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The P2Y2 Receptor Mediates Hyperglycemia‐induced Insulin Resistance in Human Skeletal Muscle Cells
Author(s) -
Nasrullah Mohammed Zahid,
Peng Qianman,
Shen Jianzhong
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.514.3
Subject(s) - insulin resistance , endocrinology , medicine , insulin receptor , insulin like growth factor 1 receptor , receptor , protein kinase b , extracellular , purinergic receptor , insulin , pi3k/akt/mtor pathway , skeletal muscle , biology , intracellular , signal transduction , chemistry , microbiology and biotechnology , growth factor
Objective It has been known that insulin resistance could lead to hyperglycemia and diabetes; however, the exact cause effect relationship between hyperglycemia and insulin resistance is not fully understood. Since over nutrition often leads to energy excess and ATP is the major cellular energy source, we hypothesized that abnormal high level of extracellular glucose promotes skeletal muscle cells to release ATP, which in turn activates the purinergic P2Y2 receptor, resulting to insulin resistance. Methods and Results Real‐time RT‐PCR analysis indicated that the P2Y2 receptor mRNA was significantly up‐regulated during human skeletal muscle cell differentiation, and functional P2Y2 receptor expression was confirmed by measuring intracellular [Ca 2+ ] i mobilization in response to ATP or UTP in mature human skeletal muscle cells (HSKMC). Interestingly, incubation of HSKMC with high glucose (25 mM) triggered significant amount of ATP release as compared with normal glucose (6.1 mM). In addition, both ATP and UTP dramatically suppressed insulin‐induced AKT activation in a dose‐dependent manner in HSKMC, which could be reversed by AR‐C118925, a selective P2Y2 receptor antagonist, suggesting a role of P2Y2 receptor in control of insulin receptor signaling. The P2Y2 receptor suppression of the AKT pathway was selective, since ATP/UTP treatment potentiated insulin‐induced ERK1/2 pathway in HSKMC. Furthermore, we found that activation of the P2Y2 receptor significantly inhibited insulin‐induced glucose uptake in HSKMC. Conclusions We concluded that ATP release and P2Y2 receptor activation is a previously unrecognized cellular signaling node linking hyperglycemia and insulin resistance in HSKMC through the PI3K‐AKT pathway, highlighting that P2Y2 receptor may be a new drug target for the treatment of diabetes and relevant metabolic diseases. Support or Funding Information Supported in part by NIH grant 1R01HL125279‐01A1 (to J.S.) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .