PMID- 21917592
OWN - NLM
STAT- MEDLINE
DCOM- 20111129
LR  - 20131121
IS  - 1535-3699 (Electronic)
IS  - 1535-3699 (Linking)
VI  - 236
IP  - 10
DP  - 2011 Oct
TI  - Refining the high-dose streptozotocin-induced diabetic non-human primate model: 
      an evaluation of risk factors and outcomes.
PG  - 1218-30
LID - 10.1258/ebm.2011.011064 [doi]
AB  - 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 >3x baseline or >5 x 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.
FAU - Graham, Melanie L
AU  - Graham ML
AD  - Department of Surgery, Schulze Diabetes Institute, University of Minnesota, 424 
      Harvard Street SE, Minneapolis, MN 55455, USA. graha066@umn.edu
FAU - Mutch, Lucas A
AU  - Mutch LA
FAU - Rieke, Eric F
AU  - Rieke EF
FAU - Kittredge, Jessica A
AU  - Kittredge JA
FAU - Faig, Aaron W
AU  - Faig AW
FAU - DuFour, Theresa A
AU  - DuFour TA
FAU - Munson, James W
AU  - Munson JW
FAU - Zolondek, Elizabeth K
AU  - Zolondek EK
FAU - Hering, Bernhard J
AU  - Hering BJ
FAU - Schuurman, Henk-Jan
AU  - Schuurman HJ
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110914
PL  - Switzerland
TA  - Exp Biol Med (Maywood)
JT  - Experimental biology and medicine (Maywood, N.J.)
JID - 100973463
RN  - 0 (C-Peptide)
RN  - 5W494URQ81 (Streptozocin)
SB  - IM
MH  - Animals
MH  - Body Surface Area
MH  - Body Weight
MH  - C-Peptide/blood
MH  - Diabetes Mellitus, Experimental/*complications
MH  - *Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Glucose Tolerance Test
MH  - Macaca fascicularis/*metabolism
MH  - Macaca mulatta/*metabolism
MH  - Male
MH  - Obesity/complications
MH  - Risk Factors
MH  - Streptozocin/administration & dosage/adverse effects/pharmacology
EDAT- 2011/09/16 06:00
MHDA- 2011/12/13 00:00
CRDT- 2011/09/16 06:00
PHST- 2011/09/16 06:00 [entrez]
PHST- 2011/09/16 06:00 [pubmed]
PHST- 2011/12/13 00:00 [medline]
AID - ebm.2011.011064 [pii]
AID - 10.1258/ebm.2011.011064 [doi]
PST - ppublish
SO  - Exp Biol Med (Maywood). 2011 Oct;236(10):1218-30. doi: 10.1258/ebm.2011.011064. 
      Epub 2011 Sep 14.