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Human ß Cells Are Exceedingly Resistant to Streptozotocin in Vivo

Departments of Pathology, Surgery, and Biomedical Engineering, Izaak Walton Killam Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada

Address all correspondence and requests for reprints to: James R. Wright, Jr., M.D., Ph.D., Department of Pathology, Izaak Walton Killam Health Center, 5850 University Avenue, Halifax, Nova Scotia B3H 1V7, Canada. E-mail: . jim.wright{at}iwk.nshealth.ca

Streptozotocin (STZ) causes ß cell death in rodents via the mechanism of DNA damage precipitating poly(ADP-ribose) synthetase activation followed by lethal nicotinamide adenine dinucleotide depletion. It is unclear whether humans are susceptible to this mechanism. Islets were isolated from STZ-sensitive (CD1 mice and Lewis rats) and resistant [fish (tilapia)] species and from man and then were transplanted into diabetic nude mice under the kidney capsule. Normoglycemic recipients with normal glucose tolerance tests on d 30 were injected with increasing iv doses of STZ and their plasma glucose levels followed for 5 d; glucose tolerance tests were repeated on nondiabetic mice. Mice were then killed; grafts and native pancreata were examined. Based upon three criteria (i.e. nonfasting plasma glucose levels, glucose tolerance tests, and islet histology), the following observations were made: 1) Recipients of rat islets were resistant to 25 mg/kg but were uniformly diabetic at doses of 50 or 75 mg/kg. 2) Recipients of mouse islets were resistant to 75 mg/kg but were uniformly diabetic at 150 or 200 mg/kg. 3) Recipients of the fish islets were resistant to 300, 400, and 450 mg/kg. 4) Recipients of human islets were resistant to 100, 200, 300, 400, and 450 mg/kg. The results in recipient mice bearing long-term rat, mouse, or fish islet grafts were the same as previously published dose-response data for each donor species. We extrapolate from our results based on human islet grafts in mice that human ß cells are exceedingly resistant to STZ.

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