title: Insulin-induced hexokinase II expression is reduced in obesity and NIDDM.
abstract: NIDDM and obesity are characterized by decreased insulin-stimulated glucose uptake in muscle. It has been suggested that impaired glucose phosphorylation to glucose-6-phosphate, catalyzed in muscle by hexokinase (HK)II, may contribute to this insulin resistance. Insulin is known to increase HKII mRNA, protein, and activity in lean nondiabetic individuals. The purpose of this study was to determine whether defects in insulin-stimulated HKII expression and activity could contribute to the insulin resistance of obesity and NIDDM. Fifteen lean nondiabetic control subjects, 17 obese nondiabetic subjects, and 14 obese NIDDM patients were studied. Percutaneous muscle biopsies of the vastus lateralis were performed in conjunction with leg balance and local indirect calorimetry measurements before and at the end of a 3-h euglycemic-hyperinsulinemic clamp (40 or 240 mU x min(-1) x m[-2]). Leg glucose uptake in response to the 40-mU insulin infusion was higher in the lean control subjects (2.53 +/- 0.35 micromol x min(-1) per x 100 ml leg vol) than in obese (1.46 +/- 0.50) or NIDDM (0.53 +/- 0.25, P < 0.05) patients. In response to 240 mU insulin, leg glucose uptake was similar in all of the groups. In response to 40 mU insulin, HKII mRNA in lean control subjects was increased 1.48 +/- 0.18-fold (P < 0.05) but failed to increase significantly in the obese (1.12 +/- 0.24) or NIDDM (1.14 +/- 0.18) groups. In response to 240 mU insulin, HKII mRNA was increased in all groups (control subjects 1.48 +/- 0.18, P < 0.05 vs. basal, obese 1.30 +/- 0.16, P < 0.05, and NIDDM 1.25 +/- 0.14, P < 0.05). Under basal conditions, HKI and HKII activities did not differ significantly between groups. Neither the 40 mU nor the 240 mU insulin infusion affected HK activity. Total HKII activity was reduced in the obese subjects (4.33 +/- 0.08 pmol x min(-1) x g(-1) muscle protein) relative to the lean control subjects (5.00 +/- 0.08, P < 0.05). There was a further reduction in the diabetic patients (3.10 +/- 0.10, P < 0.01 vs. the control subjects, P < 0.01 vs. the obese subjects). Resistance to insulin's metabolic effects extends to its ability to induce HKII expression in obesity and NIDDM.
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, 78284-7886, USA.
authors.forename: M
authors.initials: M
authors.lastname: Pendergrass
authors.forename: J
authors.initials: J
authors.lastname: Koval
authors.forename: C
authors.initials: C
authors.lastname: Vogt
authors.forename: H
authors.initials: H
authors.lastname: Yki-Jarvinen
authors.forename: P
authors.initials: P
authors.lastname: Iozzo
authors.forename: R
authors.initials: R
authors.lastname: Pipek
authors.forename: H
authors.initials: H
authors.lastname: Ardehali
authors.forename: R
authors.initials: R
authors.lastname: Printz
authors.forename: D
authors.initials: D
authors.lastname: Granner
authors.forename: R A
authors.initials: RA
authors.lastname: DeFronzo
authors.forename: L J
authors.initials: LJ
authors.lastname: Mandarino
mesh_terms: D000328:Adult; D001706:Biopsy; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006006:Glycogen Synthase / Q000378:metabolism; D006593:Hexokinase / Q000145:classification / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007262:Infusions, Intravenous; D007328:Insulin; D007866:Leg / Q000098:blood supply / Q000502:physiology; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D012039:Regional Blood Flow / Q000502:physiology
chemical_list: D007328:Insulin; D012333:RNA, Messenger; D006006:Glycogen Synthase; D006593:Hexokinase; D005947:Glucose