Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1994 Feb;93(2):870–876. doi: 10.1172/JCI117042

Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle.

Y P Zhou 1, V E Grill 1
PMCID: PMC293952  PMID: 8113418

Abstract

We tested effects of long-term exposure of pancreatic islets to free fatty acids (FFA) in vitro on B cell function. Islets isolated from male Sprague-Dawley rats were exposed to palmitate (0.125 or 0.25 mM), oleate (0.125 mM), or octanoate (2.0 mM) during culture. Insulin responses were subsequently tested in the absence of FFA. After a 48-h exposure to FFA, insulin secretion during basal glucose (3.3 mM) was several-fold increased. However, during stimulation with 27 mM glucose, secretion was inhibited by 30-50% and proinsulin biosynthesis by 30-40%. Total protein synthesis was similarly affected. Conversely, previous palmitate did not impair alpha-ketoisocaproic acid (5 mM)-induced insulin release. Induction and reversibility of the inhibitory effect on glucose-induced insulin secretion required between 6 and 24 h. Addition of the carnitine palmitoyltransferase I inhibitor etomoxir (1 microM) partially reversed (by > 50%) FFA-associated decrease in secretory as well as proinsulin biosynthetic responses to 27 mM glucose. The inhibitory effect of previous palmitate was similar when co-culture was performed with 5.5, 11, or 27 mM glucose. Exposure to palmitate or oleate reduced the production of 14CO2 from D-[U-14C]glucose, and of 14CO2 from D-[3,4-14C]-glucose, both effects being reversed by etomoxir. Conclusions: long-term exposure to FFA inhibits glucose-induced insulin secretion and biosynthesis probably through a glucose fatty acid cycle.

Full text

PDF
871

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Berne C. The metabolism of lipids in mouse pancreatic islets. The oxidation of fatty acids and ketone bodies. Biochem J. 1975 Dec;152(3):661–666. doi: 10.1042/bj1520661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bliss C. R., Sharp G. W. Glucose-induced insulin release in islets of young rats: time-dependent potentiation and effects of 2-bromostearate. Am J Physiol. 1992 Nov;263(5 Pt 1):E890–E896. doi: 10.1152/ajpendo.1992.263.5.E890. [DOI] [PubMed] [Google Scholar]
  3. Campillo J. E., Valdivia M. M., Rodriguez E., Osorio C. Effect of oleic and octanoic acids on glucose-induced insulin release in vitro. Diabete Metab. 1979 Sep;5(3):183–187. [PubMed] [Google Scholar]
  4. Capito K., Hansen S. E., Hedeskov C. J., Islin H., Thams P. Fat-induced changes in mouse pancreatic islet insulin secretion, insulin biosynthesis and glucose metabolism. Acta Diabetol. 1992;28(3-4):193–198. doi: 10.1007/BF00778997. [DOI] [PubMed] [Google Scholar]
  5. Crespin S. R., Greenough W. B., 3rd, Steinberg D. Stimulation of insulin secretion by long-chain free fatty acids. A direct pancreatic effect. J Clin Invest. 1973 Aug;52(8):1979–1984. doi: 10.1172/JCI107382. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Declercq P. E., Falck J. R., Kuwajima M., Tyminski H., Foster D. W., McGarry J. D. Characterization of the mitochondrial carnitine palmitoyltransferase enzyme system. I. Use of inhibitors. J Biol Chem. 1987 Jul 15;262(20):9812–9821. [PubMed] [Google Scholar]
  7. Ferrannini E., Barrett E. J., Bevilacqua S., DeFronzo R. A. Effect of fatty acids on glucose production and utilization in man. J Clin Invest. 1983 Nov;72(5):1737–1747. doi: 10.1172/JCI111133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Foley J. E. Rationale and application of fatty acid oxidation inhibitors in treatment of diabetes mellitus. Diabetes Care. 1992 Jun;15(6):773–784. doi: 10.2337/diacare.15.6.773. [DOI] [PubMed] [Google Scholar]
  9. Goberna R., Tamarit J., Jr, Osorio J., Fussgänger R., Tamarit J., Pfeiffer E. F. Action of B-hydroxy butyrate, acetoacetate and palmitate on the insulin release in the perfused isolated rat pancreas. Horm Metab Res. 1974 Jul;6(4):256–260. doi: 10.1055/s-0028-1093862. [DOI] [PubMed] [Google Scholar]
  10. Grill V., Rundfeldt M., Efendić S. Previous exposure to glucose enhances somatostatin secretion from the isolated perfused rat pancreas. Diabetologia. 1981 Apr;20(4):495–500. doi: 10.1007/BF00253414. [DOI] [PubMed] [Google Scholar]
  11. Halban P. A., Wollheim C. B., Blondel B., Renold A. E. Long-term exposure of isolated pancreatic islets to mannoheptulose: evidence for insulin degradation in the beta cell. Biochem Pharmacol. 1980 Oct 1;29(19):2625–2633. doi: 10.1016/0006-2952(80)90077-5. [DOI] [PubMed] [Google Scholar]
  12. Herbert V., Lau K. S., Gottlieb C. W., Bleicher S. J. Coated charcoal immunoassay of insulin. J Clin Endocrinol Metab. 1965 Oct;25(10):1375–1384. doi: 10.1210/jcem-25-10-1375. [DOI] [PubMed] [Google Scholar]
  13. KEEN H., FIELD J. B., PASTAN I. H. A simple method for in vitro metabolic studies using small volumes of tissue and medium. Metabolism. 1963 Feb;12:143–147. [PubMed] [Google Scholar]
  14. Lacy P. E., Kostianovsky M. Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes. 1967 Jan;16(1):35–39. doi: 10.2337/diab.16.1.35. [DOI] [PubMed] [Google Scholar]
  15. Malaisse W. J., Best L., Kawazu S., Malaisse-Lagae F., Sener A. The stimulus-secretion coupling of glucose-induced insulin release: fuel metabolism in islets deprived of exogenous nutrient. Arch Biochem Biophys. 1983 Jul 1;224(1):102–110. doi: 10.1016/0003-9861(83)90193-5. [DOI] [PubMed] [Google Scholar]
  16. Malaisse W. J. Insulin release : the fuel concept. Diabete Metab. 1983 Dec;9(4):313–320. [PubMed] [Google Scholar]
  17. Malaisse W. J., Malaisse-Lagae F., Sener A., Hellerström C. Participation of endogenous fatty acids in the secretory activity of the pancreatic B-cell. Biochem J. 1985 May 1;227(3):995–1002. doi: 10.1042/bj2270995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Malaisse W. J., Malaisse-Lagae F. Stimulation of insulin secretion by noncarbohydrate metabolites. J Lab Clin Med. 1968 Sep;72(3):438–448. [PubMed] [Google Scholar]
  19. Meglasson M. D., Matschinsky F. M. Pancreatic islet glucose metabolism and regulation of insulin secretion. Diabetes Metab Rev. 1986;2(3-4):163–214. doi: 10.1002/dmr.5610020301. [DOI] [PubMed] [Google Scholar]
  20. Prentki M., Vischer S., Glennon M. C., Regazzi R., Deeney J. T., Corkey B. E. Malonyl-CoA and long chain acyl-CoA esters as metabolic coupling factors in nutrient-induced insulin secretion. J Biol Chem. 1992 Mar 25;267(9):5802–5810. [PubMed] [Google Scholar]
  21. RANDLE P. J., GARLAND P. B., HALES C. N., NEWSHOLME E. A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963 Apr 13;1(7285):785–789. doi: 10.1016/s0140-6736(63)91500-9. [DOI] [PubMed] [Google Scholar]
  22. Randle P. J., Kerbey A. L., Espinal J. Mechanisms decreasing glucose oxidation in diabetes and starvation: role of lipid fuels and hormones. Diabetes Metab Rev. 1988 Nov;4(7):623–638. doi: 10.1002/dmr.5610040702. [DOI] [PubMed] [Google Scholar]
  23. Sako Y., Grill V. E. A 48-hour lipid infusion in the rat time-dependently inhibits glucose-induced insulin secretion and B cell oxidation through a process likely coupled to fatty acid oxidation. Endocrinology. 1990 Oct;127(4):1580–1589. doi: 10.1210/endo-127-4-1580. [DOI] [PubMed] [Google Scholar]
  24. Sener A., Malaisse W. J. Stimulation by D-glucose of mitochondrial oxidative events in islet cells. Biochem J. 1987 Aug 15;246(1):89–95. doi: 10.1042/bj2460089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Tamarit-Rodríguez J., Vara E., Tamarit J. Starvation-induced changes of palmitate metabolism and insulin secretion in isolated rat islets stimulated by glucose. Biochem J. 1984 Jul 15;221(2):317–324. doi: 10.1042/bj2210317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Wolf H. P., Eistetter K., Ludwig G. Phenylalkyloxirane carboxylic acids, a new class of hypoglycaemic substances: hypoglycaemic and hypoketonaemic effects of sodium 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (B 807-27) in fasted animals. Diabetologia. 1982 Jun;22(6):456–463. doi: 10.1007/BF00282590. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES