Maddison, L.A., Joest, K.E., Kammeyer, R.M., Chen, W. (2015) Skeletal muscle insulin resistance in zebrafish induces alterations in β-cell number and glucose tolerance in an age and diet dependent manner. American journal of physiology. Endocrinology and metabolism. 308(8):E662-9.
Insulin resistance creates an environment that promotes β-cell failure and development of diabetes. Understanding the events that lead from insulin resistance to diabetes is necessary for development of effective preventional and interventional strategies and model systems that reflect the pathophysiology of disease progression are an important component towards this end. We have confirmed that insulin enhances glucose uptake in zebrafish skeletal muscle and have developed a zebrafish model of skeletal muscle insulin resistance using a dominant negative IGF1r. These zebrafish exhibit blunted insulin signaling and glucose uptake in the skeletal muscle confirming insulin resistance. In young animals, we observed an increase in the number of β-cells and normal glucose tolerance indicative of compensation for insulin resistance. In older animals the β-cell mass was reduced to that of control, with appearance of impaired glucose clearance but no elevation in fasting blood glucose. Combined with overnutrition, the insulin resistant animals have an increased fasting blood glucose compared to the control animals demonstrating that the β-cells in the insulin resistant fish are in a vulnerable state. The relatively slow progression from insulin resistance to glucose intolerance in this model system has the potential in the future to test cooperating genes or metabolic conditions that may accelerate the development of diabetes and provide new therapeutic targets.