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

Elif A. Oral, Shannon M. Reilly, Andrew V. Gomez, Rasimcan Meral, Laura Butz, Nevin Ajluni, Thomas L. Chenevert, Evgenia Korytnaya, Adam H. Neidert, Rita Hench, Diana Rus, Jeffrey F. Horowitz, Bre Anne Poirier, Peng Zhao, Kim Lehmann, Mohit Jain, Ruth Yu, Christopher Liddle, Maryam Ahmadian, Michael DownesRonald M. Evans, Alan R. Saltiel

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)157-170.e7
JournalCell Metabolism
Volume26
Issue number1
DOIs
StatePublished - Jul 5 2017
Externally publishedYes

Keywords

  • amlexanox
  • clinical trial
  • energy expenditure
  • fatty liver
  • gene expression
  • inflammation
  • obesity
  • protein kinase

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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