Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Jun 15;97(12):2728–2735. doi: 10.1172/JCI118727

Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat.

D T Stein 1, V Esser 1, B E Stevenson 1, K E Lane 1, J H Whiteside 1, M B Daniels 1, S Chen 1, J D McGarry 1
PMCID: PMC507365  PMID: 8675683

Abstract

We asked whether the well known starvation-induced impairment of glucose-stimulated insulin secretion (GSIS) seen in isolated rat pancreas preparations also applies in vivo. Accordingly, fed and 18-24-h-fasted rats were subjected to an intravenous glucose challenge followed by a hyperglycemic clamp protocol, during which the plasma-insulin concentration was measured. Surprisingly, the acute (5 min) insulin response was equally robust in the two groups. However, after infusion of the antilipolytic agent, nicotinic acid, to ensure low levels of plasma FFA before the glucose load, GSIS was essentially ablated in fasted rats, but unaffected in fed animals. Maintenance of a high plasma FFA concentration by coadministration of Intralipid plus heparin to nicotinic acid-treated rats (fed or fasted), or further elevation of the endogenous FFA level in nonnicotinic acid-treated fasted animals by infusion of etomoxir (to block hepatic fatty acid oxidation), resulted in supranormal GSIS. The in vivo findings were reproduced in studies with the perfused pancreas from fed and fasted rats in which GSIS was examined in the absence and presence of palmitate. The results establish that in the rat, the high circulating concentration of FFA that accompanies food deprivation is a sine qua non for efficient GSIS when a fast is terminated. They also serve to underscore the powerful interaction between glucose and fatty acids in normal beta cell function and raise the possibility that imbalances between the two fuels in vivo could have pathological consequences.

Full Text

The Full Text of this article is available as a PDF (225.4 KB).

Selected References

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

  1. Balasse E. O., Ooms H. A., Lambilliotte J. P. Evidence for a stimulatory effect of ketone bodies on insulin secretion in man. Horm Metab Res. 1970 Nov;2(6):371–372. doi: 10.1055/s-0028-1096822. [DOI] [PubMed] [Google Scholar]
  2. Balasse E. O., Ooms H. A. Role of plasma free fatty acids in the control of insulin secretion in man. Diabetologia. 1973 Apr;9(2):145–151. doi: 10.1007/BF01230695. [DOI] [PubMed] [Google Scholar]
  3. Bedoya F. J., Ramírez R., Arilla E., Goberna R. Effect of 2-bromostearate on glucose-phosphorylating activities and the dynamics of insulin secretion in islets of Langerhans during fasting. Diabetes. 1984 Sep;33(9):858–863. doi: 10.2337/diab.33.9.858. [DOI] [PubMed] [Google Scholar]
  4. Boden G., Chen X., Rosner J., Barton M. Effects of a 48-h fat infusion on insulin secretion and glucose utilization. Diabetes. 1995 Oct;44(10):1239–1242. doi: 10.2337/diab.44.10.1239. [DOI] [PubMed] [Google Scholar]
  5. Bosboom R. S., Zweens J., Bouman P. R. Effects of feeding and fasting on the insulin secretory response to glucose and sulfonylureas in intact rats and isolated perfused rat pancreas. Diabetologia. 1973 Aug;9(4):243–250. doi: 10.1007/BF01221849. [DOI] [PubMed] [Google Scholar]
  6. Brun T., Roche E., Kim K. H., Prentki M. Glucose regulates acetyl-CoA carboxylase gene expression in a pancreatic beta-cell line (INS-1). J Biol Chem. 1993 Sep 5;268(25):18905–18911. [PubMed] [Google Scholar]
  7. Burch P. T., Trus M. D., Berner D. K., Leontire A., Zawalich K. C., Matschinsky F. M. Adaptation of glycolytic enzymes: glucose use and insulin release in rat pancreatic islets during fasting and refeeding. Diabetes. 1981 Nov;30(11):923–928. doi: 10.2337/diab.30.11.923. [DOI] [PubMed] [Google Scholar]
  8. Cahill G. F., Jr, Herrera M. G., Morgan A. P., Soeldner J. S., Steinke J., Levy P. L., Reichard G. A., Jr, Kipnis D. M. Hormone-fuel interrelationships during fasting. J Clin Invest. 1966 Nov;45(11):1751–1769. doi: 10.1172/JCI105481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Campillo J. E., Luyckx A. S., Torres M. D., Lefebvre P. J. Effect of oleic acid on insulin secretion by the isolated perfused rat pancreas. Diabetologia. 1979 Apr;16(4):267–273. doi: 10.1007/BF01221954. [DOI] [PubMed] [Google Scholar]
  10. Chen S., Ogawa A., Ohneda M., Unger R. H., Foster D. W., McGarry J. D. More direct evidence for a malonyl-CoA-carnitine palmitoyltransferase I interaction as a key event in pancreatic beta-cell signaling. Diabetes. 1994 Jul;43(7):878–883. doi: 10.2337/diab.43.7.878. [DOI] [PubMed] [Google Scholar]
  11. Corkey B. E., Glennon M. C., Chen K. S., Deeney J. T., Matschinsky F. M., Prentki M. A role for malonyl-CoA in glucose-stimulated insulin secretion from clonal pancreatic beta-cells. J Biol Chem. 1989 Dec 25;264(36):21608–21612. [PubMed] [Google Scholar]
  12. 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]
  13. 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]
  14. Esser V., Kuwajima M., Britton C. H., Krishnan K., Foster D. W., McGarry J. D. Inhibitors of mitochondrial carnitine palmitoyltransferase I limit the action of proteases on the enzyme. Isolation and partial amino acid analysis of a truncated form of the rat liver isozyme. J Biol Chem. 1993 Mar 15;268(8):5810–5816. [PubMed] [Google Scholar]
  15. 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]
  16. Greenough W. B., 3rd, Crespin S. R., Steinberg D. Hypoglycaemia and hyperinsulinaemia in response to raised free-fatty-acid levels. Lancet. 1967 Dec 23;2(7530):1334–1336. doi: 10.1016/s0140-6736(67)90917-8. [DOI] [PubMed] [Google Scholar]
  17. Grey N. J., Goldring S., Kipnis D. M. The effect of fasting, diet, and actinomycin D on insulin secretion in the rat. J Clin Invest. 1970 May;49(5):881–889. doi: 10.1172/JCI106307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hedeskov C. J., Capito K. The effect of starvation on insulin secretion and glucose metabolism in mouse pancreatic islets. Biochem J. 1974 Jun;140(3):423–433. doi: 10.1042/bj1400423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Iwashima Y., Kondoh-Abiko A., Seino S., Takeda J., Eto M., Polonsky K. S., Makino I. Reduced levels of messenger ribonucleic acid for calcium channel, glucose transporter-2, and glucokinase are associated with alterations in insulin secretion in fasted rats. Endocrinology. 1994 Sep;135(3):1010–1017. doi: 10.1210/endo.135.3.8070343. [DOI] [PubMed] [Google Scholar]
  20. Jenkins D. J., Hunter W. M., Goff D. V. Ketone bodies and evidence for increased insulin secretion. Nature. 1970 Jul 25;227(5256):384–385. doi: 10.1038/227384a0. [DOI] [PubMed] [Google Scholar]
  21. Lee Y., Hirose H., Ohneda M., Johnson J. H., McGarry J. D., Unger R. H. Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10878–10882. doi: 10.1073/pnas.91.23.10878. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Levy J., Herchuelz A., Sener A., Malaisse W. J. The stimulus-secretion coupling of glucose-induced insulin release. XX. fasting: a model for altered glucose recognition by the B-cell. Metabolism. 1976 May;25(5):583–591. doi: 10.1016/0026-0495(76)90012-3. [DOI] [PubMed] [Google Scholar]
  23. MADISON L. L., MEBANE D., UNGER R. H., LOCHNER A. THE HYPOGLYCEMIC ACTION OF KETONES. II. EVIDENCE FOR A STIMULATORY FEEDBACK OF KETONES ON THE PANCREATIC BETA CELLS. J Clin Invest. 1964 Mar;43:408–415. doi: 10.1172/JCI104925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Malaisse W. J., Malaisse-Lagae F., Mayhew D. A possible role for the adenylcyclase system in insulin secretion. J Clin Invest. 1967 Nov;46(11):1724–1734. doi: 10.1172/JCI105663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. Malaisse W. J., Malaisse-Lagae F., Wright P. H. Effect of fasting upon insulin secretion in the rat. Am J Physiol. 1967 Oct;213(4):843–848. doi: 10.1152/ajplegacy.1967.213.4.843. [DOI] [PubMed] [Google Scholar]
  27. Malaisse W. J., Sener A., Levy J. The stimulus-secretion coupling of glucose-induced insulin release. Fasting-induced adaptation of key glycolytic enzymes in isolated islets. J Biol Chem. 1976 Mar 25;251(6):1731–1737. [PubMed] [Google Scholar]
  28. McGarry J. D. Disordered metabolism in diabetes: have we underemphasized the fat component? J Cell Biochem. 1994;55 (Suppl):29–38. doi: 10.1002/jcb.240550005. [DOI] [PubMed] [Google Scholar]
  29. McGarry J. D., Foster D. W. Regulation of hepatic fatty acid oxidation and ketone body production. Annu Rev Biochem. 1980;49:395–420. doi: 10.1146/annurev.bi.49.070180.002143. [DOI] [PubMed] [Google Scholar]
  30. McGarry J. D., Guest M. J., Foster D. W. Ketone body metabolism in the ketosis of starvation and alloxan diabetes. J Biol Chem. 1970 Sep 10;245(17):4382–4390. [PubMed] [Google Scholar]
  31. McGarry J. D. What if Minkowski had been ageusic? An alternative angle on diabetes. Science. 1992 Oct 30;258(5083):766–770. doi: 10.1126/science.1439783. [DOI] [PubMed] [Google Scholar]
  32. McGarry J. D., Woeltje K. F., Kuwajima M., Foster D. W. Regulation of ketogenesis and the renaissance of carnitine palmitoyltransferase. Diabetes Metab Rev. 1989 May;5(3):271–284. doi: 10.1002/dmr.5610050305. [DOI] [PubMed] [Google Scholar]
  33. McGarry J., Wright P. H., Foster D. W. Hormonal control of ketogenesis. Rapid activation of hepatic ketogenic capacity in fed rats by anti-insulin serum and glucagon. J Clin Invest. 1975 Jun;55(6):1202–1209. doi: 10.1172/JCI108038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Moir A. M., Zammit V. A. Changes in the properties of cytosolic acetyl-CoA carboxylase studied in cold-clamped liver samples from fed, starved and starved-refed rats. Biochem J. 1990 Dec 1;272(2):511–517. doi: 10.1042/bj2720511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Mokuda O., Sakamoto Y., Hu H. Y., Kawagoe R., Shimizu N. Effects of long chain free fatty acids on glucose-induced insulin secretion in the perfused rat pancreas. Horm Metab Res. 1993 Nov;25(11):596–597. doi: 10.1055/s-2007-1002185. [DOI] [PubMed] [Google Scholar]
  36. Montague W., Taylor K. W. Regulation of insulin secretion by short chain fatty acids. Nature. 1968 Mar 2;217(5131):853–853. doi: 10.1038/217853a0. [DOI] [PubMed] [Google Scholar]
  37. Newgard C. B., McGarry J. D. Metabolic coupling factors in pancreatic beta-cell signal transduction. Annu Rev Biochem. 1995;64:689–719. doi: 10.1146/annurev.bi.64.070195.003353. [DOI] [PubMed] [Google Scholar]
  38. 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]
  39. Seyffert W. A., Jr, Madison L. L. Physiologic effects of metabolic fuels on carbohydrate metabolism. I. Acute effect of elevation of plasma free fatty acids on hepatic glucose output, peripheral glucose utilization, serum insulin, and plasma glucagon levels. Diabetes. 1967 Nov;16(11):765–776. doi: 10.2337/diab.16.11.765. [DOI] [PubMed] [Google Scholar]
  40. Tamarit-Rodriguez J., Vara E., Tamarit J. Starvation-induced secretory changes of insulin, somatostatin, and glucagon and their modification by 2-bromostearate. Horm Metab Res. 1984 Mar;16(3):115–119. doi: 10.1055/s-2007-1014715. [DOI] [PubMed] [Google Scholar]
  41. 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]
  42. UNGER R. H., EISENTRAUT A. M., MADISON L. L. The effects of total starvation upon the levels of circulating glucagon and insulin in man. J Clin Invest. 1963 Jul;42:1031–1039. doi: 10.1172/JCI104788. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Vara E., Tamarit-Rodriguez J. Glucose stimulation of insulin secretion in islets of fed and starved rats and its dependence on lipid metabolism. Metabolism. 1986 Mar;35(3):266–271. doi: 10.1016/0026-0495(86)90212-x. [DOI] [PubMed] [Google Scholar]
  44. Warnotte C., Gilon P., Nenquin M., Henquin J. C. Mechanisms of the stimulation of insulin release by saturated fatty acids. A study of palmitate effects in mouse beta-cells. Diabetes. 1994 May;43(5):703–711. doi: 10.2337/diab.43.5.703. [DOI] [PubMed] [Google Scholar]
  45. Wolters G. H., Konijnendijk W., Bouman P. R. Effects of fasting on insulin secretion, islet glucose metabolism, and the cyclic adenosine 3',5'-monophosphate content of rat pancreatic islets in vitro. Diabetes. 1977 Jun;26(6):530–537. doi: 10.2337/diab.26.6.530. [DOI] [PubMed] [Google Scholar]
  46. Zhou Y. P., Grill V. Long term exposure to fatty acids and ketones inhibits B-cell functions in human pancreatic islets of Langerhans. J Clin Endocrinol Metab. 1995 May;80(5):1584–1590. doi: 10.1210/jcem.80.5.7745004. [DOI] [PubMed] [Google Scholar]

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

RESOURCES