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.