Inhibition of IKKε and TBK1 improves glucose control in a subset of patients with type 2 diabetes

Numerous studies indicate an inflammatory link between obesity and type 2 diabetes. The inflammatory kinases IKKε 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 IKKε/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 IKKε/TBK1 inhibitors may be effective therapies for metabolic disease in an identifiable subset of patients. XXX 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 sub-group showed enhanced response, including liver fat loss, associated with increased energy expenditure.