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Am J Physiol Endocrinol Metab 264: E606-E613, 1993;
0193-1849/93 $5.00
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AJP - Endocrinology and Metabolism, Vol 264, Issue 4 E606-E613, Copyright © 1993 by American Physiological Society

ARTICLES

Amylin and CGRP induce insulin resistance via a receptor distinct from cAMP-coupled CGRP receptor

D. K. Kreutter, S. J. Orena, A. J. Torchia, L. G. Contillo, G. C. Andrews and R. W. Stevenson
Department of Metabolic Diseases, Pfizer Inc., Groton, Connecticut 06340.

Amylin and calcitonin gene-related peptide (CGRP) inhibited insulin-stimulated 2-deoxyglucose uptake in L6 myocytes and isolated soleus muscle. Both peptides were maximally active at 10 pM in L6 cells and inhibited insulin action by 40-50%. In soleus muscle amylin and CGRP inhibited insulin-stimulated uptake by 65-85%. Amylin competed with 125I-CGRP for binding to L6 cells but with 100-fold lower potency than CGRP. Occupancy of the CGRP receptor in L6 cells is coupled to adenylyl cyclase. Amylin increased the cellular content of adenosine 3',5'-cyclic monophosphate (cAMP), but consistent with binding, amylin was 100-fold less potent than CGRP. In soleus muscle, 100 nM amylin, which maximally inhibited 2-deoxyglucose uptake, had no effect cAMP content, whereas CGRP at the same concentration increased cAMP by 50%. The effect of CGRP on cAMP levels was completely suppressed by the competitive antagonist, CGRP-(8-37). In contrast, the suppression of insulin-stimulated glycogen synthesis or 2-deoxyglucose uptake by amylin was unaffected by 1 microM CGRP-(8-37). Our results demonstrate that the inhibition of insulin-stimulated glucose transport by amylin is independent of cAMP and may be mediated by a unique receptor that is distinct from the adenylyl cyclase-coupled CGRP receptor.


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