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

Abstract：

: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.

journal_name

Cell Rep

journal_title

Cell reports

authors

Saponaro C,Gmyr V,Thévenet J,Moerman E,Delalleau N,Pasquetti G,Coddeville A,Quenon A,Daoudi M,Hubert T,Vantyghem MC,Bousquet C,Martineau Y,Kerr-Conte J,Staels B,Pattou F,Bonner C

doi

10.1016/j.celrep.2019.07.009

subject

Has Abstract

pub_date

2019-08-06 00:00:00

pages

1447-1454.e4

issue

6

issn

2211-1247

pii

S2211-1247(19)30899-X

journal_volume

28

pub_type

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