Summary
The functional state of beta cells may influence the rate of their destruction in Type 1 (insulin-dependent) diabetes mellitus. We examined the effect of diazoxide, which inhibits insulin secretion, or tolbutamide, which stimulates insulin secretion, upon the incidence of diabetes in the non-obese-diabetic (NOD) mouse. Female mice were treated from 3–30 weeks of age with diet containing diazoxide 250 mg·kg−1 or tolbutamide 125 mg·kg−1. The cumulative incidence of diabetes at 35 weeks was similar in the diazoxide (16 of 24) and control (18 of 24) groups, but reduced in the tolbutamide group (10 of 23,p<0.04 vs control group). In a second experiment, treatment was started from 9 weeks of age, by which time insulitis is already present. The cumulative incidence of diabetes at 35 weeks was 16 of 24 in controls, 15 of 24 on diazoxide and 11 of 24 on tolbutamide (p=NS vs control). A third experiment compared the effect of treatment from 3 weeks with control diet or diet containing tolbutamide 125 mg·kg−1 or 500 mg·kg−1. Diabetes was reduced by tolbutamide treatment, with a cumulative incidence of 25 of 31 in controls, 18 of 30 on tolbutamide 125 mg·kg−1 (p<0.04) and 14 of 32 on 500 mg·kg−1 (p<0.002), although the difference between the two treatment groups failed to reach statistical significance. A fourth experiment showed that treatment from 3–12 weeks with diazoxide 1000 mg·kg−1 increased the extent of insulitis compared with controls and animals treated with tolbutamide 500 mg·kg−1. Elucidation of the mechanisms by which tolbutamide reduces the incidence of diabetes in the NOD mouse has implications for human intervention trials.
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References
Gotfredsen CF, Buschard K, Frandsen EK (1985) Reduction of diabetes incidence of BB Wistar rats by early prophylactic insulin treatment of diabetes-prone animals. Diabetologia 28: 933–935
Like AA (1986) Insulin injections prevent diabetes in BioBreeding/Worcester rats. Diabetes 35 [Suppl 1]: 74A (Abstract)
Atkinson MA, MacLaren NK, Luchetta R (1990) Insulitis and diabetes in NOD mice reduced by prophylactic insulin therapy. Diabetes 39: 933–937
Shah SC, Malone JI, Simpson NE (1989) A randomized trial of intensive insulin therapy in newly diagnosed insulin-dependent diabetes mellitus. N Engl J Med 320: 550–554
International Diabetes Immunotherapy Group (IDIG) (1991) Ongoing immunotherapy trials reported to IDIG. Diabetes prevention therapy 5: 16
Trube G, Rorsman P, Ohno-Shosaku T (1986) Opposite effects of tolbutamide and diazoxide on the ATP-dependent K+ channel in mouse pancreatic beta cells. Pfleugers Arch 407: 493–499
Williams AJK, Krug J, Beales PE, Procaccini E, Pozzilli P (1991) Tolbutamide, not diazoxide, reduces the incidence of diabetes in the non-obese diabetic (NOD) mouse. Diabetes 40 [Suppl 1]: 116A (Abstract)
Bingley PJ, Gale EAM (1991) Lessons from family studies. In: Harrison LC, Tait BD (eds) Clinical endocrinology and metabolism, Volume 5. Bailliere Tindall, London pp 261–284
Signore A, Pozzilli P, Gale EAM, Andreani D, Beverley PCL (1989) The natural history of lymphocyte subsets infiltrating the pancreas of NOD mice. Diabetologia 32: 282–289
Mansfield KJ, Beales PE, Williams AJK, Lampeter EF, Pozzilli P (1992) Housing, production and life-maintenance of the nonobese diabetic (NOD) mouse. Animal Technology 43: 29–37.
Morgan DR, Lazarow A (1963) Immunoassay of insulin: two antibody system. Diabetes 20: 1–9
Armitage P, Berry G (1987) Statistical methods in medical research, 2nd edn. Blackwell, Oxford, pp 429–433
Vlahos WD, Yale JF (1987) Prevention of type 1 diabetes in the BB rat by diazoxide. Clin Invest Med 10: B65 (Abstract)
Pontiroli AE, Alberetto M, Bertoletti A, Baio G, Pozza G (1984) Sulfonylureas enhance in vivo the effectiveness of insulin in type 1 (insulin-dependent) diabetes mellitus. Horm Metab Res 16 [Suppl 1]: 167–170
Pernet A, Trimble ER, Kuntschen F, Assal J-Ph, Hahn C, Renold AE (1985) Sulfonylureas in insulin-dependent (type 1) diabetes: evidence for an extrapancreatic effect in vivo. J Clin Endocrinol Metab 61: 247–251
Mooridan AD (1987) The effect of sulphonylurea on the in vivo uptake of glucose in normal rats. Diabetologia 30: 120–121
Goto Y, Kaino Y, Inoue T, Ikeuchi M, Miyagawa T, Matsuda H (1988) Insulin action on glucose uptake by soleus muscles of non-obese diabetic mice and streptozotocin diabetic mice. Metabolism 37: 74–78
Gottlieb PA, Handler ES, Appel MC, Greiner DL, Mordes JP, Rossini AA (1991) Insulin treatment prevents diabetes mellitus but not thyroiditis in RT6-depleted diabetes resistant BB/Wor rats. Diabetologia 34: 296–300
Buschard K, Brogren C-H, Ropke C, Rygaard J (1988) Antigen expression of the pancreatic beta-cells is dependent on their functional state, as shown by a specific BB rat monoclonal autoantibody IC2. APMIS 96: 342–346
Zhang ZJ, Davidson L, Eisenbarth G, Weiner HL (1991) Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin. Proc Natl Acad Sci USA 88: 10252–10256
Chan E, Hosszufalusi N, Charles MA (1991) The use of glipizide to prevent diabetes in the BB rat. Diabetes 40 [Suppl 1]: 116A (Abstract)
Curry DL, Reaven G, Reaven E (1984) Glucose-induced insulin secretion by perfused pancreas of 2- and 12-mo-old Fischer 344 rats. Am J Physiol 247: E385-E388
Goidl EA, Innes JB, Weksler ME (1976) Immunological studies of aging II. Loss of IgG and high avidity plaque-forming cells and increased suppressor cell activity in aging mice. J Exp Med 144: 1037–1048
Bunnag SC, Warner NE, Bunnag S (1966) Effect of tolbutamide on postnatal neogenesis of the islet of Langerhans in mouse. Diabetes 15: 597–603
Chick WL (1973) Beta cell replication in rat pancreatic monolayer cultures: effects of glucose, tolbutamide, glucocorticoid, growth hormone and glucagon. Diabetes 22: 687–693
Popiela H, Morre W (1991) Tolbutamide stimulates proliferation of pancreatic beta cells in culture. Pancreas 6: 464–469
Hellerstrom C, Swenne I (1985) Growth pattern of pancreatic islets in animals. In: Volk BW, Arquilla ER (eds) The diabetic pancreas, 2nd edn. Plenum Press, New York pp 53–79
Coleman DL, Kuzava JE, Leiter EH (1990) Effect of diet on incidence of diabetes in nonobese diabetic mice. Diabetes 39: 432–436
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Williams, A.J.K., Beales, P.E., Krug, J. et al. Tolbutamide reduces the incidence of diabetes mellitus, but not insulitis, in the non-obese-diabetic mouse. Diabetologia 36, 487–492 (1993). https://doi.org/10.1007/BF02743262
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DOI: https://doi.org/10.1007/BF02743262