Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Nov 8;91(23):10878–10882. doi: 10.1073/pnas.91.23.10878

Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships.

Y Lee 1, H Hirose 1, M Ohneda 1, J H Johnson 1, J D McGarry 1, R H Unger 1
PMCID: PMC45129  PMID: 7971976

Abstract

Hyperinsulinemia, loss of glucose-stimulated insulin secretion (GSIS), and peripheral insulin resistance coexist in non-insulin-dependent diabetes mellitus (NIDDM). Because free fatty acids (FFA) can induce these same abnormalities, we studied their role in the pathogenesis of the NIDDM of obese Zucker diabetic fatty (ZDF-drt) rats from 5 weeks of age (before the onset of hyperglycemia) until 14 weeks. Two weeks prior to hyperglycemia, plasma FFA began to rise progressively, averaging 1.9 +/- 0.06 mM at the onset of hyperglycemia (P < 0.001 vs. controls). At this time GSIS was absent and beta-cell GLUT-2 glucose transporter was decreased. The triacylglycerol content of prediabetic islets rose to 10 times that of controls and was correlated with plasma FFA (r = 0.825; P < 0.001), which, in turn, was correlated with the plasma glucose concentration (r = 0.873; P < 0.001). Reduction of hyperlipacidemia to 1.3 +/- 0.07 mM by pair feeding with lean littermates reduced all beta-cell abnormalities and prevented hyperglycemia. Normal rat islets that had been cultured for 7 days in medium containing 2 mM FFA exhibited increased basal insulin secretion at 3 mM glucose, and first-phase GSIS was reduced by 68%; in prediabetic islets, first-phase GSIS was reduced by 69% by FFA. The results suggest a role for hyperlipacidemia in the pathogenesis of NIDDM; resistance to insulin-mediated antilipolysis is invoked to explain the high FFA despite hyperinsulinemia, and sensitivity of beta cells to hyperlipacedemia is invoked to explain the FFA-induced loss of GSIS.

Full text

PDF
10881

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. Campbell P. J., Carlson M. G., Nurjhan N. Fat metabolism in human obesity. Am J Physiol. 1994 Apr;266(4 Pt 1):E600–E605. doi: 10.1152/ajpendo.1994.266.4.E600. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. 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]
  5. Crespin S. R., Greenough W. B., 3rd, Steinberg D. Stimulation of insulin secretion by infusion of free fatty acids. J Clin Invest. 1969 Oct;48(10):1934–1943. doi: 10.1172/JCI106160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. DeFronzo R. A. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988 Jun;37(6):667–687. doi: 10.2337/diab.37.6.667. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Elks M. L. Chronic perifusion of rat islets with palmitate suppresses glucose-stimulated insulin release. Endocrinology. 1993 Jul;133(1):208–214. doi: 10.1210/endo.133.1.8319569. [DOI] [PubMed] [Google Scholar]
  9. Giroix M. H., Baetens D., Rasschaert J., Leclercq-Meyer V., Sener A., Portha B., Malaisse W. J. Enzymic and metabolic anomalies in islets of diabetic rats: relationship to B cell mass. Endocrinology. 1992 May;130(5):2634–2640. doi: 10.1210/endo.130.5.1315252. [DOI] [PubMed] [Google Scholar]
  10. Grodsky G. M., Fanska R. E. The in vitro perfused pancreas. Methods Enzymol. 1975;39:364–372. doi: 10.1016/s0076-6879(75)39033-2. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Hisatomi A., Maruyama H., Orci L., Vasko M., Unger R. H. Adrenergically mediated intrapancreatic control of the glucagon response to glucopenia in the isolated rat pancreas. J Clin Invest. 1985 Feb;75(2):420–426. doi: 10.1172/JCI111716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Johnson J. H., Crider B. P., McCorkle K., Alford M., Unger R. H. Inhibition of glucose transport into rat islet cells by immunoglobulins from patients with new-onset insulin-dependent diabetes mellitus. N Engl J Med. 1990 Mar 8;322(10):653–659. doi: 10.1056/NEJM199003083221003. [DOI] [PubMed] [Google Scholar]
  14. Johnson J. H., Ogawa A., Chen L., Orci L., Newgard C. B., Alam T., Unger R. H. Underexpression of beta cell high Km glucose transporters in noninsulin-dependent diabetes. Science. 1990 Oct 26;250(4980):546–549. doi: 10.1126/science.2237405. [DOI] [PubMed] [Google Scholar]
  15. MacDonald M. J. High content of mitochondrial glycerol-3-phosphate dehydrogenase in pancreatic islets and its inhibition by diazoxide. J Biol Chem. 1981 Aug 25;256(16):8287–8290. [PubMed] [Google Scholar]
  16. Madison L. L., Seyffert W. A., Jr, Unger R. H., Barker B. Effect on plasma free fatty acids on plasma glucagon and serum insulin concentrations. Metabolism. 1968 Apr;17(4):301–304. doi: 10.1016/0026-0495(68)90097-8. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. 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]
  19. McGowan M. W., Artiss J. D., Strandbergh D. R., Zak B. A peroxidase-coupled method for the colorimetric determination of serum triglycerides. Clin Chem. 1983 Mar;29(3):538–542. [PubMed] [Google Scholar]
  20. Naber S. P., McDonald J. M., Jarett L., McDaniel M. L., Ludvigsen C. W., Lacy P. E. Preliminary characterization of calcium binding in islet-cell plasma membranes. Diabetologia. 1980 Nov;19(5):439–444. doi: 10.1007/BF00281823. [DOI] [PubMed] [Google Scholar]
  21. Ogawa A., Johnson J. H., Ohneda M., McAllister C. T., Inman L., Alam T., Unger R. H. Roles of insulin resistance and beta-cell dysfunction in dexamethasone-induced diabetes. J Clin Invest. 1992 Aug;90(2):497–504. doi: 10.1172/JCI115886. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ohneda M., Johnson J. H., Inman L. R., Chen L., Suzuki K., Goto Y., Alam T., Ravazzola M., Orci L., Unger R. H. GLUT2 expression and function in beta-cells of GK rats with NIDDM. Dissociation between reductions in glucose transport and glucose-stimulated insulin secretion. Diabetes. 1993 Jul;42(7):1065–1072. doi: 10.2337/diab.42.7.1065. [DOI] [PubMed] [Google Scholar]
  23. Orci L., Ravazzola M., Baetens D., Inman L., Amherdt M., Peterson R. G., Newgard C. B., Johnson J. H., Unger R. H. Evidence that down-regulation of beta-cell glucose transporters in non-insulin-dependent diabetes may be the cause of diabetic hyperglycemia. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9953–9957. doi: 10.1073/pnas.87.24.9953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Ostenson C. G., Abdel-Halim S. M., Rasschaert J., Malaisse-Lagae F., Meuris S., Sener A., Efendic S., Malaisse W. J. Deficient activity of FAD-linked glycerophosphate dehydrogenase in islets of GK rats. Diabetologia. 1993 Aug;36(8):722–726. doi: 10.1007/BF00401142. [DOI] [PubMed] [Google Scholar]
  25. Palmer J. P., Benson J. W., Walter R. M., Ensinck J. W. Arginine-stimulated acute phase of insulin and glucagon secretion in diabetic subjects. J Clin Invest. 1976 Sep;58(3):565–570. doi: 10.1172/JCI108502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. 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]
  27. Thorens B., Weir G. C., Leahy J. L., Lodish H. F., Bonner-Weir S. Reduced expression of the liver/beta-cell glucose transporter isoform in glucose-insensitive pancreatic beta cells of diabetic rats. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6492–6496. doi: 10.1073/pnas.87.17.6492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Weir G. C. Non-insulin-dependent diabetes mellitus: interplay between B-cell inadequacy and insulin resistance. Am J Med. 1982 Oct;73(4):461–464. doi: 10.1016/0002-9343(82)90321-7. [DOI] [PubMed] [Google Scholar]
  29. YALOW R. S., BERSON S. A. Immunoassay of endogenous plasma insulin in man. J Clin Invest. 1960 Jul;39:1157–1175. doi: 10.1172/JCI104130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Zhou Y. P., Grill V. E. Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. J Clin Invest. 1994 Feb;93(2):870–876. doi: 10.1172/JCI117042. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES