@article{e5826d46a1364fccb85d13f99d8bd871,
title = "Inhibition of IKKɛ and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes",
abstract = "Numerous studies indicate an inflammatory link between obesity and type 2 diabetes. The inflammatory kinases IKKɛ and TBK1 are elevated in obesity; their inhibition in obese mice reduces weight, insulin resistance, fatty liver and inflammation. Here we studied amlexanox, an inhibitor of IKKɛ and TBK1, in a proof-of-concept randomized, double-blind, placebo-controlled study of 42 obese patients with type 2 diabetes and nonalcoholic fatty liver disease. Treatment of patients with amlexanox produced a statistically significant reduction in Hemoglobin A1c and fructosamine. Interestingly, a subset of drug responders also exhibited improvements in insulin sensitivity and hepatic steatosis. This subgroup was characterized by a distinct inflammatory gene expression signature from biopsied subcutaneous fat at baseline. They also exhibited a unique pattern of gene expression changes in response to amlexanox, consistent with increased energy expenditure. Together, these data suggest that dual-specificity inhibitors of IKKɛ and TBK1 may be effective therapies for metabolic disease in an identifiable subset of patients. Oral et al. investigate the effect of the anti-inflammatory, antiallergic drug amlexanox in a proof-of-concept clinical study of type 2 diabetes and nonalcoholic fatty liver disease. Amlexanox improved blood glucose levels in diabetic patients, and a subgroup showed enhanced response, including liver fat loss, associated with increased energy expenditure.",
keywords = "amlexanox, clinical trial, energy expenditure, fatty liver, gene expression, inflammation, obesity, protein kinase",
author = "Oral, {Elif A.} and Reilly, {Shannon M.} and Gomez, {Andrew V.} and Rasimcan Meral and Laura Butz and Nevin Ajluni and Chenevert, {Thomas L.} and Evgenia Korytnaya and Neidert, {Adam H.} and Rita Hench and Diana Rus and Horowitz, {Jeffrey F.} and Poirier, {Bre Anne} and Peng Zhao and Kim Lehmann and Mohit Jain and Ruth Yu and Christopher Liddle and Maryam Ahmadian and Michael Downes and Evans, {Ronald M.} and Saltiel, {Alan R.}",
note = "Funding Information: We are indebted to the patients for volunteering in this study and making themselves available for future studies. We also acknowledge the Michigan Clinical Research Unit (MCRU) staff and the dieticians supporting the metabolic research unit (led by Sarah Ball, RD and Theresa Han-Markey, RD). We thank Dr. Morton B. Brown for assistance with statistical analyses. Dr. Corey Powell from the University of Michigan C-SCAR group reviewed the statistical analyses for consistency and scientific rigor after the manuscript had been written. Drs. Richard Auchus and Meng Tan provided DSMB support. This study was primarily supported by NIH grant R21DK098776 to E.A.O. and A.R.S. Other important support included K01DK105075 to S.M.R.; DK057978 , DK090962 , HL088093 , and HL105278 ; the Glenn Foundation ; the Leona M. and Harry B. Helmsley Charitable Trust ( 2012-PG-MED-002 ) to R.M.E; and DK100319 and DK060591 to A.R.S. Infrastructure and data management support has been provided by the NIH Clinical and Translational Science Awards grant UL1TR000433 , the Nutrition Obesity Research Centers grant P30 DK089503 , and by NIH institutional grants DK034933 and P30DK0063491 . Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = jul,
day = "5",
doi = "10.1016/j.cmet.2017.06.006",
language = "English (US)",
volume = "26",
pages = "157--170.e7",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "1",
}