Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice

Abstract

Adipose tissue inflammation and reduced pancreatic β-cell function are key issues in the development of cardiovascular disease and progressive metabolic dysfunction in type 2 diabetes mellitus. The aim of this study was to determine the effect of the DPP IV inhibitor sitagliptin on adipose tissue and pancreatic islet inflammation in a diet-induced obesity model. C57Bl/6J mice were placed on a high-fat (60% kcal fat) diet for 12 wk, with or without sitagliptin (4 g/kg) as a food admix. Sitagliptin significantly reduced fasting blood glucose by 21% as well as insulin by ∼25%. Sitagliptin treatment reduced body weight without changes in overall body mass index or in the epididymal and retroperitoneal fat mass. However, sitagliptin treatment led to triple the number of small adipocytes despite reducing the number of the very large adipocytes. Sitagliptin significantly reduced inflammation in the adipose tissue and pancreatic islet. Macrophage infiltration in adipose tissue evaluated by immunostaining for Mac2 was reduced by sitagliptin ( P < 0.01), as was the percentage of CD11b+/F4/80+ cells in the stromal vascular fraction ( P < 0.02). Sitagliptin also reduced adipocyte mRNA expression of inflammatory genes, including IL-6, TNFα, IL-12(p35), and IL-12(p40), 2.5- to fivefold as well as 12-lipoxygenase protein expression. Pancreatic islets were isolated from animals after treatments. Sitagliptin significantly reduced mRNA expression of the following inflammatory cytokines: MCP-1 (3.3-fold), IL-6 (2-fold), IL-12(p40) (2.2-fold), IL-12(p35) (5-fold, P < 0.01), and IP-10 (2-fold). Collectively, the results indicate that sitagliptin has anti-inflammatory effects in adipose tissue and in pancreatic islets that accompany the insulinotropic effect.

Pleiotropic Mechanisms for the Glucose-Lowering Action of DPP-4 Inhibitors

“…An additional mechanism may be that hyperglycemia may cause a secretion of interleukin-1b from b-cells (34). A recent study by Dobrian et al reported that sitagliptin reduces expression of inflammatory cytokines in islets from dietary-induced obesity in mice (35). We also found recently that chronic treatment of high-fat-fed mice with vildagliptin prevented fat-induced pancreatic inflammation and peri-insulitis (36).…”

Cardiovascular effects of the DPP-4 inhibitors

“…Limited animal studies have also suggested that DPP-4 inhibition may reduce the number of inflammatory cells within visceral adipose tissue and halt the progression of atherosclerosis via immunomodulation. [20][21][22] …”

The DPP4 inhibitor linagliptin delays the onset of diabetes and preserves β-cell mass in non-obese diabetic mice

“…Studies of GLP1 analogues and DPP4 inhibitors on b-cell mass have demonstrated positive effects, either by direct stimulation of b-cell replication or by inhibition of apoptosis and activation of anti-apoptotic pathways (Xu et al 1999, Stoffers et al 2000, Drucker 2003, Cho et al 2011, Dobrian et al 2011. Thus, besides their use for the treatment of T2D, GLP1 analogues and DPP4 inhibitors may also possess important cytoprotective and regenerative properties.…”