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

Document Type

Article

Abstract

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.

Medical Subject Headings

Animals; Carbidopa (pharmacology); Dopamine Agents (pharmacology); Drug Synergism; Glucose (metabolism); Glucose Tolerance Test; Glycogen (metabolism); Glycogen Synthase (metabolism); Hypoglycemic Agents (pharmacology); Insulin (pharmacology); Insulin Resistance (physiology); Levodopa (pharmacology); Male; Muscle, Skeletal (drug effects, metabolism); Rats; Rats, Wistar

Publication Date

12-1-2004

Publication Title

Journal of applied physiology (Bethesda, Md. : 1985)

ISSN

8750-7587

Volume

97

Issue

6

First Page

2339

Last Page

46

PubMed ID

15258132

Digital Object Identifier (DOI)

10.1152/japplphysiol.01219.2003

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