Chlorpromazine attenuates pancreatic β-cell function and mass through IRS2 degradation, while exercise partially reverses the attenuation

Abstract

We investigated the effect and mechanism of exercise and chlorpromazine (CPZ), a conventional anti-psychotic drug, on β-cell function and mass in 90% pancreatectomized (Px) male rats. The diabetic Px rats were divided into two groups, one of which was provided with exercise whereas the other was not. Both groups were subdivided into the three groups and administered with 0, 5 or 50 mg CPZ per kg body weight (control, low dosage of chlorpromazine (LCPZ), high dosage chlorpromazine (HCPZ)) for 8 weeks. LCPZ did not modulate glucose homeostasis. HCPZ impaired acute phase and second phase insulin secretion during hyperglycemic clamp. Apoptosis of pancreatic β-cells increased in the HCPZ group, and proliferation decreased, contributing to reduced β-cell mass. Exercise partially improved glucose-stimulated insulin secretion and β-cell mass in HCPZ-treated rats. Interestingly, insulin receptor substrate-2 (IRS2) protein levels in islets decreased by increased degradation in the HCPZ group, whereas exercise partially reversed this trend by induction of IRS2 expression. In isolated islets, 50 μM CPZ decreased IRS2 expression by promoting ubiquitin-proteasome degradation, which had been prevented by proteasome inhibitors. Furthermore, similar to the effect of HCPZ treatment, a high dosage of rottlerin, a protein kinase C-δ inhibitor, reduced IRS2 levels in the islets. In conclusion, exercise partially recovered the diabetic symptoms exacerbated by HCPZ through enhancement of β-cell function and mass in diabetic rats. This modulation by HCPZ and exercise was associated with increasing intracellular IRS2 protein levels in independent pathways.