Muscle insulin resistance in uremic humans: glucose transport, glucose transporters, and insulin receptors

Abstract

To determine the cellular basis for insulin resistance observed in patients with uremia, we investigated insulin action in vivo and in vitro using skeletal muscle obtained from patients with chronic renal failure. Uremic subjects had significantly reduced rates of insulin-stimulated glucose disposal, as determined by a 3-h intravenous glucose tolerance test and using the hyperinsulinemic euglycemic clamp technique. Hepatic glucose production was similar before (control, 76.2 +/- 6.3 vs. uremic, 74.2 +/- 6.9 mg.kg-1.min-1) and during insulin infusion at 40 mU.m-2.min-1 (control, -60.9 +/- 6.6 vs. uremic, -53.9 +/- 6.3 mg.kg-1.min-1). In incubated human skeletal muscle fiber strips, basal 2-deoxy-D-glucose transport was unchanged in uremic subjects compared with controls. However, the increase in insulin-stimulated glucose transport was significantly reduced by 50% in muscles from uremic patients (P = 0.012). In partially purified insulin receptors prepared from skeletal muscle, 125I-labeled insulin binding, beta-subunit receptor autophosphorylation, and tyrosine kinase activity were all unchanged in uremic subjects. The abundance of insulin-sensitive (muscle/fat, GLUT-4) glucose transporter protein measured by Western blot using Mab 1F8 or polyclonal antisera was similar in muscles of control and uremic patients. These findings suggest that the insulin resistance observed in skeletal muscle of uremic patients cannot be attributed to defects in insulin receptor function or depletion of the GLUT-4 glucose transporter protein. An alternative step in insulin-dependent activation of the glucose transport process may be involved.

GLUT4 Is Reduced in Slow Muscle Fibers of Type 2 Diabetic Patients

“…The speculation that decreased GLUT4 expression could contribute to this insulin resistance has been rejected by most studies (7)(8)(9)(10), except for some studies of the translocation of GLUT4 by insulin or contractions, in which impaired translocation in type 2 diabetic muscle was found (11)(12)(13). However, all of these studies were performed on homogenates of muscle consisting of a mixture of the more insulin-sensitive slowtwitch fibers and the more contraction-sensitive fast-twitch fibers.…”

“…Insulin and contractions induce translocation of GLUT4 from intracellular storage vesicles to the plasma membrane and to the transverse tubules (4 -6). Currently, most studies have failed to demonstrate reduced GLUT4 expression levels in skeletal muscle biopsy specimens from type 2 diabetic patients (7)(8)(9)(10). The insulin-stimulated translocation mechanism, however, has been found to be normal in one study (11) and impaired in others (12,13).…”

Chronic Kidney Disease, Insulin Resistance, and Incident Diabetes in Older Adults

“…In addition, unique metabolic abnormalities contribute to insulin resistance in CKD, including uremic toxins, metabolic acidosis, and vitamin D deficiency (10)(11)(12)(13)(14). The site of insulin resistance in CKD is localized to skeletal muscles (3) and a postreceptor defect has been recognized as the primary abnormality in CKD (15).…”

Insulin Resistance in CKD

“…Another factor that might be involved in derangements of glucose metabolism in patients with CKD is abnormal peripheral glucose disposal due to modified skeletal muscle composition. Friedman et al discovered that the increase in insulin-stimulated glucose transport was significantly diminished in isolated muscle fibers of uremic patients supposedly by affecting postreceptor signaling pathways (15). A new mechanism of impaired insulin signaling in the muscle by inflammation-triggered overexpression of the signal regulatory protein a in the muscle of patients with CKD was recently reported (16).…”