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Engineering of glycerol-stimulated insulin secretion in islet beta cells. Differential metabolic fates of glucose and glycerol provide insight into mechanisms of stimulus-secretion coupling.

Publication ,  Journal Article
Noel, RJ; Antinozzi, PA; McGarry, JD; Newgard, CB
Published in: J Biol Chem
July 25, 1997

Insulin secretion from beta cells in the islets of Langerhans can be stimulated by a number of metabolic fuels, including glucose and glyceraldehyde, and is thought to be mediated by metabolism of the secretagogues and an attendant increase in the ATP:ADP ratio. Curiously, glycerol fails to stimulate insulin secretion, even though it has been reported that islets contain abundant glycerol kinase activity and oxidize glycerol efficiently. We have reinvestigated this point and find that rat islets and the well differentiated insulinoma cell line INS-1 contain negligible glycerol kinase activity. A recombinant adenovirus containing the bacterial glycerol kinase gene (AdCMV-GlpK) was constructed and used to express the enzyme in islets and INS-1 cells, resulting in insulin secretion in response to glycerol. In AdCMV-GlpK-treated INS-1 cells a greater proportion of glycerol is converted to lactate and a lesser proportion is oxidized compared with glucose. The two fuels are equally potent as insulin secretagogues, despite the fact that oxidation of glycerol at its maximally effective dose (2-5 mM) occurs at a rate that is similar to the rate of glucose oxidation at its basal, nonstimulatory concentration (3 mM). We also investigated the possibility that glycerol may signal via expansion of the glycerol phosphate pool to allow enhanced fatty acid esterification and formation of complex lipids. Addition of Triacsin-C, an inhibitor of long-chain acyl-CoA synthetase, to AdCMV-GlpK-treated INS-1 cells did not inhibit glycerol-stimulated insulin secretion despite the fact that it blocked glycerol incorporation into cellular lipids. We conclude from these studies that glycerol kinase expression is sufficient to activate glycerol signaling in beta cells, showing that the failure of normal islets to respond to this substrate is due to a lack of this enzyme activity. Further, our studies show that glycerol signaling is not linked to esterification or oxidation of the substrate, but is likely mediated by its metabolism in the glycerol phosphate shuttle and/or the distal portion of the glycolytic pathway, either of which can lead to production of ATP and an increased ATP:ADP ratio.

Duke Scholars

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

July 25, 1997

Volume

272

Issue

30

Start / End Page

18621 / 18627

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Triazenes
  • Rats
  • RNA, Messenger
  • Lactic Acid
  • Islets of Langerhans
  • Insulin Secretion
  • Insulin
  • Glycerol Kinase
  • Glycerol
 

Citation

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Noel, R. J., Antinozzi, P. A., McGarry, J. D., & Newgard, C. B. (1997). Engineering of glycerol-stimulated insulin secretion in islet beta cells. Differential metabolic fates of glucose and glycerol provide insight into mechanisms of stimulus-secretion coupling. J Biol Chem, 272(30), 18621–18627. https://doi.org/10.1074/jbc.272.30.18621
Noel, R. J., P. A. Antinozzi, J. D. McGarry, and C. B. Newgard. “Engineering of glycerol-stimulated insulin secretion in islet beta cells. Differential metabolic fates of glucose and glycerol provide insight into mechanisms of stimulus-secretion coupling.J Biol Chem 272, no. 30 (July 25, 1997): 18621–27. https://doi.org/10.1074/jbc.272.30.18621.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

July 25, 1997

Volume

272

Issue

30

Start / End Page

18621 / 18627

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Triazenes
  • Rats
  • RNA, Messenger
  • Lactic Acid
  • Islets of Langerhans
  • Insulin Secretion
  • Insulin
  • Glycerol Kinase
  • Glycerol