FUNCTION AND SURVIVAL OF INTRASPLENIC ISLET AUTOGRAFTS IN DOGS

Successful transplantation of isolated islets of Langerhans has been r eported in large mammals, including man, but metabolic control has not been well-established. We studied the glucose and islet hormone respo nse to fasting, i.v. glucose bolus infusion, i.v. arginine bolus infus ion during a 35-mmol/l hyperglycaemic clamp, mixed meals, and i.v. ins ulin-induced hypoglycaemia up to 3 years after intrasplenic islet auto transplantation in six pancreatectomised dogs. The individual postpran dial 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 h ormone levels, except for reduced pancreatic polypeptide levels, Intra venous glucose and arginine-stimulated insulin were reduced to 15% of preoperative values, In contrast, postprandial normoinsulinaemia was o bserved - albeit with moderate hyperglycaemia (approximately 10 mmol/l ). Postprandial dial glucagon and glucose-dependent insulinotropic pol ypeptide (GIP) had increased. Comparison of the post-transplant insuli n responses to a meal and to intravenous challenges demonstrated maxim al stimulation of the graft by the meal. Post-transplant pancreatic po lypeptide responses to a meal and i.v. arginine were severely reduced, and no pancreatic polypeptide response to i.v, insulin-induced hypogl ycaemia 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 o f 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 pancr eatic polypeptide deficiency may have been conducive to glucose intole rance.