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

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.

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

机译：IKK 3和TBK1的抑制改善了2型糖尿病患者的副本中的葡萄糖对照

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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.

机译：许多研究表明肥胖和2型糖尿病之间的炎症联系。炎症激酶IKK 3和TBK1以肥胖升高;它们在肥胖小鼠中的抑制减轻了重量，胰岛素抵抗，脂肪肝和炎症。在这里，我们研究了Amxxanox，IKK 3和TBK1的抑制剂，在概念上的验证随机，双盲，安慰剂对照研究42型糖尿病患者和非酒精性脂肪肝疾病。治疗Amlexanox患者在血红蛋白A1C和果糖胺中产生了统计学显着的降低。有趣的是，药物响应者的子集还表现出胰岛素敏感性和肝脏脂肪变性的改善。该亚组的特征在于基线的活检皮脂的不同炎症基因表达特征。它们还表现出一种独特的基因表达模式，响应于Amlexanox，与增加的能量消耗一致。这些数据表明，IKK 3和TBK1的双特异性抑制剂可以是患者可识别子集中代谢疾病的有效疗法。

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《Cell metabolism》 |2017年第1期|共21页
作者
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.;
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作者单位

Univ Michigan Sch Med Dept Med Div Metab Endocrinol &

Diabet Ann Arbor MI 48105 USA;

Univ Michigan Life Sci Inst Ann Arbor MI 48109 USA;

Univ Calif San Diego Sch Med Dept Med La Jolla CA 92093 USA;

Univ Michigan Sch Med Dept Med Div Metab Endocrinol &

Diabet Ann Arbor MI 48105 USA;

Univ Michigan Sch Med Dept Med Div Metab Endocrinol &

Diabet Ann Arbor MI 48105 USA;

Univ Michigan Sch Med Dept Med Div Metab Endocrinol &

Diabet Ann Arbor MI 48105 USA;

Univ Michigan Sch Med Dept Radiol Ann Arbor MI 48105 USA;

Univ Michigan Sch Med Dept Med Div Metab Endocrinol &

Diabet Ann Arbor MI 48105 USA;

Univ Michigan Sch Med Dept Med Div Metab Endocrinol &

Diabet Ann Arbor MI 48105 USA;

Univ Michigan Sch Med Dept Med Div Metab Endocrinol &

Diabet Ann Arbor MI 48105 USA;

Univ Michigan Sch Med Dept Med Div Metab Endocrinol &

Diabet Ann Arbor MI 48105 USA;

Univ Michigan Sch Kinesiol Ann Arbor MI 48019 USA;

Univ Michigan Life Sci Inst Ann Arbor MI 48109 USA;

Univ Michigan Life Sci Inst Ann Arbor MI 48109 USA;

Univ Calif San Diego Sch Med Dept Med La Jolla CA 92093 USA;

Univ Calif San Diego Sch Med Dept Med La Jolla CA 92093 USA;

Salk Inst Biol Sci Gene Express Lab La Jolla CA 92037 USA;

Salk Inst Biol Sci Gene Express Lab La Jolla CA 92037 USA;

Salk Inst Biol Sci Gene Express Lab La Jolla CA 92037 USA;

Salk Inst Biol Sci Gene Express Lab La Jolla CA 92037 USA;

Salk Inst Biol Sci Gene Express Lab La Jolla CA 92037 USA;

Univ Michigan Life Sci Inst Ann Arbor MI 48109 USA;

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正文语种 eng
中图分类内分泌腺疾病及代谢病;
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专利

1. Inhibition of IKK 3 and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes [J] . Oral Elif A., Reilly Shannon M., Gomez Andrew V., Cell metabolism . 2017,第1期

机译：IKK 3和TBK1的抑制改善了2型糖尿病患者的副本中的葡萄糖对照
2. Motivational interviewing delivered by diabetes educators: does it improve blood glucose control among poorly controlled type 2 diabetes patients? [J] . Welch G, Zagarins SE, Feinberg RG, Diabetes research and clinical practice . 2011,第1期

机译：糖尿病教育者进行的动机访谈：是否能改善控制不佳的2型糖尿病患者的血糖控制？
3. The continuous glucose monitoring system is useful for detecting unrecognized hypoglycemias in patients with type 1 and type 2 diabetes but is not better than frequent capillary glucose measurements for improving metabolic control. [J] . Chico A, Vidal Rios P, Subira M, Diabetes care . 2003,第4期

机译：连续血糖监测系统可用于检测1型和2型糖尿病患者中无法识别的低血糖，但并不比频繁进行的毛细血管血糖测量更好以改善代谢控制。
4. Closed-Loop Blood Glucose Control for Type I Diabetes Patients Using PID Controller [C] . Bharat Singh, Shabana Urooj, Ravi Sharma International conference on microelectronics, electromagnetics and telecommunications . 2018

机译：使用PID控制器对I型糖尿病患者进行闭环血糖控制
5. Improving Glycemic Control for Post-orthopedic Surgery Patients with Type 2 Diabetes [D] . ?Dale, Allison 2020

机译：改善血糖控制后骨科手术患者 2型糖尿病
6. Inhibition of IKKε and TBK1 improves glucose control in a subset of patients with type 2 diabetes [O] . Elif A. Oral, Shannon M. Reilly, Andrew V. Gomez, -1

机译：抑制IKKε和TBK1可改善部分2型糖尿病患者的血糖控制
7. Inhibition of IKKɛ and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes [O] . Elif A. Oral, Shannon M. Reilly, Andrew V. Gomez, 2017

机译：IKKɛ和TBK1的抑制改善了2型糖尿病患者的血糖控制

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

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