Zhengzhao Liu, People's Republic of China
Research associate
Central laboratory
Shenzhen Second People's Hospital
Induction of diabetes in cynomolgus monkey with one injection of streptozotocin
Zhengzhao Liu1, Lisha Mou1, Ying Lu1, Wenbao Hu1, Tian He1, Zhicheng Zou1, Huidong Zhou1, Rita Bottino2, David K.C. Cooper3, Zhiming Cai1.
1Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Second People's Hospital, Shenzhen, People's Republic of China; 2Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, United States; 3Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Pittsburgh, PA, United States
Xenotransplantation.
Introduction: Islet cell transplantation has long been considered as a potential cure for type I diabetes. The shortage of human donors has drawn the attention to xenotransplantation. The preclinical study in pig-to-Non human primate xenotransplantation provide valuable model to study the immunorejection. Streptozotocin (STZ) induced diabeitc monkey is a wide used pre-clinical animal model for islet xenotransplantation. It has a variety of adverse effects, ranging from nausea, emesis, and weight loss to liver damage, renal failure, and metabolic acidosis[1]. Although it has been found difficult to achieve complete diabetes without serious adverse effects. We have found that 100mg/kg STZ i.v. can safely induce complete diabetes in cynomolgus monkey.
Materials and Methods: After carrying indwelling catheter in the carotid artery and vein[2], cynomolgus monkey received 100 mg/kg STZ (Sigma) i.v. dissolved in normal saline and infused from vein line in 5 min[3].
Results and discussion: The monkey that received 100 mg/kg STZ become fully diabetic (C-peptide, 0.33 ng/mL) with no apparent adverse effects. The stimulated C-peptide level (IVGTT) is less than 0.5 ng/mL.
A triphasic response in blood glucose was observed during the first 36 hours after STZ administration.
An initial decrease of insulin release as a result of inflammation and an inability of the beta cells to respond to glucose because of streptozotocin enters the B cell via a glucose transporter (GLUT2) and causes alkylation of DNA[4]; Further destruction and disruption of the beta cells results in a massive release of insulin leading to a fall in blood glucose level; Finally, there is a critical loss of beta cells resulting in diabetic states[2].This optimal dosage of STZ provides a useful model for islet xenotransplantation[2].
Conclusions: (1) 100mg/kg STZ induced diabetes safely in cynomolgus monkey without adverse effects. (2) A triphasic blood glucose response suggested the complete induction of diabetes. We have found that 100mg/kg STZ i.v. can safely induce complete diabetes in cynomolgus monkey.
References:
[1] Nagaraju, S., et al., Streptozotocin-associated lymphopenia in cynomolgus monkeys.Islets 2014; 6(3): p. e944441.
[2] Rood, P.P., et al., Induction of diabetes in cynomolgus monkeys with high-dose streptozotocin: adverse effects and early responses. Pancreas, 2006. 33(3): p. 287-92.
[3] Koulmanda, M., et al., The effect of low versus high dose of streptozotocin in cynomolgus monkeys (Macaca fascilularis). Am J Transplant, 2003. 3(3): p. 267-72.
[4] Szkudelski, T., The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res, 2001. 50(6): p. 537-46.
Lectures by Zhengzhao Liu
| When | Session | Talk Title | Room |
|---|---|---|---|
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Sat-20 17:00 - 18:30 |
Cell Transplant and Xenotransplantation Posters | Induction of diabetes in cynomolgus monkey with one injection of streptozotocin | Hall 5FG-Level 5 |