TCPTP-deficiency in muscle does not alter insulin signalling and glucose homeostasis

Abstract

Aims/Hypothesis

Insulin activates the insulin receptor (IR) protein tyrosine kinase and downstream phosphatidylinositol-3-kinase (PI3K)/Akt signalling in muscle to promote glucose uptake. The IR can serve as a substrate for the protein tyrosine phosphatases (PTP) 1B and TCPTP, which share a striking 74% sequence identity in their catalytic domains. PTP1B is a validated therapeutic target for the alleviation of insulin resistance in type 2 diabetes. PTP1B dephosphorylates the IR in liver and muscle to regulate glucose homeostasis, whereas TCPTP regulates IR signalling and gluconeogenesis in the liver. In this study we have assessed for the first time the role of TCPTP in the regulation of IR signalling in muscle.

Methods

We generated muscle-specific TCPTP-deficient ( MCK-Cre; Ptpn2 ^lox/lox ) mice and assessed the impact on glucose homeostasis and muscle IR signalling in chow versus high fat fed mice.

Results

Blood glucose and insulin levels, insulin and glucose tolerances and insulininduced muscle IR activation and downstream PI3K/Akt signalling remained unaltered in chow fed MCK-Cre; Ptpn2 ^lox/lox versus Ptpn2 ^lox/lox mice. In addition, body weight, adiposity, energy expenditure, insulin sensitivity and glucose homeostasis were not altered in high fat fed MCK-Cre; Ptpn2 ^lox/lox versus Ptpn2 ^lox/lox mice.

Conclusions

These results indicate that TCPTP deficiency in muscle has no effect on insulin signalling and glucose homeostasis and does not prevent the development of high fat diet-induced insulin resistance. Thus, despite their high degree of sequence identity, PTP1B and TCPTP differentially contribute to IR regulation in muscle. Our results are consistent with these two highly related PTPs having distinct contributions to IR regulation in different tissues.