Exendin-4 treatment improves metabolic control after rat islet transplantation to athymic mice with streptozotocin-induced diabetes

Abstract

Aims/hypothesis: Early islet graft survival is crucial in determining the outcome after clinical islet transplantation. Exendin-4 has anti-apoptotic and beta cell proliferative properties, which could improve islet graft survival and function. The aim of these studies was to evaluate the effect of exendin-4 on graft function after islet transplantation. Materials and methods: Rat islets were transplanted under the kidney capsule of diabetic athymic mice. First, we performed a dose-finding study and found that 30 islets just failed to cure diabetic mice. In the following two studies, we transplanted 30 islets and treated the mice that had received these islets with exendin-4 i.p. (100 ng/mouse) once daily for 1 week. Blood glucose levels and body weights were used as evaluation criteria. In the short-term study evaluation was done at day 8. This study was followed by a long-term study that was evaluated at 4 weeks. In this study, islets were precultured with exendin-4 (0.1 nmol/l) in addition to the treatment given to mouse-recipients of transplanted islets. The cured mice underwent an intraperitoneal glucose tolerance test (IPGTT). Results: In the shortterm study, 63% of exendin-4-treated mice achieved graft function compared with 21% of untreated mice (p=0.033). In the long-term study, 88% of treated mice had functioning grafts compared with 22% of controls (p=0.015). Cured mice showed a normal response in the IPGTT, comparable to that of healthy mice. Exendin-4-treated mice gained significantly more weight than their untreated counterparts. Conclusions/interpretation: Islet preculture and a short course of therapy with exendin-4 improves metabolic control after rat islet transplantation in athymic mice. The beneficial effect lasts beyond the treatment period.

Islet transplantation in rodents: do encapsulated islets really work?

“…Nonencapsulated islets may be injected into the liver (4,16,18,19,35,44,50,52) , kidney (5,14,15,16,17,24,27,28,32,34,35,42,46,47) , peritoneal cavity (11,35) , bone marrow (41) and subcutaneous tissue (22,48) . Ikebukuro et al (19) showed that islets and bone marrow cells, when injected into the liver using irradiation as immunosuppression, can increase the functionality of the cells for more than 365 days.…”

“…> 100 Lan et al (27) -> 60 Hamamoto et al (14) 2500 41 Kover et al (24) 1500 80 -120 Hiramatsu et al (17) 200 or 20 56 Socha-Urbanek et al (47) 1500 ± 200 150 Laumonier et al (28) 3000 to 3200 19.5 ± 5.8 Omer et al (35) 4000 70 Sharma et al (46) 30 30 -40 Hara et al (16) 500 to 1500 11.0 ± 2.63 Han et al …”

The nucleus tractus solitarius: a portal for visceral afferent signal processing, energy status assessment and integration of their combined effects on food intake

“…The selective agonist to the GLP-1 receptor, Ex-4, was selected as the ligand of choice to examine GLP-1R-mediated control of food intake and gastric emptying, as this compound is used, both experimentally and clinically in the treatment of diabetes mellitus and obesity. [34][35][36][37][38] Control and chronic supracollicular decerebrate rats received Ex-4 or vehicle through IP injection or through the fourth intracerebroventricular cannula. Food intake was assessed using direct oral delivery of liquid nutrient.…”

An Engineered Innate Repair Receptor Agonist, ARA 290, Protects Rat Islets from Cytokine-induced Apoptosis

“…The pancreatic islets of Lewis rats (300-350 g) were isolated as previously described [30]. Briefly, the rat pancreases were digested using collagenase P solution (0.7 mg/mL; Roche Diagnostics GmbH, Mannheim, Germany) and the islets were purified using discontinuous density gradient centrifugation (Histopaque-1119, Histopaque-1077, Sigma-Aldrich).…”