Physiological and morphometric analyses of neuropathy in sucrose-fed OLETF rats.
To investigate the characteristic features of diabetic neuropathy in type 2 diabetes mellitus, Otsuka Long-Evans Tokushima fatty (OLETF) rats, an animal model of human type 2 diabetes mellitus, and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats were fed with or without sucrose and/or an aldose reductase inhibitor, [5-(3-thienyl) tetrazol-1-yl] acetic acid (TAT), for 24 weeks, and physiological, biochemical and morphological assessments were performed. Sucrose administration caused remarkable hyperglycemia in OLETF rats but not in LETO rats. Sucrose-fed OLETF rats demonstrated delayed nerve conduction velocity, decreased coefficient of variation of R-R interval, reduced sciatic nerve blood flow, increased platelet aggregation activity, a lower concentration of erythrocyte 2,3-diphosphoglycerate, and decreased Na+/K+-ATPase activity in sciatic nerves, compared with the non-sucrose-fed OLETF and LETO rats. TAT prevented all these deficits except hyperglycemia. Sorbitol and fructose accumulation and myo-inositol depletion in tail nerves of sucrose-fed OLETF rats were ameliorated by TAT. Myelinated fiber size and density in sural nerves of sucrose-fed OLETF rats were decreased and increased, respectively, compared with non-sucrose-fed OLETF and LETO rats. These morphological abnormalities were normalized by TAT. These observations suggest that the sucrose-fed OLETF rat developed diabetic neuropathy not only electrophysiologically but also histologically, and that an aldose reductase inhibitor, TAT, possesses therapeutic value for the treatment of diabetic neuropathy.
Nakamura
J
J
The Third Department of Internal Medicine, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, 466-8550, Nagoya, Japan. jiro@tsuru.med.nagoya-u.ac.jp
Hamada
Y
Y
Sakakibara
F
F
Hara
T
T
Wakao
T
T
Mori
K
K
Nakashima
E
E
Naruse
K
K
Kamijo
M
M
Koh
N
N
Hotta
N
N
D019794:2,3-Diphosphoglycerate / Q000097:blood; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000503:physiopathology*; D019422:Dietary Sucrose / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology; D008297:Male; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D020334:Rats, Inbred OLETF; D020318:Rats, Long-Evans; D012039:Regional Blood Flow / Q000187:drug effects; D012584:Sciatic Nerve / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
D019422:Dietary Sucrose; D004791:Enzyme Inhibitors; D013777:Tetrazoles; D013876:Thiophenes; C080974:(5-(3-thienyl)tetrazol-1-yl)acetic acid; D019794:2,3-Diphosphoglycerate; D000449:Aldehyde Reductase; D000254:Sodium-Potassium-Exchanging ATPase