Diabetes mellitus is a collection of diseases that culminate in defects in carbohydrate metabolism and result in inappropriate hyperglycemia. Most individuals with this disease can be categorized into 1 of 2 groups, depending upon their insulin requirements. Individuals who require insulin therapy to maintain life have been designated as having insulin-dependent diabetes mellitus (IDDM), while individuals who can live without insulin treatment have been classified as having noninsulin-dependent diabetes mellitus (NIDDM). The single most important pathological finding in IDDM is a substantial reduction in the number of insulin-secreting pancreatic beta cells. Compelling experimental and epidemiological evidence indicates that, at least in some forms of IDDM, environmental factors, such as chemical toxins, play an important role in the etiology of this disease. Chemical toxins can precipitate IDDM through a variety of mechanisms. They can poison beta cells directly and cause the destruction of a critical mass of beta cells; alternatively, they can trigger autoimmune processes directed against beta cells; or, finally, they can augment the diabetogenic properties of another agent, such as a virus, to hasten the onset of clinical manifestations. In NIDDM, impaired beta cell function appears to be the initial event observed at the onset of this syndrome. Functional defects similar to those seen in NIDDM can be produced in laboratory animals using a specific beta cell toxin. These animals develop permanent glucose intolerance and insulin resistance as a consequence of beta cell alteration. A variety of other chemicals also have been found to produce glucose intolerance; however, this condition is transient and is resolved when the chemical is removed. This review will focus on a discussion of chemicals that are known to cause IDDM, NIDDM or transient glucose intolerance and their putative mechanisms of action. Additionally, new methods for identifying and evaluating potential toxins will be considered.
1. Ames BN (1983). Dietary carcinogens and anticar-cinogens: Oxygen radicals and degenerative diseases.Science221: 1256–1264.
2.
2. Anysley-Green A and Alberti KG (1973). Diuretics and carbohydrate metabolism: The effects of furosemide and amiloride on blood glucose, plasma insulin and cations in the rat.Diabetologia9: 34–42.
3.
3. Black J (1968). Diazoxide and the treatment of hypoglycemia: An historical review.Ann. N.Y. Acad. Sci.150: 194–203.
4.
4. Blay RA, Bigley NJ, and Giron DJ (1985). A murine model of insulin-dependent diabetes resulting from the cumulative effects of the nondiabetogenic strain of encephalomyocarditis virus and a single low dose of streptozotocin.Diabetes34: 1288–1292.
5.
5. Brunzell JD, Robertson RP, Lerner RL, Hazzard WR, Einsinck JW, Bierman EL, and Porte D (1976). Relationship between fasting plasma glucose levels and insulin secretion during intravenous glucose tolerance tests.J. Clin. Endocrinol. Metab.42: 222–229.
6.
6. Capizzi RL, Bertino JR, and Skeel RT (1971). L-asparaginase: Clinical, biochemical, pharmacological and immunological studies.Ann. Int. Med.74: 893–901.
7.
7. Chick WL, King DL, and Lauris V (1977). Techniques for the preparation and maintenance of pancreatic beta cell monolayer cultures. In: Pancreatic Beta Cell Culture, E Von Wasielewski and WL Chick (eds). Excerpta Med., Amsterdam, pp. 85–91.
8.
8. Chow SA and Fischer LJ (1984). Alterations in rat B-cell function induced by prenatal exposure to cyproheptadine.Diabetes33: 572–575.
9.
9. Chow SA and Fischer LJ (1986). Susceptibility of fetal rat endocrine pancreas to the diabetogenic action of cyproheptadine.Toxicol. Appl. Pharmacol.84: 264–277.
10.
10. Cooperstein SJ and Watkins D (1981). Action of toxic drugs on islet cells. In: The Islets of Langerhans, SJ Cooperstein and D Watkins (eds). Academic Press, New York, pp. 387–425.
11.
11. Craighead JE (1978). Current views of insulin-dependent diabetes mellitus.N. Engl. J. Med.299: 1439–1445.
12.
12. Dulin WE and Soret MG (1977). Chemically and hormonally induced diabetes. In: The Diabetic Pancreas, BW Volk and KF Wellman (eds). Plenum Publishing Co., New York pp. 425–466.
13.
13. Eberhardt MS, Wagener DK, Orchard TJ, LaPorte RE, Cavender DE, Rabin BS, Atchison RW, Kuller LH, Drash AL, and Becker DJ (1985). HLA heterogeneity of insulin-dependent diabetes mellitus at diagnosis: The Pittsburgh IDDM study.Diabetes34: 1247–1252.
14.
14. Eisenbarth GS (1986). Type I diabetes mellitus: A chronic autoimmune disease.N. Engl. J. Med.314: 1360–1368.
15.
15. Eun H-M, Pak CY, Kim CJ, McArthur RG, and Yoon JW (1987). Role of cyclosporin A in macromolecular synthesis of beta cells.Diabetes36: 952–958.
16.
16. Feldberg W and Symonds HW (1980). Hyperglycemic effect of xylazine.J. Vet. Pharmacol. Ther.3: 197–202.
17.
17. Feldberg W, Pyke DA, and Stubbs WA (1985). Phentolamine hyperglycaemia in cats. J. Physiol.366: 25P.
18.
18. Gailani S, Nussbaum A, and Ohnuma T (1971). Diabetes in patients treated with asparaginase.Clin. Pharmacol. Ther.12: 487–490.
19.
19. Gazdar AF, Chick WL, Oie HK, Sims HL, King DL, Weir GC, and Lauris V (1980). Continuous, clonal, insulin- and somatostatin-secreting cell lines established from a transplantable rat islet cell tumor.Proc. Natl. Acad. Sci. USA77: 3519–3523.
20.
20. Giroix MH, Portha B, Kergoat M, Baibe D, and Picon L (1983). Glucose insensitivity and amino acid hypersensitivity of insulin release in rats with noninsulin-dependent diabetes.Diabetes32: 445–451.
21.
21. Gunnarsson R, Berne C, and Hellerstrom C (1974). Cytotoxic effects of streptozotocin and N-nitrosomethylurea on the pancreatic beta cell with special regard to the role of nicotinamide adenine dinucleotide.Biochem. J.140: 487–494.
22.
22. Haneda M, Chan SJ, Kwok SCM, Rubenstein AH, and Steiner DF (1983). Studies on mutant human insulin genes: Identification and sequence analysis of a gene encoding [SerS24]insulin.Proc. Natl. Acad. Sci. USA80: 6366–6370.
23.
23. Hawksworth GM and Hill JJ (1974). The in vivo formation of N-nitrosamines in the rat bladder and their subsequent absorption.Br. J. Cancer29: 353–358.
24.
24. Hedler L and Marquardt P (1968). Occurrence of diethylnitrosamine in some samples of food.Food Cosmet. Toxicol.6: 341–349.
25.
25. Helgason T and Jonasson MR (1981). Evidence for a food additive as a cause of ketosis-prone diabetes.Lancetii: 716–720.
26.
26. Irvine WJ, McCallum CJ, and Gray RS (1977). Pancreatic islet-cell antibodies in diabetes mellitus correlated with the duration and type of diabetes, coexistent autoimmune disease and HLA type.Diabetes26: 138–147.
27.
27. Karam JH, Lewitt PA, Young C, Nowlain R, Frankel B, Fujiya H, Freedman Z, and Grodsky G (1980). Insulinopenic diabetes after rodenticide (Vacor) ingestion: A unique model of acquired diabetes in man.Diabetes29: 971–978.
28.
28. Kneip TJ, Daisey JM, Solomon JJ, and Hershman RJ (1983). N-nitroso compounds: Evidence for their presence in airborne particles.Science221: 1045–1046.
29.
29. Lacy PE and Kostianovsky M (1969). Method for the isolation of intact islets of Langerhans from the rat pancreas.Diabetes16: 35–39.
30.
30. LeDoux SP and Wilson GL (1984). Effects of streptozotocin on a clonal isolate of rat insulinoma cells.BBA804: 387–392.
31.
31. Like AA and Rossini AA (1976). Streptozotocin-induced pancreatic insulitis: New model of diabetes mellitus.Science193: 415–417.
32.
32. Magee PN and Barnes JM (1956). The production of malignant primary hepatic tumors in the rat by feeding dimethylnitrosamine.Br. J. Cancer10: 114–120.
33.
33. Magee PN (1975). N-nitroso compounds and related carcinogens. In: Chemical Carcinogens, CE Searle (ed). American Chemical Society, Washington, DC, pp. 491–509.
34.
34. Metz SA, Halter JB, and Robertson RP (1979). Paradoxical inhibition of insulin secretion by glucose in human diabetes mellitus.J. Clin. Endocrinol. Metab.48: 827–835.
35.
35. Mossman BT, Wilson GL, Ireland C, and Craighead JE (1985). A diabetogenic analogue of streptozotocin with dissimilar mechanisms of action on pancreatic beta cells.Diabetes34: 602–607.
36.
36. Nakhooda AF, Wollheim CB, Blondel B, and Marliss EB (1977). Secretory function of endocrine pancreatic cells in monolayer culture: Characterization and applications. In: Pancreatic Beta Cell Culture, E Von Wasielewski and WL Chick (eds). Excerpta Med., Amsterdam, pp. 119–134.
37.
37. Nielsen JH, Mandrup-Poulsen T, and Nerup J (1986). Direct effects of cyclosporin A on human pancreatic beta cells.Diabetes35: 1049–1052.
38.
38. Ohnuma T, Holland JF, and Freeman A (1970). Biochemical and pharmacological studies with asparaginase in man.Cancer Res.30: 2297–2305.
39.
39. Pfeifer MA, Halter JB, and Porte D (1981). Insulin secretion in diabetes mellitus.Am. J. Med.70: 579–588.
40.
40. Prosser PR and Karam JH (1978). Diabetes mellitus following rodenticide ingestion in man.J. Am. Med. Assoc.239: 1148–1150.
41.
41. Rickert DE, Burke J, and Fischer LJ (1975). Cyproheptadine-induced depletion of insulin in the rat.J. Pharmacol. Exp. Ther.193: 585–593.
42.
42. Robertson RP (1986). Cyclosporin-induced inhibition of insulin secretion in isolated rat islets and HIT cells.Diabetes35: 1016–1019.
43.
43. Rossini AA, Like AA, Chick WL, Appel MC, and Cahill GF (1977). Studies of streptozotocin-induced insulitis and diabetes.Proc. Natl. Acad. Sci. USA74: 2485–2489.
44.
44. Rossini AA, Appel MC, Williams RM, and Like AA (1977). Genetic influence of streptozotocin-induced insulitis and hyperglycemia.Diabetes26: 916–920.
45.
45. Rotter JI and Rimoin DL (1978). Heterogeneity in diabetes mellitus.Diabetes27: 599–608.
46.
46. Sander J and Burke G (1971). Induktion maligner Tumoren bei Ratten durch orale Gabe von 2-Imidazolidinon und Nitrit.Krebs Forsch.75: 301–310.
47.
47. Santerre RF, Cook RA, Crisel RMD, Sharp JD, Schmidt RJ, Williams DC, and Wilson CP (1981). Insulin synthesis in a clonal cell line of simian virus SV 40-transformed hamster pancreatic beta cells.Proc. Natl. Acad. Sci. USA78: 4339–4343.
48.
48. Sanz N, Karam JH, Horita S, and Bell GI (1986). Prevalence of insulin-gene mutations in non-insulin-dependent diabetes mellitus.N. Engl. J. Med.3141322: .
49.
49. Schaffer SW, Tan BH, and Wilson GL (1985). Development of a cardiomyopathy in a model of non-insulin-dependent diabetes.Am. J. Physiol.248: H179–H185.
50.
50. Sen WP (1973). Nitrosopyrrholidine and dimethyl-nitrosamine in bacon.Nature241: 473–475.
51.
51. Sener A and Malaisse WJ (1985). Resistance to alloxan of tumoral insulin-producing cells.FEBS193: 150–152.
52.
52. Sesfontein WJ and Huster P (1966). Nitrosoamines as environmental carcinogens. II. Evidence for the presence of nitrosoamines in tobacco smoke condensate.Cancer Res.26: 575–583.
53.
53. Toniolo A, Onodera T, Yoon JW, and Notkins AL (1980). Induction of diabetes by cumulative environmental insults from viruses and chemicals.Nature288: 383–385.
54.
54. Trent DF, Fletcher J, May JM, Bonner-Weir S, and Weir GC (1984). Abnormal islet and adipocyte function in young B-cell deficient rats with near normoglycemia.Diabetes33: 170–175.
55.
55. Ward WK, Beard JC, Halter JB, Pfeifer MA, and Porte D (1984). Pathophysiology of insulin secretion in non-insulin-dependent diabetes mellitus.Diabetes Care7: 491–502.
56.
56. Weir GC, Clore ET, Zmachinski CJ, and Bonner-Weir S (1981). Insulin secretion in a new experimental model for noninsulin-dependent diabetes.Diabetes30: 590–595.
57.
57. Wilson GL (1983). Use of beta cells in culture to identify diabetogenic N-nitroso compounds.In Vitro19: 25–30.
58.
58. Wilson GL and Gaines KL (1983). Effects of the rodenticide Vacor on cultured rat pancreatic beta cells.Toxicol. Appl. Pharmacol.68: 375–379.
59.
59. Wold JS, Longnecker DS, and Fischer LJ (1971). Species-dependent pancreatic islet toxicity produced by cyproheptadine: Alterations in beta-cell structure and function.Toxicol. Appl. Pharmacol.19: 188–196.
