title: Streptozotocin is responsible for the induction and progression of renal tumorigenesis in diabetic Wistar-Furth rats treated with insulin or transplanted with agarose encapsulated porcine islets.
abstract: Streptozotocin (STZ), a nitrosourea with DNA alkylating properties, has been widely used to induce hyperglycemia by specifically destroying the insulin-producing β-cells of the islets of Langerhans in experimental models of Type I diabetes. STZ's known carcinogenic properties, however, raise concerns about its suitability for long-term studies. We conducted a formal study of STZ's carcinogenic effects in long-term surviving diabetic Wistar-Furth rats. To determine if insulin therapy or islet transplantation exacerbated tumorigenesis, rats were randomly assigned to one of four experimental groups: normal animals with no treatment (Group 1, n=12); normal animals that underwent peritoneal implantation of porcine islets encapsulated in a double layer of agarose to form islet macrobeads (normal + islets; group 2, n=12); STZ treatment followed by daily exogenous insulin (STZ + insulin; group 3, n=18) and STZ treatment followed by the intraperitoneal implantation of porcine islet macrobeads (STZ + islets; group 4, n=14). At 215 days post-STZ induction, no renal proliferative lesions were observed in animals that did not receive STZ (group 1 and group 2) whereas adenoma incidences of 57% for group 3 and 34% for group 4 were observed. By terminal necropsy at day 351, the incidence and severity of renal proliferative lesions increased with tubular carcinoma observed in 67% of group 3 and 60% of group 4 animals. We conclude that the STZ-induced diabetic rat model is not suitable for long-term studies because of progressive renal tumorigenesis. Our experiments also demonstrate the safety and effectiveness of porcine islet macrobeads for the treatment of diabetes.
authors.affiliation: The Rogosin Institute-Xenia Division, Xenia, OH, USA. hvinerean@rixd.org
authors.forename: Horatiu V
authors.initials: HV
authors.lastname: Vinerean
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Gazda
authors.forename: Richard D
authors.initials: RD
authors.lastname: Hall
authors.forename: Barry H
authors.initials: BH
authors.lastname: Smith
mesh_terms: D000236:Adenoma / Q000139:chemically induced / Q000209:etiology / Q000473:pathology; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002292:Carcinoma, Renal Cell / Q000139:chemically induced / Q000209:etiology / Q000473:pathology; D003043:Cocarcinogenesis; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000601:surgery*; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use; D007328:Insulin / Q000009:adverse effects* / Q000627:therapeutic use; D016381:Islets of Langerhans Transplantation / Q000009:adverse effects* / Q000379:methods; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology; D008297:Male; D011897:Random Allocation; D051381:Rats; D011920:Rats, Inbred WF; D012685:Sepharose / Q000009:adverse effects; D013311:Streptozocin / Q000633:toxicity*; D034421:Sus scrofa; D054457:Tissue Scaffolds / Q000009:adverse effects; D014183:Transplantation, Heterologous; D016042:Transplantation, Heterotopic
chemical_list: D002273:Carcinogens; D007004:Hypoglycemic Agents; D007328:Insulin; D013311:Streptozocin; D012685:Sepharose