The Effect of Systemic Versus Portal Insulin Delivery in Pancreas Transplantation on Insulin Action and VLDL Metabolism
- André Carpentier1,
- Bruce W. Patterson4,
- Kristine D. Uffelman1,
- Adria Giacca12,
- Mladen Vranic12,
- Mark S. Cattral3 and
- Gary F. Lewis1
- 2Physiology, and
- 3Surgery, and the Multiorgan Transplant Program, University of Toronto, Toronto, Ontario, Canada
- 4Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
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 intravenous glucose–stimulated plasma insulin levels compared 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 necessary 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 during the euglycemic-hyperinsulinemic clamp was ∼40% lower in KPT-S versus KPT-P, indicating peripheral tissue but not hepatic insulin resistance in KPT-S versus KPT-P. Both transplant groups had an approximate twofold elevation of triglyceride (TG)-rich lipoprotein apolipoprotein B (apoB) and lipids versus control subjects. 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 elevation 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 overproduction and that additional factors, such as hepatic hyperinsulinemia and/or gross insulin resistance, may be an essential prerequisite in the pathogenesis of VLDL overproduction in the common form of the insulin resistance syndrome.
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:.
Received for publication 11 September 2000 and accepted in revised form 12 March 2001.
ANOVA, analysis of variance; apoA1, apolipoprotein A1; apoB, apolipoprotein B; ASR, absolute secretion rate; FCR, fractional catabolic rate; FFA, free fatty acid; GCMS, gas chromatography–mass spectrometry; Ginf, glucose infusion rate; IDL, intermediate-density lipoprotein; INS50%, Δ 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 circulation; MCR, metabolic clearance rate; Ra, production rate; Rd, disappearance rate; RSR, relative secretion rate; SA, specific activity; TG, triglyceride; TLC, thin-layer chromatography; TRL, TG-rich lipoprotein; TTR, tracer-to-tracee ratio.