Function and survival of intrasplenic islet autografts in dogs

Summary Successful transplantation of isolated islets of Langerhans has been reported in large mammals, including man, but metabolic control has not been well-established. We studied the glucose and islet hormone response to fasting, i. v. glucose bolus infusion, i.v. arginine bolus infusion during a 35-mmol/l hyperglycaemic clamp, mixed meals, and i. v. insulin-induced hypoglycaemia up to 3 years after intrasplenic islet autotransplantation in six pancreatectomised dogs. The individual postprandial insulinogenic index (ratio of 2-h postprandial insulin to glucose levels) at 1 month post-transplant, predicted (r=0.99) the time to functional graft failure (6–175 weeks). Metabolic studies at 6 months post-transplant in four dogs demonstrated normal fasting glucose and hormone levels, except for reduced pancreatic polypeptide levels. Intravenous glucose and arginine-stimulated insulin were reduced to 15% of preoperative values. In contrast, postprandial normoin-sulinaemia was observed — albeit with moderate hyperglycaemia (approximately 10 mmol/l). Postprandial glucagon and glucose-dependent insulinotropic polypeptide (GIP) had increased. Comparison of the post-transplant insulin responses to a meal and to intravenous challenges demonstrated maximal stimulation of the graft by the meal. Post-transplant pancreatic polypeptide responses to a meal and i.v. arginine were severely reduced, and no pancreatic polypeptide response to i.v. insulin-induced hypoglycaemia was observed — indicating absence of cholinergic reinnervation. Thus, glucose regulation and both the insulin secretory capacity and life expectancy of islet grafts were best documented by meal testing. Tentatively, a postprandial hyperglycaemia-enhanced incretin effect of glucose-dependent insulinotropic polypeptide and other gut hormones may account for the difference in the insulin response to i. v. glucose and a meal. Aside from the reduced insulin secretory capacity, both a deranged pulsatile delivery of insulin, hyperglucagonaemia, and pancreatic polypeptide deficiency may have been conducive to glucose intolerance.Abbreviations IEq Islet equivalent - IVGTT intravenous glucose tolerance test - GIP glucose-dependent insulinotropic polypeptide - PP pancreatic polypeptide - RIA radioimmunoassay