Skip to main content

Advertisement

SpringerLink
Log in

Improvement of glucose tolerance with immunomodulators in type 2 diabetic animals

  • Published:
Biotherapy

Abstract

Cytokine-inducers prevent insulin-dependent diabetes mellitus (IDDM) in animal models. We extended this therapy to non-insulin-dependent diabetes mellitus (NIDDM), because it was reported that diabetes of KK-Ay mice, a model for NIDDM, was recovered by allogenic bone-marrow transplantation that also prevented IDDM in animal models.

An i.p. or i.v. injection of streptococcal preparation (OK 432) lowered fasting blood glucose (FBG) levels and markedly improved glucose tolerance test (GTT) in KK-Ay mice for more than 32 h regardless of the glucose loading routes (oral, i.v. or i.p.), while an i.v. injection of BCG improved FBG and GTT for more than 4 wks without body weight loss. The improvement of FBG and GTT with OK-432 was brought about in other NIDDM animals, GK rats and Wistar fatty rats. Among various cytokines possibly induced by OK-432 and BCG, IL-1α, TNFα and lymphotoxin significantly improved FBG and GTT in KK-Ay mice, whereas IL-2 and IFNγ did not. There were no differences between the OK-432-treated KK-Ay mice and control in histology of the pancreas, degree of insulin-induced decrease in blood glucose levels, and muscle glycogen synthase activities. As to insulin secretion, there is a tendency that the OK-432-treatment less than 1 week did not affect insulin levels during GTT, whereas the treatment more than 2 weeks increased the insulin levels.

Thus, cytokine-inducers improved FBG and glucose tolerance of NIDDM animals probably via cytokines. The results imply a role of the cytokines in glucose tolerance of NIDDM, although precise immune and metabolic mechanisms remain to be elucidated.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Eisenbarth GS. Type 1 diabetes mellitus. A chronic autoimmune disease. N Engl J Med 1986; 314: 1360–1368.

    Article  PubMed  CAS  Google Scholar 

  2. Than S, Ishida H, Inaba M, Fukuba Y, Seino Y, Adachi M, Imura H, Ikehara S. Bone marrow transplantation as a strategy for treatment of non-insulin-dependent diabetes mellitus in KK-Ay mice. J Exp Med 1992; 176: 1233–1238.

    Article  PubMed  CAS  Google Scholar 

  3. Kondo K, Nozawa K, Tomida T, Ezaki K. Inbred strains resulting from Japanese mice. Bull Exp Animals 1957; 6: 107–112.

    Google Scholar 

  4. Nakamura M, Yamada K. Studies on a diabetic (KK) strain of the mouse. Diabetologia 1967; 3: 212–221.

    Article  PubMed  CAS  Google Scholar 

  5. Diani AR, Sawada GA, Hannah BA, Jodelis KS, Connell MA, Connell CL, Vidmar TJ, Wyse BM. Analysis of pancreatic islet cells and hormone content in the spontaneously diabetic KK-Ay mouse by morphometry, immunocytochemistry and radioimmunoassay. Wirchows Arch A 1987; 412: 53–61.

    Article  CAS  Google Scholar 

  6. Toyota T, Satoh J, Oya K, Shintani S, Okano T. Streptococcal preparation (OK-432) inhibits development of type 1 diabetes in NOD mice. Diabetes 1986; 35: 496–499.

    PubMed  CAS  Google Scholar 

  7. Satoh J, Shintani S, Oya K, Tanaka S, Nobunaga T, Toyota T, Goto Y. Treatment with streptococcal preparation (OK-432) suppresses anti-islet autoimmunity and prevents diabetes in BB rats. Diabetes 1988; 37: 1188–1194.

    Article  PubMed  CAS  Google Scholar 

  8. Satoh J, Seino H, Abo T, Tanaka S, Shintani S, Ohta S, Tamura K, Sawai T, Nobunaga T, Ohteki T, Kumagai K, Toyata T. Recombinant human tumor necrosis factor a suppresses autoimmune diabetes in nonobese diabetic mice. J Clin Invest 1989; 84: 1345–1348.

    Article  PubMed  CAS  Google Scholar 

  9. Satoh J, Seino H, Shintani S, Tanaka S, Ohteki T, Masuda, T, Nobunaga T, Toyota T. Inhibition of type 1 diabetes in BB rats with human tumor necrosis factor α. J Immunol 1990; 145: 1395–1399.

    PubMed  CAS  Google Scholar 

  10. Seino H, Takahashi K, Satoh J, Zhu XP, Sagara M, Masuda, T, Nobunaga T, Funahashi I, Kajikawa T, Toyata T. Prevention of autoimmune diabetes with lymphotoxin in NOD mice. Diabetes 1993; 42: 398–404.

    Article  PubMed  CAS  Google Scholar 

  11. Takahashi K, Satoh J, Seino H, Zhu XP, Sagara M, Masuda, T, Toyota T. Prevention of type 1 diabetes with lymphotoxin in BB rats. Clin Immunol Immunopathol 1993; 69: 318–323.

    Article  PubMed  CAS  Google Scholar 

  12. Goto Y, Kakizaki M. The spontaneous-diabetes rat: A model of non-insulin dependent diabetes mellitus. Proc J Acad 1981; 57: 381–384.

    Article  Google Scholar 

  13. Ikeda H, Shino A, Matsuo T, Iwatsuka H, Suzuoka Z. A new genetically obese-hyperglycemic rat (Wistar fatty). Diabetes 1981; 30: 1045–1050.

    Article  PubMed  CAS  Google Scholar 

  14. Schooley JC, Kullgren B, Allison AC. Inhibition by interleukin-1 of the action of erythropoietin on erythroid precursors and its possible role in the pathogenesis of hypoplastic anaemias. Brit J Haematol 1987; 67: 11–17.

    Article  CAS  Google Scholar 

  15. Gaffney EV, Tsai S-C. Lymphocyte-activating and growth-inhibitory activities for several sources of native and recombinant interleukin I. Cancer Res 1986; 46: 3834–3837.

    PubMed  CAS  Google Scholar 

  16. Zhou P, Quackenbush LJ, Zaleski MB.In vitro proliferation of murine spleen cells. Strain variation of proliferative responses induced by recombinant IL-2. Int Arch Allergy App Immunol 1989; 90: 162–168.

    Article  CAS  Google Scholar 

  17. Lewis M, Tartaglia LA, Lee A, Bennett GL, Rice GC, Wong GHW, Chen EY, Goeddel DV. Cloning and expression of cDNAs for two distinct murine tumor necrosis factor receptors demonstrate one receptor is species specific. Proc Natl Acad Sci USA 1991; 88: 2830–2834.

    Article  PubMed  CAS  Google Scholar 

  18. Desbunguois B, Aurbach GD. Use of polyethylene glycol to separate free and antibody-bound peptide hormones in radioimmunoassays. J Clin Endocrinol Metab 1971; 33: 732–738.

    Article  Google Scholar 

  19. Thomas JA, Schlender KK, Larner J. A rapid filter paper assay for UDP-glucose-glycogen glucosyltransferase, including an improved biosynthesis of UDP-14C-glucose. Analytical Biochem 1968; 25: 486–499.

    Article  CAS  Google Scholar 

  20. Ichimura O, Suzuki S, Sugawara Y, Osawa T. Lymphokines induction by streptococcal preparation OK-432 (picibanil) in mice: Characterization of interleukin 1 (IL-1), interleukin 2 (IL-2) and natural killer cell activating factor (NKAF). In: Hoshino T ed. OK-432. Proceeding of an international symposium held at the 13th International Congress of Chemotherapy, Vienna, September 1983. Amsterdam-Princeton-Geneva-Tokyo:, Excerpta Medica, 1984: 50–72.

    Google Scholar 

  21. Suzuki K, Fukutomi Y, Matsuoka M, Torii K, Hayashi H, Takii T, Oomoto Y, Onozaki K. Differential production of interleukin I (IL-1), IL-6, tumor necrosis factor, and IL-1 receptor antagonist by human monocytes stimulated with Mycobacterium leprae and M. bovis BCG. Int J Lepr Other Mycobact Dis 1993; 61: 609–618.

    PubMed  CAS  Google Scholar 

  22. Villar-Palasi C, Larner J. Insulin treatment and increased UDPG-glycogen transglucosylase activity in muscle. Arch Biochem Biophys 1961; 94: 436–442.

    Article  PubMed  CAS  Google Scholar 

  23. Rosell-Perez M, Villar-Palasi C, Larner J. Studies on UDPG-glycogen transglucosylase. I. Preparation and differentiation of two activities of UDGP-glycogen transglucosylase from rat skeletal muscle. Biochemistry 1962; 1: 763–768.

    Article  PubMed  CAS  Google Scholar 

  24. Watanabe Y, Iwa T. Clinical value of immunotherapy for lung cancer by the streptococcal preparation OK-432. Cancer 1984; 53: 248–253.

    Article  PubMed  CAS  Google Scholar 

  25. McCallum RE, Berry LJ. Effects of endotoxin on gluconeogenesis, glycogen synthesis, and liver glycogen synthase in mice. Infect Immunol 1973; 7: 642–654.

    CAS  Google Scholar 

  26. Yamada, K.: Effects of PSK (Krestin) on interleukin production.In: Ishigami J, ed. Recent Advance in Chemotherapy, Anticancer Section 2. Tokyo: Univ. of Tokyo Press, 1985: 876–877.

    Google Scholar 

  27. del Rey A, Besedovsky H. Antidiabetic effects of interleukin 1. Proc Natl Acad Sci USA 1989; 86: 5943–5947.

    Article  PubMed  Google Scholar 

  28. Comens PG, Wolf BA, Unanue ER, Lacy PE, McDaniel ML. Interleukin I is a potent modulator of insulin secretion from isolated rat islets of Langerhans. Diabetes 1987; 36: 963–970.

    Article  PubMed  CAS  Google Scholar 

  29. Hotamisligil GS, Spiegelman BM. Tumor necrosis factor α: A key component of the obesity-diabetes link. Diabetes 1994; 43: 1271–1278.

    Article  PubMed  CAS  Google Scholar 

  30. Lang CH, Dobrescu C, Bagby GJ. Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output. Endocrinology 1992; 130: 43–52.

    Article  PubMed  CAS  Google Scholar 

  31. Williams JG, Jurkovich GJ, Hahnel GB, Maier RV. Macrophage priming by interferon gamma: a selective process with potentially harmful effects. J Leukoc Biol 1992; 52: 579–584.

    PubMed  CAS  Google Scholar 

  32. Dinneen S, Gerich J, Rizza R. Carbohydrate metabolism in non-insulin-dependent diabetes mellitus. N Engl J Med 1992; 327: 707–713.

    Article  PubMed  CAS  Google Scholar 

  33. Leahy JL, Bonner-Weir S, Weir GC. Beta cell dysfunction induced by chronic hyperglycemia. Current ideas on mechanism of impaired glucose-induced insulin secretion. Diabetes Care 1992; 15: 442–455.

    Article  PubMed  CAS  Google Scholar 

  34. Hill M, McCallum R. Altered transcriptional regulation of phosphoenolpyruvate carboxykinase in rats following endotoxin treatment. J Clin Invest 1991; 88: 811–816.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Third Department of Internal Medicine, Tohoku University School of Medicine, I-1 Seiryo-machi, Aoba-ku, 980, Sendai, Japan

    Xiao Ping Zhu, Jo Satoh M.D., Gen Muto, Yoshiko Muto, Mikio Sagara, Kazuma Takahashi, Hiroaki Seino, Satoshi Hirai & Takayoshi Toyota

  2. Second Department of Pathology, Tohoku University School of Medicine, I-1 Seiryo-machi, Aoba-ku, 980, Sendai, Japan

    Takayuki Masuda

  3. Third Department of Internal Medicine, Yokohama City University School of Medicine, Yokohama, Japan

    Shun-ichi Tanaka

  4. Department of Metabolism and Clinical Nutrition, Kyoto University School of Medicine, Kyoto, Japan

    Hitoshi Ishida & Yutaka Seino

Authors
  1. Xiao Ping Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jo Satoh M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gen Muto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshiko Muto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mikio Sagara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kazuma Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hiroaki Seino
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Satoshi Hirai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Takayuki Masuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shun-ichi Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hitoshi Ishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yutaka Seino
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Takayoshi Toyota
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhu, X.P., Satoh, J., Muto, G. et al. Improvement of glucose tolerance with immunomodulators in type 2 diabetic animals. Biotherapy 9, 189–197 (1996). https://doi.org/10.1007/BF02620732

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02620732

Key words

Search

Navigation