, Volume 14, Issue 3, pp 141–148 | Cite as

Obese and diabetes: Two mutant genes causing diabetes-obesity syndromes in mice

  • D. L. Coleman
Review Articles


The diabetes syndromes produced by the two single gene mutations, obese (ob), and diabetes (db) are identical when both genes are expressed on the same inbred background, whereas on different backgrounds the syndrome changes from a severeobesity, moderate-diabetes to a severe life-shortening diabetes. The same initial sequence of events occurs in both conditions. Increased secretion of insulin and hyperphagia is followed by moderate hyperglycaemia with a further compensatory increase in insulin secretion followed by an expansion of the beta-cell mass. On the BL/6 inbred background, hypertrophy and hyperplasia of the beta cells continues until hyperglycaemia is controlled, whereas on the BL/Ks background, beta cell expansion fails and islet atrophy occurs causing insulinopenia, marked hyperglycaemia, and severe diabetes. The data presented here suggest that hyperphagia, hyperinsulinaemia, or both, early in development trigger the abnormal sequence of metabolic events leading to the obesity-diabetes state. These primary events interact with unknown genetic modifiers to produce either a juvenile or maturity-onset type of diabetes. An understanding of the mode of action of these background modifiers influencing the severity of diabetes in mice should lead to a better understanding of the ways in which unknown genetic and environmental factors contribute to human diabetes.

Key words

Diabetes obesity hyperphagia hyperinsulinaemia mice genetics 


  1. 1.
    Ashwell, M., Meade, C.J., Medawar, Sir P., Sowter, C: Adipose tissue: contributions of nature and nurture to the obesity of an obese mutant mouse (ob/ob). Proc. R. Soc. Lond. [Biol.] 195, 343–353 (1977)Google Scholar
  2. 2.
    Assimacopoulos-Jeannet, F., Jeanrenaud, B.: The hormonal and metabolic basis of experimental obesity. Clin. Endocrinol. Metabol. 5, 337–365 (1976)Google Scholar
  3. 3.
    Bray, G.A., York, D.A.: Genetically transmitted obesity in rodents. Physiol. Rev. 51, 598–646 (1971)Google Scholar
  4. 4.
    Chang, A.Y., Schneider, D.I.: Abnormalities in hepatic enzyme activites during development of diabetes in db mice. Diabetologia 6, 274–278 (1970)Google Scholar
  5. 5.
    Chick, W.L., Like, A.A.: Studies in the diabetic mutant mouse: IV. DBM, a modified diabetic mutant produced by outcrossing the original strain. Diabetologia 6, 252–256 (1970)Google Scholar
  6. 6.
    Coleman, D.L.: Effects of parabiosis of obese with diabetes and normal mice. Diabetologia 9, 294–298 (1973)Google Scholar
  7. 7.
    Coleman, D.L., Hummel, K.P.: Studies with the mutation, diabetes, in the mouse. Diabetologia 3, 238–248 (1967)Google Scholar
  8. 8.
    Coleman, D.L., Hummel, K.P.: Effects of parabiosis of normal with genetically diabetic mice. Am. J. Physiol. 217, 1298–1304 (1969)Google Scholar
  9. 9.
    Coleman, D.L., Hummel, K.P.: The influence of genetic background on the expression of the obese (ob) gene in the mouse. Diabetologia 9, 287–293 (1973)Google Scholar
  10. 10.
    Coleman, D.L., Hummel, K.P.: Hyperinsulinemia in preweaning diabetes (db) mice. Diabetologia 10, 607–610 (1974)Google Scholar
  11. 11.
    Coleman, D.L., Hummel, K.P.: Influence of genetic background on the expression of mutations at the diabetes locus in the mouse. II. Studies on background modifiers. Isr. J. Med. 11, 708–713 (1975)Google Scholar
  12. 12.
    Cox, J.E., Powley, T.L.: Development of obesity in diabetic mice pair-fed with lean siblings. J. Comp. Physiol. Psychol. 91, 347–358 (1977)Google Scholar
  13. 13.
    Epstein, A.N.: Feeding and drinking in suckling rats. In: D. Novin, W. Wyrwicka, and G. Bray (Eds.): Hunger, Basic Mechanisms and Clinical Implications, p. 193–202. New York: Raven Press (1976)Google Scholar
  14. 14.
    Falconer, D.S., Isaacson, J.H.: Adipose, a new inherited obesity of the mouse. J. Hered. 50, 290–292 (1959)Google Scholar
  15. 15.
    Gates, R.J., Hunt, M.I., Lazarus, N.R.: Further studies on the amelioration of the characteristics of New Zealand obese (NZO) mice following transplantation of islets of Langerhans. Diabetologia 10, 401–406 (1974)Google Scholar
  16. 16.
    Goldman, J.K., Bernardis, L.L., Frohman, L.A. Food intake in hypothalamic obesity. Am. J. Physiol. 227, 88–91 (1974)Google Scholar
  17. 17.
    Genuth, S.M., Przybylski, R.S., Rosenberg, D.M.: Insulin resistance in genetically obese hyperglycemic mice. Endocrinology 88, 1230–1238 (1971)Google Scholar
  18. 18.
    Gunnarsson, R.: Function of the pancreatic ß-cell during the development of hyperglycemia in mice homozygous for the mutations diabetes (db) and misty (m) Diabetologia 11, 431–438 (1975)Google Scholar
  19. 19.
    Herberg, L., Coleman, D.L.: Laboratory animals exhibiting obesity and diabetes syndromes. Metabolism 26, 59–98 (1977)Google Scholar
  20. 20.
    Herberg, L., Major, E., Hennings, U., Gruneklee, D., Freytag, G., Gries, F.A.: Differences in the development of the obese hyperglycemie syndrome in ob/ob and NZO mice. Diabetologia 6, 292–299 (1970)Google Scholar
  21. 21.
    Hummel, K.P., Coleman, D.L., Lane, P.W.: The influence of genetic background on expression of mutations at the diabetes locus in the mouse. I. C57BL/KsJ and C57BL/6J strains. Biochem. Genet. 7, 1–13 (1972)Google Scholar
  22. 22.
    Hummel, K.P., Dickie, M.M., Coleman, D.L.: Diabetes, a new mutation in the mouse. Science 153, 1127–1128 (1966)Google Scholar
  23. 23.
    Ingalls, A.M., Dickie, M.M., Snell, G.D.: Obese, a new mutation in the mouse. J. Hered. 41, 317–318 (1950)Google Scholar
  24. 24.
    Johnson, P.R., Hirsch, J.: Cellularity of adipose depots in six strains of genetically obese mice. J. Lipid Res. 13, 2–11 (1972)Google Scholar
  25. 25.
    Joosten, H.F.P., van der Kroon, P.H.W.: Enlargement of epididymal adipocytes in relation to hyperinsulinemia in obese mice (ob/ob). Metabolism 23, 59–66 (1974)Google Scholar
  26. 26.
    Kahn, C.R., Neville, D.M. Jr., Roth, J.: Insulin receptor interaction in the obese-hyperglycemic mouse. A model of insulin resistance. J. Biol. Chem. 248, 244–250 (1973)Google Scholar
  27. 27.
    Kahn, C.R., Neville, D.M. Jr., Gorden, P., Freychet, P., Roth, J.: Insulin receptor defect in insulin resistance. Studies in the obese-hyperglycemic mouse. Biochem. Biophys. Res. Commun. 48, 135–142 (1972)Google Scholar
  28. 28.
    Lane, P.W.: Mouse News Letter 48, 34 (1973)Google Scholar
  29. 29.
    Loten, E.G., Rabinovitch, A., Jeanrenaud, B.: In vivo studies on lipogenesis in obese hyperglycemie (ob/ob) mice: possible role of hyperinsulinemia. Diabetologia 10, 45–52 (1974)Google Scholar
  30. 30.
    Renold, A.E., Dulin, W.E. (eds.): First Brook Lodge Workshop on Spontaneous Diabetes in Laboratory Animals. Diabetologia 3, 63–286 (1967)Google Scholar
  31. 31.
    Renold, A.E., Cahill, G.F. Jr., Gerritsen, G.C. (eds.): Second Brook Lodge Workshop on Spontaneous Diabetes in Laboratory Animals. Diabetologia 6, 153–370 (1970)Google Scholar
  32. 32.
    Renold, A.E., Chang, A.Y., Muller, W.A. (eds.): Third Brook Lodge Workshop on Spontaneous Diabetes in Laboratory Animals. Diabetologia 10, 491–702 (1974)Google Scholar
  33. 33.
    Seidman, I., Horland, A.A., Teebor, G.W.: Hepatic glycolytic and gluconeogenic enzymes of the obese hyperglycemic mouse. Biochim. Biophys. Acta 146, 600–603 (1967)Google Scholar
  34. 34.
    Strautz, R.L.: Studies of hereditary obese mice (ob/ob) after implantation of pancreatic islets in millipore filter capsules Diabetologia 6 306–312 (1970)Google Scholar
  35. 35.
    Zucker, L.M.: Efficiency of energy utilization by the Zucker hereditary obese rat “fatty” Proc. Soc. Exp. Biol. Med. 148 498–500 (1975)Google Scholar

Copyright information

© Springer-Verlag 1978

Authors and Affiliations

  • D. L. Coleman
    • 1
  1. 1.The Jackson LaboratoryBar HarborUSA

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