title: Normalization of plasma glucose concentration by insulin therapy improves insulin-stimulated glycogen synthesis in type 2 diabetes.
abstract: Considerable evidence suggests that skeletal muscle insulin resistance is an inherent feature of type 2 diabetes and contributes to the pathogenesis of the disease. In patients with poorly controlled diabetes, hyperglycemia is thought to produce additional insulin resistance in muscle. The magnitude and nature of hyperglycemia-induced insulin resistance is not known. The purpose of the present study was to determine the biochemical mechanisms responsible for increased insulin-stimulated glucose disposal after the achievement of tight glycemic control with a mixed-split regimen. We performed hyperinsulinemic-euglycemic clamps with indirect calorimetry and vastus lateralis muscle biopsies in eight type 2 diabetic patients who had poor glycemic control (HbA(1c) 10.1%) and again after 3 months of intensive insulin therapy designed to produce near-normoglycemia (HbA(1c) 6.6%). Improved glycemic control increased insulin-stimulated glucose disposal (5.16 +/- 0.32 vs. 3.69 +/- 0.33 mg x kg(-1) x min(-1); P < 0.01); nonoxidative glucose disposal, which primarily reflects glycogen synthesis (2.11 +/- 0.26 vs. 0.90 +/- 0.16 mg x kg(-1) x min(-1); P < 0.01); and glycogen synthase fractional velocity (0.094 +/- 0.017 vs. 0.045 +/- 0.007; P < 0.05). There was no improvement in insulin-stimulated glucose oxidation (3.05 +/- 0.25 vs. 2.79 +/- 0.20 mg x kg(-1) x min(-1)), hexokinase II mRNA expression (increase over basal values), or hexokinase II enzymatic activity (0.51 +/- 0.16 vs. 0.42 +/- 0.18 pmol x min(-1) x microg(-1) protein). All of the increase in insulin-stimulated glucose disposal could be accounted for by increased glycogen synthesis, which is likely attributable to increased activation of glycogen synthase by insulin.
authors.affiliation: Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA.
authors.forename: Thongchai
authors.initials: T
authors.lastname: Pratipanawatr
authors.forename: Kenneth
authors.initials: K
authors.lastname: Cusi
authors.forename: Peter
authors.initials: P
authors.lastname: Ngo
authors.forename: Wilailak
authors.initials: W
authors.lastname: Pratipanawatr
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Mandarino
authors.forename: Ralph A
authors.initials: RA
authors.lastname: DeFronzo
mesh_terms: D001786:Blood Glucose / Q000032:analysis*; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D006003:Glycogen / Q000096:biosynthesis*; D006006:Glycogen Synthase / Q000378:metabolism; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009994:Osmolar Concentration; D012333:RNA, Messenger / Q000378:metabolism; D012016:Reference Values
chemical_list: D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger; D006003:Glycogen; D006006:Glycogen Synthase; D006593:Hexokinase