Amylin-induced in vivo insulin resistance in conscious rats: the liver is more sensitive to amylin than peripheral tissues.
Amylin is a polypeptide of 37 amino acids, predominantly synthesized in pancreatic Beta cells. The peptide was suggested to be dysregulated in Type 2 (non-insulin-dependent) diabetes mellitus and it antagonized certain actions of insulin in vitro in rat muscle. This led to speculation that amylin is involved in the pathogenesis of Type 2 diabetes. We have examined the in vivo effects of rat amylin, amidated at the carboxy-terminus, on insulin-mediated carbohydrate metabolism in conscious rats, using the hyperinsulinaemic (+/- 1 nmol/l) euglycaemic (6 mmol/l) clamp technique combined with [3-3H]-glucose infusion. Basal plasma amylin levels were less than or equal to 75 pmol/l. Applied amylin levels of 220 +/- 75 pmol/l (infusion rate of 12.5 pmol/min) antagonized only the insulin action on liver, resulting in a 100% increase of hepatic glucose output. Amylin levels of 4750 +/- 750 pmol/l (infusion rate of 125 pmol/min) induced a 250% increase of insulin-inhibited hepatic glucose output and, in addition, a 30% decrease of insulin-stimulated peripheral glucose up-take. Amylin did not affect: 1) the metabolic clearance rate of insulin, 2) the levels of plasma glucagon, epinephrine, norepinephrine, and corticosterone, 3) in vitro insulin binding and insulin-stimulated receptor autophosphorylation. This suggests that amylin antagonizes insulin action via binding to a yet unknown receptor.


CONCLUSIONS
amylin causes in vivo insulin resistance and the liver seems the predominant organ regulated by this hormone. The in vivo effects of amylin mimic the pathophysiological abnormalities of insulin action in Type 2 diabetes.
Koopmans
S J
SJ
Department of Endocrinology and Metabolic Diseases, University Hospital, Leiden, The Netherlands.
van Mansfeld
A D
AD
Jansz
H S
HS
Krans
H M
HM
Radder
J K
JK
Frölich
M
M
de Boer
S F
SF
Kreutter
D K
DK
Andrews
G C
GC
Maassen
J A
JA
D000682:Amyloid / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D003345:Corticosterone / Q000097:blood; D004837:Epinephrine / Q000097:blood; D005934:Glucagon / Q000097:blood; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D007333:Insulin Resistance; D058228:Islet Amyloid Polypeptide; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009638:Norepinephrine / Q000097:blood; D009928:Organ Specificity; D051381:Rats; D011919:Rats, Inbred Strains; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism
D000682:Amyloid; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D005934:Glucagon; D011972:Receptor, Insulin; D005947:Glucose; D003345:Corticosterone; D009638:Norepinephrine; D004837:Epinephrine