Human beta cells are exceedingly resistant to streptozotocin in vivo.
Streptozotocin (STZ) causes beta 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 beta cells are exceedingly resistant to STZ.
Yang
Hua
H
Department of Pathology, Izaak Walton Killam Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada.
Wright
James R
JR
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D004351:Drug Resistance; D005951:Glucose Tolerance Test; D006801:Humans; D007515:Islets of Langerhans / Q000187:drug effects* / Q000473:pathology; D016381:Islets of Langerhans Transplantation / Q000502:physiology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D051381:Rats; D011917:Rats, Inbred Lew; D013045:Species Specificity; D013311:Streptozocin / Q000633:toxicity*; D017210:Tilapia
D013311:Streptozocin