The Effect of Systemic Versus Portal Insulin Delivery in Pancreas Transplantation on Insulin Action and VLDL Metabolism Andre ´ Carpentier, 1 Bruce W. Patterson, 4 Kristine D. Uffelman, 1 Adria Giacca, 1,2 Mladen Vranic, 1,2 Mark S. Cattral, 3 and Gary F. Lewis 1 Combined kidney-pancreas transplantation (KPT) with anastomosis of the pancreatic vein to the systemic circulation (KPT-S) or to the portal circulation (KPT-P) provides a human model in which the chronic effects of portal versus systemic insulin delivery on glucose and VLDL metabolism can be examined. Despite similar plasma glucose and C-peptide levels, KPT-S (n  9) had an approximate twofold elevation of fasting and intra- venous glucose–stimulated plasma insulin levels com- pared with both KPT-P (n  7) and healthy control subjects (n  15). The plasma free fatty acid (FFA) levels were elevated in both transplant groups versus control subjects, but the plasma insulin elevation nec- essary to lower plasma FFA by 50% was approximately two times higher in KPT-S versus KPT-P and control subjects. Endogenous glucose production was similar in KPT-S and KPT-P, despite 35% higher hepatic insulin levels in the latter, and was suppressed to a greater extent during a euglycemic-hyperinsulinemic clamp in KPT-S versus KPT-P. Total-body glucose utilization dur- ing the euglycemic-hyperinsulinemic clamp was 40% lower in KPT-S versus KPT-P, indicating peripheral tissue but not hepatic insulin resistance in KPT-S ver- sus KPT-P. Both transplant groups had an approximate twofold elevation of triglyceride (TG)-rich lipoprotein apolipoprotein B (apoB) and lipids versus control sub- jects. Elevation of VLDL-apoB and VLDL-TG in both transplant groups was entirely explained by an 50% reduction in clearance of VLDL compared with healthy control subjects. In the presence of increased FFA load but in the absence of hepatic overinsulinization and marked hepatic insulin resistance, there was no eleva- tion of VLDL secretion in KPT-S versus KPT-P and control subjects. These findings suggest that chronic systemic hyperinsulinemia and peripheral tissue insulin resistance with the consequent elevation of plasma FFA flux are insufficient per se to cause VLDL overproduc- tion and that additional factors, such as hepatic hyper- insulinemia and/or gross insulin resistance, may be an essential prerequisite in the pathogenesis of VLDL over- production in the common form of the insulin resistance syndrome. Diabetes 50:1402–1413, 2001 C urrently, the most effective established insulin- replacement therapy for patients with type 1 diabetes is achieved with whole-organ pancreas transplantation, which is usually performed together with kidney transplantation (combined kidney- pancreas transplantation [KPT]). Improvements in sur- gical techniques and immunosuppressive drug regimens over the past 20 years have resulted in an increase in both patient and pancreas graft survival after transplantation as well as freedom from exogenous insulin administration in well over 80% of cases at 1 year posttransplantation in most centers (1,2). The surgical technique most commonly used in North America involves whole-organ transplanta- tion with anastomosis of the duodenal segment to the bladder for drainage of the exocrine secretions and with systemic venous anastomosis to the iliac vein (KPT-S). Because the liver, which normally clears on the first pass 40 – 60% of the insulin secreted by the pancreas, is by- passed in this procedure, KPT-S results in an overall reduction in insulin clearance (3). Consequently, trans- plant recipients who undergo this procedure become hyperinsulinemic and have reduced total-body insulin sen- sitivity (4 –9), even when compared with nondiabetic kid- ney transplant recipients on a similar antirejection drug regimen (7,8). Furthermore, these patients have a reduc- tion in insulin’s antilipolytic activity in peripheral tissues, another feature of systemic insulin resistance (9). The consequence of KPT-S on lipid metabolism is more controversial. Some investigators have shown a normal- ization of the lipid profile after transplantation compared with the pretransplantation uremic state (10,11), whereas others have shown increased levels of plasma triglycerides (TGs), apolipoprotein B (apoB), and/or VLDL-TG and VLDL- apoB after transplantation (12,13). Although immunosup- pressive agents are thought to play a role in the lipid abnormalities seen after solid-organ transplantation and could explain the findings of the latter studies, it is not clear whether peripheral hyperinsulinemia and the associ- From the Departments of 1 Medicine, 2 Physiology, and 3 Surgery, and the 3 Multiorgan Transplant Program, University of Toronto, Toronto, Ontario, Canada; and the 4 Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri. Address correspondence and reprint requests to Dr. Gary F. Lewis, Toronto General Hospital, 200 Elizabeth St., Room EN 11-229, Toronto, ON, Canada M5G 2C4. E-mail: gary.lewis@uhn.on.ca. Received for publication 11 September 2000 and accepted in revised form 12 March 2001. ANOVA, analysis of variance; apoA1, apolipoprotein A1; apoB, apolipopro- tein B; ASR, absolute secretion rate; FCR, fractional catabolic rate; FFA, free fatty acid; GCMS, gas chromatography–mass spectrometry; G inf , glucose infusion rate; IDL, intermediate-density lipoprotein; INS50%,  insulin for 50% reduction in plasma FFA; KPT, combined kidney-pancreas transplantation; KPT-P, KPT with anastomosis of the pancreatic vein to the portal circulation; KPT-S, KPT with anastomosis of the pancreatic vein to the systemic circula- tion; MCR, metabolic clearance rate; R a , production rate; R d , disappearance rate; RSR, relative secretion rate; SA, specific activity; TG, triglyceride; TLC, thin-layer chromatography; TRL, TG-rich lipoprotein; TTR, tracer-to-tracee ratio. 1402 DIABETES, VOL. 50, JUNE 2001