Dapagliflozin suppresses glucagon signaling in rodent models of diabetes

May-Yun Wang, Xinxin Yu, Young H Lee, Sara Kay McCorkle, Shiuhwei Chen, Jianping Li, Zhao Wang, Jaime A. Davidson, Philipp E Scherer, William L Holland, Roger H Unger, Michael G Roth

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of antidiabetic drug used for the treatment of diabetes. These drugs are thought to lower blood glucose by blocking reabsorption of glucose by SGLT2 in the proximal convoluted tubules of the kidney. To investigate the effect of inhibiting SGLT2 on pancreatic hormones, we treated perfused pancreata from rats with chemically induced diabetes with dapagliflozin and measured the response of glucagon secretion by alpha cells in response to elevated glucose. In these type 1 diabetic rats, glucose stimulated glucagon secretion by alpha cells; this was prevented by dapagliflozin. Two models of type 2 diabetes, severely diabetic Zucker rats and db/db mice fed dapagliflozin, showed significant improvement of blood glucose levels and glucose disposal, with reduced evidence of glucagon signaling in the liver, as exemplified by reduced phosphorylation of hepatic cAMP-responsive element binding protein, reduced expression of phosphoenolpyruvate carboxykinase 2, increased hepatic glycogen, and reduced hepatic glucose production. Plasma glucagon levels did not change significantly. However, dapagliflozin treatment reduced the expression of the liver glucagon receptor. Dapagliflozin in rodents appears to lower blood glucose levels in part by suppressing hepatic glucagon signaling through down-regulation of the hepatic glucagon receptor.

Original languageEnglish (US)
Pages (from-to)6611-6616
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number25
DOIs
StatePublished - Jun 20 2017

Keywords

  • Dapagliflozin
  • Diabetes
  • Glucagon
  • Glucagon receptor
  • SGLT2 inhibition

ASJC Scopus subject areas

  • General

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