Glucose promotes its own metabolism by acting on the cell-surface glucose-sensing receptor T1R3

Endocr J. 2014;61(2):119-31. doi: 10.1507/endocrj.ej13-0431. Epub 2013 Nov 7.

Abstract

A homodimer of taste type 1 receptor 3 (T1R3) functions as a sweet taste-sensing receptor in pancreatic β-cells. This receptor is activated by various sweet molecules including sugars such as glucose. To determine the role of this receptor in glucose-induced insulin secretion, we addressed whether or not this receptor modulates glucose metabolism in MIN6 cells. We measured changes in intracellular ATP ([ATP]i) in MIN6 cells expressing luciferase. Sucralose, an agonist of T1R3, induced immediate and sustained elevation of [ATP]i in the presence of 5.5 mM glucose. The effect of sucralose was dose-dependent and, at 5 mM, was greater than that induced by 25 mM glucose. In contrast, carbachol, GLP-1 or high concentration of potassium did not reproduce the sucralose action. Sucralose facilitated the increase in [ATP]i induced by a mitochondrial fuel methylsuccinate, and potentiated glucose-induced elevation of [ATP]i. Administration of a non-metabolizable glucose analogue, 3-O-methylglucose, which acts as an agonist of T1R3, induced a small and transient increase in [ATP]i. 3-O-Methylglucose augmented elevation of [ATP]i induced by methylsuccinate, and also enhanced glucose-induced increase in [ATP]i. Knock down of T1R3 by using shRNA attenuated [ATP]i-response to high concentration of glucose and also reduced the glucose-induced insulin secretion. These results indicate that activation of the homodimer of T1R3 facilitates the metabolic pathway in mitochondria and augments ATP production. The results obtained by using 3-O-methylglucose suggest that glucose, by acting on the homodimer of T1R3, promotes its own metabolism.

MeSH terms

  • 3-O-Methylglucose / pharmacology
  • Adenosine Triphosphate / metabolism*
  • Animals
  • Cell Line
  • Glucose / metabolism*
  • Glucose / pharmacology
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism*
  • Mice
  • RNA, Small Interfering / pharmacology
  • Receptors, G-Protein-Coupled / drug effects
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / physiology*
  • Succinates / pharmacology
  • Sucrose / analogs & derivatives
  • Sucrose / pharmacology

Substances

  • Insulin
  • RNA, Small Interfering
  • Receptors, G-Protein-Coupled
  • Succinates
  • taste receptors, type 1
  • 3-O-Methylglucose
  • Sucrose
  • Adenosine Triphosphate
  • trichlorosucrose
  • methylsuccinic acid
  • Glucose