Diabetologia (1996) 39:37-44 Diabetologia Springer-Verlag 1996 Function and survival of intrasplenic islet autografts in dogs M.P.M. van der Burg 1 , O.R. Guicherit 1 , J. B. M. J. Jansen 2, M. Friilich 3, C. B. H. W. Lamers 4, H.H.P.J. Lemkes 5, J.A. Bruijn 6, H.G. Gooszen 7 1Department of Surgery, University of Leiden, Leiden, The Netherlands 2Department of Gastroenterology, University of Nijmegen, Nijmegen, The Netherlands 3Department of Clinical Chemistry, University of Leiden, Leiden, The Netherlands 4Department of Gastroenterology, University of Leiden, Leiden, The Netherlands 5Department of Endocrinology, University of Leiden, Leiden, The Netherlands 6Department of Pathology, University of Leiden, Leiden, The Netherlands 7Department of Surgery, University of Utrecht, Utrecht, The Netherlands 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 infu- sion, i.v. arginine bolus infusion during a 35-mmol/1 hyperglycaemic clamp, mixed meals, and i.v. insulin- induced hypoglycaemia up to 3 years after intra- splenic islet autotransplantation in six pancreatec- tomised dogs. The individual postprandial insulino- genic index (ratio of 2-h postprandial insulin to glu- cose 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-trans- plant in four dogs demonstrated normal fasting glu- cose and hormone levels, except for reduced pancre- atic polypeptide levels. Intravenous glucose and argi- nine-stimulated insulin were reduced to 15 % of pre- operative values. In contrast, postprandial normoin- sulinaemia was observed - albeit with moderate hy- perglycaemia (approximately 10 mmol/1). Postpran- dial glucagon and glucose-dependent insulinotropic polypeptide (GIP) had increased. Comparison of the post-transplant insulin responses to a meal and to in- travenous challenges demonstrated maximal stimula- tion of the graft by the meal. Post-transplant pancre- atic polypeptide responses to a meal and i. v. arginine were severely reduced, and no pancreatic polypep- tide response to i.v. insulin-induced hypoglycaemia was observed - indicating absence of cholinergic re- innervation. Thus, glucose regulation and both the in- sulin secretory capacity and life expectancy of islet grafts were best documented by meal testing. Tenta- tively, a postprandial hyperglycaemia-enhanced in- cretin effect of glucose-dependent insulinotropic polypeptide and other gut hormones may account for the difference in the insulin response to i.v. glu- cose 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. [Diabetologia (1996) 39: 37-44] Key words Islet of Langerhans, transplantation, me- tabolism, dog, glucose-dependent insulinotropic polypeptide, pancreatic polypeptide. Transplantation of isolated islets of Langerhans has been successfully performed in large mammals, in- cluding man [1-5]. However, although physiological Received: 31 March 1995 and in revised form: 19 July 1995 Corresponding author: Dr. M. E M. van der Burg, Department of Surgery, Building 1-K6.R, University Hospital, PO Box 9600, Leiden, NL-2300 RC, The Netherlands Abbreviations: IEq, Islet equivalent; IVGTT, intravenous glu- cose tolerance test; GIP, glucose-dependent insulinotropic polypeptide; PR pancreatic polypeptide; RIA, radioimmu- noassay. glucose regulation - the crux of islet transplantation - is of utmost importance for prevention or halting the progression of secondary diabetic complications, met- abolic control by islet grafts has not yet been well-es- tablished. Reports on insulin independence after islet transplantation in man are anecdotal [1], and the met- abolic data are difficult to interpret. In most large ani- mal studies the focus has been on the technical aspects of islet transplantation, and functional assessment has received limited attention [2-5]. We studied metabolic contro ! after fasting, i. v. glucose, an i. v. arginine bolus during 35 mmol/1 glycaemia, and mixed meals, before