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Effects of Aldose Reductase Inhibitors on the Progression of Nerve Fiber Damage in Diabetic Neuropathy Douglas A

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Effects of Aldose Reductase Inhibitors on the Progression of Nerve Fiber Damage in Diabetic Neuropathy Douglas A 1 Diab Camp, 6:35-38 Effects of Aldose Reductase Inhibitors on the Progression of Nerve Fiber Damage in Diabetic Neuropathy Douglas A. Greene ABSTRACT Aldose reductase inhibitors improve nerve reductase inhibitor revealed a reduction in biochemistry, function, and structure in diabetic intermediates of the polyol pathway. Specific animals and increase nerve conduction in diabetic morphologic lesions that correlate with the degree patients. Nevertheless, it has been difficult to of clinical and electrophysiologic impairment also demonstrate a benefit from these agents in patients were identified. Morphologic evaluation of sural with clinically overt diabetic neuropathy. Direct nerve biopsies obtained after aldose reductase measurement of the nerve tissue penetration and inhibitor treatment suggests that these biochemical and biological potency of these biochemically effective compounds ameliorate compounds is essential to fully understand and clinically relevant structural lesions in patients evaluate their effectiveness. Human sural nerve with diabetic neuropathy. (Journal of Diabetes and biopsies obtained from diabetic neuropathic Its Complications 6;1:35-38, 1992.) patients undergoing treatment with an aldose INTRODUCTION potassium adenosine triphosphatase (ATPase), a de- crease in energy consumption of the nerve tissue, an- Only a decade ago, the long-term neuro- dalterations in nerve conduction. As a result, it ap- logic complications of diabetes mellitus pears that intra-axonal sodium accumulates at the were attributed to nerve degeneration or node of Ranvier and causes localized swelling and the demyelination. More recently, attention characteristic lesion, axo-glial dysjunction. The phar- has0 focused on a potentially reversible metabolic dis- macologic inhibition of aldose reductase represents an order in which the enzyme, aldose reductase, in re- opportunity to reduce sorbitol accumulation and to sponse to hyperglycemia, promotes increased inter- arrest or reverse nerve damage that occurs as a com- cellular conversion of glucose to sorbitol and de- plication of diabetes mellitus. creased uptake of the cyclic hexanol, myo-inositol.‘,2 Aldose reductase inhibitors block the conversion of The depletion of myo-inositol in nerve tissue appears glucose to sorbitol, the depletion of myo-inositol, and responsible for a variety of metabolic and electrophys- the impairment of sodium-potassium ATPase;2 how- iologic alterations, including a decrease in sodium- ever, their effectiveness in ameliorating clinically overt diabetic neuropathy is uncertain. Short-term studies with aldose reductase inhibitors have not been Reprint requests to be sent to: Dr. Douglas A. Greene, Michigan uniformly effective. 3-9 It may be that the accumula- Diabetes Research and Training Center, University of Michigan, tion of sorbitol contributes little to the chronic nerve 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA. fiber damage that is characteristic of diabetic neuropa- Michigan Diabetes Research and Traininp: Center. Universitv , of Michiga;, Ann Arbor, Michigan, USA ” thy. Long-term studies with aldose reductase inhibi- 0 1992 Journal of Diabetes and Its Complications 10568727/92/$5.00 36 GREENE ] Diab Comp 1992; 151 tom that focus on outcome measures of nerve fiber polyneuropathy from a normal reference population. structure and density are more likely to provide in- Further, diabetics without symptomatic peripheral sights into the etiology and pathology of chronic neuropathy appear to be grouped with the larger nor- symptomatic diabetic neuropathies. Further, detailed mal population, rather than with the patients having measurements of changes in nerve fiber parameters diabetic polyneuropathy. This system allows one to can provide an effective means of comparing different differentiate between neuropathic and non-neuro- aldose reductase inhibitors. pathic diabetics on the basis of a threshold of pa- STRUCTURAL ABNORMALITIES ASSOCIATED thology. WITH DIABETIC NEUROPATHY A similar system has been developed at our institu- tion. It is called the index of normality and is obtained Three structural abnormalities, the so-called triopathy from the product of fiber density and the percentage of diabetic neuropathy, are observed in patients with of fibers with normal appearance.2 This method dif- diabetic neuropathy: fiber loss, fiber atrophy, and fers from that of Dyck et al. lo in that it does not correct specific fiber lesions. Patients with diabetic polyneu- for age and gender. Using this and other quantitative ropathy demonstrate a reduced number of functional measures, we have investigated the effects of differ- myelinated nerve fibers, and those fibers that survive ent aldose reductase inhibitors on nerve fiber mor- are reduced in size. This decrease in axonal size is phology. exhibited as a reduction in cross-sectional area. The three components of the triopathy provide a THE EFFECTS OF ALDOSE REDUCTASE series of measurable and quantifiable morphometric INHIBITORS ON NERVE FIBER MORPHOLOGY parameters which exhibit a relationship to the dura- Three long-term, double-blind, randomized, con- tion of diabetes in patients with diabetic neuropathy. trolled studies of aldose reductase inhibitors are avail- For example, fiber loss can be quantified as a decrease able for the morphologic examination of human nerve in fiber density, measured as the number of fibers per specimens. In each study, sural nerve biopsies were square millimeter of a cross-sectional area of nerve. obtained prior to and after at least 12 months of ther- Fiber atrophy can be characterized several ways; these apy, and morphometric techniques were employed to include a decrease in the mean fiber size, an increase quantify nerve fiber changes. in the myelin endpoint, or a decrease in the ratio of Sorbinil North American Neuropathy Trial. Sural axonal to myelin area. Fiber atrophy in an axon can be nerve biopsy specimens were obtained from 16 dia- demonstrated by changes in the relationship between betics with symptomatic peripheral polyneuropathy the area of the axon and the number of myelin lamella. prior to and 12 months after sorbinil250 mg per day Because myelin assumes a wrinkled appearance when (n = 10) or placebo (n = 6) therapyq2 Although the atrophied, increases in the percentage of wrinkled mean sural nerve sorbitol concentration in sorbinil- myelin is also evidence of fiber atrophy. treated patients was significantly decreased when Specific fiber lesions can be identified by the accu- compared with baseline measurements, no significant mulation of a series of discrete abnormalities on mi- change was noted in placebo-treated patients. Of crographs or as a decrease in the percentage of nor- note, sural nerve sorbitol levels actually increased in mal-appearing fibers. Many of these changes occur one patient who discontinued the drug. This clearly initially at the node of Ranvier, and one of the earliest indicates that sorbinil enters peripheral nerve tissue lesions is the axo-glial dysjunction. This lesion is de- scribed as a loss of tight junction complexes that nor- at the site of aldose reductase and decreases sorbitol mally maintain the integrity of the node of Ranvier by accumulation by inhibiting polyol activity. anchoring terminal loops of myelin to the axolemma. A number of morphometric findings were available More advance abnormalities that occur are swelling from this study. Fiber loss was partially corrected, as of the node and perinodal region and perinodal demy- indicated by a statistically significant increase in nerve elination followed by remyelination. Frequently, in- fiber density in sorbinil-treated patients and no creased segmental demyelination also occurs. In re- change in the placebo-treated patients. The increase sponse to these injuries, increased neurofiber regen- in nerve fiber density was accounted for by a several- eration may be demonstrated with regenerating fold increase in nerve fiber regeneration. It should be sprouts occupying the area derived from the previ- noted that the failure to observe deterioration of nerve ously degenerated axon. fiber density in placebo-treated patients during the It is possible to quantify the overall degree of pa- la-month study is consistent with the slow progres- thology that is present by using a variety of different sion of diabetic polyneuropathy. scoring systems. One method uses a compound pa- The number of specific fiber lesions, including axo- rameter score (density, atrophy, and lesions) that is glial dysjunction, were increased at baseline in both normalized for age and gender.” This approach the placebo and sorbinil groups. During the study, clearly distinguishes patients with diabetic peripheral these returned to normal in the sorbinil group but 1 Diab Comp 1992; 6:l ALDOSE REDUCTASE INHIBITORS 37 were unchanged in the placebo group. Similarly, axo- reached 3.5-5.5 nmol/mg protein in patients whose nal atrophy, as evidenced by either the axon/myelin glucose nerve concentrations were between 250 and ratio or the presence of excessive myelin wrinkling, 350 nmol/mg protein. In contrast, sorbitol concentra- was improved after sorbinil, indicating that aldose re- tions in tolrestat-treated patients reached a plateau at ductase inhibition exerted a beneficial effect on fiber between 1 and 1.5 nmol/mg protein, despite sural atrophy. Sorbinil-treated patients had an increase in nerve glucose concentrations that ranged from less the overall percentage of nerve fibers that showed a than 75 to almost
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