the international diabetes federation states that there are currently 316 million people with impaired glucose tolerance ( igt ) , which will increase to 471 million people by 2035 ( 1 ) . there is considerable debate as to whether these subjects should be considered to have a medical problem ( 2 ) . however , in subjects with igt , the risk of developing type 2 diabetes ranges from 3.6 to 8.7% per year ( 3 ) . furthermore , igt is also independently associated with the traditional microvascular complications of diabetes , including retinopathy , microalbuminuria , and neuropathy ( 4 ) . there appears to be a good rationale for identifying subjects with igt , but there are limited data identifying subjects with igt who may be at greatest risk for developing diabetes and its complications . in relation to neuropathy , the specific focus of this study , the uk prospective diabetes study , showed that at the time of diagnosis of type 2 diabetes , 57% of patients already had neuropathy ( 5 ) , and longitudinal data from the rochester cohort have shown that duration and severity of exposure to hyperglycemia are related to the severity of neuropathy ( 6 ) . in a recent study of patients with 2 years of type 2 diabetes , there was also evidence of a significant neuropathy ( 7 ) . however , there is debate as to whether igt is associated with neuropathy , with some studies showing evidence of neuropathy ( 812 ) , while others do not ( 1315 ) . we recently showed that a significant small - fiber neuropathy occurred in 40.5% of 37 subjects with igt ( 16 ) . interestingly , a recent study evaluating electrochemical sweat conductance , a proxy for small - fiber neuropathy , has shown that healthy subjects with an abnormal response have a significantly increased odds ratio for the development of igt over 2 years ( 17 ) . of relevance , lifestyle modification has been shown to improve intraepidermal nerve fiber density ( ienfd ) ( 11 ) and to improve after chemical axotomy ( 18 ) . we previously showed an improvement in corneal nerve morphology after an improvement in glycemic control , lipids , and blood pressure ( 19 ) after simultaneous pancreas and kidney transplantation ( 20 ) and more recently in patients on continuous subcutaneous insulin infusion ( 21 ) , suggesting a dynamic regenerative capacity of the small fibers in relation to metabolic change . we have undertaken a longitudinal study in subjects with igt to assess whether baseline and follow - up measures of neuropathy , particularly small - fiber neuropathy , relate to changes in glucose tolerance over 3 years . we assessed 30 subjects with igt based on an oral glucose tolerance test ( ogtt ) ( 2-h glucose 7.811.1 mmol ) at central manchester and manchester children s university hospital and 17 health control subjects . exclusion criteria were any history of neuropathy due to a nondiabetic cause and any history of ocular pathology or systemic disease with corneal involvement . this study was approved by the central manchester research and ethics committee , and written informed consent was obtained from all subjects prior to participation . all study participants underwent assessment at baseline and 12 , 24 , and 36 months . participants underwent assessment of bmi , blood pressure , ogtt , hba1c , lipid profile ( total cholesterol , ldl , hdl , and triglycerides ) , albumin - to - creatinine excretion ratio , and estimated glomerular filtration rate ( egfr ) . symptoms of diabetic peripheral neuropathy were assessed using the neuropathy symptom profile ( nsp ) . neurological deficits were evaluated using the simplified neuropathy disability score ( nds ) , which is comprised of vibration perception , pinprick , temperature sensation , and presence or absence of ankle reflexes . vibration perception threshold ( vpt ) was tested using a neurothesiometer ( horwell ; scientific laboratory supplies , wilfrod , nottingham , u.k . ) . cold ( ct ) and warm ( wt ) thresholds were established on the dorsolateral aspect of the left foot ( s1 ) using the tsa - ii neurosensory analyzer ( medoc , ramat - yishai , israel ) . electro - diagnostic studies were undertaken using a dantec  keypoint  system ( dantec dynamics , bristol , u.k . ) equipped with a disa temperature regulator to keep limb temperature constantly between 32 and 35c . sural sensory nerve amplitude ( snap ) , sural sensory nerve conduction velocity ( sncv ) , and peroneal motor nerve conduction velocity ( pmncv ) and amplitude ( pmna ) were assessed by a consultant neurophysiologist . a 3-mm punch skin biopsy was taken from the dorsum of the foot , 2 cm above the second metatarsal head under local anesthesia ( 1% lidocaine ) . sections ( 50 m ) were stained using anti - human pgp 9.5 antibody ( abcam , cambridge , u.k . ) , and nerve fibers were demonstrated using sg chromogen ( vector laboratories , peterborough , u.k . ) . ienfd was quantified in accordance with established criteria and expressed as no . per millimeter ( 22 ) . twenty z - stack images per case were taken using a zeiss axioimager m2 microscope , and mean dendritic length ( mdl ) ( length of ienf from piercing the dermo - epidermal junction to its terminal in the epidermis ) was manually traced and quantified using the imagepro 6.2 program ( mediacybernetics , marlow , u.k . ) . patients underwent examination with the corneal confocal microscopy ( ccm ) ( heidelberg retinal tomograph iii rostock cornea module ; heidelberg engineering , heidelberg , germany ) as per our previously established protocol ( 23 ) . six nonoverlapping images / patient from the center of the cornea were selected and quantified in a masked fashion . three corneal nerve parameters were quantified : corneal nerve fiber density ( cnfd ) , the total number of major nerves per square millimeter of corneal tissue ; corneal nerve branch density ( cnbd ) , the number of branches emanating from all major nerve trunks per square millimeter of corneal tissue ; and corneal nerve fiber length ( cnfl ) , the total length of all nerve fibers and branches ( millimeter per square millimeter ) within the area of corneal tissue . analysis of the images was done using purposefully designed automated software called accmetrics ( 24 ) . analysis was carried out on spss for mac ( version 19.0 ; ibm corporation , armonk , ny ) . the data were tested for normality by using the shapiro wilk normality test and by visualizing the histogram and normal q - q plot . to assess within- and between - group differences , we used one - way anova ( nonparametric kruskal - wallis ) . a significant p value was considered to be < 0.05 ( post hoc tukey ) . we assessed 30 subjects with igt based on an oral glucose tolerance test ( ogtt ) ( 2-h glucose 7.811.1 mmol ) at central manchester and manchester children s university hospital and 17 health control subjects . exclusion criteria were any history of neuropathy due to a nondiabetic cause and any history of ocular pathology or systemic disease with corneal involvement . this study was approved by the central manchester research and ethics committee , and written informed consent was obtained from all subjects prior to participation . all study participants underwent assessment at baseline and 12 , 24 , and 36 months . participants underwent assessment of bmi , blood pressure , ogtt , hba1c , lipid profile ( total cholesterol , ldl , hdl , and triglycerides ) , albumin - to - creatinine excretion ratio , and estimated glomerular filtration rate ( egfr ) . symptoms of diabetic peripheral neuropathy were assessed using the neuropathy symptom profile ( nsp ) . neurological deficits were evaluated using the simplified neuropathy disability score ( nds ) , which is comprised of vibration perception , pinprick , temperature sensation , and presence or absence of ankle reflexes . vibration perception threshold ( vpt ) was tested using a neurothesiometer ( horwell ; scientific laboratory supplies , wilfrod , nottingham , u.k . ) . cold ( ct ) and warm ( wt ) thresholds were established on the dorsolateral aspect of the left foot ( s1 ) using the tsa - ii neurosensory analyzer ( medoc , ramat - yishai , israel ) . electro - diagnostic studies were undertaken using a dantec  keypoint  system ( dantec dynamics , bristol , u.k . ) equipped with a disa temperature regulator to keep limb temperature constantly between 32 and 35c . sural sensory nerve amplitude ( snap ) , sural sensory nerve conduction velocity ( sncv ) , and peroneal motor nerve conduction velocity ( pmncv ) and amplitude ( pmna ) were assessed by a consultant neurophysiologist . a 3-mm punch skin biopsy was taken from the dorsum of the foot , 2 cm above the second metatarsal head under local anesthesia ( 1% lidocaine ) . sections ( 50 m ) were stained using anti - human pgp 9.5 antibody ( abcam , cambridge , u.k . ) , and nerve fibers were demonstrated using sg chromogen ( vector laboratories , peterborough , u.k . ) . twenty z - stack images per case were taken using a zeiss axioimager m2 microscope , and mean dendritic length ( mdl ) ( length of ienf from piercing the dermo - epidermal junction to its terminal in the epidermis ) was manually traced and quantified using the imagepro 6.2 program ( mediacybernetics , marlow , u.k . ) . patients underwent examination with the corneal confocal microscopy ( ccm ) ( heidelberg retinal tomograph iii rostock cornea module ; heidelberg engineering , heidelberg , germany ) as per our previously established protocol ( 23 ) . six nonoverlapping images / patient from the center of the cornea were selected and quantified in a masked fashion . three corneal nerve parameters were quantified : corneal nerve fiber density ( cnfd ) , the total number of major nerves per square millimeter of corneal tissue ; corneal nerve branch density ( cnbd ) , the number of branches emanating from all major nerve trunks per square millimeter of corneal tissue ; and corneal nerve fiber length ( cnfl ) , the total length of all nerve fibers and branches ( millimeter per square millimeter ) within the area of corneal tissue . analysis of the images was done using purposefully designed automated software called accmetrics ( 24 ) . analysis was carried out on spss for mac ( version 19.0 ; ibm corporation , armonk , ny ) . the data were tested for normality by using the shapiro wilk normality test and by visualizing the histogram and normal q - q plot . to assess within- and between - group differences , we used one - way anova ( nonparametric kruskal - wallis ) . a significant p value was considered to be < 0.05 ( post hoc tukey ) . the control and igt subjects were age matched ( 62.3  1.8 vs. 60  2.1 years , p = 0.2 ) . subjects with igt had a significantly higher hba1c ( 42.7  0.9 vs. 38.3  0.7 mmol / mol , p < 0.0001 ) and bmi ( 32.0  1.0 vs. 27.6  0.9 kg / m , p = 0.01 ) and lower hdl ( 1.2  0.1 vs. 1.7  0.1 mmol / l , p = 0.03 ) but comparable total cholesterol , triglycerides , egfr , and blood pressure compared with control subjects . clinical and metabolic parameters and neuropathy assessment in control subjects and subjects with igt at baseline and follow - up data are means  sem . all symbols represent statistically significant differences . * p value igt baseline vs. control ; igt baseline vs. 36 months . the igt group had a significantly higher nsp ( 3.4  0.7 vs. 0.3  0.1 , p < 0.0001 ) , nds ( 2.9  0.5 vs. 1.1  0.3 , p = 0.03 ) , and vpt ( 16.2  2.1 vs. 8.4  1.5 , p = 0.02 ) compared with the control group . there was no significant difference in sncv and pmncv and amplitude between subjects with igt and the control subjects . there was no difference in ienfd ; however , mdl was significantly lower in the igt group compared with control subjects ( 25.1  1.6 vs. 63.0  4.2 m , p < 0.0001 ) . cnfd ( 24.4  1.3 vs. 30.7  1.5 no./mm , p < 0.0001 ) and cnfl ( 15.3  0.6 vs. 20.4  3.14 mm / mm , p = 0.004 ) were significantly lower , but there was no difference in cnbd between subjects with igt and control subjects . there was no correlation between hdl and ccm measures at baseline ( cnfl r = 0.2 , p = 0.2 ; cnbd r = 0.2 , p = 0.1 ; and cnfd r = 0.2 , p = 0.3 ) . control subjects showed no significant change in metabolic parameters or neuropathy measures over 3 years ( repeat skin biopsy not performed in control subjects ) . in subjects with igt , bmi , hba1c , lipids , and blood pressure remained stable , and there was a small but significant reduction in egfr ( 79.1  3.0 vs. 74.3  4.3 ml / min/1.73 m , p = 0.03 ) over 3 years ( table 1 ) . there was no significant change in nsp , nds , vpt , or thermal thresholds . there was a significant reduction in sncv ( 49.7  1.4 vs. 46.6  1.3 m / s , p = 0.007 ) and ienfd ( 6.4  0.8 vs. 3.2  0.8 no./mm , p = 0.02 ) , but no change in mdl or ccm measures , from baseline to 36 months . all subjects with igt underwent an annual ogtt over 36 months , 10 developed type 2 diabetes , 15 remained with igt , and 5 regressed to normal glucose tolerance ( ngt ) ( table 2 ) . neuropathy assessments at baseline and 36 months in subjects who reverted to ngt , remained with igt , or developed type 2 diabetes at 36 months data are means  sem . p < 0.0001 , baseline vs. control or baseline vs. 36 months . corneal confocal images from control subject at baseline ( a ) , control subject at follow - up ( b ) , igt subject who developed type 2 diabetes at baseline ( c ) , igt subject who developed type 2 diabetes at follow - up ( d ) , igt subject who remained igt at baseline ( e ) , igt subject who remained igt at follow - up ( f ) , igt subject who reverted to ngt at baseline ( g ) , and igt subject who reverted to ngt at follow - up ( h ) . red arrow , corneal nerve fiber ; yellow arrow , corneal nerve branch . in the 10 subjects who developed type 2 diabetes , their baseline cnfd ( 20.0  2.2 vs.30.7  1.5 no./mm , p = 0.003 ) , cnbd ( 25.6  5.2 vs. 37.0  2.7 no./mm , p = 0.04 ) , and cnfl ( 13.7  1.2 vs. 20.4  3.2 mm / mm , p = 0.04 ) were significantly lower compared with control subjects . over 36 months , there was a significant increase in hba1c ( 42.4  1.0 vs. 50.3  1.4 mmol / mol , p = 0.02 ) and a significant decrease in cnfl ( 13.7  1.2 vs. 11.8  1.0 mm / mm , p = 0.006 ) , mdl ( 21.9  2.1 vs. 16.5  0.32 m , p = 0.02 ) , and ienfd ( 6.5  1.2 vs. 3.9  0.9 no./mm , p = 0.002 ) , with no significant change in any other measure of neuropathy ( fig . 2 ) . of the igt subjects who had a significant ( a cnfd value < 2 sd below the mean for control subjects ) reduction in cnfd at baseline , 87.5% developed type 2 diabetes and 12.5% remained igt or reverted to ngt ( p = 0.007 ) . in subjects who had a significant ( a cnfl value < 2 sd below the mean for control subjects ) reduction in cnfl change in corneal nerve fiber morphological parameters in subjects at baseline ( black ) and 36 months ( red ) . in the 15 igt subjects who remained igt , their baseline cnfd ( 28.6  1.5 vs. 30.7  1.5 no./mm , p = 0.33 ) , cnbd ( 38.8  3.7 vs. 37.0  2.7 no./mm , p = 0.54 ) , and cnfl ( 16.8  0.8 vs. 20.4  3.2 mm / mm , p = 0.75 ) were comparable with control subjects . there was a significant reduction in ienfd ( 6.7  1.1 vs. 2.8  0.3 no./mm , p = 0.02 ) with no change in any measure of neuropathy over 36 months . in the 5 subjects who became ngt , baseline cnfd ( 25.4  1.9 vs. 30.7  1.5 no./mm , p = 0.06 ) , cnbd ( 29.3  5.6 vs. 37.0  2.7 no./mm , p = 0.07 ) , and cnfl ( 15.7  1.3 vs. 20.4  3.2 mm / mm , p = 0.24 ) did not differ from control subjects . however , there was a significant increase in cnfd ( 25.4  1.9 vs. 29.8  1.5 no./mm 
 p = 0.05 ) , cnbd ( 29.3  5.6 vs. 44.9  6.2 no./mm , p = 0.04 ) , and cnfl ( 15.7  1.3 vs. 17.2  0.9 mm / mm , p = 0.05 ) . there was a significant decrease in ienfd ( 6.5  1.1 vs. 3.0  0.4 no./mm , p = 0.02 ) with no significant change in any other measure of neuropathy over 36 months ( table 2 and fig . the control and igt subjects were age matched ( 62.3  1.8 vs. 60  2.1 years , p = 0.2 ) . subjects with igt had a significantly higher hba1c ( 42.7  0.9 vs. 38.3  0.7 mmol / mol , p < 0.0001 ) and bmi ( 32.0  1.0 vs. 27.6  0.9 kg / m , p = 0.01 ) and lower hdl ( 1.2  0.1 vs. 1.7  0.1 mmol / l , p = 0.03 ) but comparable total cholesterol , triglycerides , egfr , and blood pressure compared with control subjects . clinical and metabolic parameters and neuropathy assessment in control subjects and subjects with igt at baseline and follow - up data are means  sem . all symbols represent statistically significant differences . * p value igt baseline vs. control ; igt baseline vs. 36 months . the igt group had a significantly higher nsp ( 3.4  0.7 vs. 0.3  0.1 , p < 0.0001 ) , nds ( 2.9  0.5 vs. 1.1  0.3 , p = 0.03 ) , and vpt ( 16.2  2.1 vs. 8.4  1.5 , p = 0.02 ) compared with the control group . there was no significant difference in sncv and pmncv and amplitude between subjects with igt and the control subjects . there was no difference in ienfd ; however , mdl was significantly lower in the igt group compared with control subjects ( 25.1  1.6 vs. 63.0  4.2 m , p < 0.0001 ) . cnfd ( 24.4  1.3 vs. 30.7  1.5 no./mm , p < 0.0001 ) and cnfl ( 15.3  0.6 vs. 20.4  3.14 mm / mm , p = 0.004 ) were significantly lower , but there was no difference in cnbd between subjects with igt and control subjects . there was no correlation between hdl and ccm measures at baseline ( cnfl r = 0.2 , p = 0.2 ; cnbd r = 0.2 , p = 0.1 ; and cnfd r = 0.2 , p = 0.3 ) . control subjects showed no significant change in metabolic parameters or neuropathy measures over 3 years ( repeat skin biopsy not performed in control subjects ) . in subjects with igt , bmi , hba1c , lipids , and blood pressure remained stable , and there was a small but significant reduction in egfr ( 79.1  3.0 vs. 74.3  4.3 ml / min/1.73 m , p = 0.03 ) over 3 years ( table 1 ) . there was no significant change in nsp , nds , vpt , or thermal thresholds . there was a significant reduction in sncv ( 49.7  1.4 vs. 46.6  1.3 m / s , p = 0.007 ) and ienfd ( 6.4  0.8 vs. 3.2  0.8 no./mm , p = 0.02 ) , but no change in mdl or ccm measures , from baseline to 36 months . all subjects with igt underwent an annual ogtt over 36 months , 10 developed type 2 diabetes , 15 remained with igt , and 5 regressed to normal glucose tolerance ( ngt ) ( table 2 ) . neuropathy assessments at baseline and 36 months in subjects who reverted to ngt , remained with igt , or developed type 2 diabetes at 36 months data are means  sem . p < 0.0001 , baseline vs. control or baseline vs. 36 months . corneal confocal images from control subject at baseline ( a ) , control subject at follow - up ( b ) , igt subject who developed type 2 diabetes at baseline ( c ) , igt subject who developed type 2 diabetes at follow - up ( d ) , igt subject who remained igt at baseline ( e ) , igt subject who remained igt at follow - up ( f ) , igt subject who reverted to ngt at baseline ( g ) , and igt subject who reverted to ngt at follow - up ( h ) . red arrow , corneal nerve fiber ; yellow arrow , corneal nerve branch . in the 10 subjects who developed type 2 diabetes , their baseline cnfd ( 20.0  2.2 vs.30.7  1.5 no./mm , p = 0.003 ) , cnbd ( 25.6  5.2 vs. 37.0  2.7 no./mm , p = 0.04 ) , and cnfl ( 13.7  1.2 vs. 20.4  3.2 mm / mm , p = 0.04 ) were significantly lower compared with control subjects . over 36 months , there was a significant increase in hba1c ( 42.4  1.0 vs. 50.3  1.4 mmol / mol , p = 0.02 ) and a significant decrease in cnfl ( 13.7  1.2 vs. 11.8  1.0 mm / mm , p = 0.006 ) , mdl ( 21.9  2.1 vs. 16.5  0.32 m , p = 0.02 ) , and ienfd ( 6.5  1.2 vs. 3.9  0.9 no./mm , p = 0.002 ) , with no significant change in any other measure of neuropathy ( fig . 2 ) . of the igt subjects who had a significant ( a cnfd value < 2 sd below the mean for control subjects ) reduction in cnfd at baseline , 87.5% developed type 2 diabetes and 12.5% remained igt or reverted to ngt ( p = 0.007 ) . in subjects who had a significant ( a cnfl value < 2 sd below the mean for control subjects ) reduction in cnfl change in corneal nerve fiber morphological parameters in subjects at baseline ( black ) and 36 months ( red ) . in the 15 igt subjects who remained igt , their baseline cnfd ( 28.6  1.5 vs. 30.7  1.5 no./mm , p = 0.33 ) , cnbd ( 38.8  3.7 vs. 37.0  2.7 no./mm , p = 0.54 ) , and cnfl ( 16.8  0.8 vs. 20.4  3.2 mm / mm , p = 0.75 ) were comparable with control subjects . there was a significant reduction in ienfd ( 6.7  1.1 vs. 2.8  0.3 no./mm , p = 0.02 ) with no change in any measure of neuropathy over 36 months . in the 5 subjects who became ngt , baseline cnfd ( 25.4  1.9 vs. 30.7  1.5 no./mm , p = 0.06 ) , cnbd ( 29.3  5.6 vs. 37.0  2.7 no./mm , p = 0.07 ) , and cnfl ( 15.7  1.3 vs. 20.4  3.2 mm / mm , p = 0.24 ) did not differ from control subjects . however , there was a significant increase in cnfd ( 25.4  1.9 vs. 29.8  1.5 no./mm 
 p = 0.05 ) , cnbd ( 29.3  5.6 vs. 44.9  6.2 no./mm , p = 0.04 ) , and cnfl ( 15.7  1.3 vs. 17.2  0.9 mm / mm , p = 0.05 ) . there was a significant decrease in ienfd ( 6.5  1.1 vs. 3.0  0.4 no./mm , p = 0.02 ) with no significant change in any other measure of neuropathy over 36 months ( table 2 and fig . hughes et al . ( 25 ) found that in 50 consecutive subjects with pn and 50 consecutive control subjects , there was no significant difference in the prevalence of igt , but in the pn group serum triglycerides were significantly higher . fujimoto et al . ( 26 ) showed that subjects with igt had comparable nerve conduction studies but had a greater prevalence of retinopathy and nephropathy compared with control subjects . more recently , dyck et al . ( 27 ) showed that the frequency of pn was comparable in healthy subjects ( 1.7% ) and subjects with impaired glycemia ( 2.0% ) and was only increased in those with type 2 diabetes ( 7.8% ) . in a cohort of 393 subjects , ziegler et al . ( 28 ) found that there was an increased prevalence of polyneuropathy in those with igt ( 13% ) compared with those with impaired fasting glycemia ( 11.3% ) and control subjects ( 7.4% ) , although this was not significant . these findings may be attributed to the fact that neuropathy was diagnosed by assessing predominantly large fibers ( 13,29 ) . indeed , there are accruing data to suggest that there is an increased prevalence of painful symptoms ( 3032 ) and evidence of a small - fiber neuropathy in subjects with igt ( 10,11,16,32 ) . thus , small - fiber neuropathy may be the earliest change in the spectrum of pn , with injury beginning in the small myelinated a and unmyelinated c fibers , which over time progresses to affect larger nerves ( 33 ) . while ienfd is accepted as the gold standard for quantifying ienf pathology , interestingly , pittenger et al . ( 34 ) showed that mdl was reduced before ienfd in subjects with metabolic syndrome and may therefore be an early marker of sensory neuropathy . our data support these findings , as mdl was significantly reduced , while ienfd was comparable in the igt cohort compared with control subjects at baseline . furthermore , mdl appears to be more responsive to changes in glucose tolerance status with a further worsening in only those igt subjects who developed type 2 diabetes , while ienfd showed a reduction in all three groups . in relation to causal factors , pittenger et al . ( 34 ) also reported a correlation between pn and hdl cholesterol . in the current study , we show that hdl cholesterol was lower in the igt group compared with the control subjects ; however , this was not associated with lower ccm measures . in an 18 week open - label trial , boyd at al . ( 35 ) showed that treatment with topiramate resulted in a significant improvement in mdl at the forearm and proximal leg and an increase in ienfd at the proximal leg . ( 11 ) have shown that a 1-year diet and lifestyle intervention program leads to an increase in ienfd . however , the much larger da qing study showed that lifestyle intervention over 6 years reduced the incidence of severe retinopathy but had no impact on neuropathy , although the end point was monofilament insensitivity ( 36 ) . more recently , a 6-month twice weekly individualized exercise program significantly improved the rate of cutaneous nerve regeneration in a capsaicin nerve ablation model ( 18 ) . our recent study in patients with type 1 diabetes undergoing simultaneous pancreas kidney transplantation showed that ccm can detect small - fiber regeneration as early as 6 months postsurgery ( 37 ) . we have also shown that improvement in glycemia as well as blood pressure and lipids leads to corneal nerve regeneration ( 19 ) . this leads to the notion that if there is an improvement in glycemia , then it may improve neuropathy . in the current study , we show that subjects with igt have evidence of small - fiber neuropathy , as evidenced by a greater prevalence of painful symptoms and abnormalities in ccm as well as a reduction in mdl  in keeping with our recent study ( 16 ) . however , we now show that patients who progress to type 2 diabetes have worse baseline corneal nerve morphology and mdl at a time when they are diagnosed with igt . this is in keeping with a recent study showing that subjects with ngt , but with abnormal electrochemical sweat conductance , have a significantly increased odds ratio for the development of igt ( 17 ) . furthermore , subjects who progressed to type 2 diabetes also showed a further significant reduction in cnfl and mdl . in subjects who remained with igt , there was no baseline loss or any change over time . in subjects who reverted to ngt , the baseline ccm values did not differ significantly from control subjects , and indeed there was a significant increase in all ccm parameters . while this is a small study , the detailed quantification , particularly of the small fibers , provides insights into the dynamic relationship between small - fiber damage and repair in relation to overall glucose tolerance status . we confirm the data from our previous study showing that small - fiber neuropathy , detected using ccm , is prevalent in subjects with igt ( 16 ) . more importantly , both ccm and mdl appear to be early and dynamic markers of small - fiber neuropathy , which may allow risk stratification of subjects with igt who are likely to progress to type 2 diabetes .