al (2009) Impact of small molecule glucokinase activator on glucose metabolism, beta cell function and mass. Endocrinology 150:1147–1154PubMedCrossRef
12.
Nakamura A, Shimazaki H, Ohyama S, Eiki J, Terauchi Y (2011) Effect of long-term treatment with a small-molecule glucokinase activator on glucose metabolism, lipid profiles and hepatic function. J Diabetes Invest 2:276–279CrossRef
13.
Johnson D, Shepherd RM, Gill D, Gorman T, Smith DM, Dunne MJ (2007) Glucose-dependent modulation of insulin secretion and intracellular calcium ions by GKA50, a glucokinase activator. Diabetes 56:1694–1702PubMedCrossRef
14.
Wei P, Shi M, Barnum S, Cho H, Carlson T, Fraser JD (2009) Effects of glucokinase activators GKA50 and LY2121260 on proliferation and apoptosis in pancreatic INS-1 beta cells. Diabetologia 52:2142–2150PubMedCrossRef
15.
Withers DJ, Gutierrez JS, Towery H et al (1998) Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391:900–904PubMedCrossRef
16.
Kubota N, Tobe K, Terauchi Y et al (2000) Disruption of insulin receptor substrate-2 causes type 2 diabetes due to liver insulin resistance and lack of compensatory beta-cell hyperplasia. Diabetes 49:1880–1889PubMedCrossRef
17.
Kubota N, Terauchi Y, Tobe K et al (2004) Insulin receptor substrate 2 plays a crucial role in beta cells and the hypothalamus. J Clin Invest 114:917–927PubMed
18.
Matschinsky FM (2009) Assessing the potential of glucokinase activators in diabetes therapy. Nat Rev Drug Discov 8:399–416PubMedCrossRef
19.
Bonadonna RC, Heise T, Arbet-Engels C et al (2010) Piragliatin (RO4389620), a novel glucokinase activator, lowers plasma glucose both in the postabsorptive state and after a glucose challenge in patients with type 2 diabetes mellitus: a mechanistic study. J Clin Endocrinol Metab 95:5028–5036PubMedCrossRef
20.
Meininger GE, Scott R, Alba M et al (2011) Effects of MK-0941, a novel glucokinase activator, on glycemic control in insulin-treated patients with type 2 diabetes. Diabetes Care 34:2560–2566PubMedCrossRef
21.
Iino T, Hashimoto N, Sasaki K et al (2009) Structure-activity relationships of 3,5-disubstituted benzamides as glucokinase activators with potent in vivo efficacy. Bioorg Med Chem 17:3800–3809PubMedCrossRef
22.
Weir GC, Bonner-Weir S (2007) A dominant role for glucose in beta cell compensation of insulin resistance. J Clin Invest 117:81–83PubMedCrossRef
23.
Lingohr MK, Briaud I, Dickson LM et al (2006) Specific regulation of IRS-2 expression by glucose in rat primary pancreatic islet beta-cells. J Biol Chem 281:15884–15892PubMedCrossRef
24.
Maechler P, Jornot L, Wollheim CB (1999) Hydrogen peroxide alters mitochondrial activation and insulin secretion in pancreatic beta cells. J Biol Chem 274:27905–27913PubMedCrossRef
25.
Jhala US, Canettieri G, Screaton RA et al (2003) cAMP promotes pancreatic beta-cell survival via CREB-mediated induction of IRS2. Genes Dev 17:1575–1580PubMedCrossRef
26.
Ashcroft FM (2005) ATP-sensitive potassium channelopathies: focus on insulin secretion. J Clin Invest 115:2047–2058PubMedCrossRef
27.
Porat S, Weinberg-Corem N, Tornovsky-Babaey S et al (2011) Control of pancreatic beta cell regeneration by glucose metabolism. Cell Metab 13:440–449PubMedCrossRef
28.
Kushner JA, Ye J, Schubert M et al (2002) Pdx1 restores beta cell function in Irs2 knockout mice. J Clin Invest 109:1193–1201PubMed
29.
Suzuki R, Tobe K, Terauchi Y et al (2003) Pdx1 expression in Irs2-deficient mouse beta-cells is regulated in a strain-dependent manner. J Biol Chem 278:43691–43698PubMedCrossRef
30.
Shih DQ, Heimesaat M, Kuwajima S, Stein R, Wright CV, Stoffel M (2002) Profound defects in pancreatic beta-cell function in mice with combined heterozygous mutations in Pdx-1, Hnf-1α, and Hnf-3β. Proc Natl Acad Sci U S A 99:3818–3823PubMedCrossRef
31.
Nishikawa T, Sasahara T, Kiritoshi S et al (2003) Evaluation of urinary 8-hydroxydeoxy-guanosine as a novel biomarker of macrovascular complications in type 2 diabetes. Diabetes Care 26:1507–1512PubMedCrossRef
32.
Kaneto H, Kajimoto Y, Miyagawa J et al (1999) Beneficial effects of antioxidants in diabetes. Possible protection of pancreatic beta cells against glucose toxicity. Diabetes 48:2398–2406PubMedCrossRef
33.
Eiki J, Nagata Y, Futamura M et al (2011) Pharmacokinetic and pharmacodynamic properties of the glucokinase activator MK-0941 in rodent models of type 2 diabetes and healthy dogs. Mol Pharmacol 80:1156–1165PubMedCrossRef
34.
Kendall DM, Cuddihy RM, Bergenstal RM (2009) Clinical application of incretin-based therapy: therapeutic potential, patient selection and clinical use. Am J Med 122:S37–S50PubMedCrossRef
35.
Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110PubMedCrossRef
Metadata
Title
Control of beta cell function and proliferation in mice stimulated by small-molecule glucokinase activator under various conditions
Authors
A. Nakamura
Y. Togashi
K. Orime
K. Sato
J. Shirakawa
M. Ohsugi
N. Kubota
T. Kadowaki
Y. Terauchi
Publication date
01-06-2012
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 6/2012
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-012-2521-5

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