Diabetologia 9 Springer-Verlag 1988 "

Transcription

1 Dabetologa (188) 31: Dabetologa Sprnger-Verlag 188 " Dabetc neuropathy n the upper lmb and the effect of twelve months sorbnl treatment R. J. C. Guy 1, S. G. Glbey 1, M. Sheehy 2, P. Asselman 2 and P.J. Watkns 1 1 Dabetc and 2 Neurophysology Department, Kng's College Hosptal, Denmark Hll, London, UK Summary. Clncal and neurophysologcal studes were undertaken, wth partcular reference to the arms, n 3 patents wth dabetc neuropathy. The effects of an aldose reductase nhbtor, sorbnl, on neuropathy n these patents were studed n a 12 month double blnd placebo controlled tral. Neurophysologcal measurements, partcularly of sensory ampltude, were consderably more senstve than measurements of temperature and vbraton sensaton and reman of fundamental mportance n measurng dabetc neuropathy at an early and potentally reversble stage. There was no sgnf- cantly benefcal effect of sorbnl on clncal or neurophysologcal measurements of nerve functon n patents wth establshed dabetc neuropathy. These results ndcate that neurophysologcal technques are necessary, n conjuncton wth clncal measurements, for the assessment of 'early' dabetc neuropathy and that aldose reductase nhbtors are not effectve n the treatment of establshed dabetc neuropathy. Key words: Dabetc neuropathy, aldose reductase nhbtor, clncal tral. Polyneuropathy s a common and potentally debltatng complcaton of dabetes melltus. The precse cause of dabetc neuropathy s not known. Expermental evdence has suggested a number of possble mechansms ncludng mcrovascular dsease leadng to endoneural hypoxa [1, 2], glycosylaton of nerve protens [3], and abnormaltes of nerve transport [4]. Blood glucose control appears to be of fundamental mportance [5] and tght metabolc control may mprove nerve functon [6, 7]. Metabolc abnormaltes n dabetc nerve have been extensvely nvestgated. Abnormaltes of the polyol pathway n the dabetc nerve lead to sorbtol accumulaton [8], n assocaton wth myo-nostol depleton []. These nterrelated abnormaltes have been ncorporated nto a theoretcal model centred on nerve Na/K ATPase abnormaltes [10]. Expermental evdence suggests that abnormaltes n dabetc nerves mght be reversed by the use of aldose reductase nhbtors leadng to reducton of sorbtol levels [11] or by myo-nostol supplementaton [12]. Neuropathy does not affect all dabetc patents, vares n ts severty and the manner of ts presentaton, and s dffcult to quantfy, partcularly n ts early stages. Bopsy studes have shown both demyelnaton and axonal degeneraton [3]. Neurophysologcal abnormaltes are often present even n the absence of clncal neuropathy [14]. Thus, measurement s a problem n the assessment of dabetc neuropathy: senstve neurophysologcal measurements may not be specfc for dabetc neuropathy, and clncal measurements of sensory thresholds may not be suffcently senstve to detect neuropathy at an early stage. Clncally apparent dabetc neuropathy rarely shows spontaneous mprovement. n the present study we compare the results for neurophysologcal tests and measurements of sensory thresholds n patents wth establshed dabetc neuropathy and report the results of a double blnd placebo controlled study of 12 months treatment wth the aldose reductase nhbtor sorbnl. We have examned n partcular the upper lmb because much less s known regardng dabetc neuropathy n ths area and because t s much less severe than n the legs and perhaps more lkely to respond to treatment. Subjects and methods Subjects Thrty-nne patents wth clncal dabetc neuropathy that had been present for at least 6 months were recruted for a 12 month double blnd placebo controlled study of treatment wth the aldose reduc-

2 R. J. C. Guy et al.: Dabetc neuropathy and sorbnl treatment 215 Table 1. Detals of the patents studed Age Dabetes Dabetes Number wth (years) duraton Type 1/Type 2 Pan or Foot Autonomc a Retno b Proten c (years) paraesthesa ulcers symptoms -pathy -ura Sorbnl _+11 16/ n=21 (13M/8F) Placebo 44 _ _ / n=18 (M/F) Results as mean _+ SD. a dabetc darrhoea, postural hypotenson, or gustatory sweatng; b background or prolferatve; ~ persstently albustx postve tase nhbtor, sorbnl. The followng were used as crtera for neuropathy: absent ankle jerks and sensory loss (abnormal vbraton and/or temperature sensaton) n the feet; typcal and severe symptoms of neuropathc pan or paraesthesa as unsolcted complants on the part of patents wth clncal evdence of neuropathy (absent ankle reflexes and/or abnormal temperature or vbraton sensaton n the foot) [15] and no clncal evdence of perpheral vascular dsease (palpable foot pulses or demonstraton of an ankle/brachal systolc blood pressure rato of > 1). Neuropathc pan was defned as typcally burnng, worse at nght, unrelated to exercse and wth no other cause (vascular or neurologcal) beng found. All patents were questonned about symptoms of autonomc neuropathy defned as follows: dabetc darrhoea-ntermttent and especally nocturnal darrhoea, wth or wthout faecal ncontnence and wth no evdence of other gastrontestnal dsease; gustatory sweatng - facal sweatng precptated by eatng specfc foods; postural hypotenson - hypotensve symptoms on standng wth a drop n systolc blood pressure of over 30 mm Hg. Crtera for ncluson n the study were: establshed dabetes melttus of over 6 months duraton, no change of therapy other than mnor dosage changes for the prevous 6months; age less than 60 years. Excluson crtera were: heavy protenura (detected on A1- bustx testng and found to be n excess of 2 g/24-h urne collecton); actve lver dsease; alternatve causes of perpheral neuropathy (e. g. alcohol abuse, thyrod dsease, vtamn B12 defcency); a hstory of allergy to hydanton drugs; dabetc mononeuropathy, radculopathy or amyotrophy; symptomatc nerve entrapment syndromes at the tme of consderaton for recrutment; symptomatc perpheral vascular dsease. Patents presentng to the dabetc clnc over a 12 month perod who fulflled these crtera were asked to take part n the study. Thus, a heterogeneous group of patents wth a wde range of neuropathy were recruted. Table gves clncal detals of the patents studed. Ffteen of the patents had a hstory of neuropathc foot ulceraton of whom 6 also had troublesome neuropathc pan, and 22 had as ther major complant symptoms of pan or parasthesae. Two patents had nether pan nor ulceraton but both had severe sensory neuropathy n the feet affectng all modaltes and "charcot" neuroarthropathy affectng one foot n one case and troublesome autonomc symptoms n the other. Twenty-nne of the 3 patents (15 males, 14 females; mean_ S D age 43_ years; duraton of dabetes 22 + t 1 years) had Type (nsuln-dependent) dabetes defned as ketoss-prone, dagnosed under the age of 30 years and nsuln treated throughout. Ten patents (7males, 3females; age years; duraton of dabetes 13_+ years) had Type 2 (non-nsulndependent) dabetes defned as dabetes controlled by det or oral hypoglycaemc agents for 2 years or more followng dagnoss, wth no hstory of ketoss or weght loss at the tme of dagnoss; 5 of these patents were on nsuln and 5 on oral hypogtycaemcs. All the patents on nsuln were on once or twce daly subcutaneous doses of hghly purfed pork nsuln. No patent was transferred from oral hypoglycaemcs to nsuln treatment durng the study although dosage changes were allowed. No specal restrctons were placed on the patents n the study wth respect to analgesc or hypnotc treatment of nenropathc pan or nsomna. One patent dropped out before startng the sorbnl tral. Fve patents dropped out durng the course of the study; all were female. One patent wthdrew from the placebo group wth nausea and vomtng whch she attrbuted to the treatment. Four patents wthdrew from the treatment group, 3 wth symptoms of general malase and skn rrtaton, 1 wth a hypersenstvty reacton to sorbnl: malase, erythema, and lymphadenopathy whch resolved on stoppng treatment. Lver functon tests were montored throughout and no patent showed bochemcal evdence of a drug related hepatts. Tral desgn. After a 4 week run-n on placebo capsules suppled by the manufacturer the patents were randomly assgned n a double blnd fashon to 52 weeks treatment wth ether placebo tablets or sorbnl 250 mg (Pfzer Central Research, Sandwch, Kent, UK) [16] once daly. Major assessments of neuropathy were performed at -4 (when randomsaton was undertaken), 0, 24 and 52 weeks, wth revews at 4 to 8 week ntervals to check for sde effects and measurement of glycosylated haemoglobn (HBA0 by electroendosmoss (Comng Ltd, Halstead, Essex, UK), lver functon tests, haemotologcal ndces, and complance (by tablets counts). The tral was approved by the hosptal ethcal commttee and all pat. ents gave nformed consent. Methods All clncal assessments were undertaken by one of two nvestgators. Nerve conducton studes and measurement of somatosensoryevoked potentals were performed by the same nvestgators throughout. Clncal examnaton. Ths conssted of a detaled hstory and clncal examnaton at the tme of recrutment and at each major vst wth specal emphass on the perpheral nervous system, Measurement of sensaton. Two-pont dscrmnaton was measured on the pulp of the domnant ndex fnger usng a par of dvders and expressed n mllmetres. Temperature and vbraton sensaton were measured n the domnant hand and foot usng establshed technques. Temperature sensaton was measured on the thenar emnence of the hand and on the foot mmedately below the lateral malleolus usng a Marstock devce (Somedc, Stockholm, Sweden [17]) and expressed as the warm-cool dfference n degrees centgrade. Vbraton sensaton was measured on the ndex fnger and hallux usng a hand-held bothesometer (Bomedcal nstruments, Newbury, Oho, USA) and expressed n volts [18]. Prevous work n ths department has establshed the reproducblty of these technques and a normal range for subjects under the age of 55 years [151. Autonomc functon testng. A Lectromed nstantaneous heart rate meter, MX2P amplfer, and MX212 chart recorder (Lectromed, St. Quen, Jersey, Channel slands), were used to measure heart rate varaton on deep breathng [11, heart rate ncrease on standng, and the response to a standard valsalva manoeuvre [20]. Blood pressure change on standng was measured usng a standard mercury sphygmomanometer. Neurophysology. The domnant arm and leg were used. The lmb was wanned f necessary to gve a skn temperature of 34~ The

3 216 R. J. C. Guy et al.: Dabetc neuropathy and sorbnl treatment Table 2. Neurophysologcal measurements Sensory nerve acton potental ampltude Radal Medan fnger 3 Sural Sensory nerve conducton velocty Radal Medan Sural Motor nerve conducton velocty Medan wrst to elbow segment (wth F response latency) across carpal tunnel (at ntal vst only) Posteror tbal knee to ankle (wth F response latency) Motor acton potental ampltude Medan nerve (stmulated at wrst) Posteror tbal nerve (at ankle) 3 ~5 >15 O g ;.;,'..;:,.. Table 3. Dabetc control: HBA1 levels throughout sorbnl study Baselne 6 months 12 months Sorbnl 11.0_ Placebo Results as mean SD. Unts are % glycosylaton of haemoglobn. Normal value < 8% Table 4. Comparson of temperature sensaton, vbraton threshold, and autonomc functon tests Temperature 0.6 hand p < Vbraton hand Temperature foot Vbraton foot Vbraton Temperature Vbraton HRV ~ hand hand foot Results shown as correlaton coeffcents. a Heart rate varaton p < p < NS p < p < NS p < p < p < >15 Temperature (*C) Fg.l. Comparson of temperature and vbraton sensaton n the hand. Dotted lnes ndcate upper 5% confdence lmts of normal. There was a hghly sgnfcant correlaton between the two measurements (r = 0.6; p < ) baselne value. Mean values at tmes 0, 6, and 12 months were calculated for each of the 27 varables measured and the mean change n each varable across the 12 month perod calculated. The statstcal sgnfcance of the change recorded n each varable was calculated usng a Wlcoxon rank sum test on the ndvdual patent changes (wth normal approxmaton and a contnuty correcton). An average rate of change for each patent was also calculated usng a least squares regresson coeffcent and the sgnfcance of ths change for the treatment and placebo groups respectvely was derved by performng a Wlcoxon rank sum test. The results from both tests were very smlar, p values from the latter test only are quoted n Table 3. Correlaton coeffcents were used for comparson of cross-sectonal data. The level of sgnfcance was taken as p < skn was cleaned and abraded to lower resstance f necessary. An earth electrode was always placed between stmulatng and recordng stes. Twelve neurophysologcal parameters (7 n the arm, 5 n the leg) were measured usng a MEDELEC MS6 (Medelec, Wokng, Surrey, UK) recordng system (Table 2). 5% confdence ntervals of results from normal control subjects n ths laboratory were used as a normal range. Somatosensory-evoked potentals. Somatosensory-evoked potentals were measured for both upper lmbs usng a Dgtmer D200 (Dgtmer Welwyn Garden Cty, Herts., UK) sgnal analyser system. The response to supramaxmal stmulaton of the medan nerve was measured by recordng electrodes at 3 levels: over Erb's pont, the second cervcal vertebra, and the hand area of the contratateral sensory cortex (at a pont 2 cm behnd and 7 cm down from the vertex parallel to a lne from the vertex towards the tragus). The average of at least 256 sweeps was used to measure peak to peak ampltude and latency to peaks at all 3 levels, a total of 6 measurements at each vst. Statstcal analyss No sgnfcant dfferences were found between values for weeks -4 and 0 and the results for these two vsts were averaged to gve a Results Neuropathy n the upper lmb Temperature and vbraton sensaton. Temperature and vbraton sensatons n the hand showed a hgh degree of correlaton wth each other (r = 0.6; p < ; Fg. 1) and weaker but stll sgnfcant correlatons wth sensory thresholds n the foot (Table 4). Temperature and vbraton sensaton and autonomc functon. Our results ndcate that vagal functon s affected before temperature sensaton n the hand: 10 out of 3 patents had abnormal heart rate varaton (HRV) but normal hand temperature sensaton, and only 2 patents abnormal temperature sensaton wth a normal HRV. Temperature and vbraton sensaton n the foot showed hghly sgnfcant correlatons wth HRV (r = 0.43, p < 0.006; r = 0.56, p < , respectvely), suggestng that vagal damage was occurrng at

4 R. J. C. Guy et al.: Dabetc neuropathy and sorbnl treatment 217 > ffl "~lo _. L... ~ o.!. 5 lb 15 )15 Temperature sensaton (~ Fg. 2. Comparson of temperature sensaton n the hand and medan nerve sensory acton potental (SAP). Dotted lnes ndcate the upper 5% confdence lmt of normal for temperature sensaton and the lower lmt of normal for medan SAP. r = 0.30 (NS) Z ~ 20 O Q & o -_ at & ~A A & s b 2b 3o 4o so 6o 7b Radal NCV (m/s) Fg. 3. Evdence for carpal tunnel compresson. Medan nerve conducton velocty (NCV) across the carpal tunnel aganst radal sensory nerve conducton velocty. Dotted lnes ndcate lower lmts of normal. represent patents wth dsproportonate slowng of medan nerve conducton. A represent patents who have n addton thenar muscle acton potental latency > 4 ms Table 5. Comparson of clncal and neurophysologcal measurements Radal SAP Medan SAP Post tb NCV Medan Post tb Temp. Temp. Vb. Vb. HRV SAP NCV hand foot hand foot p = p = p = 0.03 p = 0.000p = 0.04 p = p = p=0.005 NS p=0.03 p=o.04p=o.ooo5p=o.o NS p = NS p = p = All results shown as correlaton coeffcents. SAP: Sensory-acton potental; NCV: Nerve conducton velocty; Vb.: Vbraton threshold; Temp.: Temperature sensaton s163 a smlar stage n the development of dabetc neuropathy as abnormal sensaton n the foot and before abnormal sensaton n the hand. Neurophysologcal measurements Results for neurophysologcal measurements were compared to establshed normal ranges n ths laboratory. There was a hgh prevalence of abnormal neurophysologcal fndngs and n partcular sensory measurements. Thus, 37 out of 3 patents had medan sensory acton potental (SAP) values of less than 20 xv (mean + SD ~tv) and 34/3 radal SAP values<20 lxv ( lxv). There was a sgnfcant correlaton between medan and radal SAP (r = 0.55; p=0.003). Temperature and vbraton sensaton and neurophysologcal tests. A much hgher proporton of patents showed abnormal neurophysologcal tests n the arms, partcularly medan and radal SAP, than had abnormal vbraton or temperature sensaton n the hand. Fgure 2 llustrates ths, showng that medan sensory acton potental s a more senstve measure of abnormalty n the arm than temperature sensaton: 2 out of 3 patents had normal values for both measurements, 4 patents had abnormal values for both measurements, and 33 had normal temperature sensaton but abnormal medan SAP. No patent showed normal medan SAP wth abnormal temperature sensaton. Other comparsons between sensaton and neurophysologcal measurements n the arm showed the same pattern. No smple correlaton exsted between neurophysologcal tests n the arm and temperature and vbraton sensaton n the hand. n contrast, measurements of sensory acton potental n the arms correlated closely wth both temperature and vbraton sensaton n the foot (see Table 5). Somatosensory-evoked potentals n 3 of the 3 patents somatosensory-evoked potentals (SEP) responses could not be measured for techncal reasons. Seventeen out of the remanng 36 patents had evdence of delayed conducton (> 22 m/s from hand to contralateral sensory cortex). A strkng feature of the SEP measurements was ther poor correlaton wth other neurophysologcal measurements. The only statstcally sgnfcant assocaton found was between SEP latency to the axlla and motor nerve conducton velocty n the medan (r=-0.565; p = 0.003) and posteror tbal (r = ; p = 0.002) nerves. Carpal tunnel compresson The presence or hstory of symptomatc carpal tunnel compresson excluded patents from ths study. Neurophysologcal evdence for carpal tunnel compresson

5 218 ncludes slowng of medan motor nerve conducton across the carpal tunnel (normal > 48 m/s), and delay (> 4 m/s) of the evoked surface recorded thenar muscle acton potental followng stmulaton of the medan nerve at the wrst [211. The results showed a hgh prevalence of asymptomatc carpal tunnel compresson: 18 out of 3 patents showed slowng of medan nerve conducton velocty across the carpal tunnel (normal > 48 m/s) together wth normal radal sensory nerve conducton (Fg.3). Eleven of these 18 patents also had delay of the thenar muscle acton potental as confrmatory evdence of carpal tunnel compresson. Neuropathy and dabetc control There was no assocaton between any of the measurements made n hand or foot and dabetc control at the tme of testng as measured by HBA~ concentraton. Sorbnl tral None of the measurements made, whether n the hand or foot, showed any statstcally sgnfcant benefcal effect of sorbnl. Table 2 gves detals of the neurophysologcal measurements made. Dabetc control Blood glucose control as assessed by HBA1 levels was smlar n both groups throughout the study (Table 3). Clncal assessment No patent showed an overall mprovement n hs or her neuropathy as judged by clncal examnaton durng the perod of study. Patents wth panful symptoms or paraesthesae were asked at the end of the tral to make a purely subjectve assessment as to whether ther symptoms had changed over the course of the study. Seven out of 12 patents on Sorbnl who had symptoms of pan or parasthesa at the onset of the study reported that ther symptoms had mproved, compared to 3 out of 12 on placebo (p = 0.053). Temperature and vbraton sensaton Table 6 shows the results of sensory tests n the arm. The heterogeneous nature of the patents studed resulted n a wde range of results. There was no statstcally sgnfcant dfference between the two groups n any of the measurements made. Autonomc functon tests There was no statstcally sgnfcant dfference between the two groups for any of the measurements made. Results for heart rate varaton are shown n Table 6. R. J. C. Guy et al.: Dabetc neuropathy and sorbnl treatment Table 6. Results for the Sorbnl tral. Heart rate varaton and measurements n the upper lmb Varable Baselne 12 months p (normal) placebo sorbnl placebo sorbnl Heart rate varaton (> 12 beats/ran) Vbraton 8.0 4, threshold a (<6.3 V) Temperature sensaton ~ (<4.5 ~ 2 pont dscrmnaton (ram) SEP latency to cortex (< ms) Medan nerve F response (< 30 ms) Medan _+ 7.0 motor NCV (>48 m/s) Medan mxed NCV 56.O 4.3 (> 48 m/s) Medan _+ 5.0 (fnger 3) SAP (>20 ~V) Radal t _+ 4.4 SAP (>20 ~v) Radal sensory NCV 4. _+ 7. (> 48 m/s) ~ , NCV: nerve conducton velocty SAP: sensory acton potental; SEP: somatosensory evoked potental, a n the hand; p values derved by Wlcoxon rank sum test. m/s: metres per second; ms: mllseconds Nerve conducton and somatosensory-evoked potentals Twelve nerve conducton and 6 somatosensory-evoked potental varables were measured. None showed any statstcally sgnfcant benefcal effect of sorbnl compared to placebo. Table 6 gves detals of some of the results for measurements n the arms. Dscusson Ths study of dabetc neuropathy shows frstly, that electrophysologcal measurements are more senstve n detectng neuropathy than clncal sensory tests of thermal and vbraton thresholds and secondly, that admnstraton of an aldose reductase nhbtor for 12 months s not of beneft n establshed neuropathy affectng ether the legs or the arms (where t s less severe). t s not yet clear whether very early neuropathy

6 R. J. C. Guy et al.: Dabetc neuropathy and sorbnl treatment responds to admnstraton of aldose reductase nhbtors. A wde varety of technques may be used to assess neuropathy. Small fbres appear to be affected early n the course of the dsease and, snce mcroneurography [22] s not generally avalable, functon was assessed by measurng thermal sensaton and autonomc functon. Our results show, however, that sensory thresholds are much less senstve n detectng early neuropathy than neurophysologcal measurements, notably sensory acton potentals whch reflect at least n part slowng of nerve conducton n large myelnated fbres wth temporal dsperson of the sensory potental [23]. These neurophysologcal measurements can be affected by dabetc control [24] but almost certanly reflect the exstence of neuropathy; measurements n the arm correlate well wth sensory defects n the feet. Thus they are early ndcators of neuropathy and ther seral measurement s of great mportance n a study of ths knd, especally when they are combned wth clncal measurements of sensory thresholds. Dabetc neuropathy n the upper lmb s less severe than n the lower lmb, and dstal segments of nerves are affected before proxmal segments [14, 23]. Ths s generally attrbuted to the ncreased vulnerablty of longer nerves [25]. For these reasons the assessment of neuropathy n ths study has nvolved a partcular emphass on the relatvely less severely nvolved upper lmbs, whch mght be expected to be more responsve to treatment. nterpretaton of medan nerve functon must, however, be crcumspect, snce neurophysologcal evdence of carpal tunnel compresson s shown here to be extremely common even when patents wth clncally apparent features have been excluded. Publshed clncal trals of aldose reductase nhbtors n neuropathy have nvolved treatment for up to 6 months. Very small effects on nerve conducton n asymptomatc patents [26] and some mprovement of autonomc functon have been reported [27], although n many nstances there have been no demonstrable changes n nerve functon. Relef of pan [28] and paraesthesa [2] has been descrbed; ths has not been reproduced n other studes [30] and more detaled nvestgaton s requred. The present study descrbes the use of sorbnl for 12 months and s among the largest trals reported so far. No statstcally sgnfcant effect could be demonstrated on any of a wde varety of measurements of nerve functon whether sensory or motor, and nvolvng both small and large nerve fbre functon. The measurements made ncluded neurophysologcal studes, autonomc functon tests, and, for the frst tme, sensory-evoked potentals and sensory evaluaton of thermal and vbraton thresholds. A strkng feature of the patents n ths study as a group was ther dsappontngly poor metabolc control before and durng the study as shown by glycosylated haemoglobn values. Ths s n keepng wth the 21 prevalng belef that poor metabolc control over a perod of years renders patents more susceptble to neuropathy and other dabetc complcatons [31]. t also begs the queston as to whether good metabolc control s more dffcult to acheve n patents wth neuropathy than n dabetc patents wthout complcatons. Several studes have suggested that ntensve nsuln therapy leadng to mproved metabolc control s of value n the treatment of patents wth neuropathy, symptomatc or otherwse [5-7, 32]. However, just as wth aldose reductase nhbtors, prospectve studes of patents wth no dscernble evdence of neuropathy or at a very early stage of neuropathy may be necessary to provde a defntve answer to ths mportant queston. There s, therefore, now ample evdence that aldose reductase nhbtors do not have a major benefcal effect on establshed dabetc neuropathy even when, as n the present study, the arms rather than the more severely affected legs have been examned. Whether treatment wth aldose reductase nhbtors much earler n the course of dabetes mght be valuable remans to be evaluated. Clearly, future work needs to be drected to patents wth lttle f any evdence of neuropathy. Demonstraton of a clncal effect n such patents would be of the greatest mportance n understandng the pathogeness of dabetc neuropathy and would also have mportant clncal mplcatons. We conclude, however, that aldose reductase nhbtors are unlkely to be of value n the treatment of establshed dabetc neuropathy. Acknowledgements. We gratefully acknowledge Pfzer Central Research, Sandwch, Kent, UK, for ther help wth the tral, and Pfzer nc. for fnancal support for RJCG. References 1. 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