Final Report Summary - LIFEWITHOUTINSULIN (Metabolic actions of brain leptin receptors signaling in type 1 diabetes)
The main objective of this project was to identify molecular targets for improving treatment of a diabetic condition affecting tens of millions worldwide: insulin deficiency (ID). Currently, ID patients are treated with insulin therapy that is suboptimal due, in part, to the risk associated with the ability of insulin to bring circulating blood content down to life-threatening levels. Recent exciting results have indicated that leptin monotherapy (with no use of insulin) permits survival and significantly ameliorates diabetes of ID rodents1,2. Thus, understanding the mechanisms (molecules and cell-types) by which leptin improves ID is of great interest. Here, we provide with data supporting that the brain mediates the anti-diabetic action of leptin in the context of ID. Also, by using genetically-engineered mice lacking insulin and expressing or lacking leptin receptors only in specific neuronal population we identified hypothalamic GABAergic neurons as main mediators on the anti-diabetic action of leptin in the context of ID. We have also identified a molecule that circulates in the blood whose amount is influenced by leptin. Increasing the circulating levels of this molecule (i.e. S100A) improves ID symptoms and survival in mice. We believe that these findings could have a huge societal impact. In fact, S100A9-based therapeutics could represent means to improve insulin therapy in ID and hence improve quality and quantity of life of ID patients.