The effect of systemic versus portal insulin delivery in pancreas transplantation on insulin action and VLDL metabolism

Combined kidney-pancreas transplantation (KPT) with anastomosis of the panc reatic vein to the systemic circulation (KPT-S) or to the portal circulatio n (KPT-P) provides a human model in which the chronic effects of portal ver sus systemic insulin delivery on glucose and VLDL metabolism can be examine d. Despite similar plasma glucose and C-peptide levels, KPT-S (n = 9) had a n approximate twofold elevation of fasting and intravenous glucose-stimulat ed plasma insulin levels compared with both KPT-P (n = 7) and healthy contr ol subjects (n = 15), The plasma free fatty acid (FFA) levels were elevated in both transplant groups versus control subjects, but the plasma insulin elevation necessary to lower plasma FFA by 50% was approximately two times higher in KPT-S versus KPT-P and control subjects. Endogenous glucose produ ction was similar in KPT-S and RPT-P, despite similar to 35% higher hepatic insulin levels in the latter, and was suppressed to a greater extent durin g a euglycemic-hyperinsulinemic clamp in KPT-S versus KPT-P. Total-body glu cose utilization during the euglycemic-hyperinsulinemic clamp was similar t o 40% lower in KPT-S versus KPT-P, indicating peripheral tissue but not; he patic insulin resistance in KPT-S ver sns KPT-P, Both transplant groups had an approximate twofold elevation of triglyceride (TG)-rich lipoprotein apo lipoprotein B (apoB) and lipids versus control subjects. Elevation of VLDL- apoB and VLDL-TG in both transplant groups was entirely explained by an sim ilar to 50% reduction in clearance of VLDL compared with healthy control su bjects. In the presence of increased FFA load but in the absence of hepatic overinsulinization and marked hepatic insulin resistance, there was no ele vation of VLDL secretion in KPT-S versus KPT-P and control subjects. These findings suggest that chronic systemic hyperinsulinemia and peripheral tiss ue insulin resistance with the consequent elevation of plasma FFA flux are insufficient per se to cause VLDL overproduction and that additional factor s, such as hepatic hyperinsulinemia and/or gross insulin resistance, may be an essential prerequisite in the pathogenesis of VLDL overproduction in th e common form of the insulin resistance syndrome.