The objective is to investigate the hypothesis that the muscle wasting in myotonic dystrophy results from deficient muscle anabolism due to an inherited defect in the muscle membrane which has compromised the anabolic actions of insulin on skeletal muscle. This hypothesis will be tested with the human forearm technique. Patients with myotonic dystrophy will be studied to determine if there is a decrease in the action of insulin in stimulating the retention of amino acids and the uptake of glucose by forearm muscle during three separate 120-minute euglycemic insulin infusions (20, 80, and 200 mU/m2/min) achieving insulin concentrations in the low, high and supraphysiologic range. Stable isotope methodology using 13C-leucine will be employed in conjunction with forearm studies to assess insulin-stimulated uptake of leucine during the graduated euglycemic insulin infusions. Measurements of forearm amino acid balance and glucose uptake will be correlated with the degree of whole body insulin sensitivity as measured by the glucose infusion rate. These studies will examine the relationship between insulin resistance and decreased protein anabolism in patients with myotonic dystrophy. The forearm technique will also be utilized during (20 mU/m2/min) euglycemic insulin infusions to assess the effects of physiologic stimuli which acutely enhance the action of insulin: ingestion of 15 grams of glucose; and 30 minutes of moderate forearm exercise. These euglycemic insulin infusions will be initiated when metabolic parameters have returned to a stable baseline following the physiologic stimuli. Results will be compared to those obtained during identical insulin infusions not preceeded by a physiologic stimulus. These studies will provide useful indirect information about the mechanism producing insulin resistance in myotonic dystrophy. Results in myotonic dystrophy patients will be compared to normal man and to neuromuscular disease controls to clarify whether abnormalities in insulin action are nonspecific alterations due to muscle wasting. Characterization of the pathophysiology of amino acid and glucose metabolism in myotonic dystrophy may permit insights into means of correcting or bypassing identified defects in insulin action. The results may also lead to the development of new approaches to treatment of other insulin resistant disorders.
| Kingston, W J; Moxley, R T (1989) Treatment of muscular dystrophies. Gen Pharmacol 20:263-8 |
| Gaffney, J F; Kingston, W J; Metlay, L A et al. (1989) Left ventricular thrombus and systemic emboli complicating the cardiomyopathy of Duchenne's muscular dystrophy. Arch Neurol 46:1249-52 |
| Kingston, W J; Moxley 3rd, R T (1988) Inflammatory myopathies. Neurol Clin 6:545-61 |
