The GLP1R Agonist Liraglutide Reduces Hyperglucagonemia Induced by the SGLT2 Inhibitor Dapagliflozin via Somatostatin Release

Cell Rep. 2019 Aug 6;28(6):1447-1454.e4. doi: 10.1016/j.celrep.2019.07.009.


The newest classes of anti-diabetic agents include sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor (GLP1R) agonists. The SGLT2 inhibitor dapagliflozin reduces glucotoxicity by glycosuria but elevates glucagon secretion. The GLP1R agonist liraglutide inhibits glucagon; therefore, we hypothesize that the cotreatment of dapagliflozin with liraglutide could reduce hyperglucagonemia and hyperglycemia. Here we use five complementary models: human islet cultures, healthy mice, db/db mice, diet-induced obese (DIO) mice, and somatostatin receptor-2 (SSTR2) KO mice. A single administration of liraglutide and dapagliflozin in combination improves glycemia and reduces dapagliflozin-induced glucagon secretion in diabetic mice. Chronic treatment with liraglutide and dapagliflozin produces a sustainable reduction of glycemia compared with each drug alone. Moreover, liraglutide reduces dapagliflozin-induced glucagon secretion by enhancing somatostatin release, as demonstrated by SSTR2 inhibition in human islets and in mice. Collectively, these data provide mechanistic insights into how intra-islet GLP1R activation is critical for the regulation of glucose homeostasis.

Keywords: GLP1R; dapagliflozin; glucagon; insulin; liraglutide; somatostatin; type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzhydryl Compounds / adverse effects*
  • Diabetes Mellitus, Experimental / drug therapy*
  • Glucagon / drug effects*
  • Glucosides / adverse effects*
  • Humans
  • Liraglutide / pharmacology
  • Liraglutide / therapeutic use*
  • Male
  • Mice
  • Somatostatin / drug effects*


  • Benzhydryl Compounds
  • Glucosides
  • dapagliflozin
  • Somatostatin
  • Liraglutide
  • Glucagon