PMID- 37311491
OWN - NLM
STAT- MEDLINE
DCOM- 20230731
LR  - 20230731
IS  - 1873-4847 (Electronic)
IS  - 0955-2863 (Linking)
VI  - 119
DP  - 2023 Sep
TI  - gamma-glutamylcysteine alleviates insulin resistance and hepatic steatosis by 
      regulating adenylate cyclase and IGF-1R/IRS1/PI3K/Akt signaling pathways.
PG  - 109404
LID - S0955-2863(23)00137-7 [pii]
LID - 10.1016/j.jnutbio.2023.109404 [doi]
AB  - Type 2 diabetes mellitus (T2DM), a complex metabolism disease, which was 
      characterized by metabolic disorders including hyperglycemia, has become a major 
      health problem due to the increasing prevalence worldwide. gamma-glutamylcysteine 
      (gamma-GC) as an immediate precursor of glutathione (GSH) was originally used for the 
      treatment of sepsis, inflammation bowel disease, and senescence. Here, we 
      evaluated the capacity of gamma-GC on diabetes-related metabolic parameters in db/db 
      mice and insulin resistance (IR) amelioration in cells induced by palmitic acid 
      (PA). Our data suggested that gamma-GC treatment decreased body weight, reduced 
      adipose tissue size, ameliorated ectopic fat deposition in liver, increased the 
      GSH content in liver, improved glucose control and other diabetes-related 
      metabolic parameters in vivo. Moreover, in vitro experiments showed that gamma-GC 
      could maintain the balance of free fatty acids (FFAs) and glucose uptake through 
      regulating the translocation of CD36 and GLUT4 from cytoplasm to plasma membrane. 
      Furthermore, our finding also provided evidence that gamma-GC could activate Akt not 
      only via adenylate cyclase (AC)/cAMP/PI3K signaling pathway, but also via 
      IGF-1R/IRS1/PI3K signaling pathway to improve IR and hepatic steatosis. Blocking 
      either of two signaling pathways could not activate Akt activation induced by 
      gamma-GC. This unique characteristic ensures the important role of gamma-GC in glucose 
      metabolism. Collectively, these results suggested that gamma-GC could serve as a 
      candidate dipeptide for the treatment of T2DM and related chronic diabetic 
      complications via activating AC and IGF-1R/IRS1/PI3K/Akt signaling pathways to 
      regulate CD36 and GLUT4 trafficking.
CI  - Copyright (c) 2023 Elsevier Inc. All rights reserved.
FAU - Zhou, Jinyi
AU  - Zhou J
AD  - Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College 
      of Life Science, Nanjing Normal University, Jiangsu, Nanjing, China.
FAU - Shi, Yingying
AU  - Shi Y
AD  - Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College 
      of Life Science, Nanjing Normal University, Jiangsu, Nanjing, China.
FAU - Yang, Chen
AU  - Yang C
AD  - Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College 
      of Life Science, Nanjing Normal University, Jiangsu, Nanjing, China.
FAU - Lu, Shuai
AU  - Lu S
AD  - Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College 
      of Life Science, Nanjing Normal University, Jiangsu, Nanjing, China.
FAU - Zhao, Lishuang
AU  - Zhao L
AD  - Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College 
      of Life Science, Nanjing Normal University, Jiangsu, Nanjing, China.
FAU - Liu, Xianli
AU  - Liu X
AD  - Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College 
      of Life Science, Nanjing Normal University, Jiangsu, Nanjing, China.
FAU - Zhou, Da
AU  - Zhou D
AD  - Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan 
      University, Shanghai, People's Republic of China. Electronic address: 
      zhou.da@zshospital.sh.cn.
FAU - Luo, Lan
AU  - Luo L
AD  - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, 
      Nanjing University, Jiangsu, Nanjing, China. Electronic address: 
      lanluo@nju.edu.cn.
FAU - Yin, Zhimin
AU  - Yin Z
AD  - Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College 
      of Life Science, Nanjing Normal University, Jiangsu, Nanjing, China. Electronic 
      address: yinzhimin@njnu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230611
PL  - United States
TA  - J Nutr Biochem
JT  - The Journal of nutritional biochemistry
JID - 9010081
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 4.6.1.1 (Adenylyl Cyclases)
RN  - M984VJS48P (gamma-glutamylcysteine)
RN  - 0 (Insulin)
RN  - 0 (Dipeptides)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Insulin Resistance
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - *Diabetes Mellitus, Type 2/metabolism
MH  - Adenylyl Cyclases/metabolism
MH  - Insulin/metabolism
MH  - Signal Transduction
MH  - Dipeptides
MH  - *Fatty Liver/drug therapy
OTO - NOTNLM
OT  - CD36
OT  - GLUT4
OT  - hepatic steatosis
OT  - insulin resistance
OT  - type 2 diabetes mellitus
OT  - gamma-glutamylcysteine
EDAT- 2023/06/14 01:10
MHDA- 2023/07/31 06:42
CRDT- 2023/06/13 19:10
PHST- 2023/03/29 00:00 [received]
PHST- 2023/06/02 00:00 [revised]
PHST- 2023/06/07 00:00 [accepted]
PHST- 2023/07/31 06:42 [medline]
PHST- 2023/06/14 01:10 [pubmed]
PHST- 2023/06/13 19:10 [entrez]
AID - S0955-2863(23)00137-7 [pii]
AID - 10.1016/j.jnutbio.2023.109404 [doi]
PST - ppublish
SO  - J Nutr Biochem. 2023 Sep;119:109404. doi: 10.1016/j.jnutbio.2023.109404. Epub 
      2023 Jun 11.