Glucose turnover and insulin sensitivity in rats with pancreatic islet transplants.

Abstract

To study the metabolic effects of insulin derived from islet grafts, oral glucose tolerance (OGT) and glucose turnover were examined in streptozotocin-induced diabetic Lewis rats rendered normoglycemic by syngeneic islet grafts in the renal subcapsular space (REN), in REN with renal vein-to-mesenteric vein anastomosis (REN-RMA), in the liver (intrahepatic [IH]), or in a parahepatic omental pouch (POP) and compared with normal rats. Normal OGT was found at 1 month posttransplant in all animals receiving approximately 3,000 islets, with hyperinsulinemic responses in the REN group compared with the other groups, and with higher C-peptide responses in the IH group than in the other groups (P < 0.05 by one-way analysis of variance). Glucose turnover studies in the insulin-stimulated steady state (INS-SS; infusion of insulin at 10 pmol x kg(-1) x min(-1)) at 2 months posttransplant showed that whole body glucose disappearance rates (Rd) were similar in all groups, but the REN group had higher steady-state insulin levels than the other groups. Glucose infusion rates (GIRs) were lower in the REN and IH groups than in the other groups. Apparent endogenous glucose production (EGP) was not completely inhibited in the REN and IH groups, while complete inhibition was observed in the other groups. When INS-SS insulin levels were matched to the level in REN rats by increasing the insulin infusion rate to 20 pmol x kg(-1) x min(-1) in REN-RMA, IH, and normal rats, GIR and Rd were elevated, exceeding those values in REN rats, but GIR in IH rats was still lower than in REN-RMA and normal rats. Thus, 1) in the REN group, impairment of inhibition of EGP and of stimulation of Rd by exogenous insulin contribute to insulin resistance; 2) in the IH group, incomplete inhibition of EGP is the major determinant of insulin resistance; and 3) with portal delivery of insulin in the REN-RMA and POP groups, normal insulin sensitivity is preserved. The present study confirms that hepatic portal delivery of islet secretions is necessary for physiological regulation of glucose metabolism. The study also suggests the IH grafts do not provide physiological regulation of glucose metabolism, raising the question of whether the liver is an appropriate site for insulin-secreting tissue replacement therapy in diabetes.

Collagen IV-Modified Scaffolds Improve Islet Survival and Function and Reduce Time to Euglycemia

“…However, the current percutaneous transhepatic approach is not optimal, owing to complications specific to the intravascular hepatic site and the inability to remove the islet graft should serious complications develop. [42][43][44][45] We applied biodegradable, microporous PLG scaffolds for extrahepatic islet transplantation. 12 The scaffold had a thickness of 2 mm, a diameter of 5 mm, and a pore size in the range of 250 to 425 mm.…”

Evidence of Functional Impairment of Syngeneically Transplanted Mouse Pancreatic Islets Retrieved from the Liver

“…It is interesting that other disturbances in the function of intraportally transplanted islets have also been described. Disturbed physiological regulation of glucose metabolism with increased C-peptide concentrations and insulin resistance occur, as well as defective glucagon response, during hypoglycemia (41)(42)(43). Taken together, there is ample evidence that the intraportal site confers several disadvantages for an optimal endocrine function of transplanted islets.…”

Brain Death Significantly Reduces Isolated Pancreatic Islet Yields and Functionality In Vitro and In Vivo After Transplantation in Rats

“…Diabetes was defined as nonfasting glucose levels Ͼ250 mg/dl for at least 3 consecutive days. Twenty-four hours after isolation, 3,000 IEQ were injected into the portal vein via 25-G needle connected to PE50 tubing as described (16). Islet viability.…”

“…After 2, 4, and 6 h of mechanical ventilation with and without CNS injury, a midline abdominal incision was made; the bile duct was cannulated and injected with 5 ml of cold M199 medium containing 1.5 mg/ml rodent Liberase (Roche Diagnostics, Indianapolis, IN). Islets were isolated as described (16). An aliquot of islets was counted as islet equivalent (IEQ) under a scaled microscope using diphenylthiocarbazone (Sigma) staining.…”