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

Nakamura, Akinobu; Terauchi, Yasuo; Ohyama, Seiichi; Kubota, Junko; Shimazaki, Hiroko; Nambu, Tadahiro; Takamoto, Iseki; Kubota, Naoto; Eiki, Jun-ichi; Yoshioka, Narihito; Kadowaki, Takashi; Koike, Takao

doi:10.1210/en.2008-1183

Cited by 58 publications

(78 citation statements)

References 43 publications

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“…In a study of beta cell function, it was reported that a GKA stimulated insulin secretion in a Ca 2+ -dependent manner in rodent islets and MIN6 cells [13], and we and others have reported that GKAs promoted beta cell proliferation and increased production of IRS2 [11,14], which is critically required for beta cell growth and survival [3,[15][16][17]. However, the exact mechanisms by which GKAs stimulate beta cell function and proliferation are largely unknown.…”

Section: Introductionmentioning

confidence: 97%

“…Since the report by Grimsby et al in 2003 [5], several glucokinase activators (GKAs) have been developed, and these have been shown to lower blood glucose in several animal models of type 2 diabetes [5][6][7][8][9][10][11][12]. In a study of beta cell function, it was reported that a GKA stimulated insulin secretion in a Ca 2+ -dependent manner in rodent islets and MIN6 cells [13], and we and others have reported that GKAs promoted beta cell proliferation and increased production of IRS2 [11,14], which is critically required for beta cell growth and survival [3,[15][16][17].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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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.

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Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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“…There is considerable interest in the development of GKAs as potential therapies for type 2 diabetes because glucokinase activity plays an essential role in glucose-sensing by beta cells and glucose metabolism by hepatocytes [2][3][4][5]. The importance of this enzyme in glucose homeostasis was first widely recognised with the discovery of clinical syndromes resulting from loss-of-function and gain-of-function glucokinase gene mutations [6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…Various lines of indirect evidence suggest that pharmacological interventions that augment glucokinase activity may favour mechanisms that slow or prevent beta cell loss [22,23] or promote beta cell proliferation in vivo [3,[24][25][26][27]. The present experiments were undertaken to address an ongoing need for data to test and shed further light on this hypothesis.…”

Section: Introductionmentioning

confidence: 99%

Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat

Futamura¹,

Yao

et al. 2012

Diabetologia

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Aims/hypothesis Glucokinase activators (GKAs) are currently being developed as new therapies for type 2 diabetes and have been shown to enhance beta cell survival and proliferation in vitro. Here, we report the effects of chronic GKA treatment on the development of hyperglycaemia and beta cell loss in the male Zucker diabetic fatty (ZDF) rat, a model of type 2 diabetes with severe obesity. Methods Cell protection by GKA was studied in MIN6 and INS-1 cells exposed to hydrogen peroxide. Glucose homeostasis and beta cell mass were evaluated in ZDF rats dosed for 41 days with Cpd-C (a GKA) or glipizide (a sulfonylurea) as food admixtures at doses of approximately 3 and 10 mg kg −1 day −1 . Results Incubation of MIN6 and INS-1 832/3 insulinoma cell cultures with GKA significantly reduced cell death and impairment of intracellular NADH production caused by exposure to hydrogen peroxide. Progression from prediabetes (normoglycaemia and hyperinsulinaemia) to overt diabetes (hyperglycaemia and hypoinsulinaemia) was significantly delayed in male ZDF rats by in-feed treatment with Cpd-C, but not glipizide. Glucose tolerance, tested in the fifth week of treatment, was also significantly improved by Cpd-C, as was pancreatic insulin content and beta cell area. In a limited immunohistochemical analysis, Cpd-C modestly and significantly enhanced the rate of beta cell proliferation, but not rates of beta cell apoptosis relative to untreated ZDF rats. Conclusions/interpretation These findings suggest that chronic activation of glucokinase preserves beta cell mass and delays disease in the ZDF rat, a model of insulin resistance and progressive beta cell failure.

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“…In ␤-cells, GK is the glucose sensor that controls the rate of glycolysis, hence insulin secretion, within the physiological range of glucose concentrations (28). Given the pivotal role of GK in glucose homeostasis, small-molecule GK activators (GKAs) were developed that augment GSIS and hepatic glucose utilization (17), thereby improving glucose homeostasis in rodent and human type 2 diabetes (T2D) (3,7,11,13,29,31,33,48). However, although some GKAs may improve ␤-cell survival and GSIS under glucotoxic conditions, the loss of GKA effectiveness during long-term treatment of T2D (22, 47) raises questions about their possible toxicity, e.g., through sustained ␤-cell stimulation.…”

mentioning

confidence: 99%

Glucokinase activation is beneficial or toxic to cultured rat pancreatic islets depending on the prevailing glucose concentration

Roma

Duprez

Jonas³

2015

American Journal of Physiology-Endocrinology and Metabolism

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Roma LP, Duprez J, Jonas JC. Glucokinase activation is beneficial or toxic to cultured rat pancreatic islets depending on the prevailing glucose concentration. Am J Physiol Endocrinol Metab 309: E632-E639, 2015. First published August 11, 2015; doi:10.1152/ajpendo.00154.2015.-In rat pancreatic islets, ␤-cell gene expression, survival, and subsequent acute glucose stimulation of insulin secretion (GSIS) are optimally preserved by prolonged culture at 10 mM glucose (G10) and markedly altered by culture at G5 or G30. Here, we tested whether pharmacological glucokinase (GK) activation prevents these alterations during culture or improves GSIS after culture. Rat pancreatic islets were cultured 1-7 days at G5, G10, or G30 with or without 3 M of the GK activator Ro 28-0450 (Ro). After culture, ␤-cell apoptosis and islet gene mRNA levels were measured, and the acute glucose-induced increase in NAD(P)H autofluorescence, intracellular calcium concentration, and insulin secretion were tested in the absence or presence of Ro. Prolonged culture of rat islets at G5 or G30 instead of G10 triggered ␤-cell apoptosis and reduced their glucose responsiveness. Addition of Ro during culture differently affected ␤-cell survival and glucose responsiveness depending on the glucose concentration during culture: it was beneficial to ␤-cell survival and function at G5, detrimental at G10, and ineffective at G30. In contrast, acute GK activation with Ro increased the glucose sensitivity of islets cultured at G10 but failed at restoring ␤-cell glucose responsiveness after culture at G5 or G30. We conclude that pharmacological GK activation prevents the alteration of ␤-cell survival and function by long-term culture at G5 but mimics glucotoxicity when added to G10. The complex effects of glucose on the ␤-cell phenotype result from changes in glucose metabolism and not from an effect of glucose per se. apoptosis; glucotoxicity; insulin secretion; pancreatic ␤-cell GLUCOSE STIMULATION OF INSULIN SECRETION (GSIS) by endocrine pancreatic ␤-cells depends on the acceleration of glucose metabolism through glycolysis and the TCA cycle, with enhanced production of metabolic coupling factors (25,39,41). Besides these rapid effects, glucose exerts complex long-term effects on the ␤-cell phenotype (2,10,16,18,27,45). During long-term culture of rodent islets, ␤-cell gene expression, survival, and glucose responsiveness are optimally preserved in the presence of 10 mM glucose (G10), whereas they are markedly altered by culture at either nonstimulating (G5) or very high (G30) glucose concentrations. In other words, culture at G10 vs. G5 is beneficial, whereas culture at G30 vs. G10 is detrimental to ␤-cell gene expression, survival, and glucose responsiveness. The beneficial effect of culture at G10 vs. G5 is usually attributed to the stimulation of energetic metabolism. In contrast, the deleterious effects of culture at G30 vs. G10, which we later refer to as glucotoxicity, could result from the further increase in metabolism with increased production o...

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

Cited by 58 publications

References 43 publications

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

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

Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat

Glucokinase activation is beneficial or toxic to cultured rat pancreatic islets depending on the prevailing glucose concentration

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