In:
American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 280, No. 5 ( 2001-05-01), p. E712-E719
Abstract:
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 clamp study with muscle biopsies and then received a low-dose insulin infusion for 24 ( n = 6) or 72 h ( n = 14) (plasma insulin concentration = 121 ± 9 or 143 ± 25 pmol/l, respectively). 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 −1 · ng −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 hyperinsulinemia may contribute directly (independent of change in muscle glycogen concentration) to the development of insulin resistance by its impact on the GS pathway.
Type of Medium:
Online Resource
ISSN:
0193-1849
,
1522-1555
DOI:
10.1152/ajpendo.2001.280.5.E712
Language:
English
Publisher:
American Physiological Society
Publication Date:
2001
detail.hit.zdb_id:
1477331-4
SSG:
12
