Decreased insulin‐stimulated 3–0‐methylglucose transport in in vitro incubated muscle strips from type II diabetic subjects

Abstract

Peripheral insulin resistance in type II diabetes mellitus has been attributed to alterations in skeletal muscle glucose metabolism. However the direct dose-response relationship between insulin and glucose transport has not yet been studied in human skeletal muscle. We investigated 3-0-methylglucose transport in in vitro incubated skeletal muscle strips from eight healthy controls (age 61 +/- 6 yrs) and six lean type II diabetic patients treated with oral antidiabetic medication (age 73 +/- 3 yrs). Rectus abdominis muscle samples (approximately 1 g), obtained during elective abdominal surgery, were clamped at their resting length in vivo, whereupon strips (20-50 mg) were prepared for in vitro incubation. Measurements of high-energy phosphates and glycogen levels revealed that the muscle strips maintained energy levels during the incubation period. Glucose transport responded to insulin in a dose-response manner in the control group, with a 2-fold increase following maximal stimulation. Muscle strips from the diabetic group demonstrated a marked decrease in the insulin dose-response curve (P less than 0.01), when compared to healthy muscle strips. At a maximal insulin concentration (10,000 microU x ml-1), the response of the diabetic muscle tissue was 50% less than that of the healthy control tissue (P less than 0.05). This report demonstrates a dose-response curve for insulin stimulated 3-0-methylglucose transport in in vitro incubated human skeletal muscle strips. Furthermore, in type II diabetic muscle, our results provide evidence for one or several defects at a postreceptor level.

Aberrant p38 mitogen-activated protein kinase signalling in skeletal muscle from Type 2 diabetic patients

“…While insulin signalling to IRS-1 and PI 3-kinase is impaired in skeletal muscle from Type 2 diabetic patients, phosphorylation of the mitogen-activated protein kinase (MAPK) extracellular regulated kinase (ERK1/2) is normal [4,5], suggesting diversity in insulin action along metabolic and mitogenic signalling pathways in Type 2 diabetes. Impaired insulin-mediated whole body glucose uptake in Type 2 diabetes [1,2,3,4,5], as well as in several other insulin resistant states such as morbid obesity [6,7], polycystic ovary syndrome [8], gestat-MAPK's are part of a large family of related serine/threonine protein kinases that include the ERK1/2, p38 MAPK and c-jun and form a major signalling system to facilitate signal transduction to appropriate genomic, rather than direct metabolic responses [16,17]. However, p38 MAPK has recently been proposed to play a metabolic role in the regulation of insulinstimulated glucose transport by either altering the "intrinsic activity of GLUT4" or by facilitating the transition of GLUT4 from an occluded to a fully activated (exposed) state at the plasma membrane [18].…”

Regulation of Glucose Transport and Insulin Signaling by Troglitazone or Metformin in Adipose Tissue of Type 2 Diabetic Subjects

“…The lipid products of PI3K contribute to activation of the serine kinase Akt (protein kinase B), followed by translocation of the insulin-regulated glucose transporter isoform, GLUT4, from intracellular pools to the plasma membrane (3,4). Numerous investigations have established PI3K as essential, if not sufficient, for glucose transport stimulation (3,4), whereas the role of Akt is still controversial (5,6). Each of these events and proteins represent a potential site or cause of insulin resistance.…”

“…Glucose intolerance in type 2 diabetes is manifested by defects in glucose transport into muscle (6,7) and adipose tissue (8). In adipose tissue from diabetic subjects, defective glucose transport has been shown to result from a reduced complement of insulin-stimulated GLUT4 in intracellular pools (9).…”

Fermented Milk, Kefram-Kefir Enhances Glucose Uptake into Insulin-Responsive Muscle Cells

“…The dysfunction of insulin secretion from the pancreas resulted in IDDM and the lowered response to insulin resulted in NIDDM. In the NIDDM patients, insulin-stimulated glucose uptake into muscle cells was reduced in both in vivo (DeFronzo et al, 1992) and in vitro (Dohm et al, 1988;Andreasson et al, 1991).…”