Induction of Diabetes in Cynomolgus Monkeys With High-dose Streptozotocin

Rood, Pleunie P.M.; Bottino, Rita; Balamurugan, A. N.; Smetanka, Cynthia; Ezzelarab, Mohamed; Busch, J.O.; Hara, Hidetaka; Trucco, Massimo; Cooper, David K. C.

doi:10.1097/01.mpa.0000235307.04110.a2

Cited by 37 publications

(49 citation statements)

References 22 publications

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“…IVGTTs, OGTTs, ASTs and MMTs were performed 8-35 days (median 11 days) after induction of diabetes. Immunohistochemical analyses of pancreatic sections from four diabetic monkeys showed <1% of insulin-positive cells compared with ∼70% of insulin-positive cells in healthy controls, as reported previously [16].…”

Section: Methodssupporting

confidence: 87%

“…In this regard, recent data indicate that wild-type neonatal or adult pig islets can survive for weeks in monkey recipients [2,3]. One of these studies [3], as well as our own studies [4,16], were performed in cynomolgus monkeys. These Old World monkeys represent a good model for islet transplantation studies [3,7,36].…”

Section: Discussionmentioning

confidence: 96%

“…These Old World monkeys represent a good model for islet transplantation studies [3,7,36]. They can be rendered diabetic by the administration of streptozotocin [7,16,38,39] or by total pancreatectomy [2,40], and prior to islet transplantation the induced diabetes can be controlled by insulin injections for long periods of time.…”

Section: Discussionmentioning

confidence: 99%

“…injection of streptozotocin 125-150 mg/kg (Zanosar; Sicor Pharmaceuticals, Irvine, CA, USA) in a single dose, as described in [16].…”

Section: Methodsmentioning

confidence: 99%

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Metabolic aspects of pig-to-monkey (Macaca fascicularis) islet transplantation: implications for translation into clinical practice

et al. 2007

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Aims/hypothesis Attempts to use an alternative source of islets to restore glucose homeostasis in diabetic patients require preclinical islet xenotransplantation models to be tested. These models raise questions about metabolic compatibility between species and the most appropriate metabolic parameters to be used to monitor graft function. The present study investigated and compared relevant gluco-metabolic parameters in pigs, monkeys and the pig-to-monkey islet transplantation model to gain insight into the potential clinical outcome of pig-to-human islet transplantation. Methods Basal and IVGTT-stimulated blood glucose, Cpeptide, insulin and glucagon levels were assessed in nondiabetic pigs and monkeys. The same parameters were used to evaluate the performance of porcine islet xenografts in diabetic monkeys. Results Non-diabetic cynomolgus monkeys showed lower levels of fasting and stimulated blood glucose but higher levels of C-peptide and insulin than non-diabetic pigs. The reported levels in humans lie between those of monkeys and pigs, and differences in metabolic parameters between pigs and humans appear to be smaller than those between pigs and cynomolgus monkeys. The transplantation data indicated that the degree of graft function (evaluated by the measurement of C-peptide levels) necessary to normalise blood glucose in the recipient was determined by the recipient levels rather than by the donor levels. Conclusions/interpretation The differences between donor and recipient species may affect the transplantation outcome and need to be considered when assessing graft function in xenotransplantation models. Given the differences between monkeys and humans as potential recipients of pig islets, it should be easier to reach glucose homeostasis in pig-to-human than in pig-to-non-human primate islet xenotransplantation.

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Section: Methodssupporting

confidence: 87%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

“…injection of streptozotocin 125-150 mg/kg (Zanosar; Sicor Pharmaceuticals, Irvine, CA, USA) in a single dose, as described in [16].…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Metabolic aspects of pig-to-monkey (Macaca fascicularis) islet transplantation: implications for translation into clinical practice

et al. 2007

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“…Blood glucose levels were measured at pre-STZ injection, and 6, 20, and 28 h post-STZ injection. Corroborating previous studies [25,27], a representative triphasic blood glucose response to STZ was observed in monkeys treated with 100 mg kg 1 (STZ 100) and 68 mg kg 1 (STZ 68) of STZ (7.5 mmol L 1 at 6 h post-STZ, followed by 1.5 mmol L 1 at 20 h post-STZ, and 8 mmol L 1 at 28 h post-STZ). However, the insulindependent monkey treated with 60 mg kg 1 of STZ (STZ 60-ID) did not exhibit the above mentioned blood glucose response.…”

Section: Resultssupporting

confidence: 79%

Characterizing the induction of diabetes in juvenile cynomolgus monkeys with different doses of streptozotocin

Zou

Wang

et al. 2012

Sci. China Life Sci.

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Juvenile (23 years old) cynomolgus monkeys are frequently used as recipients in non-human primate islet transplantation studies. The aim of this study was to examine the effects of different doses of streptozotocin (STZ), and find the optimal dose for inducing diabetes in these monkeys. Fifteen juvenile (23 years old) cynomolgus monkeys were separated into three groups and administered with different doses of STZ (100, 68 or 60 mg kg 1 ). Basal and glucose-stimulated blood glucose, insulin, and C-peptide levels, as well as body weights were monitored. Hepatic and renal function tests and pancreatic immunohistochemistry were performed before and after STZ treatment. Monkeys treated with both 100 and 68 mg kg 1 of STZ exhibited continuous hyperglycemia, which coincided with a nearly complete loss of islet -cells. Two monkeys received 60 mg kg 1 of STZ, but only one became completely diabetic. During the first week following STZ treatment, hepatic and renal function slightly increased in these three groups. However, 24 hours post-STZ, serum total bile acid levels were significantly increased in monkeys treated with 100 mg kg 1 than those treated with 68 mg kg 1 of STZ (P<0.05). These data suggest that 100 mg kg 1 and 68 mg kg 1 of STZ can safely induce diabetes in cynomolgus monkeys aged 23 years, but 68 mg kg 1 of STZ, rather than 100 mg kg 1 of STZ, may be more appropriate for inducing diabetes in these monkeys. Furthermore, body surface area, rather than body weight, was a more reliable determinant of dosage, where 700 mg m 2 of STZ should be the lower limit for inducing diabetes in juvenile monkeys. cynomolgus monkeys, diabetes, streptozotocinCitation:

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Induction of diabetes in cynomolgus monkey with one shot of analytical grade streptozotocin

Liu

et al. 2020

Anim Models and Exp Med

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Backgrounds: Streptozotocin (STZ)-induced diabetic monkey is a wide used preclinical animal model for the investigation of diabetes such as islet transplantation and development of diabetic drugs. There are serious side effects of this method, including nausea, emesis, weight loss, liver damage, renal failure, and metabolic acidosis.In order to reduce the side effects, diabetic monkeys were induced using clinicalgrade STZ. However, clinical-grade STZ is not available in China. Here, we establised a method by using 100 mg/kg analytical-grade STZ to induce complete diabetes in cynomolgus monkey without generating adverse effects to liver and renal.Methods: Three cynomolgus monkeys were used in this study. 100 mg/kg STZ dissolved in normal saline and infused through vein line in 5 minutes after indwelling catheter in the carotid artery and jugular vein. After the STZ administration, blood glucose levels were examined every 1 or 2 hours in the first 48 hours. Then, blood glucose levels were examined twice per day during the first week after the STZ injection. Insulin and C-peptide levels were measured by ELISA. Blood chemistry of hepatic and renal function tests were performed. Insulin and glucagon expression in the islet of diabetic monkey and normal monkey were examined by immunohistochemistry assays.Results: The stimulated C-peptide level (Intravenous glucose tolerance test) which is less than 0.5 ng/mL, the triphasic blood glucose response and the destroyed β cell suggested the complete induction of diabetes model. No apparent adverse effects were observed including no signs of vomiting and toxicity after STZ injection. Conclusion:In summary, we established a safe and reproducible STZ-induced diabetic cynomolgus monkey model for islet transplantation which will be used to develop novel approaches for the treatment of diabetes. How to cite this article: Liu Z, Lu Y, Hu W, et al. Induction of diabetes in cynomolgus monkey with one shot of analytical grade streptozotocin. Animal Model Exp Med. 2020;3:79-86.

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Induction of Diabetes in Cynomolgus Monkeys With High-dose Streptozotocin

Abstract: (1) High-dose Zanosar STZ induced diabetes safely in cynomolgus monkeys without adverse effects. (2) A triphasic blood glucose response suggested the complete induction of diabetes.

Cited by 37 publications

References 22 publications

Metabolic aspects of pig-to-monkey (Macaca fascicularis) islet transplantation: implications for translation into clinical practice

Metabolic aspects of pig-to-monkey (Macaca fascicularis) islet transplantation: implications for translation into clinical practice

Characterizing the induction of diabetes in juvenile cynomolgus monkeys with different doses of streptozotocin

Induction of diabetes in cynomolgus monkey with one shot of analytical grade streptozotocin

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