Objective: The authors evaluated systemic venous insulin release as a cause of the hyperinsulinemia (HINS) associated with pancreatic transplantation (PTX) with respect to the mechanism and metabolic consequences. Summary Background Data: Many investigators believe the postoperative anatomy associated with common PTX techniques to be the sole cause of the two- to threefold posttransplantation HINS. However, this concept remains to be conclusively proved and characterized quantitatively. Methods: The authors used three approaches to achieve their objectives. First, a computer model was generated based on established data concerning blood flow and tissue insulin extraction to determine whether it was mathematically possible for HINS to be caused by systemic insulin release. Second, HINS clamps were applied to normal dogs using the Andres clamp technique to quantify the in vivo differences in peripheral insulin levels and the metabolic consequences of systemic versus portal insulin infusion. Third, prolonged insulin half-life was evaluated as a possible mechanism of HINS from systemic insulin release by determination of biexponential rates of plasma disappearance from an endogenous pulse of insulin in surgically induced dog models of systemic and portal insulin release. Results: First, the computer model calculated a 1.4- to 2.9-fold increase in peripheral venous insulin levels with systemic versus portal insulin release, verifying mathematically the concept of HINS resulting from systemic insulin release. Second, the actual systemic insulin infusion produced a 1.3- to 1.4-fold increase in peripheral venous insulin levels compared with portal infusion (p < 0.05). No significant differences in hepatic glucose output, total glucose disposal, or glucose infusion requirements were seen. Third, although the basal insulin level was twofold higher in the surgically induced animal models with systemic insulin release (p < 0.003), there were no differences in biexponential insulin clearance parameters. Conclusions: The HINS produced by systemic insulin release did not significantly alter glucose metabolism and was not the result of altered peripheral insulin clearance parameters. In vivo systemic venous insulin infusion studies produce HINS, but not to the degree calculated by mathematic modeling or that occurs after clinical PTX, making it likely that other factors also play a role in the HINS after PTX.
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