Glucokinase activator PSN-GK1 displays enhanced antihyperglycaemic and insulinotropic actions

Fyfe, Matthew C. T.; White, John R.; Taylor, Amanda; Chatfield, R.; Wargent, Edward T.; Printz, Richard L.; Sulpice, Thierry; McCormack, James G.; Procter, Martin J.; Reynet, Christine; Widdowson, Peter; Wong-Kai-In, Philippe

doi:10.1007/s00125-007-0646-8

Cited by 88 publications

(70 citation statements)

References 47 publications

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“…It is also possible that Gck expression level might have an effect on the inhibition of upregulation of Irs2 and Pdx1 induced by 5.6 mmol/l glucose plus GKA. Second, with regard to the experiment with the db/db mice, GKA compounds act to reduce glucose levels in the db/db mouse model, as shown with MK-0941 and other agents [8,33]. The background of the db/db mice or the difference in compounds could influence the effect of GKAs.…”

Section: P22 Phox Expression (Au)mentioning

confidence: 99%

“…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: P22 Phox Expression (Au)mentioning

confidence: 99%

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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“…GKAs have demonstrated prominent antihyperglycaemic activity in animal models [12][13][14][15] and in clinical trials [16,17]. It is, however, currently uncertain whether long-term improvements in glycaemic control can be achieved with these agents.…”

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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“…Using this method of fatty acyl-CoA esters results in low potential antidiabetic agents. Another method for screening is measuring biological effects: 2-deoxy-D-[ 3 H]glucose uptake by primary rat hepatocytes (Efanov et al, 2005;Fyfe et al, 2007) (Brocklehurst et al, 2004;Futamura et al, 2006)]. Test compounds shift glucokinase in its active conformation, which facilitates both binding to the allosteric site located in the hinge 204 VERSPOHL region of the enzyme (Efanov et al, 2005) and phosphorylation of the substrate glucose .…”

Section: B Glucokinase Activatorsmentioning

confidence: 99%

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

Verspohl

2012

Pharmacological Reviews

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Glucokinase activator PSN-GK1 displays enhanced antihyperglycaemic and insulinotropic actions

Cited by 88 publications

References 47 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

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

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