Glucose turnover and insulin sensitivity in rats with pancreatic islet transplants

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 mas found at 1 month posttransplant in all animals receiving similar to 3,000 islets, with hyperinsulinemic responses in the REN group compared with the other groups, and with higher C-peptide responses in the ill group than in the other groups (P < 0.05 by one-may analysis of variance). Glucose turnover studies in the insulin-stimulated steady state (INS-SS; infusion of insulin at 10 pmol.kg(-1).min(-1)) at 2 months posttransplant showed that whole body glucose disappearance rates (R-d) were similar in all groups, but the REN group had higher steady-state insulin levels than the other groups. Glucose infusion rates (GIRs) mere 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 ill groups, while complete inhibition mas observed in the other groups. When ZNS-SS insulin levels mere matched to the level in REN rats by increasing the insulin infusion rate to 20 pmol.kg(-1).min(-1) in REN-RMA ill, and normal rats, GIR and R-d mere 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 R-d 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 IB 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.