title: The effects of exendin-4 treatment on graft failure: an animal study using a novel re-vascularized minimal human islet transplant model.
abstract: Islet transplantation has become a viable clinical treatment, but is still compromised by long-term graft failure. Exendin-4, a glucagon-like peptide 1 receptor agonist, has in clinical studies been shown to improve insulin secretion in islet transplanted patients. However, little is known about the effect of exendin-4 on other metabolic parameters. We therefore aimed to determine what influence exendin-4 would have on revascularized minimal human islet grafts in a state of graft failure in terms of glucose metabolism, body weight, lipid levels and graft survival. Introducing the bilateral, subcapsular islet transplantation model, we first transplanted diabetic mice with a murine graft under the left kidney capsule sufficient to restore normoglycemia. After a convalescent period, we performed a second transplantation under the right kidney capsule with a minimal human islet graft and allowed for a second recovery. We then performed a left-sided nephrectomy, and immediately started treatment with exendin-4 with a low (20μg/kg/day) or high (200μg/kg/day) dose, or saline subcutaneously twice daily for 15 days. Blood was sampled, blood glucose and body weight monitored. The transplanted human islet grafts were collected at study end point and analyzed. We found that exendin-4 exerts its effect on failing human islet grafts in a bell-shaped dose-response curve. Both doses of exendin-4 equally and significantly reduced blood glucose. Glucagon-like peptide 1 (GLP-1), C-peptide and pro-insulin were conversely increased. In the course of the treatment, body weight and cholesterol levels were not affected. However, immunohistochemistry revealed an increase in beta cell nuclei count and reduced TUNEL staining only in the group treated with a low dose of exendin-4 compared to the high dose and control. Collectively, these results suggest that exendin-4 has a potential rescue effect on failing, revascularized human islets in terms of lowering blood glucose, maintaining beta cell numbers, and improving metabolic parameters during hyperglycemic stress.
authors: Institute for Surgical Research and Section for Transplantation Surgery, Oslo University Hospital, Oslo, Norway.
authors: Afaf
authors: A
authors: Sahraoui
authors: AstraZeneca R&D, Mölndal, Sweden.
authors: Maria Sörhede
authors: MS
authors: Winzell
authors: AstraZeneca, Alderley Park, Cheshire, United Kingdom.
authors: Tracy
authors: T
authors: Gorman
authors: AstraZeneca R&D, Mölndal, Sweden.
authors: Dave M
authors: DM
authors: Smith
authors: AstraZeneca R&D, Mölndal, Sweden.
authors: Stanko
authors: S
authors: Skrtic
authors: Institute for Surgical Research and Section for Transplantation Surgery, Oslo University Hospital, Oslo, Norway.
authors: Merete
authors: M
authors: Hoeyem
authors: Institute for Surgical Research and Section for Transplantation Surgery, Oslo University Hospital, Oslo, Norway.
authors: Shadab
authors: S
authors: Abadpour
authors: Department of Radiology, Oncology and Radiation Sciences, Uppsala University Hospital, Uppsala, Sweden.
authors: Lars
authors: L
authors: Johansson
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Olle
authors: O
authors: Korsgren
authors: Institute for Surgical Research and Section for Transplantation Surgery, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors: Aksel
authors: A
authors: Foss
authors: Institute for Surgical Research and Section for Transplantation Surgery, Oslo University Hospital, Oslo, Norway.
authors: Hanne
authors: H
authors: Scholz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000378:metabolism; D002452:Cell Count; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000628:therapy; D000077270:Exenatide; D005215:Fasting / Q000097:blood; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005951:Glucose Tolerance Test; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000150:complications / Q000188:drug therapy; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000473:pathology; D007515:Islets of Langerhans / Q000098:blood supply* / Q000187:drug effects; D016381:Islets of Langerhans Transplantation; D008297:Male; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014688:Venoms / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide