TRANSLATIONAL PHYSIOLOGY Levodopa with carbidopa diminishes glycogen concentration, glycogen synthase activity, and insulin-stimulated glucose transport in rat skeletal muscle

Smith, Jill L., Jeong-Sun Ju, Bithika M. Saha, Brad A. Racette, and Jonathan S. Fisher. Levodopa with carbidopa diminishes glycogen concentration, glycogen synthase activity, and insulin-stimulated glucose transport in rat skeletal muscle. J Appl Physiol 97: 2339–2346, 2004; doi:10.1152/japplphysiol.01219.2003.—We hypothesized that levodopa with carbidopa, a common therapy for patients with Parkinson’s disease, might contribute to the high prevalence of insulin resistance reported in patients with Parkinson’s disease. We examined the effects of levodopa-carbidopa on glycogen concentration, glycogen synthase activity, and insulin-stimulated glucose transport in skeletal muscle, the predominant insulin-responsive tissue. In isolated muscle, levodopa-carbidopa completely prevented insulin-stimulated glycogen accumulation and glucose transport. The levodopa-carbidopa effects were blocked by propranolol, a -adrenergic antagonist. Levodopa-carbidopa also inhibited the insulin-stimulated increase in glycogen synthase activity, whereas propranolol attenuated this effect. Insulin-stimulated tyrosine phosphorylation of insulin receptor substrate (IRS)-1 was reduced by levodopa-carbidopa, although Akt phosphorylation was unaffected by levodopacarbidopa. A single in vivo dose of levodopa-carbidopa increased skeletal muscle cAMP concentrations, diminished glycogen synthase activity, and reduced tyrosine phosphorylation of IRS-1. A separate set of rats was treated intragastrically twice daily for 4 wk with levodopa-carbidopa. After 4 wk of treatment, oral glucose tolerance was reduced in rats treated with drugs compared with control animals. Muscles from drug-treated rats contained at least 15% less glycogen and 50% lower glycogen synthase activity compared with muscles from control rats. The data demonstrate -adrenergic-dependent inhibition of insulin action by levodopa-carbidopa and suggest that unrecognized insulin resistance may exist in chronically treated patients with Parkinson’s disease.