Zinc is critical for the activation of cell signalling molecules in skeletal muscle: implications for insulin resistance and type 2 diabetes

Insulin resistance (IR) is a major risk factor for the development of chronic disease including type 2 diabetes mellitus (T2D). Skeletal muscle is the major site of peripheral insulin resistance and glucose intolerance and is the major storage tissue for zinc. Zinc plays an important role in glucose homeostasis through the regulation of various cell signaling pathways and evidence suggests that it acts as an insulin-mimetic in the control of cellular metabolism. We have evidence that zinc activates important molecules implicated in glucose metabolism in skeletal muscle. Accordingly, skeletal muscle cells were treated with 10 nM insulin and/or 20 μM zinc over 0-60 minutes and assayed for the phosphorylation of AKT (pAKT), an important molecule involved in activating downstream pathways of glucose mobilisation and uptake. We found that zinc could activate pAKT in a time-dependent manner. Similarly, we identified that zinc also activates ERK1/2 (cell proliferation and survival), PRAS40 (crucial for insulin-stimulated mTOR), and GSK-3β (glycogen synthesis). While zinc is an important component of maintaining cellular homeostasis; it will be important to further define its mechanisms of zinc action in regulating insulin sensitivity in peripheral tissue such as skeletal muscle. This study may result in fundamental outcomes that will provide a platform to help understand other organ systems and disease states. For example, many approved or being studied drugs that target zinc signalling might prove useful for the treatment of T2D or other diseases.