Effects of trandolapril and verapamil on glucose transport in insulin-resistant rat skeletal muscle.
We have used an animal model of insulin resistance-the obese Zucker (fa/fa) rat-to test whether oral administration of the non-sulfhydryl-containing angiotensin-converting enzyme (ACE) inhibitor, trandolapril, alone or in combination with the Ca2+-channel blocker, verapamil, can induce a beneficial effect on insulin-stimulated glucose transport and metabolism in skeletal muscle. Insulin-stimulated 2-deoxyglucose (2-DG) uptake in the isolated epitrochlearis muscle was less than 50% as great in obese animals compared with lean (Fa/-) controls (P < .05), but was significantly improved in the obese group by both short-term (6 hours, +33%) and long-term (14 days,+70%) oral treatment with trandolapril. Verapamil treatment alone did not alter insulin-stimulated 2-DG uptake in muscle, but simultaneous administration of verapamil and trandolapril resulted in the most pronounced effect on insulin-stimulated 2-DG uptake (+106%). Long-term treatment with trandolapril alone and in combination with verapamil significantly increased muscle glycogen (+26% to 27%), glucose transporter GLUT-4 protein (+27% to 31%), and hexokinase activity (+21% to 49%), and decreased plasma insulin levels (-23% to -29%). Muscle citrate synthase activity was enhanced only when trandolapril and verapamil were administered in combination (+24%). We conclude that the long-acting, non-sulfhydryl-containing ACE inhibitor, trandolapril, alone and in combination with the Ca2+-channel blocker, verapamil, can significantly improve insulin-stimulated glucose transport activity in skeletal muscle of the insulin-resistant obese Zucker rat, and that this improvement is associated with favorable adaptive responses in GLUT-4 protein levels, glycogen storage, and activities of relevant intracellular enzymes of glucose catabolism.
Jacob
S
S
Forschergruppe Hypertonie und Diabetes, Max-Grundig-Klinik, Bühlerhöhe, Germany.
Henriksen
E J
EJ
Fogt
D L
DL
Dietze
G J
GJ
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D005260:Female; D005947:Glucose / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology*; D007333:Insulin Resistance; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009765:Obesity / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D014700:Verapamil / Q000494:pharmacology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D002121:Calcium Channel Blockers; D007211:Indoles; C052035:trandolapril; D014700:Verapamil; D005947:Glucose