REDUCED EXPRESSION OF HEXOKINASE-II IN INSULIN-RESISTANT DIABETES

The regulation of hexokinase II (HKII) was examined in fat and skeleta l muscle of an animal model of non-insulin-dependent diabetes mellitus , the KKA(Y) mouse. These tissues require insulin for facilitated tran sport of glucose and express the insulin-responsive transporter GLUT4. The combined data from two experiments (n = 12 for each experimental condition) demonstrated mean concentrations of plasma insulin in pmol/ l and glucose in mmol/l of 122 and 7.2 (control nondiabetic C57 mouse) vs. 1,118 and 29.6 (diabetic mouse), respectively. The tissues of dia betic mice compared with control mice demonstrated a reduction of HKII mRNA abundance of 68% in epididymal fat (P = 0.0001) and 34% in the q uadriceps muscles (P < 0.001), with concordant reduction in the abunda nce of GLUT4 mRNA of 60% in epididymal fat (P < 0.001). In comparison with the results in untreated diabetic mice, diabetic animals treated with the insulin-sensitizing drug pioglitazone demonstrated an increas e in the abundance of HKII mRNA with a concordant increase of GLUT4 mR NA in epididymal fat (P = 0.03 and < 0.01, respectively), and an incre ase of HKII mRNA in the quadriceps muscles (P < 0.05). Separate experi ments demonstrated a reduction of HKII protein abundance by 61% in epi didymal fat (P < 0.001, n = 12 for each experimental condition) and by 71% in the quadriceps muscles (P < 0.001, n = 6 for each experimental condition). In comparison with untreated diabetic mice, there was an increase in the abundance of HKII protein in epididymal fat of animals treated with pioglitazone (P < 0.05). Additional experiments showed a reduction of HKII protein activity in untreated diabetic mice of 24% in the quadriceps muscles (P < 0.05, n = 6 for each experimental condi tion). Because HKII deficits can be reversed, it appears that abnormal expression of HKII may occur secondary to insulin resistance; neverth eless such changes may exacerbate hyperglycemia.