Diabetes and the myo-inositol paradox.
To test the general applicability of the hypothesis that diabetes mellitus causes increased polyol pathway activity, decreased tissue free myo-inositol, and resultant pathological changes in tissues susceptible to the ravages of diabetes, we measured glucose, sorbitol, and myo-inositol with quantitative histochemical techniques in layers of the cornea, the aortic myointima, the cardiac left ventricle and atrioventricular node (AVN), and retina and kidney after 19 days or 2 mo (mildly diabetic non-insulin-treated [MD] and severely diabetic insulin-treated [SD] groups) in the alloxan-induced diabetes model. In the aqueous humor, glucose rose linearly with increased serum glucose, sorbitol was markedly increased in the MD and SD groups, and myo-inositol did not change in any diabetic group. There was no change in glucose or sorbitol in aortic myointima in any group, but myoinositol was decreased in 19-day diabetic rabbits by 26%, unchanged in MD rabbits but paradoxically increased by 60% in SD rabbits. Glucose, sorbitol, and myo-inositol increased in all three corneal layers in SD rabbits but only in epithelium and stroma in 19-day and MD rabbits. AVN glucose and sorbitol did not change in 19-day diabetic, MD, or SD diabetic rabbits. AVN myo-inositol was three times higher than ventricular myo-inositol and did not appear to change in SD rabbits. Retinal pigmented epithelium myo-inositol was decreased 30% in SD rabbits. Glomerular myo-inositol was also decreased, but not significantly, in SD rabbits. We conclude that the paradoxical increase in corneal and aortal myo-inositol raises fundamental questions about the general applicability of the myo-inositol-depletion hypothesis.
Diabetes Center, University of Pennsylvania, Philadelphia 19104.
A
A
Loy
K G
KG
Lurie
A
A
Ghosh
J M
JM
Wilson
L C
LC
MacGregor
F M
FM
Matschinsky
D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D003315:Cornea / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D007294:Inositol / Q000097:blood / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D011817:Rabbits; D012016:Reference Values; D012160:Retina / Q000378:metabolism; D013012:Sorbitol / Q000378:metabolism*
D001786:Blood Glucose; D007294:Inositol; D013012:Sorbitol