Inhibition of IKK 3 and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes

被引：138

作者：

Oral, Elif A. ^{[1
,2
]}

Reilly, Shannon M. ^{[3
,4
,5
]}

Gomez, Andrew V. ^{[4
,5
]}

Meral, Rasimcan ^{[1
,2
]}

Butz, Laura ^{[1
,2
]}

Ajluni, Nevin ^{[1
,2
]}

Chenevert, Thomas L. ^{[6
]}

Korytnaya, Evgenia ^{[1
,2
]}

Neidert, Adam H. ^{[1
,2
]}

Hench, Rita ^{[1
,2
]}

Rus, Diana ^{[1
,2
]}

Horowitz, Jeffrey F. ^{[7
]}

Poirier, BreAnne ^{[3
]}

Zhao, Peng ^{[3
,4
,5
]}

Lehmann, Kim ^{[4
,5
]}

Jain, Mohit ^{[4
,5
]}

Yu, Ruth ^{[8
]}

Liddle, Christopher ^{[8
,9
,10
]}

Ahmadian, Maryam ^{[8
]}

Downes, Michael ^{[8
]}

Evans, Ronald M. ^{[8
]}

Saltiel, Alan R. ^{[3
,4
,5
,11
]}

机构：

[1] Univ Michigan, Sch Med, Dept Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48105 USA

[2] Univ Michigan, Sch Med, Brehm Ctr Diabet, Ann Arbor, MI 48105 USA

[3] Univ Michigan, Life Sci Inst, Ann Arbor, MI 48109 USA

[4] Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA

[5] Univ Calif San Diego, Sch Med, Dept Pharmacol, La Jolla, CA 92093 USA

[6] Univ Michigan, Sch Med, Dept Radiol, Ann Arbor, MI 48105 USA

[7] Univ Michigan, Sch Kinesiol, Ann Arbor, MI 48019 USA

[8] Salk Inst Biol Sci, Gene Express Lab, La Jolla, CA 92037 USA

[9] Univ Sydney, Westmead Inst Med Res, Westmead Hosp, Storr Liver Ctr, Westmead, NSW 2145, Australia

[10] Univ Sydney, Sydney Med Sch, Westmead Hosp, Westmead, NSW 2145, Australia

[11] Univ Calif San Diego, Inst Diabet & Metab Hlth, 9500 Gilman Dr, La Jolla, CA 92093 USA

来源：

CELL METABOLISM | 2017年 / 26卷 / 01期

关键词：

ADIPOSE-TISSUE; INSULIN-RESISTANCE; PARTIAL LIPODYSTROPHY; AMLEXANOX AA-673; OBESITY; INFLAMMATION; EXPRESSION; LIPOLYSIS; MACROPHAGES; EPINEPHRINE;

D O I：

10.1016/j.cmet.2017.06.006

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页码：157 / +

页数：21

共 55 条

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