Diazoxide Preconditioning of Nonhuman Primate Pancreas Improves Islet Isolation Outcomes by Mitochondrial Protection

Autor: Joshua E. Mendoza-Elias, Yi He, Jose Oberholzer, Enza Marchese, Matthew A. Bochenek, Meirigeng Qi, Yuan Xing, Yong Wang, James J. McGarrigle
Rok vydání: 2020
Předmět:
Blood Glucose
Male
endocrine system
medicine.medical_specialty
endocrine system diseases
Endocrinology
Diabetes and Metabolism
medicine.medical_treatment
Vasodilator Agents
Organ Preservation Solutions
Islets of Langerhans Transplantation
Apoptosis
Pancreas transplantation
Diabetes Mellitus
Experimental
03 medical and health sciences
Islets of Langerhans
Mice
0302 clinical medicine
Endocrinology
Diabetes mellitus
Internal medicine
Internal Medicine
medicine
Diazoxide
Animals
Pancreas
geography
geography.geographical_feature_category
Hepatology
business.industry
medicine.disease
Islet
Cytoprotection
Mitochondria
Macaca fascicularis
medicine.anatomical_structure
Glucose
030220 oncology & carcinogenesis
Reperfusion Injury
Ischemic preconditioning
030211 gastroenterology & hepatology
Female
business
Reactive Oxygen Species
medicine.drug
Zdroj: Pancreas. 49(5)
ISSN: 1536-4828
Popis: Objectives Previously, we showed that diazoxide (DZ), an effective ischemic preconditioning agent, protected rodent pancreas against ischemia-reperfusion injury. Here, we further investigate whether DZ supplementation to University of Wisconsin (UW) solution during pancreas procurement and islet isolation has similar cytoprotection in a preclinical nonhuman primate model. Methods Cynomolgus monkey pancreata were flushed with UW or UW + 150 μM DZ during procurement and preserved for 8 hours before islet isolation. Results First, a significantly higher islet yield was observed in UW + DZ than in UW (57,887 vs 23,574 IEq/pancreas and 5396 vs 1646 IEq/g). Second, the DZ treated islets had significantly lower apoptotic cells per islet (1.64% vs 9.85%). Third, DZ significantly inhibited ROS surge during reperfusion with a dose-response manner. Fourth, DZ improved in vitro function of isolated islets determined by mitochondrial potentials and calcium influx in responses to glucose and KCI. Fifth, the DZ treated islets had much higher cure rate and better glycemia control in diabetic mice transplant model. Conclusions This study showed a strong mitochondrial protection of DZ on nonhuman primate islets against ischemia-reperfusion injury that provides strong evidence for its clinical application in islet and pancreas transplantation.
Databáze: OpenAIRE
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