Decreased insulin responsiveness of glucose uptake in cultured human skeletal muscle cells from insulin-resistant nondiabetic relatives of type 2 diabetic families.

Abstract

To investigate the contribution of inherited biochemical defects to the peripheral insulin resistance of type 2 diabetes, we studied cultured skeletal muscle from 10 insulin-resistant nondiabetic first-degree relatives of type 2 diabetic families and 6 control subjects. Insulin stimulation of glucose uptake and glycogen synthesis was maximal in myoblasts. Insulin-stimulated glucose uptake (fold-stimulation over basal uptake) was decreased in relative compared with control myoblasts at 0.001 µmol/l (0.93 ± 0.05 [mean ± SE] vs. 1.15 ± 0.06, P < 0.05) and 0.1 µmol/l (1.38 ± 0.10 vs. 1.69 ± 0.08, P = 0.025) insulin. Insulin responsiveness was markedly impaired in 5 of the relative myoblast cultures, and in 4 of these, there was an associated increase in basal glucose uptake (76.7 ± 7.0 vs. 47.4 ± 5.5 pmol · min -1 · mg -1 protein, relative vs. control; P < 0.02). Expression of insulin receptor substrate 1, phosphatidylinositol 3-kinase, protein kinase B, and glycogen synthase was normal in the relative cultures with impaired insulin responsiveness. Glycogen synthesis was also normal in the relative cultures. We conclude that the persistence of impaired insulin responsiveness in some of the relative cultures supports the role of inherited factors in the insulin resistance of type 2 diabetes and that the association with increased basal glucose uptake suggests that the 2 abnormalities may be linked.

WY-14643 and 9-cis-retinoic acid induce IRS-2/PI 3-kinase signalling pathway and increase glucose transport in human skeletal muscle cells: differential effect in myotubes from healthy subjects and Type 2 diabetic patients

“…As indicated previously [28], cells established from Type 2 diabetic patients had the same rate of myoblast growth and fusion into myotubes as cells from control subjects. In agreement with other studies [21,23,24,25], there was no apparent morphological difference between differentiated muscle cells from non-diabetic and diabetic subjects.…”

“…Primary cultures of human muscle cells display numerous features of mature skeletal muscle [21,22]. More importantly, myotubes established from Type 2 diabetic patients conserve the diabetic phenotype, including decreased insulin responsiveness of glucose uptake and glycogen synthase activation [21,23,24,25,26,27], as well as altered insulin stimulation of PI 3-kinase activity [26,28]. These cell cultures are thus a relevant and interesting model to verify whether and how drug treatments could improve insulin action in human muscle cells.…”

Isoform-specific defects of insulin stimulation of Akt/protein kinase B (PKB) in skeletal muscle cells from type 2 diabetic patients

“…3). This cell model displays several features of mature skeletal muscle, and myotubes derived from type 2 diabetic patients have consistently been shown to retain an insulin resistant phenotype with altered insulin-dependent glucose and lipid metabolism [29,30,36,37] and defective insulin signalling [20,36]. These defects include strong reduction in the activation of PI3K in response to insulin [20,21].…”

Skeletal Muscle Insulin Resistance in Normoglycemic Subjects With a Strong Family History of Type 2 Diabetes Is Associated With Decreased Insulin-Stimulated Insulin Receptor Substrate-1 Tyrosine Phosphorylation

“…The defect in activation of glycogen synthase is also present in normoglycemic subjects with a family history of diabetes (8). Moreover, the defect in insulin-stimulated glycogen synthase activity persists when skeletal muscle cells from type 2 diabetic patients are cultured under "normoglycemic" conditions (20); in that study, Jackson et al (20) reported that protein expression of insulin receptor substrate (IRS)-1, p85, Akt, and glycogen synthase was normal. However, the defect in insulin activation of glycogen synthase could have resulted from a proximal defect in the activity of the insulin receptor signal transduction system and not be intrinsic to glycogen synthase.…”