Chronic Inhibition of Dipeptidyl Peptidase-4 With a Sitagliptin Analog Preserves Pancreatic β-Cell Mass and Function in a Rodent Model of Type 2 Diabetes

Abstract

Inhibitors of dipeptidyl peptidase-4 (DPP-4), a key regulator of the actions of incretin hormones, exert antihyperglycemic effects in type 2 diabetic patients. A major unanswered question concerns the potential ability of DPP-4 inhibition to have beneficial disease-modifying effects, specifically to attenuate loss of pancreatic ␤-cell mass and function. Here, we investigated the effects of a potent and selective DPP-4 inhibitor, an analog of sitagliptin (des-fluoro-sitagliptin), on glycemic control and pancreatic ␤-cell mass and function in a mouse model with defects in insulin sensitivity and secretion, namely high-fat diet (HFD) streptozotocin (STZ)-induced diabetic mice. Significant and dose-dependent correction of postprandial and fasting hyperglycemia, HbA 1c , and plasma triglyceride and free fatty acid levels were observed in HFD/STZ mice following 2-3 months of chronic therapy. Treatment with des-fluoro-sitagliptin dose dependently increased the number of insulin-positive ␤-cells in islets, leading to the normalization of ␤-cell mass and ␤-cell-to-␣-cell ratio. In addition, treatment of mice with des-fluoro-sitagliptin, but not glipizide, significantly increased islet insulin content and improved glucose-stimulated insulin secretion in isolated islets. These findings suggest that DPP-4 inhibitors may offer long-lasting efficacy in the treatment of type 2 diabetes by modifying the courses of the disease. Diabetes 55: [1695][1696][1697][1698][1699][1700][1701][1702][1703][1704] 2006 I n patients with type 2 diabetes, several key pathogenic abnormalities contribute to increased blood glucose levels, including abnormal insulin secretion caused by impaired ␤-cell function and insulin resistance in target tissues (1). Insulin resistance appears to be an important early lesion that is accompanied by compensatory increases in pancreatic ␤-cell insulin release (2). In patients destined to develop type 2 diabetes, however, ␤-cell function deteriorates progressively and Ͼ50% of ␤-cell function is typically lost by the time hyperglycemia is diagnosed (2-5). This loss of ␤-cell function and/or mass leads to rising blood glucose levels and to frank diabetes.The incretin hormone glucagon-like peptide-1 (GLP-1) plays a key role in the regulation of insulin secretion and glucose homeostasis. Administration of GLP-1 and its analogs or the GLP-1 mimetic exendin-4 has shown remarkable glucose-lowering efficacy in diabetic subjects (6 -8). Importantly, these agents have demonstrated beneficial effects on increasing islet neogenesis and differentiation as well as modulating ␤-cell mass in part by reducing apoptosis in animal models of diabetes (9 -12). These findings have engendered significant interest in the potential of GLP-1-based therapeutics to enhance ␤-cell function and thereby modify the course of disease in subjects with type 2 diabetes.Orally administered dipeptidyl peptidase-4 (DPP-4; or CD26) inhibitors have emerged as a new class of antidiabetic agents owing to their ability to extend the biological effects o...

Is Pancreatic Diabetes (Type 3c Diabetes) Underdiagnosed and Misdiagnosed?

“…It is currently unclear whether long-term use of such agents will prevent or slow down the continuous decline in ␤-cell function and mass associated with progression of type 2 diabetes. Animal experiments show an increase in ␤-cell mass within weeks of treatment with dipeptidyl peptidase IV inhibitors and enhanced ␤-cell preservation (38).…”

Beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and a high-fat diet

“…Previous studies have shown that low-dose STZ injection leads to the partial destruction of pancreatic beta cells and a high-fat diet (HFD) induces insulin resistance in rodents [21][22][23]. The degree of beta cell destruction and insulin resistance can be adjusted by dosage, duration and condition of STZ injection and HFD feeding [11,24].…”

“…The degree of beta cell destruction and insulin resistance can be adjusted by dosage, duration and condition of STZ injection and HFD feeding [11,24]. The effects of various glucose-lowering drugs (sulfonylurea, metformin, thiazolidinedione etc) have been examined in mice treated with low-dose STZ and HFD as a model of type 2 diabetes [22,23]. In the present study, we too generated a mouse model mimicking human type 2 diabetes using low-dose STZ and HFD to examine the effect of leptin infusion.…”

Treatment of autoimmune diabetes in NOD mice by Toll-like receptor 2 tolerance in conjunction with dipeptidyl peptidase 4 inhibition

“…We also studied possible changes in alpha cells that could be affected by DPP4 inhibitors [7] and could influence glucose profile of diabetic mice. Contrary to the widespread conception that beta cells are selectively destroyed in type 1 diabetes, alpha cell mass was significantly reduced in untreated diabetic NOD mice compared with prediabetic NOD mice (ESM Fig.…”

“…However, the supply of islets for transplantation is limited, precluding widespread application of islet transplantation for the treatment of type 1 diabetes. Strategies with potential beneficial effects on beta cell mass include glucagon-like peptide 1 (GLP-1) agonists [5,6] or inhibitors of dipeptidyl peptidase 4 (DPP4) [7,8], which degrades GLP-1 [9]. We have reported that a DPP4 inhibitor ameliorated diabetes induced by streptozotocin (STZ), and that this was attributable an increased beta cell mass [10].…”