Canagliflozin Potentiates GLP-1 Secretion and Lowers the Peak of GIP Secretion in Rats Fed a High-Fat High-Sucrose Diet

Biochem Biophys Res Commun. 2017 Oct 14;492(2):161-165. doi: 10.1016/j.bbrc.2017.08.031. Epub 2017 Aug 10.

Abstract

The glucose-induced secretion of incretins, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), is dependent on luminal glucose levels and transport of glucose via the sodium-glucose transporter 1 (SGLT1) in the small intestine. Because GLP-1 and GIP function in decreasing and increasing the body weight, respectively, we aimed to analyze the effect of transient inhibition of SGLT1 by canagliflozin on incretin secretion in an obese rat model. Male Sprague-Dawley rats were maintained on a high-fat high-sucrose diet for 6-7 weeks, and plasma GLP-1 and GIP levels were measured during an oral glucose tolerance test (OGTT). In addition, GLP-1 secretion was examined in a murine GLP-1 producing enteroendocrine cell line, GLUTag. Concomitant administration of 10 mg/kg canagliflozin with glucose loading suppressed glucose excursion, increased total GLP-1 levels, and reduced total GIP levels in systemic circulation, as revealed in the OGTT. Total and active GLP-1 levels were increased in portal blood, whereas total and active GIP levels tended to be decreased 15 min after the administration of canagliflozin with glucose. Canagliflozin (at 0.1-30 μM) did not directly affect release of GLP-1 in vitro. These results suggest that the oral administration of canagliflozin suppresses GIP secretion via the inhibition of SGLT1 in the upper part of the intestine and enhances GLP-1 secretion by increasing the glucose delivery to the lower part of the small intestine in an obese rodent model.

Keywords: Canagliflozin; Diet–induced obesity; Glucagon-like peptide-1; Glucose-dependent insulinotropic polypeptide; SGLT2 inhibitor; Sodium-glucose cotransporter 1(SGLT1).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Canagliflozin / pharmacology*
  • Canagliflozin / therapeutic use
  • Cell Line
  • Diet, High-Fat / adverse effects
  • Dietary Carbohydrates / adverse effects
  • Gastric Inhibitory Polypeptide / blood
  • Gastric Inhibitory Polypeptide / metabolism*
  • Glucagon-Like Peptide 1 / blood
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucose / metabolism
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Incretins / blood
  • Incretins / metabolism
  • Insulin / blood
  • Insulin / metabolism
  • Male
  • Obesity / blood
  • Obesity / drug therapy*
  • Obesity / etiology
  • Obesity / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sodium-Glucose Transporter 1 / antagonists & inhibitors
  • Sodium-Glucose Transporter 1 / metabolism
  • Sucrose / adverse effects

Substances

  • Blood Glucose
  • Dietary Carbohydrates
  • Hypoglycemic Agents
  • Incretins
  • Insulin
  • Sodium-Glucose Transporter 1
  • Canagliflozin
  • Sucrose
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1
  • Glucose