Abstract
Glucagon-like peptide-1 (GLP-1, 7-36) is capable of restoring normal glucose tolerance in aging, glucose-intolerant Wistar rats and is a potent causal factor in differentiation of human islet duodenal homeobox-1-expressing cells into insulin-releasing beta cells. Here we report stable isotope-based dynamic metabolic profiles of rat pancreatic epithelial (ARIP) and human ductal tumor (PANC-1) cells responding to 10 nM GLP-1 treatment in 48 h cultures. Macromolecule synthesis patterns and substrate flow measurements using gas chromatography/mass spectrometry (MS) and the stable [1,2-13C2]glucose isotope as the tracer showed that GLP-1 induced a significant 20% and 60% increase in de novo fatty acid palmitate synthesis in ARIP and PANC-1 cells, respectively, and it also induced a significant increase in palmitate chain elongation into stearate utilizing glucose as the primary substrate. Distribution of 13C in other metabolites indicated no changes in the rates of nucleic acid ribose synthesis, glutamate oxidation, or lactate production. Tandem high-performance liquid chromatography-ion trap MS analysis of the culture media demonstrated mass insulin secretion by GLP-1-treated tumor cells. Metabolic profile changes in response to GLP-1-induced cell differentiation include selective increases in de novo fatty acid synthesis from glucose and consequent chain elongation, allowing increased membrane formation and greater insulin availability and release.
Highlights
Glucagon-like peptide-1 (GLP-1, 7-36) is capable of restoring normal glucose tolerance in aging, glucose-intolerant Wistar rats and is a potent causal factor in differentiation of human islet duodenal homeobox-1-expressing cells into insulin-releasing  cells
This paper demonstrates that cell differentiation and regulation of insulin release after GLP-1 treatment are accompanied by important metabolic adaptive changes that primarily affect the contribution of glucose to de novo fatty acid synthesis and chain elongation of the saturated long-chain species primarily utilized for triglyceride and membrane synthesis
The studied GLP-1 dose was selected based on reports that it triggers an effective ligand-specific cAMP response in receptor-transfected COS-7 cells [21] and effectively induces ARIP and PANC-1/presence of the islet duodenal homeobox-1 (PDX-1) cells to differentiate into insulin-secreting cells [3]
Summary
Glucagon-like peptide-1 (GLP-1, 7-36) is capable of restoring normal glucose tolerance in aging, glucose-intolerant Wistar rats and is a potent causal factor in differentiation of human islet duodenal homeobox-1-expressing cells into insulin-releasing  cells. We report stable isotope-based dynamic metabolic profiles of rat pancreatic epithelial (ARIP) and human ductal tumor (PANC-1) cells responding to 10 nM GLP-1 treatment in 48 h cultures. Metabolic profile changes in response to GLP-1-induced cell differentiation include selective increases in de novo fatty acid synthesis from glucose and consequent chain elongation, allowing increased membrane formation and greater insulin availability and release.—Bulotta, A., R. This paper demonstrates that cell differentiation and regulation of insulin release after GLP-1 treatment are accompanied by important metabolic adaptive changes that primarily affect the contribution of glucose to de novo fatty acid synthesis and chain elongation of the saturated long-chain species primarily utilized for triglyceride and membrane synthesis.
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