Ultrastructural observations on myelinated fibres in experimental diabetes: Effect of the aldose reductase inhibitor ponalrestat given alone or in conjunction with insulin therapy

• Published in: Journal of the neurological sciences Vol. 85; no. 2; pp. 131 - 147
• Main Authors: Bhoyrul, S., Sharma, A.K., Stribling, D., Mirrlees, D.D., Peterson, R.G., Farber, M.O., Thomas, P.K.
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier B.V 01.06.1988; Elsevier Science
• Subjects: Aldehyde Reductase - antagonists & inhibitors; Aldehyde Reductase - therapeutic use; Aldose reductase inhibition; Animals; Biological and medical sciences; Blood Glucose - metabolism; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - enzymology; Diabetes Mellitus, Experimental - pathology; Diabetes. Impaired glucose tolerance; Drug Therapy, Combination; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Experimental diabetes mellitus; Hypoglycemia - drug therapy; Insulin - therapeutic use; Insulin therapy; Male; Medical sciences; Morphometry; Nerve Degeneration; Nerve Fibers, Myelinated - drug effects; Nerve Fibers, Myelinated - ultrastructure; Neuropathy; Phthalazines; Rats; Rats, Inbred Strains; Streptozocin; Sugar Alcohol Dehydrogenases - antagonists & inhibitors; Time Factors; Experimental diabetes mellitus; Insulin therapy; Neuropathy; Aldose reductase inhibition; Morphometry; Endocrinopathy; Animal model; Rat; Diabetes mellitus; Rodentia; Enzyme inhibitor; Myelinated nerve fiber; Insulin; Protein hormone; Vertebrata; Chemotherapy; Mammalia; Treatment; Aldose reductase; Ultrastructure; Combined treatment
• ISSN: 0022-510X; 1878-5883
• DOI: 10.1016/0022-510X(88)90151-7

Six groups of rats were studied over a 12-week period: onset and end controls, untreated diabetics, ponalrestat-treated diabetics, insulin-treated diabetics, and diabetics treated with ponalrestat and insulin. The concentrations of glucose, sorbitol and fructose significantly increased and that of myo-inositol significantly decreased in the sciatic nerve of untreated diabetic animals. Ponalrestat administration completely normalized sorbitol levels and partially corrected fructose and myo-inositol concentrations without altering nerve glucose levels. The biochemical abnormalities were also corrected in both the insulin-treated and insulin and ponalrestat-treated diabetic animals. Myelinated fibre cross-sectional areas and axonal areas were significantly less in the tibial nerve of diabetic animals as compared with age-matched controls. Insulin treatment partially corrected the reduction in fibre and axonal area but teased fibre preparations showed an excess of axonal degeneration as compared with controls, untreated diabetics and ponalrestat-treated diabetics. Ponalrestat given alone or in conjunction with insulin therapy did not correct the reduction in fibre or axonal area and single isolated fibres from diabetic animals treated with ponalrestat and insulin showed a marked excess of axonal degeneration, probably related to hypoglycaemia. The study fails to reveal any significant beneficial effect of aldose reductase inhibition on the structural abnormalities in peripheral nerve in experimental diabetes.