UBC Theses and Dissertations
The metabolic effects of leptin therapy in a mouse model of type 1 diabetes. Denroche, Heather Courtney
Type 1 diabetes is a life-long disease, with devastating consequences and no cure. While the hormone insulin has been the only effective treatment to date for type 1 diabetes, emerging evidence has revealed that the fat-derived hormone leptin can also exert profound glucose lowering effects, and reduce mortality in type 1 diabetes. This has generated interest in the therapeutic potential of leptin as an anti-diabetic treatment, and propelled leptin into clinical trials for type 1 diabetes. The fact that leptin monotherapy (without insulin administration) can so potently lower blood glucose in insulin-deficient diabetes is surprising, given that for almost a century, insulin has been assumed to be the only hormone that can lower blood glucose in type 1 diabetes. The overarching goal of this thesis was to perform pre-clinical studies to elucidate the mechanism of the anti-diabetic effects of leptin in type 1 diabetes. To this end, we thoroughly assessed the changes in metabolic and energy homeostasis that occur in a mouse model of type 1 diabetes receiving leptin therapy. The roles of hepatic and neuronal leptin receptor signalling in the anti-diabetic action of leptin were also investigated, through tissue specific disruption of leptin signalling using the Cre-lox method. In addition, we assessed whether leptin therapy can serve as an adjuvant to islet transplantation therapy in type 1 diabetes. This thesis revealed that leptin therapy lowers blood glucose in a mouse model of type 1 diabetes, correlating with decreased hepatic glucose production and enhanced insulin sensitivity. The anti-diabetic action of leptin is not blunted in mice with disrupted neuronal leptin signalling outside of the arcuate and ventromedial hypothalamus, or in mice with disrupted hepatic leptin signalling, suggesting that leptin acts through alternate or redundant pathways to lower blood glucose. Finally, low-dose leptin administration dramatically enhanced the ability of islet transplants to restore euglycemia, suggesting that leptin and islet co-therapy could be a successful therapeutic strategy for type 1 diabetes. Collectively the findings in this thesis contribute insight into the mechanism of action, and the therapeutic potential of leptin as a treatment for type 1 diabetes.
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