Glucocorticoid induction of epinephrine synthesizing enzyme in rat skeletal muscle and insulin resistance.
Rat skeletal muscle contains two enzymes which can make epinephrine: phenylethanolamine N-methyltransferase (PNMT) and nonspecific N-methyltransferase. We studied the time-course and mechanism by which the glucocorticoid dexamethasone increases muscle PNMT activity. We also examined the hypothesis that increased muscle E synthesis may contribute to glucocorticoid-induced insulin resistance. Dexamethasone (1 mg/kg s.c. for 12 d) increased muscle PNMT activity seven-fold but did not change NMT activity. Immunotitration with an anti-PNMT antibody indicated that the PNMT elevation was due to increased numbers of PNMT molecules. Dexamethasone rapidly increased PNMT activity and this elevation was largely maintained 6 d after glucocorticoid treatment stopped. Muscle epinephrine levels were transiently elevated by dexamethasone. Dexamethasone-treated rats had elevated insulin levels after a glucose load, and chronic administration of the PNMT inhibitor SKF 64139 reversed this increase. Chronic SKF 64139 improved glucose tolerance in normal rats. Dexamethasone induced muscle synthesis of the epinephrine-forming enzyme PNMT. A PNMT inhibitor lowered insulin levels in glucocorticoid-treated rats and glucose levels in untreated rats. These findings are compatible with antagonism of insulin-mediated glucose uptake by epinephrine synthesized in skeletal muscle.
Kennedy
B
B
Department of Medicine, University of California, San Diego Medical Center 92103.
Elayan
H
H
Ziegler
M G
MG
D000313:Adrenal Medulla / Q000502:physiology; D000315:Adrenalectomy; D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D004837:Epinephrine / Q000096:biosynthesis*; D007333:Insulin Resistance; D008297:Male; D008780:Methyltransferases / Q000378:metabolism; D009132:Muscles / Q000378:metabolism*; D010625:Phenylethanolamine N-Methyltransferase / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
D003907:Dexamethasone; D008780:Methyltransferases; D010625:Phenylethanolamine N-Methyltransferase; D004837:Epinephrine