Hyperinsulinemia after pancreatic transplantation. Prediction by a novel computer model and in vivo verification.

OBJECTIVE: The authors evaluated systemic venous insulin release as a cause of the hyperinsulinemia (HNS) 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.

The effect of pancreatic polypeptide on glucose disposal after surgical alterations of the pancreas.

Surgical alterations of the pancreas result in anatomic changes that can affect postoperative glucose metabolism. Pancreas transplantation results in reduction of beta-cell mass, systemic release of insulin, and denervation. The authors hypothesized that such alterations affect peripheral glucose disposal to induce an "insensitivity" to endogenously (systemically) released insulin. Additionally, they hypothesized that surgically induced deficiency of the postprandial hormone, pancreatic polypeptide, might contribute to altered glucose disposal. The authors studied two surgical models in dogs known to be devoid of pancreatic polypeptide--70% proximal pancreatectomy (PPx) and PPx plus distal pancreas autotransplantation (PAT/B). Oral glucose challenge and euglycemic hyperinsulinemic clamp studies were performed before and after a 16-day "pulsed" infusion of pancreatic polypeptide. Both surgical procedures resulted in elevations in the integrated glucose response after oral glucose, which was not affected by pancreatic polypeptide infusion. Euglycemic clamp studies showed decreased hepatic glucose output (Ra) and overall glucose disposal (Rd) in the fasted state for both surgical groups. The transplant animals demonstrated significant decreases in Rd during the hyperinsulinemic challenge (3.2 +/- 0.01 versus 5.7 +/- 0.01 mg/kg/minute at 60 to 120 minutes for PAT/B versus control). After 16 days of pancreatic polypeptide infusion, however, basal Ra, as well as basal and 60- to 120-minute Rd values, were returned to control values in the transplant group. The authors conclude that pancreas transplantation results in altered glucose disposal, possibly due to an altered effectiveness of systemically released insulin. They conclude that pancreatic polypeptide is an important modulator of peripheral insulin action. Therefore, the role of pancreatic polypeptide must be taken into account when evaluating postoperative glucose metabolism in canine models of pancreas transplantation.

Pancreas transplantation. An initial experience with systemic and portal drainage of pancreatic allografts.

Pancreas transplantation has evolved dramatically since its introduction in 1966. As new centers for transplantation have developed, the evaluation of complications associated with pancreas transplantation has led to advances in surgical technique. Furthermore, surgical alterations of the pancreas resulting from transplantation (systemic release of insulin and denervation) are of unproven consequence on glucose metabolism. Since 1988, the authors have performed 21 transplants (16 combined pancreas/kidney, 3 pancreas alone, which includes 1 retransplantation, 1 pancreas after previous kidney transplant, and 1 "cluster") in 20 patients aged 18 to 49 years; mean, 35 +/- 1 years. Overall patient survival is 95%. Three pancreatic grafts failed within the first year because of technical failure; one additional pancreas was lost to an immunologic event on postoperative day 449, for an overall pancreatic graft survival of 81%. No renal grafts were lost. To evaluate causes of graft failure, demographic data were compared, which included age and sex of the donor and the recipient, operative time, intraoperative blood transfusion, and ischemic time of the graft. No statistically significant differences were found between groups except for ischemic time (11.7 +/- 6.4 hours for the technical success group versus 19.8 +/- 3.7 hours for the technical failure group; p less than 0.05 by unpaired Student's t test). Quadruple immunosuppression was used, which included prednisone, cyclosporine, azathioprine, and antilymphoblast globulin. A mean of 1.2 (range, 0 to 3) rejection episodes per patient occurred. Mean hospital stay was 24 +/- 11 days. Surgical and infectious complications were evaluated by comparing the technical success (TS) group (n = 17) with the technical failure (TF) group. Surgical complications in the TS group revealed a mean of 1.3 episodes per patient, whereas the TF group had 3.7 episodes per patient. The TS also had a reduced incidence of infectious complications compared with the TF (1.7 versus 4.3 episodes per patient). Cytomegalovirus was common in both groups, accounting for 11 infectious episodes, and occurred on a mean postoperative day of 38. Mean postoperative HbA1C levels dropped to 5 +/- 1% from 11 +/- 3%. The authors developed a new technique that incorporates portal drainage of the pancreatic venous effluent in three recipients. Preoperative metabolic studies disclosed a mean fasting glucose of 211 +/- 27 mg/dL and a mean stimulated glucose value of 434 +/- 41 mg/dL for all patients; the mean fasting insulin was 23 +/- 4 microU/mL.(ABSTRACT TRUNCATED AT 400 WORDS)

Surgical alterations of the pancreas and insulin-independent glucose disposal.

Systemic drainage of pancreatic venous effluent and denervation of the pancreas that follows pancreatic transplantation has been shown to alter postoperative glucose disposal despite elevated levels of peripheral insulin in response to a glucose challenge. Since an appreciable fraction of postprandial glucose disposal takes place in the absence of insulin (insulin-independent glucose disposal--IIGD), we have investigated potential changes in this aspect of carbohydrate metabolism before and after bladder-drained pancreatic auto-transplantation (PAT/B) as well as partial pancreatectomy (PPx). The hyperglycemic clamp protocol with a background infusion of somatostatin was performed on control (PREOP) dogs as well as PAT/B and PPx animals. The rate of glucose disposal (M Value) during the period of hypoinsulinemia induced by Somatostatin (SST) was measured and reported. Whereas glucose disposal during steady state hyperglycemia was significantly diminished for both PPx and PAT/B in the absence of SST, IIGD was unaltered across all three groups studied. We therefore conclude that surgical alteration of the pancreas results in abnormal glucose disposal during steady state hyperglycemia despite apparently normal to supranormal levels of peripheral insulin, and that alterations in IIGD are not responsible for these differences.

Glucose metabolism after pancreas autotransplantation. The effect of open duct versus urinary bladder drainage technique.

Glucose metabolism and insulin secretion after pancreas transplantation may be affected by the technique used for ductal drainage. We evaluated peripheral glucose and insulin levels after oral (oral glucose tolerance test [OGTT]) and sustained stable hyperglycemic challenge (clamp) in dogs who had undergone pancreas autotransplantation with intraperitoneal drainage (PAT) or with urinary bladder to pancreatic duct anastomosis (PAT/B). Both groups had basal glucose values comparable to normal controls; PAT/B animals had fasting hyperinsulinemia. Pancreas autotransplantation animals had an increased integrated glucose response to OGTT and blunted insulin response to hyperglycemic clamp. Urinary bladder to pancreatic duct anastomosis animals had a significantly decreased integrated glucose response to OGTT compared to PAT and an exaggerated insulin response to hyperglycemic challenge, which approximated normal control values by the last 30-minute period of the clamp. Interestingly M values, which approximate glucose metabolized during the hyperglycemic challenge, were depressed in both surgical groups. It is concluded that the technique of bladder drainage allows a 'normalization' of peripheral levels of insulin that is associated with amelioration of an altered glucose response after oral challenge. However the clamp studies show that, despite the improvement in insulin response, an insensitivity may exist to a wide range of endogenous levels after pancreas transplantation.

Glipizide treatment of pancreas autotransplantation: effects on alterations in glucose-insulin relationships.

Pancreas transplantation has been proven effective in supplying an endogenous insulin supply in diabetics. However, alterations in glucose metabolism after transplantation suggest a possible "insensitivity" to its action in the periphery. We hypothesized that sulfonylurea treatment of canines who had received segmental pancreas autotransplants would correct these alterations by altering peripheral insulin sensitivity. Glipizide therapy (5 mg p.o. b.i.d.) did appear, in fact, to enhance basal insulin sensitivity by lowering fasting glucose (100 +/- 3 to 81 +/- 11 mg/dl pre-treatment to post-treatment) while not affecting basal insulin levels. However, glipizide therapy was associated with decreased insulin response to challenge by either oral glucose (2 gm/kg) or sustained intravenous hyperglycemia (150 mg/dl above basal). We conclude that our model of pancreas autotransplantation documents alterations in glucose metabolism which are devoid of the effect of immunosuppression. Glipizide treatment appears to affect fasting sensitivity to insulin, but results in a decrement of insulin response to oral or intravenous glucose challenge.

Insulin-dependent and insulin-independent effects after surgical alterations of the pancreas.

Anatomic alterations of the pancreas result in physiologic alterations that have not been completely analyzed. Insulin plays a major role in carbohydrate metabolism; nevertheless, as much as 50% of a hyperglycemic load may be metabolized independent of insulin. We analyzed the effects of surgical alterations of the pancreas on postoperative glucose metabolism, including insulin-independent effects. Mongrel female dogs underwent one of three procedures: proximal partial pancreatectomy (PPx), PPx plus diversion of pancreatic venous effluent to the systemic circulation (SC), or PPx plus segmental pancreatic autotransplantation (PAT). Intravenous glucose tolerance tests, with or without a background infusion of somatostatin (SST; 400 ng/kg/min) were performed on all animals preoperatively and postoperatively. SST completely suppressed secretion of assayable peripheral insulin. The rate of glucose disposal during SST suppression approximates the rate of insulin-independent glucose disposal (IIGD). Although there was a significant decrease in the rate of glucose disposal during SST infusion when compared with the rate without SST, no differences in IIGD were found between postoperative groups. IIGD was calculated at 50% to 55% for control, PPx, and SC groups and at 67% for PAT. Peripheral sensitivity to an exogenous insulin infusion (euglycemic clamp) was unchanged by any of the procedures. We conclude that surgical alteration of the pancreas, including pancreas transplantation, results in altered glucose handling in the face of "normal" peripheral levels of insulin. Changes in IIGD and analysis of peripheral sensitivity to insulin do not explain these alterations completely.