Glucagon dynamics during hypoglycaemia and food‐re‐challenge following treatment with vildagliptin in insulin‐treated patients with type 2 diabetes

Abstract

Vildagliptin action to block GLP-1 and GIP inactivation by DPP-4 improves glucagon dynamics during hypoglycaemia, hyperglycaemia and food re-challenge.

Addition of sitagliptin or metformin to insulin monotherapy improves blood glucose control <i>via</i> different effects on insulin and glucagon secretion in hyperglycemic Japanese patients with type 2 diabetes

“…Recently, an observational study by Nakagami et al [29] and a randomized crossover study by Farngren et al [30] showed DPP-4 inhibitors to reduce glucagon secretion after meal challenge in insulin-treated patients with or without oral antidiabetic drugs. The latter study also showed that vildagliptin, another DPP-4 inhibitor, did not compromise glucagon secretion during hypoglycemia, highlighting its ideal effects on glucagon dynamics for insulin-treated patients under threat of hypoglycemia.…”

“…The latter study also showed that vildagliptin, another DPP-4 inhibitor, did not compromise glucagon secretion during hypoglycemia, highlighting its ideal effects on glucagon dynamics for insulin-treated patients under threat of hypoglycemia. In these studies, 40% [29] and 65% [30] subjects were also treated with metformin. Since metformin has been suggested to augment the effects of DPP-4 inhibitors by increasing production of GLP-1 [17], whether glucagon suppressing effects were caused by the DPP-4 inhibitors alone has yet to be clarified.…”

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

“…On the contrary, one study in drug-naive individuals with type 2 diabetes demonstrated that DPP-4 inhibition by vildagliptin enhances alpha cell responsiveness to the stimulatory effect of hypoglycaemia [52], and sustained glucagon counterregulation to hypoglycaemia has been shown for vildagliptin in insulin-treated patients with type 2 diabetes [69] and in patients with type 1 diabetes [67]. This demonstrates that DPP-4 inhibition has a dual effect on glucagon secretion such that when glucose levels are elevated glucagon levels are reduced whereas during hypoglycaemia glucagon levels are increased [11].…”

DPP-4 inhibition contributes to the prevention of hypoglycaemia through a GIP–glucagon counterregulatory axis in mice

“…The rationale for this approach was that GIP stimulates glucagon secretion at low glucose levels [17], that DPP-4 inhibition elevates levels of the active form of GIP [18][19][20][21][22][23] and that glucagon is a counterregulatory hormone [7,9]. We thus explored the hyperinsulinaemic-hypoglycaemic clamp in GIPR −/− mice.…”

“…Increased glucose sensitivity in alpha cells at low glucose with augmented glucagon counterregulation in hypoglycaemia might be achieved by the incretin hormone glucose-dependent insulinotropic polypeptide (GIP), as GIP has been shown to potentiate glucagon secretion at hypoglycaemic levels in healthy men [17]. Since DPP-4 inhibition prevents the inactivation of GIP and thereby raises the circulating level of active GIP, as has been reported in the mouse and in multiple other species [18][19][20][21][22][23], this incretin ho rmone may m ediate prote ction from hypoglycaemia during DPP-4 inhibition. However, whether or not DPP-4 inhibition actually limits hypoglycaemia via a GIP-glucagon counterregulatory axis is still not known.…”