Increased Plasma Amylin in Type 1 Diabetic Patients After Kidney and Pancreas Transplantation A sign of impaired -cell function? MARIETTA STADLER, MD 1,2,3 CHRISTIAN ANDERWALD, MD, MPHARM 4 TINA KARER, MD 1,3 ANDREA TURA, PHD 5 THOMAS K¨ ASTENBAUER, PHD 1 MARTIN AUINGER, MD 3 CHRISTIAN BIEGLMAYER, MD 6 OSWALD WAGNER, MD 6 FLORIAN KRONENBERG, MD 3 PETER NOWOTNY 4 GIOVANNI PACINI, DSC 5 RUDOLF PRAGER, MD 1,3 OBJECTIVE — In response to hyperglycemia, -cells release insulin and C-peptide, as well as islet amyloid pancreatic polypeptide, which is involved in glucose homeostasis. After successful pancreas-kidney transplantation (PKT), type 1 diabetic patients may revert to a nondiabetic metabolism without exogenous insulin therapy and re-secrete all -cell hormones. RESEARCH DESIGN AND METHODS — Using mathematical models, we investigated hormone (amylin, insulin, C-peptide) and metabolite (glucose, free fatty acids) kinetics, -cell sensitivity to glucose, and oral glucose insulin sensitivity index (OGIS) in 11 nondiabetic type 1 diabetic patients after PKT (BMI 25  1 kg/m 2 , 47  2 years of age, 4 women/7 men, glucocor- ticoid-free), 6 matching nondiabetic patients after kidney transplantation (25  1 kg/m 2 , 50  5 years, 3 women/3 men, on glucocorticoids), and 9 matching nondiabetic control subjects (24  1 kg/m 2 , 47  2 years, 4 women/5 men) during a 3-h 75-g oral glucose tolerance test (OGTT). RESULTS — PKT patients had higher fasting amylin (19  3 vs. control subjects: 7  1 pmol/l) and insulin (20  2 vs. control subjects: 10  1 U/ml; each P  0.01) levels. Kidney transplant subjects showed increased OGTT plasma insulin at 90 min and C-peptide levels (each P  0.05). In PKT patients, plasma glucose from 90 to 150 min was 9 –31% higher (P  0.05 vs. control subjects). Amylin clearance was comparable in all groups. Amylin’s plasma concentra- tions and area under the concentration curve were up to twofold higher in PKT patients during OGTT (P  0.05). OGIS was not significantly different between groups. -Cell sensitivity to glucose was reduced in PKT patients (-64%, P  0.009). Fasting plasma amylin was inversely associated with -cell sensitivity to glucose (r =-0.543, P  0.004). CONCLUSIONS — After successful PKT, type 1 diabetic patients with nondiabetic glycemia exhibit increased fasting and post– glucose load plasma amylin, which appears to be linked to impaired -cell function. Thus, higher amylin release in proportion to insulin might also re- flect impaired -cell function in type 1 dia- betic patients after PKT. Diabetes Care 29:1031–1038, 2006 S imultaneous pancreas-kidney trans- plantation (PKT) is the treatment of choice in type 1 diabetic patients with end-stage renal disease. Successful pancreas transplantation in type 1 dia- betic patients results in sustained normal- ization of fasting plasma glucose and HbA 1c (A1C) levels without exogenous insulin therapy (1– 8), which additionally protects the transplanted kidney from ex- posure to hyperglycemia. However, qual- itative and quantitative defects of -cell function have been demonstrated in most, but not all, PKT patients with non- diabetic glycemic control (9 –13). Autoimmune -cell destruction in type 1 diabetic patients does not only re- sult in an absolute deficiency of insulin, but also a deficiency of C-peptide and islet amyloid polypeptide (amylin), both of which are cosecreted with insulin, but are not of vital importance. Although the role of C-peptide in metabolism is still de- bated (14), amylin is clearly involved in glucose homeostasis through the inhibi- tion of gastric emptying and postprandial hepatic glucose production, eventually reducing postprandial glucose excursions (15). Most recently, the synthetic amylin analog pramlintide was shown to improve glycemic control in type 1 diabetic pa- tients, leading to a reduction of daytime glucose excursion and improvement of A1C (16 –19). Although amylin secretion has not yet been investigated in type 1 diabetic pa- tients after successful PKT, it may be com- pletely restored in these patients. Based on this assumption, the association be- tween amylin secretion and plasma con- centration on the one hand and glycemia, -cell function, and insulin sensitivity on the other, in patients after pancreas trans- plantation, might provide further insight ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● From the 1 Ludwig Boltzmann Institute of Metabolic Diseases and Nutrition, Vienna, Austria; the 2 Depart- ment of Medical Genetics, Division of Genetic Epidemiology, Molecular and Clinical Pharmacology, Inns- bruck Medical University, Innsbruck, Austria; the 3 3rd Medical Department of Metabolic Diseases and Nephrology, Lainz Hospital, Vienna, Austria; the 4 Department of Internal Medicine 3, Division of Endocri- nology and Metabolism, Medical University Vienna, Vienna, Austria; the 5 Metabolic Unit, Institute of Bio- medical Engineering, Padova, Italy; and the 6 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Vienna, Vienna, Austria. Address correspondence and reprint requests to Marietta Stadler, MD, Lainz Hospital, 3rd Medical Department, Wolkersbergenstrasse 1, 1130 Vienna, Austria. E-mail: marietta.stadler@wienkav.at. Received for publication 6 July 2005 and accepted in revised form 31 January 2006. M.S. and C.A. contributed equally to this work. Abbreviations: AUC, area under the concentration curve; FFA, free fatty acid; OGIS, oral glucose insulin sensitivity index; OGTT, oral glucose tolerance test; PKT, pancreas-kidney transplantation. A table elsewhere in this issue shows conventional and Syste `me International (SI) units and conversion factors for many substances. DOI: 10.2337/dc05-1247 © 2006 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Pathophysiology/Complications O R I G I N A L A R T I C L E DIABETES CARE, VOLUME 29, NUMBER 5, MAY 2006 1031