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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 β-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 β-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^sub 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 β-cells in islets, leading to the normalization of β-cell mass and β-cell-to-α-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 55:1695-1704, 2006
In patients with type 2 diabetes, several key pathogenic abnormalities contribute to increased blood glucose levels, including abnormal insulin secretion caused by impaired β-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 β-cell insulin release (2). In patients destined to develop type 2 diabetes, however, β-cell function deteriorates progressively and >50% of β-cell function is typically lost by the time hyperglycemic is diagnosed (2-5). This loss of β-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 β-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...