Abstract
Intraportal islet transplantation (IPIT) may potentially cure Type 1 diabetes mellitus; however, graft failure in the early post-transplantation period presents a major obstacle. In this study, we tested the ability of nicotinamide to prevent early islet destruction in a syngeneic mouse model. Mice (C57BL/6) with chemically-induced diabetes received intraportal transplants of syngeneic islet tissue in various doses. Islets were cultured for 24 h in medium with or without 10 mM nicotinamide supplementation. Following IPIT, islet function was confirmed by an intraperitoneal glucose tolerance test (IPGTT) and hepatectomy. The effects of nicotinamide were evaluated by blood glucose concentration, serum monocyte chemoattractant protein-1 (MCP-1) concentration, and immunohistology at 3 h and 24 h after IPIT. Among the various islet doses, an infusion of 300 syngeneic islets treated with nicotinamide exhibited the greatest differences in glucose tolerance between recipients of treated and untreated (i.e., control) islets. One day after 300 islet equivalent (IEQ) transplantation, islets treated with nicotinamide were better granulated than the untreated islets (P=0.01), and the recipients displayed a slight decrease in serum MCP-1 concentration, as compared to controls. After 15 days, recipients of nicotinamide-pretreated islets showed higher levels of graft function (as measured by IPGTT) than controls. The pretreatment also prolonged graft survival (>100 days) and function; these were confirmed by partial hepatectomy, which led to the recurrence of diabetes. Pretreatment of islet grafts with nicotinamide may prevent their deterioration on the early period following IPIT in a syngeneic mouse model.
Highlights
Pancreatic islet transplantation is one of the most effective treatments for type 1 diabetes (Shapiro et al, 2000; Goss et al, 2002; Markmann et al, 2003)
The mechanism for the protective effect of nicotinamide pretreatment on islet tissue transplants is not well understood, it may involve the scavenging of free radicals or the reduction of immunological injury to beta-cells (Buscema et al, 1992; Andersen et al, 1994)
We examined the effect of the nicotinamide pretreatment on graft stability and function in a syngeneic mouse model of diabetes
Summary
Pancreatic islet transplantation is one of the most effective treatments for type 1 diabetes (Shapiro et al, 2000; Goss et al, 2002; Markmann et al, 2003). The general use of this treatment is limited, by the need for a large number of islet transplants (usually obtained from two organ donors) to achieve normoglycemia. To investigate the mechanisms of islet graft failure, many studies have used rodent models, most often with the kidney capsule as the transplantation site (Jung et al, 2006, 2008). Islets transplanted under the kidney capsule are protected from dynamic conditions in surrounding compartments, such as the post-gastrointestinal blood flow through the liver; and data from studies that use this model may not apply directly to intraportal islet transplantation (IPIT) (Hara et al, 2004). Islets infused intraportally do not survive as well as transplants under the kidney capsule (Goto et al, 2004; Yin et al, 2006), which suggests that the intraportal infusions encounter more complex challenges
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