Islet transplantation is an effective method to obtain long-term glycemic control for patients with type 1 diabetes, yet its widespread use is limited by an inadequate supply of donor islets. The hormone leptin has profound glucose-lowering and insulin-sensitizing action in type 1 diabetic rodent models. We hypothesized that leptin administration could reduce the dose of transplanted islets required to achieve metabolic control in a mouse model of type 1 diabetes. We first performed a leptin dose response study in C57Bl/6 mice with streptozotocin (STZ)-induced diabetes to determine a leptin dose insufficient to reverse hyperglycemia. Subsequently, we compared the ability of suboptimal islet transplants of 50 or 125 syngeneic islets to achieve glycemic control in STZ-diabetic C57Bl/6 mice treated with or without this dose of leptin. The dose response study revealed that leptin reverses STZ-diabetes in a dose-dependent manner. Supraphysiological leptin levels were necessary to restore euglycemia, but simultaneously increased risk of hypoglycemia, and also lost efficacy after 12 days of administration. In contrast, 1 µg/day leptin only modestly reduced blood glucose, but maintained efficacy throughout the study duration. We then administered 1 µg/day leptin to diabetic mice transplanted with 50 or 125 islets. While these islet doses were insufficient to ameliorate hyperglycemia alone, co-administration of leptin with islet transplantation robustly improved control of glucose and lipid metabolism, without increasing circulating insulin levels. This study reveals that low-dose leptin administration can reduce the number of transplanted islets required to achieve metabolic control in STZ-diabetic mice.
- Received December 5, 2012.
- Accepted May 3, 2013.
- © 2013 by the American Diabetes Association.
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