Immune Function in Obese, Diabetic, Hyperinsulinemic C57BL/KsJ-db+/db+ and C57BL/6J-ob/ob Mice

  • Barry S. Handwerger
  • Gabriel Fernandes
  • David M. Brown


The mutant C57BL/KsJ-db+/db+ (db/db) mouse was first described by Hummel and co-workers of the Jackson Laboratory (Hummel et al., 1966). The mutant diabetes (db) gene is inherited as an autosomal recessive with full penetrance. In the homozygous state, the db gene is associated with a metabolic disturbance closely resembling adultoneset, insulin-independent diabetes mellitus. The diabetic syndrome in db/db mice is characterized by obesity, hyperphagia, polydypsia, polyuria, and marked hyperglycemia (Hummel et al., 1966; Coleman and Hummel, 1967, 1969; Herberg and Coleman, 1977; Coleman 1978, 1982). Adult db/db mice weigh up to 70 g, while age- and sex-matched littermates only weight up to 30 g. On an ad libitum diet, the average daily food intake of mice is approximately twice normal. Blood sugars run between 350 and 650 mg/dl (normal 100–200 mg/dl). During the first 4–6 months of age plasma insulin concentrations are markedly elevated in the range of 300–600 μU/ml. After approximately 6 months of age, plasma insulin concentrations fall to within the normal range of 10–100 µU/ml. Early in the course of the disease, during the period of hyperinsulinemia, the islets of Langerhans are characterized by β cell hypertrophy and hyperplasia with β cell degranulation (Like and Chick 1970). The mice are insulin-resistant and have a decrease in the number of insulin receptors on insulin-sensitive target tissues (Kahn et al., 1973, Chang et al., 1975, Raizada et al., 1980). Later in the disease, concomitant with the drop in plasma insulin concentration, progressive atrophy of islet cells occurs (Like and Chick, 1970).


Spleen Cell Suppressor Cell Plasma Insulin Concentration Mixed Lymphocyte Culture Blastogenic Response 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Azar, M., Brown, D. M. and Handwerger, B.S., 1983, unpublished observations.Google Scholar
  2. Bray, G. A., and York, D. A., 1971, Genetically transmitted obesity in rodents, Physiol. Rev. 51: 598–646.PubMedGoogle Scholar
  3. Chandra, R. K., and Au, B., 1980, Single nutrient deficiency and cell-mediated immune responses. I. Zinc, Am. J. Clin. Nutr. 33: 736–738.PubMedGoogle Scholar
  4. Chang, K-J, Huang, D., and Cuatrecasas, P., 1975, The defect in insulin receptors in obese, hyperinsulinemic mice: A probable accompaniment of more generalized alterations in membrane glycoproteins, Biochem. Biophys. Res. Commun. 64: 566–573.PubMedCrossRefGoogle Scholar
  5. Chic, W. L., and Like A. A., 1970, Studies in the diabetic mutant mouse: IV. DBM, a modified diabetic mutant produced by outcrossing the original strain. Diabetologia 6: 252–256.CrossRefGoogle Scholar
  6. Coleman, D. L., 1978, Obesity and diabetes: Two mutant genes causing diabetes—obesity syndromes in mice, Diabetologia 14: 141–148.PubMedCrossRefGoogle Scholar
  7. Coleman, D. L., 1982, Diabetes—obesity syndromes in mice, Diabetes 31: 1–6.PubMedCrossRefGoogle Scholar
  8. Coleman, D. L., and Hummel K. P., 1967, Studies of the mutation, diabetes, in the mouse, Diabetologia 3: 238–248.PubMedCrossRefGoogle Scholar
  9. Coleman, D. L., and Hummel, K. P., 1969, The mutation diabetes, in the mouse, in: Diabetes Proceedings of the Sixth Congress of the International Diabetes Foundation ( J. Ostman and R. D. G. Milner, eds), pp. 813–820, Excerpta Medica Foundation, Amsterdam.Google Scholar
  10. Colley, D. G., 1973, Eosinophils and immune mechanisms. I. Eosinophil stimulation promoter (ESP): A lymphokine induced by specific antigen or phytohemagglutinin, J. Immunol. 110: 1419–1423.PubMedGoogle Scholar
  11. Djeu, J. Y., Heinbaugh, J. A. Holden, H. T., and Herberman, R. B., 1978, Augmentation of mouse natural killer cell activity by interferon and interferon inducers, J. Immunol. 122: 175–181.Google Scholar
  12. Femandes, G., Handwerger, B. S. Yunis, E. J., and Brown, D. M., 1978, Immune response in the mutant diabetic C57BL/Ks-db+ mouse: Discrepancies between in vitro and in vivo immunological assays, J. Clin. Invest. 61: 243–250.CrossRefGoogle Scholar
  13. Fernandes, G., Nair, M., Once, K. Tanaka, T., Floyd, R. and Good, R. A., 1979, Impairment of cell-mediated immunity functions by dietary zinc deficiency in mice, Proc. Natl. Acad. Sci. USA 76: 457–461.PubMedCrossRefGoogle Scholar
  14. Goldfine, I. D., Gardner, J. D., and Neville, D. M., Jr., 1972, Insulin action in isolated rat thymocytes: I. Binding of 125I-insulin and stimulation of a-aminoisobutyric acid transport, J. Biol. Chem. 247: 6919–6926.Google Scholar
  15. Handwerger, B. S., Femandes, G., and Brown, D. M., 1979, Immune response in diabetic mice: Influence of in vivo metabolic environment, Diabetes 28: 398.Google Scholar
  16. Handwerger, B. S., and Koren, K. S., 1976, The nature of the effector cell in antibody-dependent, cell-mediated cytolysis (ADCC): The cytolytic activity of murine tumor cells and peritoneal macrophages, Clin. Immunol. Immunopathol. 5: 272–281.PubMedCrossRefGoogle Scholar
  17. Handwerger, B. S., Toseth, J., Riehm, T., Femandes, G., and Brown, D. M. 1982, Immunologic function in obese, diabetic C57BL/Ks-db+/db+ mice and streptozotocin-induced murine diabetes: Further characterization of the defects in plaque-forming cell (PFC) and cytotoxic cell responses, Diabetes 31 (Suppl. 2): 20A.Google Scholar
  18. Helderman, J. H., and Strom, T. B., 1978, Specific insulin binding sites on T and B lymphocytes as a marker of cell activation, Nature 274: 62–63.PubMedCrossRefGoogle Scholar
  19. Herberg, L., and Coleman, D. L., 1977, Laboratory animals exhibiting obesity and diabetes syndromes, Metabolism 26: 59–99.PubMedCrossRefGoogle Scholar
  20. Hoffman, R. A., Simmonds, R. L., Brown, D. M. and Handwerger, B. S., 1983, unpublished observations.Google Scholar
  21. Hummel, K. P., Dickie, M. M., and Coleman, D. L., 1966, Diabetes, a new mutation in the mouse, Science 153: 1127–1128.PubMedCrossRefGoogle Scholar
  22. Ingalls, A. M., Dickie, M. M., Snell, G. D., 1950, Obese, a new mutation in the house mouse, J. Hered. 41: 317–318, 1950.PubMedGoogle Scholar
  23. Kahn, C. R., Soll, A., Neville, D. M., Jr., and Roth, J., 1973, Severe deficiency in insulin receptors: A common denominator in the insulin resistance of obesity, Clin. Res. 21: 628.Google Scholar
  24. Kazura, J. W., Gandola, C., Rodman, H. R., and Mahmoud, A. A. F., 1979, Deficient production of the lymphokine eosinophil stimulation promoter in chemically induced and mutant diabetes mellitus in mice, J. Immunol. 123: 2114–2117.PubMedGoogle Scholar
  25. Keane, W. F., Brown, D. M. and Handwerger, B. S., 1983, unpublished observations.Google Scholar
  26. Levine, A. S., Morley, J. R., McClain, J. E., Handwerger, B. S., and Brown, D.M., 1981, Zinc status in diabetic mice, Clin. Res. 29: 703A.Google Scholar
  27. Like, A. A., and Chick, W. L., 1970, Studies in the diabetic mutant mouse. I. Light microscopy and radioautography of pancreatic islets, Diabetologia 6: 207–215.PubMedCrossRefGoogle Scholar
  28. Mahmoud, A. A., Rodman, H. M., Mandel, M. A., and Warren, K. S.., 1976, Induced and spontaneous diabetes mellitus and suppression of cell-mediated immunologic responses. Granuloma formation delayed dermal reactivity and allograft rejection, J. Clin. Invest. 57: 362–367.PubMedCrossRefGoogle Scholar
  29. Mandel, M. A., 1979, Immune competence and diabetes mellitus. II. Experimental mouse studies, J. Surg. Res. 26: 199–205.PubMedCrossRefGoogle Scholar
  30. Mandel, M. A., and Mahmoud, A. A. F., 1978, Impairment of cell-mediated immunity in mutant diabetic mice (db/db), J. Immunol. 120: 1375–1377.PubMedGoogle Scholar
  31. Meade, C. J., Brandon, D. R., Smith, W., Simmonds, R. G., Harris, S., and Sowter, C. 1981, The relationship between hyperglycaemia and renal immune complex deposition in mice with inherited diabetes, Clin. Exp. Immunol. 43: 109–120.PubMedGoogle Scholar
  32. Meade, C. J., Sheena, J., and Martin, J., 1979, Effects of the obese (ob/ob) genotype on spleen cell immune function, Int. Arch. Allergy Appl. Immunol. 58: 121–127.PubMedCrossRefGoogle Scholar
  33. Nichols, W. K., Spellman, J. B., and Daynes, R. A., 1978, Immune responses of diabetic animals: Comparison of genetically obese and streptozotocin-diabetic mice, Diabetologia 14: 343–349.PubMedCrossRefGoogle Scholar
  34. Pasko, K. L., Salvin, S. B., and Winkelstein, A., 1981, Mechanisms in the in vivo release of lymphokines. V. Responses of alloxan-treated and genetically diabetic mice, Cell. Immunol. 62: 205–209.PubMedCrossRefGoogle Scholar
  35. Raizada, M. H., Tan, G., Deo, R., and Fellows, R. E., 1980, Cells cultured from the diabetic (db/db) mouse have a permanent decrease in insulin receptors, Endocrinology 107: 1652–1655.PubMedCrossRefGoogle Scholar
  36. Rich, R. R., and Rich, S. S., 1975, Biological expressions of lymphocyte activation IV. Concanavalin A-activated suppressor cells in mouse mixed lymphocyte reactions. J. Immunol. 114: 1112–1115.PubMedGoogle Scholar
  37. Roberts, P. J., and Hayry, P., 1976, Spone matrix allografts: A model for analysis of killer cells infiltrating mouse allografts, Transplantation 21: 437–445.PubMedCrossRefGoogle Scholar
  38. Roodman, G. D., Asconsao J. L., Kenyon, P. D., Zanjami, E. D. Brown, D. M., and Handwerger, B. S., 1982, unpublished observations.Google Scholar
  39. Schwartz, R. H. Bianco, A. R., Handwerger, B. S., and Kahn, C. R., 1975, A demonstration that monocytes, rather than lymphocytes, are the insulin binding cells in human periperal blood mononuclear leukocyte preparations. Application for studies of insulin resistance in man. Proc. Natl. Acad. Sci. USA 72: 474–478.PubMedCrossRefGoogle Scholar
  40. Sheena, J., and Meade, C. J., 1978, Mice bearing the ob/ob mutation have impaired immunity, Im. Arch. Allergy Appl. Immunol. 57: 263–268.CrossRefGoogle Scholar
  41. Tada, M., Honuma, S., Abo, T., and Kumagai, K., 1980, Murine antibody-dependent cell-mediated cytotoxicity: Failure to detect effector cells equivalent to human K cells, J. Immunol. 124: 1929–1936.PubMedGoogle Scholar
  42. Torseth J., Brown, D. M., and Handwerger, B. A., 1983, unpublished observations.Google Scholar
  43. Warren, K. S., 1976, Schistosomiasis: A multiplicity of immunopathology, J. Invest. Dermatol. 67: 464–469.PubMedCrossRefGoogle Scholar
  44. Webb, S. R., Loria, R. M., Madge, G. E., and Kibrick, S., 1976, Susceptibility of mice to group B coxsackie virus is influenced by the diabetic gene, J. Exp. Med. 143: 1239–1248.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1984

Authors and Affiliations

  • Barry S. Handwerger
    • 1
  • Gabriel Fernandes
    • 2
  • David M. Brown
    • 3
    • 4
    • 5
  1. 1.Rheumatology Research Unit, Departments of Medicine and ImmunologyMayo Clinic and Mayo Medical SchoolRochesterUSA
  2. 2.Division of Clinical Immunology and Arthritis, Department of MedicineUniversity of Texas, San AntonioSan AntonioUSA
  3. 3.Department of PediatricsUniversity of Minnesota School of MedicineMinneapolisUSA
  4. 4.Department of Laboratory MedicineUniversity of Minnesota School of MedicineMinneapolisUSA
  5. 5.Department of PathologyUniversity of Minnesota School of MedicineMinneapolisUSA

Personalised recommendations