PMID- 31127058
OWN - NLM
STAT- MEDLINE
DCOM- 20200211
LR  - 20211204
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Linking)
VI  - 68
IP  - 8
DP  - 2019 Aug
TI  - Polarity Protein AF6 Controls Hepatic Glucose Homeostasis and Insulin Sensitivity 
      by Modulating IRS1/AKT Insulin Pathway in an SHP2-Dependent Manner.
PG  - 1577-1590
LID - 10.2337/db18-0695 [doi]
AB  - Insulin resistance is a major contributing factor in the development of metabolic 
      disease. Although numerous functions of the polarity protein AF6 (afadin and 
      MLLT4) have been identified, a direct effect on insulin sensitivity has not been 
      previously described. We show that AF6 is elevated in the liver tissues of 
      dietary and genetic mouse models of diabetes. We generated liver-specific AF6 
      knockout mice and show that these animals exhibit enhanced insulin sensitivity 
      and liver glycogen storage, whereas overexpression of AF6 in wild-type mice by 
      adenovirus-expressing AF6 led to the opposite phenotype. Similar observations 
      were obtained from in vitro studies. In addition, we discovered that AF6 directly 
      regulates IRS1/AKT kinase-mediated insulin signaling through its interaction with 
      Src homology 2 domain-containing phosphatase 2 (SHP2) and its regulation of 
      SHP2's tyrosine phosphatase activity. Finally, we show that knockdown of hepatic 
      AF6 ameliorates hyperglycemia and insulin resistance in high-fat diet-fed or 
      db/db diabetic mice. These results demonstrate a novel function for hepatic AF6 
      in the regulation of insulin sensitivity, providing important insights about the 
      metabolic role of AF6.
CI  - (c) 2019 by the American Diabetes Association.
FAU - Dai, Cheng
AU  - Dai C
AD  - CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute 
      of Nutrition and Health, Shanghai Institutes for Biological Sciences, University 
      of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
FAU - Wang, Xinyu
AU  - Wang X
AD  - CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute 
      of Nutrition and Health, Shanghai Institutes for Biological Sciences, University 
      of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
FAU - Wu, Yanjun
AU  - Wu Y
AD  - CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute 
      of Nutrition and Health, Shanghai Institutes for Biological Sciences, University 
      of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
FAU - Xu, Yi
AU  - Xu Y
AD  - CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute 
      of Nutrition and Health, Shanghai Institutes for Biological Sciences, University 
      of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
FAU - Zhuo, Shu
AU  - Zhuo S
AD  - CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute 
      of Nutrition and Health, Shanghai Institutes for Biological Sciences, University 
      of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
FAU - Qi, Meiyan
AU  - Qi M
AD  - CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute 
      of Nutrition and Health, Shanghai Institutes for Biological Sciences, University 
      of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
FAU - Ji, Weiwei
AU  - Ji W
AD  - CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute 
      of Nutrition and Health, Shanghai Institutes for Biological Sciences, University 
      of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
FAU - Zhan, Lixing
AU  - Zhan L
AUID- ORCID: 0000-0003-4949-4358
AD  - CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute 
      of Nutrition and Health, Shanghai Institutes for Biological Sciences, University 
      of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China 
      lxzhan@sibs.ac.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190524
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Afdn protein, mouse)
RN  - 0 (Insulin)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Irs1 protein, mouse)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11)
RN  - EC 3.6.4.1 (Myosins)
RN  - EC 3.6.4.4 (Kinesins)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Diabetes Mellitus, Experimental/*metabolism
MH  - Diet, High-Fat
MH  - Glucose/*metabolism
MH  - Glucose Tolerance Test
MH  - Hepatocytes/metabolism
MH  - Homeostasis/*physiology
MH  - Insulin/*metabolism
MH  - Insulin Receptor Substrate Proteins/metabolism
MH  - Insulin Resistance/*physiology
MH  - Kinesins/genetics/*metabolism
MH  - Liver/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Myosins/genetics/*metabolism
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 11/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Signal Transduction/physiology
EDAT- 2019/05/28 06:00
MHDA- 2020/02/12 06:00
CRDT- 2019/05/26 06:00
PHST- 2018/06/28 00:00 [received]
PHST- 2019/05/21 00:00 [accepted]
PHST- 2019/05/28 06:00 [pubmed]
PHST- 2020/02/12 06:00 [medline]
PHST- 2019/05/26 06:00 [entrez]
AID - db18-0695 [pii]
AID - 10.2337/db18-0695 [doi]
PST - ppublish
SO  - Diabetes. 2019 Aug;68(8):1577-1590. doi: 10.2337/db18-0695. Epub 2019 May 24.