title: Exendin-4 increases the expression of hypoxia-inducible factor-1α in rat islets and preserves the endocrine cell volume of both free and macroencapsulated islet grafts.
abstract: In this study, we evaluated the effects of exendin-4 on free and encapsulated islet grafts in a rodent model. We also investigated the role of a transcription factor, hypoxia-inducible factor-1 (HIF-1), in mediating the beneficial effects of exendin-4. Diabetic athymic mice were transplanted  with free rat islets under the kidney capsule or with macroencapsulated rat islets SC with or without exendin-4, islet preculture (exendin-4 0.1 nM for 20 h), and/or recipient treatment (IP 100 ng/day, day 0-7). The mice were followed for 4 weeks and the graft function and β-cell  volume were evaluated. The effects of exendin-4 on islet HIF-1α mRNA and protein expression and on ATP content in a rat insulinoma cell line (INS-1E) were also examined. Preculture with exendin-4 followed by recipient treatment improved the outcome of both free (73% graft function vs.  26% in controls, p = 0.03) and macroencapsulated islet grafts (100% vs. 25% in controls, p = 0.02). In macroencapsulated grafts, the exendin-4-treated group had significantly larger endocrine volume, less graft necrosis, and more blood vessels around the capsule. In rat islets  cultured with exendin-4, HIF-1α mRNA and protein expression were significantly enhanced. ATP content was increased in exendin-4-treated INS-1E cells under hypoxic conditions. The improved functional outcome after transplantation of a marginal islet mass with a brief initial treatment  with exendin-4 is related to a larger surviving endocrine cell volume. Exendin-4 may improve islet graft resistance to hypoxia during the peritransplant period by increasing the expression of HIF-1α.
authors.affiliation: CLINTEC, Division of Transplantation Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Jia
authors.forename: Amit
authors.initials: A
authors.lastname: Sharma
authors.forename: Makiko
authors.initials: M
authors.lastname: Kumagai-Braesch
authors.forename: Annika M
authors.initials: AM
authors.lastname: Wernerson
authors.forename: Anne K
authors.initials: AK
authors.lastname: Sörenby
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Annika B
authors.initials: AB
authors.lastname: Tibell
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D048429:Cell Size / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D004703:Endocrine System / Q000033:anatomy & histology*; D000077270:Exenatide; D018398:Homeodomain Proteins / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015534:Trans-Activators / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*
chemical_list: D018398:Homeodomain Proteins; D007004:Hypoglycemic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D015534:Trans-Activators; D014688:Venoms; C084010:pancreatic and duodenal homeobox 1 protein; D000255:Adenosine Triphosphate; D000077270:Exenatide; D053148:Caspase 3