Glucagon-Like Peptide 1 Stimulates Lipolysis in Clonal Pancreatic β-Cells (HIT)

  1. Gordon C. Yaney,
  2. Vildan N. Civelek,
  3. Ann-Marie Richard,
  4. Joseph S. Dillon,
  5. Jude T. Deeney,
  6. James A. Hamilton,
  7. Helen M. Korchak,
  8. Keith Tornheim,
  9. Barbara E. Corkey and
  10. Aubrey E. Boyd III
  1. From the Obesity Research Center (G.C.Y., V.N.C., A.-M.R, J.T.D., J.A.H., K.T., B.E.C.), Evans Department of Medicine, and the Departments of Biochemistry (B.E.C., K.T.) and Biophysics (J.A.H.), Boston Medical Center, Boston, Massachusetts; the Division of Endocrinology (J.S.D.), University of Iowa School of Medicine, Iowa City, Iowa; and the Immunology Division (H.M.K.), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
  1. Address correspondence and reprint requests to Dr. Barbara E. Corkey, Obesity Research Center, EBRC-808, Boston Medical Center, 650 Albany St., Boston, MA 02118. E-mail: bcorkey{at} .


Glucagon-like peptide 1 (GLP-1) is the most potent physiological incretin for insulin secretion from the pancreatic β-cell, but its mechanism of action has not been established. It interacts with specific cell-surface receptors, generates cAMP, and thereby activates protein kinase A (PKA). Many changes in pancreatic β-cell function have been attributed to PKA activation, but the contribution of each one to the secretory response is unknown. We show here for the first time that GLP-1 rapidly released free fatty acids (FFAs) from cellular stores, thereby lowering intracellular pH (pHi) and stimulating FFA oxidation in clonal β-cells (HIT). Similar changes were observed with forskolin, suggesting that stimulation of lipolysis was a function of PKA activation in β-cells. Triacsin C, which inhibits the conversion of FFAs to long-chain acyl CoA (LC-CoA), enhanced basal FFA efflux as well as GLP-1-induced acidification and efflux of FFAs from the cell. Increasing the concentration of the lipase inhibitor orlistat progressively and largely diminished the increment in secretion caused by forskolin. However, glucose-stimulated secretion was less inhibited by orlistat and only at the highest concentration tested. Because the acute addition of FFAs also increases glucose-stimulated insulin secretion, these data suggest that the incretin function of GLP-1 may involve a major role for lipolysis in cAMP-mediated potentiation of secretion.


  • A.E.B. is deceased.

  • ACS, acyl CoA synthetase; AM, acetoxymethyl ester; BCECF, 2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein; DAG, diacylglycerol; FFA, free fatty acid; GLP-1, glucagon-like peptide 1; HSL, hormone-sensitive lipase; LC-CoA, long-chain acyl CoA; PA, phosphatidic acid; PCR, polymerase chain reaction; pHi, intracellular pH; PKA, protein kinase A.

    • Accepted September 11, 2000.
    • Received February 17, 2000.
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