Will GLP-1R analogues exert proliferative or cytoprotective actions in isolated transplanted islets?
Exendin-4 has been shown to enhance Pdx-1 expression, but not insulin expression, in human islet-like cell clusters treated for 4 days in vitro, and exendin-4 treatment of rats (10 days of injections initiated 48 hrs after the transplantation procedure) with transplanted clusters induced functional maturation of transplanted cells, and promoted the differentiation and growth of clusters transplanted under the kidney capsule, as assessed 8 weeks following the transplant. See Exendin 4 Up-Regulates Expression of PDX 1 and Hastens Differentiation and Maturation of Human Fetal Pancreatic Cells. J Clin Endocrinol Metab. 2002 Oct 1;87(10):4775-4781
Does activation of GLP-1R signaling promote cell survival in the context of islet transplantation? King et al examined this question in experimental murine islet transplantation, with or without exendin-4. If islets were cultured prior to transplantation, concomitant treatment with exendin-4 improved the experimental outcome, as outlined in Islet transplantation outcomes in mice are better with fresh islets and exendin-4 treatment. Diabetologia. 2005 Aug 23; [Epub ahead of print]. However, treatment of the recipient mice with exendin-4 without islet pre-treatment did not have beneficial effects on glucose homeostasis.
Sharma and colleagues examined glucose homeostasis in diabetic athymic mice transplanted with rat islets concomitant with exendin-4 administration. Exendin-4 was also used to treat the islets prior to transplantation. Exendin-4 produced significant improvements in graft function and in the amelioration of experimental diabetes as described in Exendin-4 treatment improves metabolic control after rat islet transplantation to athymic mice with streptozotocin-induced diabetes. Diabetologia. 2006 Apr 12; [Epub ahead of print]
Acute infusion of GLP-1 also produced modest but detectable increases in insulin levels in human subjects with islets transplants, as described in Effect of glucagon-like peptide-1 (7-37) on beta-cell function after islet transplantation in type 1 diabetes. Diabetes Res Clin Pract. 2006 Apr 16; [Epub ahead of print]
Transplantation of rat islets (30 islets) under the kidney capsule of diabetic nude mice (STZ), with or without a single daily dose of exendin-4 (100 ng/mouse) for 8 days produced striking improvements in glucose tolerance demonstrated at the 4 week time point, 3 weeks after the last dose of exendin-4. There was little quantitative data provided about islet mass or the mechanisms activated by exendin-4 that produced these effects. See Exendin-4 treatment improves metabolic control after rat islet transplantation to athymic mice with streptozotocin-induced diabetes. Diabetologia. 2006 Jun;49(6):1247-53
Similarly beneficial results have been obtained using the GLP-1R agonist liraglutide in a murine model of islet transplantation in mice. Following islet transplantation in diabetic BALC mice, liraglutide therapy was associated with more rapid induction of normoglycemia, improved insulin secretion and reduced b-cell apoptosis in transplanted islets Liraglutide, a long-acting human glucagon-like peptide 1 analogue, improves glucose homeostasis in marginal mass islet transplantation in mice. Endocrinology. 2008 May 29. [Epub ahead of print]