Glucagon-Like Peptide 1 Stimulates Lipolysis in Clonal Pancreatic β-Cells (HIT)
- Gordon C. Yaney,
- Vildan N. Civelek,
- Ann-Marie Richard,
- Joseph S. Dillon,
- Jude T. Deeney,
- James A. Hamilton,
- Helen M. Korchak,
- Keith Tornheim,
- Barbara E. Corkey and
- Aubrey E. Boyd III
- 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.
- 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}med-med1.bu.edu .
Abstract
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.
Footnotes
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A.E.B. is deceased.
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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.
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- Accepted September 11, 2000.
- Received February 17, 2000.
- by the American Diabetes Association, Inc.
