期刊
CELL METABOLISM
卷 26, 期 1, 页码 157-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2017.06.006
关键词
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资金
- NIH [R21DK098776, K01DK105075, DK057978, DK090962, HL088093, HL105278]
- Glenn Foundation
- Leona M. and Harry B. Helmsley Charitable Trust [2012-PG-MED-002, DK100319, DK060591]
- NIH Clinical and Translational Science Awards grant [UL1TR000433]
- Nutrition Obesity Research Centers grant [P30 DK089503]
- NIH institutional grants [DK034933, P30DK0063491]
Numerous studies indicate an inflammatory link between obesity and type 2 diabetes. The inflammatory kinases IKK 3 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 IKK 3 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 IKK 3 and TBK1 may be effective therapies for metabolic disease in an identifiable subset of patients.
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