Pas de Deux
Glucagon and Thyroid Hormone Moving in Perfect Synchrony
This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.
Chemical hybridization of glucagon and thyroid hormone optimizes therapeutic impact for metabolic disease
Finan et al
The implementation of thyroid hormone (T3) or glucagon as lipid-lowering, antidiabetic, and antiobesity agents have not been successful to date because of serious adverse side effects. Using a synthetic hybrid glucagon/T3 conjugate, Finan et al have established a novel therapeutic approach for the reversal of dyslipidemia, obesity, and insulin resistance associated with the metabolic syndrome, while limiting cardiovascular side effects.
Obesity-associated dyslipidemia is the primary risk factor for cardiovascular and other metabolic diseases.1 Increased circulating lipid levels contribute to atherosclerosis and coronary artery disease,2 whereas increased lipid deposition in tissues, such as adipose tissue, skeletal muscle, and liver, increases the risk of insulin resistance.3 Statins have been a mainstay of dyslipidemia treatment since their introduction in the 1980s. Statins reduce cardiovascular disease incidence through a reduction of circulating low-density lipoprotein and reduced atherosclerotic lesion formation, but minimally address other lipid-related species (triglycerides, high-density lipoprotein) and ectopic accumulation of tissue lipids.4
In a recent article published in Cell, Finan et al5 report a novel pharmacological tool with impressive metabolic benefits. The backbone consists of 2 well-established hormones: glucagon and thyroid hormone. These 2 entities are chemically conjugated and the authors refer to it as glucagon/T3. This hybrid molecule corrects multiple aspects of obesity-associated dyslipidemia that are not addressed by current therapeutics. With relatively short (2- to 3-week) administrations of glucagon/T3, the authors effectively managed to reduce low-density lipoprotein-cholesterol, reverse steatohepatitis, prevent atherosclerotic plaque accumulation, improve glucose tolerance, and reduce body weight in a variety of rodent models of obesity. Exposure to this novel compound has broad physiological implications: First, it provides a method to leverage 2 pathways for the treatment of metabolic disease that have to …