Reduced expression of hexokinase II in insulin-resistant diabetes.
The regulation of hexokinase II (HKII) was examined in fat and skeletal muscle of an animal model of non-insulin-dependent diabetes mellitus, the KKAY mouse. These tissues require insulin for facilitated transport 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 diabetic mice compared with control mice demonstrated a reduction of HKII mRNA abundance of 68% in epididymal fat (P = 0.0001) and 34% in the quadriceps muscles (P < 0.001), with concordant reduction in the abundance 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 increase in the abundance of HKII mRNA with a concordant increase of GLUT4 mRNA in epididymal fat (P = 0.03 and < 0.01, respectively), and an increase of HKII mRNA in the quadriceps muscles (P < 0.05). Separate experiments demonstrated a reduction of HKII protein abundance by 61% in epididymal 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).(ABSTRACT TRUNCATED AT 250 WORDS)
Braithwaite
S S
SS
Medical Service, Edward Hines, Jr. VA Hospital, Hines, Illinois 60141-5000.
Palazuk
B
B
Colca
J R
JR
Edwards
C W
CW
Hofmann
C
C
D000818:Animals; D015152:Blotting, Northern; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000201:enzymology* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000201:enzymology* / Q000503:physiopathology; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D051275:Glucose Transporter Type 4; D006593:Hexokinase / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000032:analysis / Q000235:genetics; D009124:Muscle Proteins; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics
D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; C495693:Slc2a4 protein, mouse; D006593:Hexokinase