Effects of glucokinase activators GKA50 and LY2121260 on proliferation and apoptosis in pancreatic INS-1 beta cells

Wei, Ping; Shi, Michael; Barnum, Sandra J.; Cho, H.; Carlson, Thomas J.; Fraser, James D.

doi:10.1007/s00125-009-1446-0

Cited by 41 publications

(36 citation statements)

References 34 publications

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“…Such lack of effect contrasts with recent reports showing that two GKAs (GKA50 and YH-GKA) that are chemically different from Ro acutely reversed the glucotoxic alterations of ␤-cell function (35,46). Although we tested the effect of Ro only in this protocol, other GKAs were found ineffective under similar conditions, indicating that the effect of GKA50 and YH-GKA unlikely resulted from GK activation (46).…”

Section: E636contrasting

confidence: 87%

“…If GKAs undoubtedly trigger liver steatosis (4,6,34), their potential toxicity to ␤-cells remains unclear (4,35,38,43,44,46). Thus, although some GKAs proved beneficial to ␤-cell survival and GSIS under glucotoxic conditions and in islets from T2D patients (8,35,46), their secondary failure during long-term treatment (22,31,47) reopened the question of their toxicity to ␤-cells. This possible caveat of GKAs has been previously considered nonrelevant on the ground that ␤-cell stimulation is reduced following the GKA-mediated reduction in glycemia (12).…”

Section: E636mentioning

confidence: 99%

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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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Section: E636contrasting

confidence: 87%

Section: E636mentioning

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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“…Although chronic administration of GKA did not change b-cell mass in the above study, sustained exposure of INS1 cells to GKA promoted b-cell replication and, in addition, one compound, GKA50, reduced apoptosis (Nakamura et al 2009, Wei et al 2009). Further evidence to support the lack of detrimental effect on b-cell mass comes from demonstration that a short (3 days) treatment in vivo, when glucose concentration was high, increased the rate of b-cell proliferation (Nakamura et al 2009).…”

Section: Discussionmentioning

confidence: 55%

Upregulation of β-cell genes and improved function in rodent islets following chronic glucokinase activation

Gill¹,

Brocklehurst²,

Brown³

et al. 2011

Journal of Molecular Endocrinology

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Glucokinase (GK) plays a critical role in controlling blood glucose; GK activators have been shown to stimulate insulin secretion acutely both in vitro and in vivo. Sustained stimulation of insulin secretion could potentially lead to b-cell exhaustion; this study examines the effect of chronic GK activation on b-cells. Gene expression and insulin secretion were measured in rodent islets treated in vitro with GKA71 for 72 h. Key b-cell gene expression was measured in rat, mouse and global GK heterozygous knockout mouse islets (gk del/wt ). Insulin secretion, after chronic exposure to GKA71, was measured in perifused rat islets. GKA71 acutely increased insulin secretion in rat islets in a glucose-dependent manner. Chronic culture of mouse islets with GKA71 in 5 mmol/l glucose significantly increased the expression of insulin, IAPP, GLUT2, PDX1 and PC1 and decreased the expression of C/EBPb compared with 5 mmol/l glucose alone. Similar increases were shown for insulin, GLUT2, IAPP and PC1 in chronically treated rat islets. Insulin mRNA was also increased in GKA71-treated gk del/wt islets. No changes in GK mRNA were observed. Glucose-stimulated insulin secretion was improved in perifused rat islets following chronic treatment with GKA71. This was associated with a greater insulin content and GK protein level. Chronic treatment of rodent islets with GKA71 showed an upregulation of key b-cell genes including insulin and an increase in insulin content and GK protein compared with glucose alone.

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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: 98%

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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Effects of glucokinase activators GKA50 and LY2121260 on proliferation and apoptosis in pancreatic INS-1 beta cells

Cited by 41 publications

References 34 publications

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

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

Upregulation of β-cell genes and improved function in rodent islets following chronic glucokinase activation

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

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