Both myo-inositol to chiro-inositol epimerase activities and chiro-inositol to myo-inositol ratios are decreased in tissues of GK type 2 diabetic rats compared to Wistar controls.
Previous data from our and other labs demonstrated a decreased chiro-inositol content in urine and tissues of human subjects and animals with type 2 diabetes. In urine this decrease in chiro-inositol was accompanied by an increase in myo-inositol content. Decreased urine levels of chiro-inositol in monkeys were next correlated with the severity of underlying insulin resistance determined by five separate assays. To investigate the decreased chiro-inositol and the accompanying increased myo-inositol excretions in urine in humans and monkeys, we postulated a defect in the epimerization of myo-inositol to chiro-inositol. [(3)H]Myo-inositol was then shown to be converted to [(3)H]chiro-inositol in rats in vivo and in fibroblasts in vitro in a process stimulated by insulin. We next demonstrated that the conversion of [(3)H]myo-inositol to [(3)H]chiro-inositol in vivo was markedly decreased in GK type 2 diabetic rats compared to Wistar controls in liver, muscle, and fat, insulin sensitive tissues. Decreases of 20-25% conversion to baseline levels of under 5% conversion were observed. In the present work, we initially compared the total contents of myo-inositol and chiro-inositol in GK type 2 diabetic rat kidney, liver, and muscle compared to Wistar controls. We demonstrated a consistent decreased total chiro-inositol to myo-inositol ratio in kidney, liver, and muscle compared to controls. We next established the presence of a myo-inositol to chiro-inositol epimerase activity in rat liver cytosol. Enzyme activity was shown to be time and enzyme concentration dependent with a broad pH optimum. It required NADH and NADPH for full activity, which is compatible with its action via an oxido-reductive mechanism. Lastly, we demonstrated that the epimerase enzyme bioactivity was significantly decreased in muscle, liver, and fat cytosolic extracts of GK type 2 diabetic rats versus Wistar controls. Decreased myo-inositol to chiro-inositol epimerase activity may therefore play a role in explaining the decreased chiro-inositol to myo-inositol urine and tissue ratios observed here and in previous animal and human studies. Further it may also possibly play a role in the underlying insulin resistance.
Sun
Tie-hua
TH
Insmed Incorporated, 4851 Lake Brooke Dr., Glen Allen, VA 23060, USA.
Heimark
Douglas B
DB
Nguygen
Thang
T
Nadler
Jerry L
JL
Larner
Joseph
J
D000273:Adipose Tissue / Q000737:chemistry; D000818:Animals; D002457:Cell Extracts / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000378:metabolism; D007294:Inositol / Q000032:analysis* / Q000378:metabolism*; D007668:Kidney / Q000737:chemistry; D008099:Liver / Q000737:chemistry / Q000201:enzymology; D008297:Male; D018482:Muscle, Skeletal / Q000737:chemistry; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D013401:Sugar Alcohol Dehydrogenases / Q000378:metabolism*
D002457:Cell Extracts; D007294:Inositol; D013401:Sugar Alcohol Dehydrogenases; C023947:inositol NAD epimerase