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

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.

Glucose Induces Mouse β-Cell Proliferation via IRS2, MTOR, and Cyclin D2 but Not the Insulin Receptor

“…GK activity is required for IRS2 expression and β-cell proliferation in response to high-fat feeding, and restoring IRS2 expression corrects β-cell mass and proliferation (11). GK activators were considered a potential therapeutic approach to increase β-cell mass and function, but disappointingly, long-term GK activation does not increase mouse β-cell mass or proliferation (49,74,75). These studies suggest that if physiological pathways regulating β-cell proliferation in response to hyperglycemia are to be useful therapeutically, pathways must be targeted further downstream.…”

“…Cell cycle regulation in β-cells resembles that of other quiescent cell types, with the transition from Gap-1 (G1) to DNA synthesis (S) phase a critical point of regulation (44,45). Glucose promotes expression of cyclin D2 (6,46–49), a key regulator of mouse β-cell proliferation (50,51). Although cyclin D2 was believed to not be expressed in human β-cells, this locus has recently been genetically linked to human insulin secretory capacity (52,53).…”

Glucokinase Activation Ameliorates ER Stress–Induced Apoptosis in Pancreatic β-Cells

“…Glucokinase activators (GKAs) have been shown to reduce blood glucose levels in several diabetic animal models and type 2 diabetic patients (10,11,17–19). GKAs promote β-cell proliferation, which is driven by the increased expression of IRS-2 and the activation of its downstream signaling pathway (11,20,21).…”

Making β Cells from Adult Cells Within the Pancreas

“…The role of GCK in the regulation of β-cell mass has been further studied in mice, in which the loss of one GCK allele led to the loss of a compensatory increase in β-cell replication in response to a high-fat diet [45]; the proliferation could be restored with a glucokinase activator (GKA) [46]. Furthermore, this GKA augmented β-cell proliferation in wild-type mice, an effect that was blunted in Irs2 −/− mice and by oxidative stress [47]. GKAs have a broader impact on glucose metabolism not only by stimulating insulin secretion but also by enhancing hepatic glucose uptake [48].…”