COMPLICATIONS - METABOLIC

S. He¹, Y. Chen², Y.R. Lu², L. Wei², X. Jin², L. Zeng², Y. Ren³, J. Zhang², L. Wang⁴, H. Li⁴, J.Q. Cheng^5
1Key Lab Of Transplantation Engineering And Immunology, West China Hospital of Sichuan University, Chengdu/CHINA, ²Laboratory Of Transplant Engineering And Immunology, West China Hospital, Sichaun University, Chengdu/CHINA, ³Department Of Endocrine, West China Hospital, Sichaun University, Chengdu/CHINA, ⁴, National Center for Safety Evaluation of Traditional Chinese Medicine, Chengdu/CHINA, ⁵Laboratory Of Transplant Engineering And Immunology,, West China Hospital, Sichaun University, Chengdu/CHINA

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Introduction:Nonhuman primates (NHPs) diabetic models are valuable for preclinical investigation and new drug evaluation of diabetes, and specifically, they are important for islets transplantation researches. Hypoglycemia is a major threat to the health of the diabetic NHPs, however, limited experiences were reported on prevention and treatment of hypoglycemia in NHPs diabetic models. In this study, we analyzed the risk factors of hypoglycemia, and established a set of methods for observation, early warning and timely treatment of hypoglycemia in diabetic monkeys. Methods:Twenty two rhesus monkeys were induced to diabetes through total pancreatectomy (group 1); partial pancreatectomy with low-dose Streptozotocin(STZ) administration (group 2); high-dose STZ administration (group 3) and multiple low-dose administration (group 4). Laboratory tests were regularly performed, and the models were evaluated by the parameters as BG, IVGTT, Insulin, and C-peptide. Logistic regression analysis was carried out with gender, body weight, the methods of modeling, diabetes duration, exercise, mental health, the amount of exogenous insulin, HbA1c, blood creatine and triglyceride as the risk factors of hypoglycemia. Furthermore, the relationships between the four methods of diabetes induction, renal function, glycemic control and hypoglycemia were studied using one-way ANOVA and T-test. Results:All the monkeys of this study were successfully induced to diabetes, but some differences were observed between groups. C-P levels in group 1 and 3 were much lower than the other two groups (P <0.001). IVGTT results showed that the group 2 and 4 have slender responses for the glucose stimulation, compared to the unresponsive results in the other two groups. The hypoglycemia was improved rapidly by our treatment. The logistic regression analysis suggested that the modeling methods (B=1.891,OR=6.629, P=0.026), blood creatinine (Crea) (B=0.053, OR=1.054, P=0.036) and HbA1c (B=0.998,OR=0.369,P=0.144) were possibly most relative to hypoglycemia. In 4851 monkey-days, the average probability of hypoglycemia occurrence is 0.56(standardized to per 100 monkey-days). And in the group1, 2, 3 and 4, the probability ratios were 0.99, 0.12, 0.41 and 0.8 respectively. Additionally, the Crea and triglyceride levels of all monkeys were significantly increased after 5~9 months of being diabetes (P <0.05), and the hypoglycemic probability was increased by increasing Crea (Wilcoxon test, p=0.014). Moreover, the coefficient of variation (CV) of FBG of group 1, 2, 3 and 4 was 0.71, 0.35, 0.53 and 0.50 respectively. In the same group, the CV in monkeys with hypoglycemia was higher than that in monkeys without hypoglycemia. Conclusion:The present study successfully developed diabetic models in rhesus monkeys through four methods, and established effect treatment program for hypoglycemia. Different induction strategies resulted in differences in diabetes progress, glycemic control effect, and particularly hypoglycemia severity. The diabetic monkeys induced by partial pancreatectomy with low-dose STZ are not susceptible to hypoglycemia and the glycemic controls are stable. The modeling methods and blood creatine level had some relationships with hypoglycemia probability, which should be pay more attention to in the researches on diabetic monkeys.

Disclosure: All authors have declared no conflicts of interest.