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.