Physiological hyperinsulinemia impairs insulin-stimulated glycogen synthase
activity and glycogen synthesis.
Iozzo, Patricia, Thonchai Pratipanawatr, Hanno Pijl, Christoph Vogt, Vineeta Kumar,
Ruben Pipek, Masafumi Matsuda, Lawrence J. Mandarino, Kenneth J. Cusi, and Ralph
A. Defronzo.
Division of Diabetes, Departments of 1Medicine and Biochemistry,2 The University
of Texas Health Science Center at San Antonio, San Antonio, Texas 78284
APStracts 8:0018E, 2001.
Although chronic hyperinsulinemia has been shown to induce insulin resistance, the basic
cellular mechanisms responsible for this phenomenon are unknown. The present study
was performed 1) to determine the time-related effect of physiological hyperinsulinemia
on glycogen synthase (GS) activity, hexokinase II (HKII) activity and mRNA content,
and GLUT-4 protein in muscle from healthy subjects, and 2) to relate hyperinsulinemia-
induced alterations in these parameters to changes in glucose metabolism in vivo. Twenty
healthy subjects had a 240-min euglycemic insulin (plasma insulin concentration = 121 ±
9 or 143 ± 25 pmol/l) clamp study with muscle biopsies and then received a low-dose
insulin infusion for 24 (n = 6) or 72 h (n = 14). During the baseline insulin clamp, GS
fractional velocity (0.075 ± 0.008 to 0.229 ± 0.02, P < 0.01), HKII mRNA content
(0.179 ± 0.034 to 0.354 ± 0.087, P < 0.05), and HKII activity (2.41 ± 0.63 to 3.35 ±
0.54 pmol•min«minus»1•ng«minus»1, P < 0.05), as well as whole body glucose
disposal and nonoxidative glucose disposal, increased. During the insulin clamp
performed after 24 and 72 h of sustained physiological hyperinsulinemia, the ability of
insulin to increase muscle GS fractional velocity, total body glucose disposal, and
nonoxidative glucose disposal was impaired (all P < 0.01), whereas the effect of insulin
on muscle HKII mRNA, HKII activity, GLUT-4 protein content, and whole body rates of
glucose oxidation and glycolysis remained unchanged. Muscle glycogen concentration
did not change [116 ± 28 vs. 126 ± 29 µmol/kg muscle, P = nonsignificant (NS)] and was
not correlated with the change in nonoxidative glucose disposal (r = 0.074, P = NS). In
summary, modest chronic hypernsulinemia may contribute directly (independent of
change in muscle glycogen concentration) to the development of insulin resistance by its
impact on the GS pathway.
Received 17 March 2000; accepted in final form 18 January 2001
APS Manuscript Number E132-0.
Article publication pending Am J Physiol Endocrinol Metab
ISSN 1080-4757 Copyright 2001 The American Physiological Society.
Published in APStracts on 27 February 2001