Diabetologia

, Volume 38, Issue 2, pp 173–179 | Cite as

Caloric restriction in obese pre-diabetic rats prevents beta-cell depletion, loss of beta-cell GLUT 2 and glucose incompetence

  • M. Ohneda
  • L. R. Inman
  • R. H. Unger
Originals

Summary

Pre-diabetic male Zucker diabetic fatty rats (ZDF) become diabetic between 8 and 10 weeks of age. At that time their beta cells exhibit high basal insulin secretion, absent insulin response to glucose and loss of GLUT 2 glucose transporter. Beta-cell volume, which is increased at the onset of non-insulin-dependent diabetes, declines precipitously by age 18 weeks. To determine if expression of this diabetic phenotype was dependent upon the increased food intake of these rats, they were diet-matched to lean littermates for 12 weeks beginning at 6 weeks of age. Untreated control ZDF rats received an unrestricted diet for 3 months. All of the controls became hyperglycaemic by 8 weeks of age, whereas all diet-matched rats remained euglycaemic throughout the 3 months, despite the fact that at 18 weeks of age their mean body weight equaled that of obese rats on an unrestricted diet. In the former rats glucose-stimulated insulin secretion was absent at 12 weeks of age and GLUT-2-positive beta cells had fallen below 30%. The volume fraction of their beta cells was 2.6 times normal at this age but by 18 weeks of age it had declined by 75%. Diet restriction for 3 months prevented the loss of glucose-stimulated insulin secretion and the reduction of beta-cell GLUT-2 and beta-cell volume fraction. However, neither the elevated basal insulin secretion nor the exaggerated arginine-stimulated insulin secretion of the obese rats was reversed or prevented by caloric restriction. We conclude that in diabetic ZDF rats the glucose incompetence of beta cells and the reduction of beta-cell GLUT 2, which coincide with the onset of hyperglycaemia, and the subsequent loss of beta-cell volume, occur only when the caloric intake is excessive. The increased basal insulin secretion and exaggerated insulin response to arginine appear to be relatively independent of caloric intake.

Key words

GLUT 2 Zucker rats caloric restriction beta-cell depletion 

Abbreviations

NIDDM

Non-insulin-dependent diabetes mellitus

ZDF

Zucker diabetic fatty rats

GSIS

glucose-stimulated insulin secretion

GLUT-2

glucose transporter

References

  1. 1.
    Newburgh LH (1942) Control of hyperglycemia of obese diabetes by weight reduction. Ann Int Med 17: 935–942Google Scholar
  2. 2.
    Savage PJ, Bennion LJ, Flock EV et al. (1979) Diet-induced improvement of abnormalities in insulin and glucagon secretion and in insulin receptor binding in diabetes mellitus. J Clin Endocrinol Metab 48: 999–1007Google Scholar
  3. 3.
    Hidaka H, Nagulesparan M, Klimes I et al. (1982) Improvement of insulin secretion but not insulin resistance after short term control of plasma glucose in obese type II diabetics. J Clin Endocrinol Metab 54: 217–222Google Scholar
  4. 4.
    Peterson RG, Shaw WN, Neel M-A, Little LA, Eichberg J (1990) Zucker diabetic fatty rat as a model for non-insulin-dependent diabetes mellitus. ILAR News 32: 16–22Google Scholar
  5. 5.
    Pfeiffer MA, Halter JB, Porte D Jr (1981) Insulin secretion in diabetes mellitus. Am J Med 70: 579–588Google Scholar
  6. 6.
    Unger RH (1991) Diabetic hyperglycemia: link to impaired glucose transport in pancreatic Β-cells. Science 251: 1200–1205Google Scholar
  7. 7.
    Orci L, Ravazzola M, Baetens D et al. (1990) Evidence that down-regulation of Β-cell glucose transporters in non-insulin-dependent diabetes may be the cause of diabetic hyperglycemia. Proc Natl Acad Sci (USA) 87: 9953–9957Google Scholar
  8. 8.
    Johnson JH, Ogawa A, Chen L et al. (1990) Underexpression of Β-cell high Km glucose transporters in noninsulin-dependent diabetes. Science 250: 546–549Google Scholar
  9. 9.
    Grodsky GM, Fanska RE (1975) The in vitro perfused pancreas. Methods Enzymol 39: 364–372Google Scholar
  10. 10.
    Hisatomi A, Maruyama H, Orci L, Vasko M, Unger RH (1985) Adrenergically mediated intrapancreatic control of the glucagon response to glucopenia in the isolated rat pancreas. J Clin Invest 75: 420–426Google Scholar
  11. 11.
    Herbert V, Lau KS, Gottlieb CW, Bleicher SJ (1965) Coated charcoal immunoassay of insulin. J Clin Endocrinol Metab 25: 1375–1384Google Scholar
  12. 12.
    Yalow RS, Berson SA (1960) Immunoassay of endogenous plasma insulin in man. J Clin Invest 39: 1157–1175Google Scholar
  13. 13.
    Weibel ER (1979) Practical methods for biological morphometry. In: Stereological Methods. Vol. 1. Academic Press, Inc., London pp. 101–161Google Scholar
  14. 14.
    Malaisse WJ, Magetto C, Leclercq-Meyer V, Sener A (1993) Interference of glycogenolysis with glycolysis in pancreatic islets from glucose-infused rats. J Clin Invest 91: 432–436Google Scholar
  15. 15.
    Thorens B, Weir GC, Leahy JL, Lodish HF, Bonner-Weir S (1990) Reduced expression of the liver/beta-cell glucose transporter isoform in glucose-insensitive pancreatic beta cells of diabetic rats. Proc Natl Acad Sci USA 87: 9953–9957Google Scholar
  16. 16.
    Ohneda M, Johnson JH, Inman LR et al. (1993) GLUT-2 expression and function in Β-cells of GK rats with NIDDM: dissociation between reductions in glucose transport and glucose-stimulated insulin secretion. Diabetes 42: 1065–1072Google Scholar
  17. 17.
    Thorens B, Wu YJ, Leahy JL, Weir GC (1992) The loss of GLUT2 expression by glucose-unresponsive Β-cells of db/db mice is reversible and is induced by the diabetic environment. J Clin Invest 90: 77–85Google Scholar
  18. 18.
    Ogawa A, Johnson JH, Ohneda M et al. (1992) Roles of insulin resistance and Β-cell dysfunction in dexamethasone-induced diabetes. J Clin Invest 90: 497–504Google Scholar
  19. 19.
    Ohneda M, Johnson JH, Inman LR, Unger RH (1993) GLUT-2 function in glucose-unresponsive Β-cells of dexamethasone-induced diabetes in rats. J Clin Invest 92: 1950–1956Google Scholar
  20. 20.
    Wyse B, Dulin W (1970) The influence of age and dietary conditions on diabetes in the db mouse. Diabetologia 6: 268–273Google Scholar
  21. 21.
    Sako Y, Grill VE (1990) 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 127: 1580–1589Google Scholar
  22. 22.
    Capito K, Hansen SE, Hedeskov CJ, Islin H, Thams P (1992) Fat-induced changes in mouse pancreatic islet insulin secretion, insulin biosynthesis and glucose metabolism. Acta Diabetol 28: 193–198Google Scholar
  23. 23.
    Elks ML (1993) Chronic perifusion of rat islets with palmitate suppresses glucose-stimulated insulin release. Endocrinology 133: 208–214Google Scholar
  24. 24.
    Zhou Y-P, Grill VE (1994) 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 93: 870–876Google Scholar
  25. 25.
    Lee Y, Hirose H, Ohneda M, Johnson JH, McGarry JD, Unger RH (1994) Β-cell lipotoxicity in the pathogenesis of noninsulin-dependent diabetes mellitus (NIDDM) of obese rats: impairment in adipocyte-Β-cell relationships. Proc Natl Acad Sci 91: 10878–10882Google Scholar
  26. 26.
    Atef N, Brulé C, Bihoreau M-T, Ktorza A, Picon L, Pénicaud L (1991) Enhanced insulin secretory response to acetylcholine by perifused pancreas of 5-day-old preobese Zucker rats. Endocrinology 129: 2219–2224Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • M. Ohneda
    • 1
  • L. R. Inman
    • 1
    • 2
  • R. H. Unger
    • 1
    • 2
  1. 1.Center for Diabetes Research and Gifford Laboratories, Departments of Internal Medicine and PathologyUniversity of Texas Southwestern Medical CenterDallasUSA
  2. 2.Department of Veterans Affairs Medical CenterDallasUSA

Personalised recommendations