Insulin receptor binding motif tagged with IgG4 Fc (Yiminsu) works as an insulin sensitizer to activate Akt signaling in hepatocytes.
Insulin resistance is a key feature of obesity and type 2 diabetes mellitus (T2DM). Interaction of insulin with the insulin receptor (IR) leads to both its auto-phosphorylation and phosphorylation of tyrosine residues on the IR substrate (IRS) proteins, initiating the activation of intracellular signaling cascades. The metabolic effects of IRS are known to be mediated through pathways involving phosphatidyl-inositol 3-kinase (PI-3K), which result in the activation of Akt signaling. The C-terminal region of the IR ectodomain is required to facilitate the conformational changes that are required for high-affinity binding to insulin. Furthermore, the CH2 and CH3 domains in the Fc fragments of immunoglobulins are responsible for their binding to the Fc receptor, which triggers transcytosis. In this study, we created a fusion peptide of the C-terminal end of the human IR ectodomain with the IgG4 Fc fragment, including an intervening polyG fragment to ensure enough space for insulin binding. We named this new peptide "Yiminsu", meaning an insulin sensitizer. The results of our analyses show that Yiminsu significantly facilitates insulin signaling via the activation of Akt in hepatocytes in a dose- and time-dependent manner. Further studies are required to determine whether Yiminsu can act as an insulin sensitizer.
Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan, China.
J
J
Wang
Department of Cardiovascular Medicine, First Affiliated Hospital of the University of South China.
T
T
Zou
Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan, China.
H X
HX
Yang
Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (Incubation), Hunan University of Chinese Medicine, Changsha, Hunan, China.
Y Z
YZ
Gong
Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (Incubation), Hunan University of Chinese Medicine, Changsha, Hunan, China.
X J
XJ
Xie
Metammune LLC and Moldepot Inc., Morrisville, NC, USA dkbio@qq.com.
H Y
HY
Liu
Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (Incubation), Hunan University of Chinese Medicine, Changsha, Hunan, China.
D F
DF
Liao
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D003001:Cloning, Molecular / Q000379:methods; D003412:Cricetulus; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D011961:Receptors, Fc / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism
D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D007328:Insulin; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D014443:Tyrosine; D058539:Phosphatidylinositol 3-Kinase; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt