Hypoxia decreases glucagon-like peptide-1 secretion from the GLUTag cell line

Biol Pharm Bull. 2015;38(4):514-21. doi: 10.1248/bpb.b14-00612.

Abstract

Glucagon-like peptide-1 (GLP-1), an incretin hormone, is secreted from L cells located in the intestinal epithelium. It is known that intestinal oxygen tension is decreased postprandially. In addition, we found that the expression of hypoxia-inducible factor-1α (HIF-1α), which accumulates in cells under hypoxic conditions, was significantly increased in the colons of mice with food intake, indicating that the oxygen concentration is likely reduced in the colon after eating. Therefore, we hypothesized that GLP-1 secretion is affected by oxygen tension. We found that forskolin-stimulated GLP-1 secretion from GLUTag cells, a model of intestinal L cells, is suppressed in hypoxia (1% O2). Forskolin-stimulated elevations of preproglucagon (ppGCG) and proprotein convertase 1/3 (PC1/3) mRNA expression were decreased under hypoxic conditions. The finding that H89, a protein kinase A (PKA) inhibitor, inhibited the forskolin-stimulated increase of ppGCG and PC1/3 indicated that the cAMP-PKA pathway is involved in the hypoxia-induced suppression of the genes. Hypoxia decreased hexokinase 2 mRNA and protein expression and increased lactate dehydrogenase A mRNA and protein expression. Concomitantly, lactate production was increased and ATP production was decreased. Together, the results indicate that hypoxia decreases glucose utilization for ATP production, which probably causes a decrease in cAMP production and in subsequent GLP-1 production. Our findings suggest that the postprandial decrease in oxygen tension in the intestine attenuates GLP-1 secretion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Cell Line
  • Colforsin / pharmacology
  • Colon / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Eating / physiology
  • Glucagon-Like Peptide 1 / metabolism*
  • Hypoxia / metabolism*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Isoquinolines / pharmacology
  • Lactic Acid / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Proglucagon / genetics
  • Proprotein Convertase 1 / genetics
  • Protein Kinase Inhibitors / pharmacology
  • RNA, Messenger / metabolism
  • Sulfonamides / pharmacology

Substances

  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Isoquinolines
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • Sulfonamides
  • Colforsin
  • Lactic Acid
  • Proglucagon
  • Glucagon-Like Peptide 1
  • Adenosine Triphosphate
  • Cyclic AMP-Dependent Protein Kinases
  • Proprotein Convertase 1
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide