Inhibition of IKKɛ and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes

• Published in: Cell metabolism 2017-07, Vol.26 (1), p.157-170.e7
• Main Authors: Oral, Elif A., Reilly, Shannon M., Gomez, Andrew V., Meral, Rasimcan, Butz, Laura, Ajluni, Nevin, Chenevert, Thomas L., Korytnaya, Evgenia, Neidert, Adam H., Hench, Rita, Rus, Diana, Horowitz, Jeffrey F., Poirier, BreAnne, Zhao, Peng, Lehmann, Kim, Jain, Mohit, Yu, Ruth, Liddle, Christopher, Ahmadian, Maryam, Downes, Michael, Evans, Ronald M., Saltiel, Alan R.
• Format: Article
• Language: English
• Subjects: Aged; Aminopyridines - therapeutic use; amlexanox; Blood Glucose - analysis; Blood Glucose - metabolism; clinical trial; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Double-Blind Method; energy expenditure; Energy Metabolism - drug effects; fatty liver; Female; gene expression; Glycated Hemoglobin - analysis; Glycated Hemoglobin - metabolism; Humans; I-kappa B Kinase - antagonists & inhibitors; I-kappa B Kinase - metabolism; inflammation; Male; Middle Aged; Non-alcoholic Fatty Liver Disease - blood; Non-alcoholic Fatty Liver Disease - complications; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - metabolism; obesity; Obesity - blood; Obesity - complications; Obesity - metabolism; protein kinase; Protein Kinase Inhibitors - therapeutic use; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2017.06.006

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. [Display omitted] •12 weeks of amlexanox treatment significantly reduced HbA1c in obese, diabetic subjects•Amlexanox treatment did not affect all subjects equally•The amlexanox-treated responders had higher baseline inflammation•Energy-expenditure-associated genes were increased in responders 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.