Leptin Administration Improves Islet Transplant Efficacy in Streptozotocin-induced Diabetic Mice

Abstract

Islet transplantation is a promising therapy to restore long-term glucose control for people with type 1 diabetes (T1D), but is limited by inadequate supply of donor tissue. High doses of leptin alone can reverse hyperglycemia in rodent models of T1D, yet can also produce hypoglycemia and leptin resistance. Thus we sought to determine whether low-dose leptin could instead be combined with islet transplantation, to reduce the amount of islets required to reverse diabetes in a mouse model of T1D. Streptozotocin-induced diabetic mice received suboptimal doses of 50 or 125 islets transplanted under the kidney capsule, along with either leptin (at a low dose that alone does not ameliorate diabetes) or vehicle for 6 weeks. Mice treated with 50 or 125 islets in the presence of leptin exhibited a robust reduction in fasted blood glucose levels within 12 days of surgery (15.4 ± 3.7 and 10.1 ± 5.7 mmol/L respectively) whereas mice transplanted with 50 or 125 islets in the absence of leptin remained diabetic throughout the study (blood glucose greater than 20 mmol/L). Furthermore, leptin treated recipients of 50 and 125 islets had improved glucose tolerance (∼28 and 27% lower area under the curve respectively), and reduced circulating lipids, β-hydroxybutryate, and hemoglobin A1c, compared to their vehicle treated controls. Thus, low-dose leptin administration can robustly improve the ability of a small number of transplanted islets to reverse hyperglycemia in streptozotocin-treated mice, and may be a potential avenue to reduce the amount of donor islets required to treat people with T1D.