title: Function and survival of intrasplenic islet autografts in dogs.
abstract: 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 normoinsulinaemia 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.
authors.affiliation: Department of Surgery, University of Leiden, Netherlands.
authors.forename: M P
authors.initials: MP
authors.lastname: van der Burg
authors.forename: O R
authors.initials: OR
authors.lastname: Guicherit
authors.forename: J B
authors.initials: JB
authors.lastname: Jansen
authors.forename: M
authors.initials: M
authors.lastname: Frölich
authors.forename: C B
authors.initials: CB
authors.lastname: Lamers
authors.forename: H H
authors.initials: HH
authors.lastname: Lemkes
authors.forename: J A
authors.initials: JA
authors.lastname: Bruijn
authors.forename: H G
authors.initials: HG
authors.lastname: Gooszen
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D004435:Eating; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000097:blood; D005934:Glucagon / Q000097:blood; D005951:Glucose Tolerance Test; D006085:Graft Survival; D007003:Hypoglycemia; D007328:Insulin / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D000078790:Insulin Secretion; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000502:physiology*; D010191:Pancreatic Polypeptide / Q000097:blood; D013154:Spleen; D013997:Time Factors; D014182:Transplantation, Autologous; D016042:Transplantation, Heterotopic
chemical_list: D001786:Blood Glucose; D007328:Insulin; D005749:Gastric Inhibitory Polypeptide; D010191:Pancreatic Polypeptide; D005934:Glucagon; D001120:Arginine