AMYLIN AND CGRP INDUCE INSULIN RESISTANCE VIA A RECEPTOR DISTINCT FROM CAMP-COUPLED CGRP RECEPTOR

Amylin and calcitonin gene-related peptide (CGRP) inhibited insulin-st imulated 2-deoxyglucose uptake in L6 myocytes and isolated soleus musc le. Both peptides were maximally active at 10 pM in L6 cells and inhib ited insulin action by 40-50%. In soleus muscle amylin and CGRP inhibi ted insulin-stimulated uptake by 65-85%. Amylin competed with I-125-CG RP 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 cycl ase. Amylin increased the cellular content of adenosine 3',5'-cyclic m onophosphate (cAMP), but consistent with binding, amylin was 100-fold less potent than CGRP. In soleus muscle, 100 nM amylin, which maximall y inhibited 2-deoxyglucose uptake, had no effect cAMP content, whereas CGRP at the same concentration increased cAMP by 50%. The effect of C GRP on cAMP levels was completely suppressed by the competitive antago nist, CGRP-(8-37). In contrast, the suppression of insulin-stimulated glycogen synthesis or 2-deoxyglucose uptake by amylin was unaffected b y 1 muM CGRP-(8-37). Our results demonstrate that the inhibition of in sulin-stimulated glucose transport by amylin is independent of cAMP an d may be mediated by a unique receptor that is distinct from the adeny lyl cyclase-coupled CGRP receptor.