3 years ago

SGLT2 inhibition and glucagon secretion in humans

C. Saponaro, F. Pattou, C. Bonner

Publication date: November 2018

Source: Diabetes & Metabolism, Volume 44, Issue 5

Author(s): C. Saponaro, F. Pattou, C. Bonner

Abstract

With the increasing prevalence of type 2 diabetes (T2D), therapies aimed at delineating diabetes pathophysiology and understanding their mechanisms of action are of critical importance. As such, growing interest in the clinical pharmacology of sodium–glucose cotransporter 2 (SGLT2) and its inhibition by gliflozins in the treatment of T2D is becoming increasingly evident. SGLT2 inhibition results in urinary glucose excretion, thereby reducing blood glucose levels. The importance of this homoeostasis mechanism is evident from several clinical trials demonstrating that patients taking this class of compounds have reductions in glycaemia, body weight and blood pressure compared with other antidiabetic agents. Yet, while such outcomes are very encouraging, some studies have reported elevated plasma glucagon levels and endogenous glucose production (EGP), two traits that are already prevalent in T2D. However, these findings were later explained by the specific expression of SGLT2 by pancreatic alpha cells, where glucagon secretion is directly regulated. Although conflicting data are now emerging on SGLT2 regulation of glucagon secretion, as SGLT2 is not expressed in the intestines, circulating glucagon concentrations are most likely of pancreatic origin. Thus, the present review considers the mechanism of action of SGLT2 inhibitors in the regulation of glucagon secretion, and the discrepancies in data from mice compared with people. The pragmatic use of human islets to accurately decipher SGLT2 inhibition in the regulation of glucagon secretion is also discussed.

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