In vivo insulin resistance induced by amylin primarily through inhibition of insulin-stimulated glycogen synthesis in skeletal muscle.
We examined the in vivo mechanisms of amylin-induced resistance in concious rats (n = 18). During 180-min euglycemic insulin-clamp (21.5 pmol.kg-1.min-1) studies, amylin (50, 200, or 500 pmol.kg-1.min-1; plasma concentration from 3 x 10(-10) to 9 x 10(-9) M) infusion determined a 19-27% reduction in glucose uptake (117.8 +/- 7.0 vs. 145.8 +/- 11.0, 107.1 +/- 9.2 vs. 145.1 +/- 6.7, and 105.0 +/- 7.2 vs. 144.4 +/- 7.0 mumol.kg-1.min-1 at 50, 200, or 500 pmol.kg-1.min-1, respectively, P less than 0.01) versus insulin alone, whereas 10-pmol.kg-1.min-1 amylin infusion (plasma concn 5 x 10(-11) M) failed to affect insulin-mediated glucose disposal. After amylin infusion, the contribution of whole-body glycolysis to overall glucose disposal increased from 43-48 to 62-79%, whereas muscle glycogen synthesis decreased significantly at all peptide concentrations greater than 3 x 10(-10) M, completely accounting for the decrease in glucose uptake. Skeletal muscle glucose-6-phosphate concentration rose from 0.219 +/- 0.038 mumol/g (insulin alone) to 0.350 +/- 0.018, 0.440 +/- 0.020, and 0.505 +/- 0.035 mumol/g (insulin plus amylin at 50, 200, or 500 pmol.kg-1.min-1, P less than 0.01). Suppression of hepatic glucose production by insulin was unaffected by a 50-pmol.kg-1.min-1 amylin infusion (18.5 +/- 4.3 vs. 21.7 +/- 2.9 mumol.kg-1.min-1), whereas it was slightly but significantly impaired by amylin infusion at 200 pmol.kg-1.min-1 (17.8 +/- 3.9 vs. 24.7 +/- 4.5 mumol.kg-1.min-1, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Frontoni
S
S
Department of Medicine, University of Texas Health Science Center, San Antonio 78284-7886.
Choi
S B
SB
Banduch
D
D
Rossetti
L
L
D000682:Amyloid / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D006003:Glycogen / Q000096:biosynthesis*; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D007332:Insulin Infusion Systems; D007333:Insulin Resistance; D058228:Islet Amyloid Polypeptide; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009132:Muscles / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values
D000682:Amyloid; D001786:Blood Glucose; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D006003:Glycogen