Levodopa with carbidopa diminishes glycogen concentration, glycogen synthase activity, and insulin-stimulated glucose transport in rat skeletal muscle.
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 beta-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 levodopa-carbidopa. 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 approximately 50% lower glycogen synthase activity compared with muscles from control rats. The data demonstrate beta-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.
Smith
Jill L
JL
Dept. of Biology, St. Louis University, 3507 Laclede Ave., St. Louis, MO 63103, USA. smithjl@slu.edu
Ju
Jeong-Sun
JS
Saha
Bithika M
BM
Racette
Brad A
BA
Fisher
Jonathan S
JS
D000818:Animals; D002230:Carbidopa / Q000494:pharmacology*; D015259:Dopamine Agents / Q000494:pharmacology*; D004357:Drug Synergism; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000378:metabolism*; D006006:Glycogen Synthase / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D015259:Dopamine Agents; D007004:Hypoglycemic Agents; D007328:Insulin; D007980:Levodopa; D006003:Glycogen; D006006:Glycogen Synthase; D005947:Glucose; D002230:Carbidopa