Amylin and CGRP induce insulin resistance via a receptor distinct from cAMP-coupled CGRP receptor.
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.
Department of Metabolic Diseases, Pfizer Inc., Groton, Connecticut 06340.
D K
DK
Kreutter
S J
SJ
Orena
A J
AJ
Torchia
L G
LG
Contillo
G C
GC
Andrews
R W
RW
Stevenson
D000682:Amyloid / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism* / Q000494:pharmacology*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D003847:Deoxyglucose / Q000378:metabolism*; D006003:Glycogen / Q000096:biosynthesis; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D058228:Islet Amyloid Polypeptide; D007700:Kinetics; D008297:Male; D009132:Muscles / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018003:Receptors, Calcitonin; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology*
D000682:Amyloid; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments; D018003:Receptors, Calcitonin; D011956:Receptors, Cell Surface; C058636:calcitonin gene-related peptide (8-37); D006003:Glycogen; D003847:Deoxyglucose; D000242:Cyclic AMP; D015740:Calcitonin Gene-Related Peptide