This proposal focuses on a clinical proof of concept study to evaluate a novel hypothesis. We hypothesize that the noncanonical Ikb kinases IKKe and TBK1 are """"""""counterinflammatory"""""""" kinases that keep inflammatory pathways in check while helping to support a positive energy balance. Therefore, inhibition of this pathway selectively wil improve positive energy balance and insulin resistance supported by inflammation. In an effort to begin to test this hypothesis, a high-throughput screen was carried out to identify IKKe inhibitors. The most potent and specific inhibitor discovered was Amlexanox;an older drug originally developed in Japan for the treatment of asthma and allergic rhinitis, and later in the US for aphthous ulcers, but without a well understood mechanism of action. It has been in use since 1987, and has a favorable side effect profile. Rodent data obtained in our laboratory has been very promising, showing exciting metabolic effects with amelioration of insulin resistance, glucose and lipid metabolism along with improvement in hepatic steatosis and an increase in energy expenditure. We now propose an early proof-of concept clinical study to translate our laboratory observations using Amlexanox in humans with 3 specific aims: 1) to test the metabolic efficacy in improvement of glucose and insulin resistance parameters in obese Type 2 diabetics. 2) To test the efficacy on amelioration of hepatic steatosis. 3) To develop biomarkers for treatment of patients with type 2 diabetes by Amlexanox. If successful, this proposal may open the door to a novel treatment pathway for the ever-growing metabolic disturbances that are threatening tens of millions of Americans.
Tens of millions of Americans are afflicted with obesity, a state of positive energy balance promoted by insulin. Work from our group as well as others have shown that the stress of excess energy balance initiates a set of homeostatic responses that include the generation of adipose tissue and liver inflammation with the purpose of blocking energy storage by promoting insulin resistance. We recently observed that there is a secondary counterinflammatory feedback loop that keeps inflammation at bay and maintains a positive energy balance. The current proposal will be the first proof-of concept human study probing the relevance of the counterinflammatory pathway in human energy metabolism.
|Oral, Elif A; Reilly, Shannon M; Gomez, Andrew V et al. (2017) Inhibition of IKK? and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes. Cell Metab 26:157-170.e7
|Reilly, Shannon M; Ahmadian, Maryam; Zamarron, Brian F et al. (2015) A subcutaneous adipose tissue-liver signalling axis controls hepatic gluconeogenesis. Nat Commun 6:6047