Intraportal Transplantation of Pancreatic Islets Into Livers of Diabetic Rats: Reinnervation of Islets and Regulation of Insulin Secretion by the Hepatic Sympathetic Nerves

Abstract

Two weeks after intraportal transplantation of 2,000 neonatal pancreatic islets, recipient rats completely recovered from streptozotocin-induced diabetes. The reversal of diabetes could be documented by the normalization of blood glucose levels, by a restored weight gain, by normal glucagon and insulin levels in blood, and by a disappearance of polyuria and polydipsia. The reversal remained stable for at least 9 months. This study determined whether intraportally transplanted pancreatic islets were reinnervated after transplantation and whether the secretion of insulin and glucagon from pancreatic islets might be modulated by the vegetative innervation of recipient livers. Predominantly catecholaminergic but also cholinergic nerve fibers were detected not only within the portal tracts around hepatic arteries, portal veins, and bile ducts, but also at the borderline of hepatocytes and beta-cells and in islet cell complexes between beta-cells. Corresponding electron micrographs showed beta-cells in close contact with axons of nonmyelinated nerve fibers. Isolated livers were single pass perfused via both the hepatic artery and the portal vein. An increase in glucose level from 5 to 14 mmol/l enhanced hepatic glucose uptake and increased insulin secretion from transplanted islets with a biphasic secretion profile but had no effect on glucagon output. Stimulation of the nerve plexus around the hepatic artery and the portal vein (7.5 Hz, 2 min), which activates primarily the sympathetic system, not only reduced glucose uptake and perfusion flow but also completely reversed the glucose-stimulated increase in insulin secretion. Nerve stimulation did not influence glucagon secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Implantation Site–Dependent Dysfunction of Transplanted Pancreatic Islets

“…The endocrine function of retrieved intraportally transplanted islets seemed even more impaired than expected based on previous results from perfusion of graft-bearing livers in rat (12,22,23). We have previously thoroughly evaluated our technique to retrieve intraportally transplanted islets and found that the procedure in itself is unlikely to damage the islet cells (5).…”

Islet Cell Hormonal Responses to Hypoglycemia After Human Islet Transplantation for Type 1 Diabetes

“…Both parasympathetic and sympathetic innervations contribute in a redundant fashion to ␣-cell activation during hypoglycemia (13,34). The absent pancreatic polypeptide response to hypoglycemia demonstrated here suggests a lack of parasympathetic innervation, although sympathetic innervation of intrahepatic islets might occur along vascular channels (35). Although innervation does not appear necessary for an intact ␣-cell response to hypoglycemia after transplantation of a denervated whole pancreas (36 -38), neural activation may be more important when the mass of cells is reduced as after islet transplantation.…”

Posttransplant oxygen inhalation improves the outcome of subcutaneous islet transplantation: A promising clinical alternative to the conventional intrahepatic site

“…43,44 Correlation was shown between the success rate for diabetes reversal and the minimal number of syngeneic islets: 100% reversal with 1000 islets (approximately 3500 islets/ kg), 33% with 700 islets (2500 islets/kg), and 0% with 500 islets (1700 islets/kg). In the 1990s, 2000 syngeneic islets were reported to reverse diabetes in LEW rats.…”