title: Long-term insulin independence and improvement in insulin secretion after supplemental islet infusion under exenatide and etanercept.
abstract: BACKGROUND
  Progressive graft dysfunction (GDF) and loss of insulin independence (II) have been invariably observed in islet transplant recipients under the "Edmonton protocol." To reestablish II, we performed supplemental islet infusions (SI) in recipients of allogeneic islet transplant alone, displaying GDF. To improve the engraftment and long-term graft function of SI, exenatide (EXN) and etanercept treatment at islet infusion, and long-term EXN treatment were tested in a non-randomized pilot clinical trial.
  
  
  METHODS
  Patients with GDF received SI under Edmonton-like immunosuppression with daclizumab induction, either without interventions (SI-control; n=5) or with EXN and etanercept treatment (SI-EXN; n=4). Clinical and metabolic profiles were assessed during 18-month follow-up.
  
  
  RESULTS
  Long-term II (18 months) was observed in 100% of SI-EXN and in 20% of SI-control (P=0.04). SI-EXN subjects demonstrated restoration of function better than that seen after initial islet infusions. Comparison of SI-EXN and SI-control groups demonstrated better responses in SI-EXN subjects at 3 months post-SI. During the 18 months of follow-up, function was sustained in the SI-EXN subjects better than in SI-controls. Acute effects of EXN during mixed meal tolerance test and intravenous glucose tolerance test results in improved first and second phase insulin release in response to intravenous glucose tolerance test and suppressed postprandial hyperglucagonemia after mixed meal tolerance test.
  
  
  CONCLUSIONS
  These results suggest that the combination of EXN and etanercept improve engraftment and long-term islet survival and function in subjects undergoing SI. This data, however, must be interpreted with some caution because of small sample size, lack of randomization, and sequential comparison with historical controls.
authors.affiliation: Clinical Islet Transplant Program, Diabetes Research Institute, University of Miami Leonard M Miller School of Medicine, Miami, FL, USA.
authors.forename: Raquel N
authors.initials: RN
authors.lastname: Faradji
authors.forename: Thipaporn
authors.initials: T
authors.lastname: Tharavanij
authors.forename: Shari
authors.initials: S
authors.lastname: Messinger
authors.forename: Tatiana
authors.initials: T
authors.lastname: Froud
authors.forename: Antonello
authors.initials: A
authors.lastname: Pileggi
authors.forename: Kathy
authors.initials: K
authors.lastname: Monroy
authors.forename: Davide
authors.initials: D
authors.lastname: Mineo
authors.forename: David A
authors.initials: DA
authors.lastname: Baidal
authors.forename: Pablo
authors.initials: P
authors.lastname: Cure
authors.forename: Gaston
authors.initials: G
authors.lastname: Ponte
authors.forename: Armando J
authors.initials: AJ
authors.lastname: Mendez
authors.forename: Gennaro
authors.initials: G
authors.lastname: Selvaggi
authors.forename: Camillo
authors.initials: C
authors.lastname: Ricordi
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Alejandro
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002096:C-Peptide / Q000097:blood; D000068800:Etanercept; D000077270:Exenatide; D005500:Follow-Up Studies; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000379:methods*; D008875:Middle Aged; D010455:Peptides / Q000627:therapeutic use*; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D017211:Treatment Failure; D014688:Venoms / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007004:Hypoglycemic Agents; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D007328:Insulin; D010455:Peptides; D018124:Receptors, Tumor Necrosis Factor; D014688:Venoms; D000077270:Exenatide; D000068800:Etanercept