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

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

Author information

1
University of Lille, U1190-EGID, 59000 Lille, France; INSERM, U1190, 59000 Lille, France.
2
University of Lille, U1190-EGID, 59000 Lille, France; INSERM, U1190, 59000 Lille, France; CHU Lille, Clinique Médicale: Endocrinologie Diabétologie Métabolismes, 59000 Lille, France.
3
Cancer Research Center of Toulouse (CRCT), INSERM U1037, University Toulouse III Paul Sabatier, Toulouse, France; Equipe Labellisée Ligue Contre le Cancer, Toulouse, France.
4
University of Lille, U1011-EGID, 59000 Lille, France; INSERM, U1011, 59000 Lille, France; CHU Lille, Service Biochimie Automatisée Pathologies des Protéines, 59000 Lille, France; Institut Pasteur de Lille, 59000 Lille, France.
5
University of Lille, U1190-EGID, 59000 Lille, France; INSERM, U1190, 59000 Lille, France; CHU Lille, Service de Chirurgie Métabolique et Endocrienne, 59000 Lille, France.
6
University of Lille, U1190-EGID, 59000 Lille, France; INSERM, U1190, 59000 Lille, France; Institut Pasteur de Lille, 59000 Lille, France. Electronic address: caroline.bonner@univ-lille.fr.

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.

KEYWORDS:

GLP1R; dapagliflozin; glucagon; insulin; liraglutide; somatostatin; type 2 diabetes

PMID:
31390560
DOI:
10.1016/j.celrep.2019.07.009
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