DPP4 inhibitor vildagliptin preserves β-cell mass through amelioration of endoplasmic reticulum stress in C/EBPB transgenic mice

Abstract

The development of type 2 diabetes is accompanied by a progressive decline in b-cell mass and function. Vildagliptin, a dipeptidyl peptidase 4 inhibitor, is representative of a new class of antidiabetic agents that act through increasing the expression of glucagon-like peptide-1. The protective effect of this agent on b cells was studied in diabetic mice. Diabetic pancreatic b cell-specific C/EBPB transgenic (TG) mice exhibit decreased b-cell mass associated with increased apoptosis, decreased proliferation, and aggravated endoplasmic reticulum (ER) stress. Vildagliptin was orally administered to the TG mice for a period of 24 weeks, and the protective effects of this agent on b cells were examined, along with the potential molecular mechanism of protection. Vildagliptin ameliorated hyperglycemia in TG mice by increasing the serum concentration of insulin and decreasing the serum concentration of glucagon. This agent also markedly increased b-cell mass, improved aggravated ER stress, and restored attenuated insulin/IGF1 signaling. A decrease in pancreatic and duodenal homeobox 1 expression was also observed in b cells isolated from our mouse model, but this was also restored by vildagliptin treatment. The expression of C/EBPB protein, but not mRNA, was unexpectedly downregulated in vildagliptin-treated TG mice and in exenatide-treated MIN6 cells. Activation of the GLP1 pathway induced proteasome-dependent C/EBPB degradation in b cells as the proteasome inhibitor MG132 restored the downregulation of C/EBPB protein by exenatide. Vildagliptin elicits protective effects on pancreatic b cells, possibly through C/EBPB degradation, and has potential for preventing the progression of type 2 diabetes.

Vildagliptin Stimulates Endothelial Cell Network Formation and Ischemia-induced Revascularization via an Endothelial Nitric-oxide Synthase-dependent Mechanism

“…Previous reports also indicate that inhibition of DPP-4 directly regulates the endothelial cell growth and migration induced by inflammatory cytokines (32). In the present study, vildagliptin increased circulating GLP-1 levels 1.8-fold in WT mice, in agreement with previous reports (27,33). In HUVECs, GLP-1 enhanced AkteNOS signaling and promoted the formation of capillary-like structures to a greater extent than vildagliptin, but the ability of vildagliptin to mediate these effects with no GLP-1 in HUVECs suggests that the vasculo-protective effects of vildagliptin occur at least partially through a mechanism that is independent of GLP-1.…”

“…We therefore assessed plasma levels of active GLP-1, SDF-1␣, and adiponectin in WT mice treated with or without vildagliptin for 7 and 21 days after induced hind limb ischemia. Vildagliptin treatment did not affect blood glucose levels on days 7 and 21 following surgery in non-diabetic WT mice, as described in previous reports (27). There were significant increases in active GLP-1 and adiponectin, but not SDF-1␣ in the plasma of WT mice following treatment with vildagliptin compared with treatment with vehicle control on postoperative days 7 and 21 (Table 1).…”

Dipeptidyl peptidase-4 inhibitor sitagliptin improves pancreatic β-cell function in hypertensive diabetic patients treated with angiotensin receptor blockers

“…Shimizu et al developed pancreatic β-cell-specific C/EBPB transgenic mice and showed that GLP-1, the circulating level of which was increased by DPP-4 inhibitor through inhibiting degradation, induced C/ EBPB degradation, leading to the attenuation of endoplasmic reticulum stress in β-cells. 20 However, an additive effect of ARBs and DPP-4 inhibitors on β-cell function has not been fully investigated. Wang et al demonstrated that combination treatment of GLP-1 and the ARB candesartan exerted an additive anti-apoptotic effect in isolated mouse pancreatic islets.…”

Hope and fear for new classes of type 2 diabetes drugs: is there preclinical evidence that incretin-based therapies alter pancreatic morphology?

“…In streptozotocin (STZ)-treated diabetic mice and other models of b-cell insufficiency, early administration of either a GLP1R agonist or a DPP4 inhibitor is able to preserve a greater b-cell mass. (vildagliptin, des-fluoro-sitagliptin and NVP-DPP728) for 2-5 months in young chow-fed C57BL/6 mice did not increase b-cell mass (Reimer et al 2002, Rankin et al 2012, Shimizu et al 2012. Only one of these studies reported a slight increase in b-cell proliferation with des-fluoro-sitagliptin treatment, but it was only a fraction of the increase observed with high-fat feeding alone (Rankin et al 2012).…”

“…In a mouse model that expresses hIAPP at levels roughly equal to those of the endogenous mouse protein, sitagliptin treatment for 1 year was able to maintain b-cell mass at levels that were very similar to those in the non-transgenic control mice (Aston-Mourney et al 2013). In other genetically modified animals, such as the Irs2 knockout and Cebpb transgenic mice, vildagliptin treatment (0.3 mg/ml in drinking water) for 20 weeks in both these strains was able to increase b-cell mass to levels approaching those observed in normal mice, and this was associated with either a reduction in apoptosis or an increase in b-cell proliferation (Sato et al 2012, Shimizu et al 2012. In Gck-deficient mice, sitagliptin treatment for 20 weeks was able to maintain almost normal b-cell mass, which was accompanied by a reduction in the rates of b-cell apoptosis and a small increase in proliferation (Shirakawa et al 2011a).…”