title: Refining the high-dose streptozotocin-induced diabetic non-human primate model: an evaluation of risk factors and outcomes.
abstract: In preparation for islet transplantation, diabetes was induced using streptozotocin (STZ) in non-human primates ranging from juveniles to adults with diverse body types: we studied the process with respect to the diabetic state and emergence of adverse events (AEs) and their severity, and identified risk factors for clinical and laboratory AEs. Pharmaceutical-grade STZ was given based on body surface area (BSA) (1050-1250 mg/m(2), equivalent to 80-108 mg/kg) or on body weight (BW) (100 mg/kg) to 54 cynomolgus and 24 rhesus macaques. AEs were related to risk factors, i.e. obesity parameters, BW and BSA, age and STZ dose in mg/m(2). Clinical AEs during the first days after infusion prompted euthanasia of three animals. Except for those three animals, diabetes was successfully induced as shown by circulating C-peptide levels, the intravenous glucose tolerance test and/or arginine stimulation test. C-peptide after infusion weakly correlated (P = 0.048) with STZ dose in mg/m(2). Grade ≥3 nephrotoxicity or hepatotoxicity (serum markers >3× baseline or >5 × baseline, respectively) occurred in about 10% of cases and were generally mild and reversible. Grade ≥2 clinical AEs occurred in seven of 78 animals, reversed in four cases and significantly correlated with obesity parameters. Taking girth-to-height ratio (GHtR) as an indicator of obesity, with threshold value 0.92-0.95, the positive predictive value of obesity for AEs was 92% and the specificity 94%. We conclude that diabetes is successfully induced in non-obese animals using a 100 mg/kg pharmaceutical grade STZ dose. Obesity is a significant risk factor, and animals with a higher than normal GHtR should preferably receive a lower dose. The incidence of relevant clinical or laboratory AEs is low. Careful monitoring and supportive medical intervention can result in recovery of AEs.
authors.affiliation: Department of Surgery, Schulze Diabetes Institute, University of Minnesota, 424 Harvard Street SE, Minneapolis, MN 55455, USA. graha066@umn.edu
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Graham
authors.forename: Lucas A
authors.initials: LA
authors.lastname: Mutch
authors.forename: Eric F
authors.initials: EF
authors.lastname: Rieke
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Kittredge
authors.forename: Aaron W
authors.initials: AW
authors.lastname: Faig
authors.forename: Theresa A
authors.initials: TA
authors.lastname: DuFour
authors.forename: James W
authors.initials: JW
authors.lastname: Munson
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Zolondek
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Hering
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Schuurman
mesh_terms: D000818:Animals; D001830:Body Surface Area; D001835:Body Weight; D002096:C-Peptide / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005951:Glucose Tolerance Test; D008252:Macaca fascicularis / Q000378:metabolism*; D008253:Macaca mulatta / Q000378:metabolism*; D008297:Male; D009765:Obesity / Q000150:complications; D012307:Risk Factors; D013311:Streptozocin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D002096:C-Peptide; D013311:Streptozocin