Refining the high-dose streptozotocin-induced diabetic non-human primate model: An evaluation of risk factors and outcomes

Melanie L. Graham, Lucas A. Mutch, Eric F. Rieke, Jessica A. Kittredge, Aaron W. Faig, Theresa A. Dufour, James W. Munson, Elizabeth K. Zolondek, Bernhard J. Hering, Henk Jan Schuurman

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1218-1230
Number of pages13
JournalExperimental Biology and Medicine
Volume236
Issue number10
DOIs
StatePublished - Oct 2011

Bibliographical note

Funding Information:
The authors gratefully acknowledge the important contributions of Angela Craig for excellent veterinary care of the animals and Nicholas Robinson in the analysis of histopathological data. Our study was supported by the Schulze Family Foundation, the National Institutes of Health and the Juvenile Diabetes Research Foundation.

Keywords

  • Adverse events
  • Diabetes induction
  • Non-human primate
  • Obesity
  • Refinement
  • Streptozotocin

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