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. Using five complementary models (db/db mice, healthy C57BL/6J mice, human islet cultures, diet-induced obese mice, and SSTR2 KO mice), Saponaro et al. demonstrate that the combination of liraglutide and dapagliflozin improves glycemia and reduces dapagliflozin-induced glucagon secretion via somatostatin release.

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

Saponaro, Chiara
Primo
;
2019-01-01

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. Using five complementary models (db/db mice, healthy C57BL/6J mice, human islet cultures, diet-induced obese mice, and SSTR2 KO mice), Saponaro et al. demonstrate that the combination of liraglutide and dapagliflozin improves glycemia and reduces dapagliflozin-induced glucagon secretion via somatostatin release.
2019
Saponaro, Chiara; Gmyr, Valéry; Thévenet, Julien; Moerman, Ericka; Delalleau, Nathalie; Pasquetti, Gianni; Coddeville, Anais; Quenon, Audrey; Daoudi, ...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/1301599
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