Pathophysiology of hyperinsulinemia following pancreas transplantation: Altered pulsatile versus basal insulin secretion and the role of specific transplant anatomy in dogs

Objective: To evaluate the effect of the anatomical alterations of the pancreas required for transplantation on pulsatile insulin secretion. Summary Background Data: Pancreas transplantation involves anatomical changes that have unknown consequences on glucose homeostasis. Pancreas transplant patients are free of exogenous insulin requirements, yet appear to have endogenous hyperinsulinemia. The effect of surgical alterations on posttransplant insulin release is not completely known, specifically with regards to possible alterations in patterns of pulsatile release. Methods: Pulsatile and invariant basal insulin secretion was studied in normal dogs (n = 4) and three canine models of the anatomical alterations of pancreas transplantation: 70% partial pancreatectomy (PPX, n = 4), partial pancreatectomy with splenocaval venous diversion (SC, n = 4), and partial pancreatectomy with remnant autotransplantation (PAT, n = 4). Plasma insulin kinetics were determined for each dog, and then blood sampled at 1-minute intervals in a fasted and IV glucose-stimulated state twice to delineate the time structure of insulin secretion by multiple parameter deconvolution analysis utilizing dog-specific insulin half-lives. Results: Fasting plasma glucose concentrations in each group were similar, but all surgical groups were hyperglycemic with IV glucose challenge. Secretory pulse amplitude was decreased with decreased β cell mass (PPX), partially normalized with systemic insulin release (SC), and further normalized with denervation (PAT). Interpulse interval and pulse duration were increased in all surgical groups when stimulated. Denervation of PAT resulted in a threefold increase in fasting basal invariant insulin secretion. Stimulated basal insulin secretion is inconsequential. Conclusions: Hyperinsulinemia and apparent insulin insensitivity after pancreas transplantation may be due to increased less potent basal secretion in the fasting state and less frequent, less discrete pulsatile insulin secretion in the simulated state.