Early neural and vascular dysfunctions in diabetic rats are largely sequelae of increased sorbitol oxidation.
These experiments were undertaken to assess the importance of cytoplasmic (c) sorbitol oxidation versus mitochondrial (m) pyruvate oxidation in mediating neural and vascular dysfunction attributable to hyperglycemia in diabetic rats. Increased oxidation of sorbitol is coupled to enzymatic reduction of free oxidized NAD(+)c to reduced NADHc, manifested by an increased ratio of NADH to NAD(+)c. Likewise, increased oxidation of pyruvate is coupled to reduction of NAD(+)m to NADHm, which increases the NADH/NAD(+)m ratio. Specific inhibitors of sorbitol production or sorbitol oxidation normalized: increased diabetic nerve NADH/NAD(+)c, impaired nerve-conduction velocity, and vascular dysfunction in sciatic nerve, retina, and aorta; however, they had little or no impact on increased NADH/NAD(+)m. These observations provide, for the first time, strong in vivo evidence for the primacy of sorbitol oxidation versus. pyruvate oxidation in mediating the metabolic imbalances, impaired nerve conduction, and vascular dysfunction evoked by diabetes. These findings are consistent with (a) the fact that oxidation of sorbitol produces "prooxidant" NADHc uncoupled from subsequent production of "antioxidant" pyruvate required for reoxidation of NADHc to NAD(+)c by lactate dehydrogenase, and (b) the hypothesis that neural and vascular dysfunction in early diabetes are caused primarily by increased NADHc, which fuels superoxide production by NADH-driven oxidases.
Ido
Yasuo
Y
Boston Medical Center, EBRC 820, Diabetes & Metabolism Unit, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Nyengaard
Jens R
JR
Chang
Kathy
K
Tilton
Ronald G
RG
Kilo
Charles
C
Mylari
Banavara L
BL
Oates
Peter J
PJ
Williamson
Joseph R
JR
D000818:Animals; D001808:Blood Vessels / Q000503:physiopathology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009243:NAD / Q000378:metabolism; D009420:Nervous System / Q000503:physiopathology; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013012:Sorbitol / Q000378:metabolism*
D009243:NAD; D013012:Sorbitol