title: The diabetic phenotype is conserved in myotubes established from diabetic subjects: evidence for primary defects in glucose transport and glycogen synthase activity.
abstract: The most well-described defect in the pathophysiology of type 2 diabetes is reduced insulin-mediated glycogen synthesis in skeletal muscles. It is unclear whether this defect is primary or acquired secondary to dyslipidemia, hyperinsulinemia, or hyperglycemia. We determined the glycogen synthase (GS) activity; the content of glucose-6-phosphate, glucose, and glycogen; and the glucose transport in satellite cell cultures established from diabetic and control subjects. Myotubes were precultured in increasing insulin concentrations for 4 days and subsequently stimulated acutely by insulin. The present study shows that the basal glucose uptake as well as insulin-stimulated GS activity is reduced in satellite cell cultures established from patients with type 2 diabetes. Moreover, increasing insulin concentrations could compensate for the reduced GS activity to a certain extent, whereas chronic supraphysiological insulin concentrations induced insulin resistance in GS and glucose transport activity. Our data suggest that insulin resistance in patients with type 2 diabetes comprises at least two important defects under physiological insulin concentrations: a reduced glucose transport under basal conditions and a reduced GS activity under acute insulin stimulation, implicating a reduced glucose uptake in the fasting state and a diminished insulin-mediated storage of glucose as glycogen after a meal.
authors.affiliation: Department of Endocrinology, Odense University Hospital, Odense, Denmark. janne.dyhr@ouh.dk
authors.forename: Michael
authors.initials: M
authors.lastname: Gaster
authors.forename: Ingrid
authors.initials: I
authors.lastname: Petersen
authors.forename: Kurt
authors.initials: K
authors.lastname: Højlund
authors.forename: Pernille
authors.initials: P
authors.lastname: Poulsen
authors.forename: Henning
authors.initials: H
authors.lastname: Beck-Nielsen
mesh_terms: D000328:Adult; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism*; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007700:Kinetics; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity; D010641:Phenotype; D012016:Reference Values
chemical_list: D007328:Insulin; D019298:Glucose-6-Phosphate; D006006:Glycogen Synthase; D005947:Glucose