Intestinal CART is a regulator of GIP and GLP-1 secretion and expression

Mol Cell Endocrinol. 2018 Nov 15;476:8-16. doi: 10.1016/j.mce.2018.04.002. Epub 2018 Apr 6.

Abstract

Impaired incretin effect is a culprit in Type 2 Diabetes. Cocaine- and amphetamine-regulated transcript (CART) is a regulatory peptide controlling pancreatic islet hormone secretion and beta-cell survival. Here we studied the potential expression of CART in enteroendocrine cells and examined the role of CART as a regulator of incretin secretion and expression. CART expression was found in glucose-dependent insulinotropic polypeptide (GIP)-producing K-cells and glucagon-like peptide-1 (GLP-1)-producing L-cells in human duodenum and jejunum and circulating CART levels were increased 60 min after a meal in humans. CART expression was increased by fatty acids and GIP, but unaffected by glucose in GLUTag and STC-1 cells. Exogenous CART had no effect on GIP and GLP-1 expression and secretion in GLUTag or STC-1 cells, but siRNA-mediated silencing of CART reduced GLP-1 expression and secretion. Furthermore, acute intravenous administration of CART increased GIP and GLP-1 secretion during an oral glucose-tolerance test in mice. We conclude that CART is a novel constituent of human K- and L-cells with stimulatory actions on incretin secretion and that interfering with the CART system may be a therapeutic avenue for T2D.

Keywords: CART; Cocaine- and amphetamine-regulated transcript; Enteroendocrine cells; GIP; GLP-1; Incretin hormones.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Fatty Acids / metabolism
  • Female
  • Gastric Inhibitory Polypeptide / metabolism*
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucose / metabolism
  • Glucose Tolerance Test
  • Humans
  • Incretins / metabolism
  • Intestines / chemistry*
  • Male
  • Mice
  • Middle Aged
  • Nerve Tissue Proteins / blood
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism

Substances

  • Fatty Acids
  • Incretins
  • Nerve Tissue Proteins
  • RNA, Messenger
  • cocaine- and amphetamine-regulated transcript protein
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1
  • Glucose