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 × 10−10 to 9 × 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 μmol · kg−1 · min−1 at 50, 200, or 500 pmol · kg−1 · min−1, respectively, P < 0.01) versus insulin alone, whereas 10-pmol · kg−1 · min−1 amylin infusion (plasma concn 5 × 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 >3 × 10−10 M, completely accounting for the decrease in glucose uptake. Skeletal muscle glucose-6-phosphate concentration rose from 0.219 ± 0.038 μmol/g (insulin alone) to 0.350 ± 0.018, 0.440 ± 0.020, and 0.505 ± 0.035 μmol/g (insulin plus amylin at 50, 200, or 500 pmol · kg−1 · min−1, P < 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 μmol · 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 μmol · kg−1 · min−1, P < 0.05). whereas peripheral glucose uptake and muscle glycogen synthesis were not further reduced. Our results suggest that amylin antagonizes the ability of insulin to promote total-body glucose uptake primarily by decreasing muscle glycogen synthesis, which, in turn, determines an increase in muscle glucose-6-phosphate levels and glycolysis and a reduction in glucose transport/phosphorylation.
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Original Articles|
May 01 1991
In Vivo Insulin Resistance Induced by Amylin Primarily Through Inhibition of Insulin-Stimulated Glycogen Synthesis in Skeletal Muscle
Simona Frontoni;
Simona Frontoni
Department of Medicine, University of Texas Health Science Center
San Antonio, Texas
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Soo Bong Choi;
Soo Bong Choi
Department of Medicine, University of Texas Health Science Center
San Antonio, Texas
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Donna Banduch;
Donna Banduch
Department of Medicine, University of Texas Health Science Center
San Antonio, Texas
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Luciano Rossetti
Luciano Rossetti
Department of Medicine, University of Texas Health Science Center
San Antonio, Texas
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Address correspondence and reprint requests to Luciano Rossetti, MD, Diabetes Division, Department of Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284–7886.
Diabetes 1991;40(5):568–573
Article history
Received:
August 17 1990
Revision Received:
December 26 1990
Accepted:
December 26 1990
PubMed:
2022302
Citation
Simona Frontoni, Soo Bong Choi, Donna Banduch, Luciano Rossetti; In Vivo Insulin Resistance Induced by Amylin Primarily Through Inhibition of Insulin-Stimulated Glycogen Synthesis in Skeletal Muscle. Diabetes 1 May 1991; 40 (5): 568–573. https://doi.org/10.2337/diab.40.5.568
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