title: Long-term metabolic and hormonal effects of exenatide on islet transplant recipients with allograft dysfunction.
abstract: The initial success of islet transplantation (ITx) is followed by graft dysfunction (GDF) and insulin reintroduction. Exenatide, a GLP-1 agonist, increases insulin and decreases glucagon secretion and has potential for beta-cell regeneration. To improve functional islet mass, exenatide treatment was given to ITx recipients with GDF. The objective of this study was to assess metabolic and hormonal effects of exenatide in GDF. In this prospective, single-arm, nonrandomized study, 11 type 1 diabetes recipients of ITx with GDF had HbA1c, weight, insulin requirements, and 5-h mixed meal tolerance test (MMTT; with/without exenatide given before test) at baseline, 3, 6, and 12 months after initiating exenatide treatment. Baseline MMTT showed postprandial hyperglycemia and hyperglucagonemia. Daily exenatide treatment resulted in improved glucose, increased amylin/insulin ratio, and decreased proinsulin/insulin ratio as assessed by MMTT. Glucagon responses remained unchanged. Exenatide administration 1 h before MMTT showed decreased glucagon and glucose at 0 min and attenuation in their postprandial rise. Time-to-peak glucose was delayed, followed by insulin, proinsulin, amylin, and C-peptide, indicating glucose-driven insulin secretion. Five subjects completed 12-month follow-up. Glucose and glucagon suppression responses after MMTT with exenatide were no longer observed. Retrospective 3-month analysis of these subjects revealed higher and sustained glucagon levels that did not suppress as profoundly with exenatide administration, associated with higher glucose levels and increased C-peptide responses. In conclusion, Exenatide suppresses the abnormal postprandial hyperglucagonemia and hyperglycemia observed in GDF. Changes in amylin and proinsulin secretion may reflect more efficient insulin processing. Different degrees of responsiveness to exenatide were identified. These may help guide the clinical management of ITx recipients.
authors.affiliation: Clinical Islet Transplant Program, Diabetes Research Institute, University of Miami Leonard M Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Raquel N
authors.initials: RN
authors.lastname: Faradji
authors.forename: Tatiana
authors.initials: T
authors.lastname: Froud
authors.forename: Shari
authors.initials: S
authors.lastname: Messinger
authors.forename: Kathy
authors.initials: K
authors.lastname: Monroy
authors.forename: Antonello
authors.initials: A
authors.lastname: Pileggi
authors.forename: Davide
authors.initials: D
authors.lastname: Mineo
authors.forename: Thipaporn
authors.initials: T
authors.lastname: Tharavanij
authors.forename: Armando J
authors.initials: AJ
authors.lastname: Mendez
authors.forename: Camillo
authors.initials: C
authors.lastname: Ricordi
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Alejandro
mesh_terms: D000328:Adult; D000682:Amyloid / Q000378:metabolism; D019540:Area Under Curve; D002096:C-Peptide / Q000378:metabolism; D003710:Demography; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy; D000077270:Exenatide; D005260:Female; D005934:Glucagon / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000209:etiology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000494:pharmacology*; D055031:Primary Graft Dysfunction / Q000188:drug therapy*; D011446:Prospective Studies; D014184:Transplantation, Homologous; D014688:Venoms / Q000494:pharmacology*
chemical_list: D000682:Amyloid; D002096:C-Peptide; D007004:Hypoglycemic Agents; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D010455:Peptides; D014688:Venoms; D005934:Glucagon; D000077270:Exenatide; D005947:Glucose