Improved glucose regulation in type 2 diabetic patients with DPP-4 inhibitors: focus on alpha and beta cell function and lipid metabolism

Abstract

Inhibition of dipeptidyl peptidase-4 (DPP-4) is an established glucose-lowering strategy for the management of type 2 diabetes mellitus. DPP-4 inhibitors reduce both fasting and postprandial plasma glucose levels, resulting in reduced HbA 1c with low risk for hypoglycaemia and weight gain. They act primarily by preventing inactivation of the incretin hormones glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, thereby prolonging the enhanced endogenous levels of these hormones after meal ingestion. This in turn causes islet and extrapancreatic effects, including increased glucose sensing in islet alpha and beta cells. These effects result in increased insulin secretion and decreased glucagon secretion being more effective in hyperglycaemic states and reduced insulin secretion and increased glucagon secretion being more effective during hypoglycaemia. Other secondary pharmacological actions of DPP-4 inhibitors include mobilisation and burning of fat during meals, decrease in fat extraction from the gut, reduction of fasting lipolysis and liver fat and increase in LDL particle size. These actions contribute to the clinical effects of DPP-4 inhibition, and the reduced demand for insulin could also lead to a durability benefit. This review summarises the current knowledge of the secondary pharmacological actions of DPP-4 inhibitors that lead to improved glucose regulation in patients with type 2 diabetes, focusing on alpha and beta cell function and lipid metabolism.

Stromal Derived Factor 1 alpha (SDF-1a) in a Dual Therapy with the DPP-4 Inhibitor 1 Vildagliptin does not Enhance Beta Cell Function but Improves Glucose Clearance after Oral Glucose in Streptozotocin Diabetic Mice

“…The enhancement of beta cell function by vildagliptin is well established [11] and shown here also when beta cell mass is severely depleted. Habener and colleagues have demonstrated that beta cell damage or stress up-regulates islet SDF-1 mRNA expression and secretion of SDF-1 from beta cells (8).…”

“…This would suggest that actions of vildagliptin are dependent on augmentation of extra islet effects [11], which, however, requires further mechanistic studies.…”

DPP-4 inhibitor treatment: β-cell response but not HbA_1c reduction is dependent on the duration of diabetes

“…Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of oral antidiabetic drugs for treatment of T2DM 3. Physiologically, DPP-4 inhibitors increase the availability of active glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in plasma, which in turn, improves the sensitivity of pancreatic β- and α-cells to glucose 3,4…”

C-Peptide Levels Predict the Effectiveness of Dipeptidyl Peptidase-4 Inhibitor Therapy

“…GLP-1 regulates blood glucose mainly by acting on pancreatic islet cells via mechanisms that include the stimulation of insulin secretion [1]. GLP-1 preserves beta cell by inhibiting apoptosis, although increase in beta cell mass has not been observed with any GLP-1 based therapy in man, even in rodents [4]. GLP-1 also inhibits glucagon secretion and suppresses gastric emptying, gastric secretion, and exocrine pancreatic secretion.…”