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The metabolic effects of leptin therapy and glucagon suppression therapy in mouse models of diabetes

University of British Columbia

It has long been thought that the only hormone capable of reversing the catabolic consequences of diabetes is insulin. However, various studies have demonstrated that the adipocyte-derived hormone leptin can potently lower blood glucose levels in rodent models of insulin-deficient diabetes. In addition, the hormone glucagon is elevated in type 1 and type 2 diabetes, and glucagon suppression therapy has shown promise as an agent to treat diabetes in mice. Given the interest in both of these therapies, leptin treatment and glucagon antagonism were propelled into clinical trials for patients with type 1 and type 2 diabetes respectively. The overarching goal of this thesis was to perform preclinical studies to investigate the mechanism of the glucose lowering actions of leptin and the effects of glucagon suppression therapy in mouse models of diabetes. To achieve this, we probed the role of increased leptin action as a result of insulin therapy, determined the function of insulin-like growth factor binding protein-2 (IGFBP2) in the glucose lowering actions of leptin, investigated the necessity of insulin for leptin treatment and glucagon suppression therapy, and explored the potential of glucagon suppression therapy via glucagon receptor (Gcgr) small interfering ribonucleic acid (siRNA) delivered by lipid nanoparticle (LNP) technology. This thesis reveals that elevated leptin levels may contribute to the glucose lowering effect of insulin therapy in insulin-deficient diabetes. In addition, we demonstrate that physiological levels of IGFBP2 are neither sufficient nor required for the action of leptin on glucose homeostasis. Moreover, leptin can normalize many metabolic parameters in the complete absence of insulin, but blood glucose levels are volatile and the length of survival is finite. Furthermore, Gcgr siRNA can improve many diabetic symptoms in mouse models of type 1 and type 2 diabetes. Finally, we report that the metabolic manifestations associated with a complete lack of insulin cannot be overcome by Gcgr gene inactivation. Collectively the findings in this thesis contribute insight into the mechanism of action, and the therapeutic potential of leptin administration and glucagon suppression therapy as a treatment for diabetes.

Text

2017-07-04

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/62127

Cell and Developmental Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/