Abstract
Clinical islet transplantations are performed through infusion of islets via the portal vein into the liver. This study aimed at characterizing the influence of the implantation microenvironment on islet graft metabolism and function. Islets were transplanted into their normal environment, i.e., the pancreas, or intraportally into the liver of mice. One month posttransplantation, the transplanted islets were retrieved and investigated for changes in function and gene expression. Insulin content, glucose-stimulated insulin release, (pro)insulin biosynthesis, and glucose oxidation rate were markedly decreased in islets retrieved from the liver, both when compared with islets transplanted into the pancreas and endogenous islets. Islets transplanted into the pancreas showed normal insulin content, (pro)insulin biosynthesis, and glucose oxidation rate but increased basal insulin secretion and impaired glucose stimulation index. Gene expression data for retrieved islets showed downregulation of pancreatic and duodenal homeobox gene-1, GLUT-2, glucokinase, mitochondrial glycerol-phosphate dehydrogenase, and pyruvate carboxylase, preferentially in intraportally transplanted islets. Islets transplanted into their normal microenvironment, i.e., the pancreas, display gene expression changes when compared with endogenous islets but only moderate changes in metabolic functions. In contrast, site-specific properties of the liver markedly impaired the metabolic functions of intraportally transplanted islets.
Highlights
Insulin content, glucose-stimulated insulin release,insulin biosynthesis, and glucose oxidation rate were markedly decreased in islets retrieved from the liver, both when compared with islets transplanted into the pancreas and endogenous islets
Islets transplanted into the pancreas showed normal insulin content,insulin biosynthesis, and glucose oxidation rate but increased basal insulin secretion and impaired glucose stimulation index
Gene expression data for retrieved islets showed downregulation of pancreatic and duodenal homeobox gene-1, GLUT-2, glucokinase, mitochondrial glycerol-phosphate dehydrogenase, and pyruvate carboxylase, preferentially in intraportally transplanted islets. Islets transplanted into their normal microenvironment, i.e., the pancreas, display gene expression changes when compared with endogenous islets but only moderate changes in metabolic functions
Summary
Identification and cell composition of transplanted islets retrieved from liver and pancreas. Retrieved intraportally transplanted islets did not increase insulin release at all on exposure to high glucose. Intraportally transplanted islets had markedly lower insulin content compared both with control YC-3.0 and with intrapancreatically transplanted islets (Fig. 3). The glucose oxidation rate in transplanted islets retrieved from the pancreas was similar to that in control YC-3.0 islets. Islets retrieved from the liver had a markedly lower glucose oxidation rate than that both in control YC-3.0 and in intrapancreatically transplanted islets (Fig. 4). Transplanted islets retrieved from the liver had a markedly decreased (pro)insulin biosynthesis compared both with control YC-3.0 and intrapancreatically transplanted islets (Fig. 5A). The mRNA levels of PDX-1 were markedly decreased in islets transplanted to the liver and pancreas compared with control YC-3.0 islets (Fig. 6A). No differences in the mRNA levels of uncoupling protein 2 were observed in the different groups (Fig. 6G)
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