INSULIN-INDUCED HEXOKINASE-II EXPRESSION IS REDUCED IN OBESITY AND NIDDM

NIDDM and obesity are characterized by decreased insulin-stimulated gl ucose uptake in muscle. It has been suggested that impaired glucose ph osphorylation to glucose-6-phosphate, catalyzed in muscle by hexokinas e (HK)II, may contribute to this insulin resistance. Insulin is known to increase HKII mRNA, protein, and activity in lean nondiabetic indiv iduals. The purpose of this study was to determine whether defects in insulin-stimulated HKII expression and activity could contribute to th e insulin resistance of obesity and NIDDM. Fifteen lean nondiabetic co ntrol subjects, 17 obese nondiabetic subjects, and 14 obese NIDDM pati ents were studied. Percutaneous muscle biopsies of the vastus laterali s were performed in conjunction with leg balance and local indirect ca lorimetry measurements before and at the end of a 3-h euglycemic-hyper insulinemic clamp (40 or 240 mU.min(-1).m(-2)). Leg glucose uptake in response to the 40-mU insulin infusion was higher in the lean control subjects (2.53 +/- 0.35 mu mol.min(-1) per.100 ml leg vol) than in obe se (1.46 +/- 0.50) or NIDDM (0.53 +/- 0.25, P < 0.05) patients. In res ponse 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 subjec ts 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) gr oups. In response to 240 mU insulin, HKII mRNA was increased in all gr oups (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 con ditions, 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.min(-1).g(-1) muscle protein) relative to the lean cont rol 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 subj ects, P < 0.01 vs. the obese subjects). Resistance to insulin's metabo lic effects extends to its ability to induce HKII expression in obesit y and NIDDM.