Sulfonyl(thio)urea derivative induction of insulin secretion is mediated by potassium, calcium, and sodium channel signal transduction

J Cell Physiol. 2019 Jul;234(7):10138-10147. doi: 10.1002/jcp.27680. Epub 2018 Nov 11.

Abstract

Aim: To investigate the mechanism of action of sulfonyl(thio)urea derivative (SD) on glycemia and on insulin secretion in pancreatic islets.

Methods: Wistar rats were divided into hyperglycemic control group, rats received 4 g/kg body weight glucose plus sitagliptin 10 mg/kg (p.o.); hyperglycemic plus SD 10 mg/kg (p.o.); hyperglycemic plus SD plus sitagliptin. Blood was collected before glucose overloading (zero time), and at 15, 30, 60, and 180 min after glucose, from the afore mentioned groups for glycemia and glucagon-like peptide 1 (GLP-1) measurements and intestinal disaccharidases activity. Pancreatic islets were isolated for the calcium influx and insulin secretion in in vitro studies.

Results: SD reduced glycemia and increased GLP-1 secretion, while inhibited sucrase and lactase activity. This SD (1.0 and 10.0 µM) stimulated calcium influx in a similar percentile to that of glibenclamide, and in a nonsynergic manner. In addition, the trigger effect of SD on calcium influx was through the K+ -ATP-dependent channels, and partially by activating voltage-dependent K + channels and voltage-dependent calcium channels. Furthermore, SD-stimulated Na + and Ca 2+ entry, induced by the transient receptor potential ankyrin 1 and by modulation of Na + /Ca 2+ exchange. The activation of these pathways by SD culminated in in vitro insulin secretion, reinforcing the critical role of K + -ATP channels in the secretagogue effect of SD.

Conclusions: SD diminish glycemia by inducing GLP-1 secretion and inhibiting disaccharidases. To our knowledge, this is the first report of an insulin secretagogue effect of SD that is mediated by potassium and calcium, as well as sodium, signal transduction.

Keywords: VDCC; insulin secretagogue; potassium channels; sodium channels; sulfonyl(thio)urea.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channels / drug effects
  • Calcium Channels / metabolism
  • Glucagon-Like Peptide 1 / metabolism
  • Hyperglycemia / metabolism
  • Hypoglycemic Agents / pharmacology*
  • Insulin Secretion / drug effects*
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Male
  • Potassium Channels, Voltage-Gated / drug effects
  • Potassium Channels, Voltage-Gated / metabolism
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects*
  • Sitagliptin Phosphate / pharmacology
  • Sulfonylurea Compounds / pharmacology*
  • Voltage-Gated Sodium Channels / drug effects
  • Voltage-Gated Sodium Channels / metabolism

Substances

  • Calcium Channels
  • Hypoglycemic Agents
  • Potassium Channels, Voltage-Gated
  • Sulfonylurea Compounds
  • Voltage-Gated Sodium Channels
  • Glucagon-Like Peptide 1
  • Sitagliptin Phosphate