The studies in this application focus upon the most common form of muscular dystrophy, myotonic dystrophy. This autosomal dominant disorder is felt to be due to an inherited defect in the cell membrane. The patients have marked resistance to insulin stimulation of glucose uptake by forearm muscles. This insulin resistance may results from the putative membrane defect which has compromised the function of the insulin receptor. The present proposal will test the following hypothesis: Muscle wasting in myotonic dystrophy results form a hereditary defect that has not only decreased the action of insulin in stimulating muscle glucose uptake, but has also damaged the ability of insulin to slow the rate of muscle breakdown and its ability to increase muscle protein synthesis. To test this hypothesis patients with myotonic dystrophy, comparably wasted patients with other neuromuscular diseases, and normals will be studied. The investigations will use the human forearm technique in combination with a three hour euglycemic insulin infusion to examine insulin-mediated retention of amino acids and insulin stimulation of glucose and potassium uptake. The four different rates of insulin infusion used (20, 30, 40, and 80 mU/m2/min) will achieve steady-state elevations of insulin in the low, middle and high physiologic ranges, infusion of the stable isotope, L-(ring 2H5)-phenylalanine during the glucose clamp procedures will allow measurement of the effectiveness of insulin in controlling the rate of skeletal muscle breakdown, in stimulating amino acid uptake, and in promoting protein synthesis. The net balance of 3-methylhistidine across forearm muscle will be determined before and during each of the insulin infusions. The release of 3-methylhistidine by muscle will provide another measure of the insulin infusions. The release of 3-methylhistidine by muscle will provide another measure of the anticatabolic action of insulin on protein degradation in patients with myotonic dystrophy. These findings will complement the results obtained with the 2H5 phenylalanine infusion. The investigations will define more clearly the relationship between the insulin resistance and muscle wasting that occurs in myotonic dystrophy. The findings will clarify whether the muscle wasting is associated with a decrease in the ability of insulin to regulate muscle protein breakdown or with a decrease in the ability of insulin to stimulate protein synthesis or both. This formation will help to promote the development of new therapeutic strategies and might also lead to new approaches in the treatment of other insulin resistant states, such as, diabetes and obesity. The present investigations will also provide additional new, diabetes and obesity. The present investigations will also provide additional new information about the actions of insulin on the regulation of protein metabolism in normal man.
