The effects of exendin-4 treatment on graft failure: an animal study using a novel re-vascularized minimal human islet transplant model

PLoS One. 2015 Mar 20;10(3):e0121204. doi: 10.1371/journal.pone.0121204. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Blood Glucose / metabolism
  • C-Peptide / metabolism
  • Cell Count
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / therapy
  • Exenatide
  • Fasting / blood
  • Glucagon / metabolism
  • Glucagon-Like Peptide 1 / metabolism
  • Glucose Tolerance Test
  • Graft Survival / drug effects*
  • Humans
  • Hyperglycemia / blood
  • Hyperglycemia / complications
  • Hyperglycemia / drug therapy
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / pathology
  • Islets of Langerhans / blood supply*
  • Islets of Langerhans / drug effects
  • Islets of Langerhans Transplantation*
  • Male
  • Mice, Inbred BALB C
  • Models, Animal
  • Peptides / administration & dosage
  • Peptides / pharmacology*
  • Peptides / therapeutic use
  • Venoms / administration & dosage
  • Venoms / pharmacology*
  • Venoms / therapeutic use

Substances

  • Blood Glucose
  • C-Peptide
  • Insulin
  • Peptides
  • Venoms
  • Glucagon-Like Peptide 1
  • Glucagon
  • Exenatide

Grants and funding

This study was funded through a research program established at Oslo University Hospital (OUS) supported by AstraZeneca in a scientific collaboration (OUS project number 37813). AS and HS received financial support from this program funding. MH has no relevant disclosures. The funder provided support in the form of salaries for authors MSW, TG, DMS, SS and LJ, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the author contributions section.