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 beta-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 beta-cells increased in the HCPZ group, and proliferation decreased, contributing to reduced beta-cell mass. Exercise partially improved glucose-stimulated insulin secretion and beta-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 microM 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-delta inhibitor, reduced IRS2 levels in the islets. In conclusion, exercise partially recovered the diabetic symptoms exacerbated by HCPZ through enhancement of beta-cell function and mass in diabetic rats. This modulation by HCPZ and exercise was associated with increasing intracellular IRS2 protein levels in independent pathways.

The benefits of physical exercise for the health of the pancreatic β‐cell: a review of the evidence

“…The effect of exercise on β‐cell mass has not been examined in humans. Studies have, however, directly explored the effect of exercise training on β‐cell mass in animal models, primarily murine and rat models of diabetes (Choi et al., 2006, Choi, Jang, & Park, 2005, Coskun, Ocakci, Bayraktaroglu, & Kanter, 2004, Huang et al., 2011, Kiraly et al., 2007, Kiraly et al., 2008, Laker et al., 2011, Li et al., 2013, Park et al., 2008, Park et al., 2008, Park, Hong, Lee, & Sung, 2007, Park, Kim, & Kang, 2013, Pold et al., 2005). Diabetes was induced in these models either chemically (streptozotocin or chlorpromazine) or via surgical pancreatectomy.…”

“…Experimental studies have shown that there are three main mechanisms leading to increased β‐cell mass (Choi et al., 2005, Choi et al., 2006, Coskun et al., 2004, Kiraly et al., 2007, Kiraly et al., 2008, Laker et al., 2011, Park et al., 2007, Park et al., 2008, Park et al., 2008, Park et al., 2013, Paula et al., 2015, Pold et al., 2005). These can be divided into increased β‐cell proliferation, reduced β‐cell death (apoptosis), or increased β‐cell viability.…”

“…Studies demonstrate an increase in β‐cell proliferation following an exercise programme (Calegari et al., 2012, Choi et al., 2005, Choi et al., 2006, Kiraly et al., 2007, Kiraly et al., 2008, Park et al., 2007, Park et al., 2008, Park et al., 2008, Paula et al., 2015). These studies were all conducted in rats, and largely by four research groups.…”

“…Proliferation was measured by bromodeoxyuridine (BrdU) incorporation and was almost twice that of non‐exercised rats treated under the same conditions following both exercise interventions (Kiraly et al., 2007, Kiraly et al., 2008). The second group utilised the Sprague–Dawley rat (Choi et al., 2005, Choi et al., 2006, Park et al., 2007, Park et al., 2008, Park et al., 2008). These animals were rendered diabetic either through 90% pancreatectomy or chlorpromazine treatment and followed an exercise programme of 30 min running for up to 4 days per week.…”

“…Within these categories, we have tried to clarify the mechanism through which these effects manifest (Table 1). β‐Cell mass can be influenced through effects on β‐cell proliferation (Calegari et al., 2012, Kiraly et al., 2007, Kiraly et al., 2008, Li et al., 2013), apoptosis or increased viability (Calegari et al., 2012, Choi, Jang, Hong, Jun, & Park, 2006, Park, Hong, Lee, Sung, & Kim, 2008, Paula et al., 2015, Paula et al., 2018). β‐Cell function can be influenced through effects on glucose sensing, insulin content and insulin secretion.…”