Functional Expression of WNK Kinases and Insulin Signaling Effectors in Diabetic Skeletal Muscle

Abstract

WNK (with‐no‐lysine [K]) kinases (WNK1‐4) are serine/threonine protein kinases with an atypical placement of the catalytic lysine and tissue‐specific expression. WNK1, ubiquitously expressed including skeletal muscle, is known as a downstream effector of insulin signaling and WNKs have been implicated in protein trafficking highly correlated with insulin resistance or diabetes. However, expression pattern and functional role of WNKs in skeletal muscle and linkage between WNKs and insulin signaling effectors such as PKB/Akt and glucose transports in skeletal muscle with type II diabetes are ill‐defined. In the present study, WNK1 and WNK2, not WNK4 are expressed in C2C12. The expression levels of WNK1 and WNK2 significantly decreased in db/db mice, a type II diabetic model, compared to that of wild type mice. Phosphorylated Akt in skeletal muscle decreased in db/db mice supporting insulin resistance in skeletal muscle. Insulin stimulates Akt followed by WNK1 phosphorylation. Insulin stimulation of WNK1 is blunted by phosphoinositide‐3‐kinase inhibitors. Together, an expression of GLUT4, a downstream effector of Akt and/or WNK1, markedly reduced in db/db mice, whereas GLUT1 expression level is not altered suggesting that GLUT1 and GLUT4 are differently regulated in type II diabetic skeletal muscle. Therefore, these results may provide new insights for increased susceptibility to insulin resistance and diabetes in skeletal muscle.[This research was supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (NRF‐2013R1A1A2060764)]