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© 2020 by the American Diabetes Association. OBJECTIVE To assess the diagnostic utility of corneal confocal microscopy (CCM) for diabetic peripheral neuropathy (DPN) and the risk factors for corneal nerve loss. RESEARCH DESIGN AND METHODS A total of 490 participants, including 72 healthy control subjects, 149 with type 1 diabetes, and 269 with type 2 diabetes, underwent detailed assessment of peripheral neuropathy and CCM in relation to risk factors. RESULTS Corneal nerve fiber density (CNFD) (P < 0.0001 and P < 0.0001), corneal nerve fiber branch density (CNBD) (P < 0.0001 and P < 0.0001), and corneal nerve fiber length (CNFL) (P < 0.0001 and P = 0.02) were significantly lower in patients with type 1 and type 2 diabetes compared with control subjects. CNFD (P < 0.0001), CNBD (P < 0.0001), and CNFL (P < 0.0001) were lower in type 1 diabetes compared with type 2 diabetes. Receiver operating characteristic curve analysis for the diagnosis of DPN demonstrated a good area under the curve for CNFD of 0.81, CNBD of 0.74, and CNFL of 0.73. Multivariable regression analysis showed a significant association among reduced CNFL with age (b =-0.27, P = 0.007), HbA1c (b=-1.1; P = 0.01), and weight (b=-0.14; P = 0.03) in patients with type 2 diabetes and with duration of diabetes (b=-0.13; P = 0.02), LDL cholesterol (b=1.8, P = 0.04), and triglycerides (b =-2.87; P = 0.009) in patients with type 1 diabetes. CONCLUSIONS CCM identifies more severe corneal nerve loss in patients with type 1 diabetes compared with type 2 diabetes and shows good diagnostic accuracy for DPN. Furthermore, the risk factors for a reduction in corneal nerve fiber length differ between type 1 and type 2 diabetes.

© 2020 by the American Diabetes Association. OBJECTIVE To assess the diagnostic utility of corneal confocal microscopy (CCM) for diabetic peripheral neuropathy (DPN) and the risk factors for corneal nerve loss. RESEARCH DESIGN AND METHODS A total of 490 participants, including 72 healthy control subjects, 149 with type 1 diabetes, and 269 with type 2 diabetes, underwent detailed assessment of peripheral neuropathy and CCM in relation to risk factors. RESULTS Corneal nerve fiber density (CNFD) (P < 0.0001 and P < 0.0001), corneal nerve fiber branch density (CNBD) (P < 0.0001 and P < 0.0001), and corneal nerve fiber length (CNFL) (P < 0.0001 and P = 0.02) were significantly lower in patients with type 1 and type 2 diabetes compared with control subjects. CNFD (P < 0.0001), CNBD (P < 0.0001), and CNFL (P < 0.0001) were lower in type 1 diabetes compared with type 2 diabetes. Receiver operating characteristic curve analysis for the diagnosis of DPN demonstrated a good area under the curve for CNFD of 0.81, CNBD of 0.74, and CNFL of 0.73. Multivariable regression analysis showed a significant association among reduced CNFL with age (b =-0.27, P = 0.007), HbA1c (b=-1.1; P = 0.01), and weight (b=-0.14; P = 0.03) in patients with type 2 diabetes and with duration of diabetes (b=-0.13; P = 0.02), LDL cholesterol (b=1.8, P = 0.04), and triglycerides (b =-2.87; P = 0.009) in patients with type 1 diabetes. CONCLUSIONS CCM identifies more severe corneal nerve loss in patients with type 1 diabetes compared with type 2 diabetes and shows good diagnostic accuracy for DPN. Furthermore, the risk factors for a reduction in corneal nerve fiber length differ between type 1 and type 2 diabetes.

Low foot ulcer risk in South Asian, compared with European, people with type 2 diabetes in the UK has been attributed to their lower levels of neuropathy. We have undertaken a detailed study of corneal nerve morphology and neuropathy risk factors, to establish the basis of preserved small nerve fibre function in South Asians versus Europeans.In a cross-sectional, population-based study, age- and sex-matched South Asians (n=77) and Europeans (n=78) with type 2 diabetes underwent neuropathy assessment using corneal confocal microscopy, symptoms, signs, quantitative sensory testing, electrophysiology and autonomic function testing. Multivariable linear regression analyses determined factors accounting for ethnic differences in small fibre damage. -adjusted ethnic difference in corneal nerve fibre length (P=0.032) were pack-years smoked (P=0.13), BMI (P=0.062) and triglyceride levels (P=0.062).South Asians have better preserved small nerve fibre integrity than equivalent Europeans; furthermore, classic, modifiable risk factors for coronary heart disease are the main contributors to these ethnic differences. We suggest that improved autonomic neurogenic control of cutaneous blood flow in Asians may contribute to their protection against foot ulcers.

AIMS/HYPOTHESIS: Small cohort studies raise the hypothesis that corneal nerve abnormalities (including corneal nerve fibre length [CNFL]) are valid non-invasive imaging endpoints for diabetic sensorimotor polyneuropathy (DSP). We aimed to establish concurrent validity and diagnostic thresholds in a large cohort of participants with and without DSP. METHODS: Nine hundred and ninety-eight participants from five centres (516 with type 1 diabetes and 482 with type 2 diabetes) underwent CNFL quantification and clinical and electrophysiological examination. AUC and diagnostic thresholds were derived and validated in randomly selected samples using receiver operating characteristic analysis. Sensitivity analyses included latent class models to address the issue of imperfect reference standard. RESULTS: Type 1 and type 2 diabetes subcohorts had mean age of 42 ± 19 and 62 ± 10 years, diabetes duration 21 ± 15 and 12 ± 9 years and DSP prevalence of 31% and 53%, respectively. Derivation AUC for CNFL was 0.77 in type 1 diabetes (p < 0.001) and 0.68 in type 2 diabetes (p < 0.001) and was approximately reproduced in validation sets. The optimal threshold for automated CNFL was 12.5 mm/mm2 in type 1 diabetes and 12.3 mm/mm2 in type 2 diabetes. In the total cohort, a lower threshold value below 8.6 mm/mm2 to rule in DSP and an upper value of 15.3 mm/mm2 to rule out DSP were associated with 88% specificity and 88% sensitivity. CONCLUSIONS/INTERPRETATION: We established the diagnostic validity and common diagnostic thresholds for CNFL in type 1 and type 2 diabetes. Further research must determine to what extent CNFL can be deployed in clinical practice and in clinical trials assessing the efficacy of disease-modifying therapies for DSP.

Affective touch sensation is conducted by a sub-class of C-fibres in hairy skin known as C-Tactile (CT) afferents. CT afferents respond maximally to gentle skin stroking at velocities between 1 and 10 cm/s. Parkinson’s disease (PD) is characterised by markedly reduced cutaneous C-fibres. It is not known if affective touch perception is influenced by C-fibre density and if affective touch is impaired in PD compared to healthy controls. We predicted that perceived pleasantness to gentle stroking in PD would correlate with C-afferent density and that affective touch perception would be impaired in PD compared to healthy controls. Twenty-four PD patients and 27 control subjects rated the pleasantness of brush stroking at an optimum CT stimulation velocity (3 cm/s) and two sub-optimal velocities (0.3 and 30 cm/s). PD patients underwent quantification of C-fibre density using skin biopsies and corneal confocal microscopy. All participants rated a stroking velocity of 3 cm/s as the most pleasant with significantly lower ratings for 0.3 and 30 cm/s. There was a significant positive correlation between C-fibre density and pleasantness ratings at 3 and 30 cm/s but not 0.3 cm/s. Mean pleasantness ratings were consistently higher in PD patients compared to control subjects across all three velocities. This study shows that perceived pleasantness to gentle touch correlates significantly with C-fibre density in PD. The higher perceived pleasantness in PD patients compared to controls suggests central sensitisation to peripheral inputs, which may have been enhanced by dopamine therapy.

To investigate alterations in walking strategy and dynamic sway (unsteadiness) in people with impaired glucose tolerance and people with Type 2 diabetes in relation to severity of neuropathy and vitamin D levels.A total of 20 people with Type 2 diabetes, 20 people with impaired glucose tolerance and 20 people without either Type 2 diabetes or impaired glucose tolerance (control group) underwent gait analysis using a motion analysis system and force platforms, and detailed assessment of neuropathy and serum 25 hydroxy-vitamin D levels.Ankle strength (P=0.01) and power (P=0.003) during walking and walking speed (P=0.008) were preserved in participants with impaired glucose tolerance but significantly lower in participants with Type 2 diabetes compared with control participants; however, step width (P=0.005) and dynamic medio-lateral sway (P=0.007) were significantly higher and posterior maximal movement (P=0.000) was lower in participants with impaired glucose tolerance, but preserved in those with Type 2 diabetes compared with the control group. Dynamic medio-lateral sway correlated with corneal nerve fibre length (P=0.001) and corneal nerve branch density (P=0.001), but not with vibration perception threshold (P=0.19). Serum 25 hydroxy-vitamin D levels did not differ significantly among the groups (P=0.10) and did not correlate with any walking variables or measures of dynamic sway.Early abnormalities in walking strategy and dynamic sway were evident in participants with impaired glucose tolerance, whilst there was a reduction in ankle strength, power and walking speed in participants with Type 2 diabetes. Unsteadiness correlated with small-, but not large-fibre neuropathy and there was no relationship between vitamin D levels and walking variables. This article is protected by copyright. All rights reserved.

To investigate alterations in walking strategy and dynamic sway (unsteadiness) in people with impaired glucose tolerance and people with Type 2 diabetes in relation to severity of neuropathy and vitamin D levels.A total of 20 people with Type 2 diabetes, 20 people with impaired glucose tolerance and 20 people without either Type 2 diabetes or impaired glucose tolerance (control group) underwent gait analysis using a motion analysis system and force platforms, and detailed assessment of neuropathy and serum 25 hydroxy-vitamin D levels.Ankle strength (P=0.01) and power (P=0.003) during walking and walking speed (P=0.008) were preserved in participants with impaired glucose tolerance but significantly lower in participants with Type 2 diabetes compared with control participants; however, step width (P=0.005) and dynamic medio-lateral sway (P=0.007) were significantly higher and posterior maximal movement (P=0.000) was lower in participants with impaired glucose tolerance, but preserved in those with Type 2 diabetes compared with the control group. Dynamic medio-lateral sway correlated with corneal nerve fibre length (P=0.001) and corneal nerve branch density (P=0.001), but not with vibration perception threshold (P=0.19). Serum 25 hydroxy-vitamin D levels did not differ significantly among the groups (P=0.10) and did not correlate with any walking variables or measures of dynamic sway.Early abnormalities in walking strategy and dynamic sway were evident in participants with impaired glucose tolerance, whilst there was a reduction in ankle strength, power and walking speed in participants with Type 2 diabetes. Unsteadiness correlated with small-, but not large-fibre neuropathy and there was no relationship between vitamin D levels and walking variables. This article is protected by copyright. All rights reserved.

Aim: To quantify muscle strength and size in subjects with impaired glucose tolerance (IGT) in relation to intramuscular non-contractile tissue, the severity of neuropathy and vitamin D level. Methods: A total of 20 subjects with impaired glucose tolerance and 20 control subjects underwent assessment of strength and size of knee extensor, flexor and ankle plantar and dorsi-flexor muscles, as well as quantification of intramuscular non-contractile tissue and detailed assessment of neuropathy and serum 25-hydroxy vitamin D levels. Results: In subjects with impaired glucose tolerance, proximal knee extensor strength (P = 0.17) and volume (P = 0.77), and knee flexor volume (P = 0.97) did not differ from those in control subjects. Ankle plantar flexor strength was significantly lower (P = 0.04) in the subjects with impaired glucose tolerance, with no difference in ankle plantar flexor (P = 0.62) or dorsiflexor volume (P = 0.06) between groups. Intramuscular non-contractile tissue level was significantly higher in the ankle plantar flexors and dorsiflexors (P = 0.03) of subjects with impaired glucose tolerance compared with control subjects, and it correlated with the severity of neuropathy. Ankle plantar flexor muscle strength correlated significantly with corneal nerve fibre density (r = 0.53; P = 0.01), a sensitive measure of small fibre neuropathy, and was significantly lower in subjects with vitamin D deficiency (P = 0.02). Conclusions: People with impaired glucose tolerance have a significant reduction in distal but not proximal leg muscle strength, which is not associated with muscle atrophy, but with increased distal intramuscular non-contractile tissue, small fibre neuropathy and vitamin D deficiency.

Affective touch sensation is conducted by a sub-class of C-fibres in hairy skin known as C-Tactile (CT) afferents. CT afferents respond maximally to gentle skin stroking at velocities between 1 and 10 cm/s. Parkinson’s disease (PD) is characterised by markedly reduced cutaneous C-fibres. It is not known if affective touch perception is influenced by C-fibre density and if affective touch is impaired in PD compared to healthy controls. We predicted that perceived pleasantness to gentle stroking in PD would correlate with C-afferent density and that affective touch perception would be impaired in PD compared to healthy controls. Twenty-four PD patients and 27 control subjects rated the pleasantness of brush stroking at an optimum CT stimulation velocity (3 cm/s) and two sub-optimal velocities (0.3 and 30 cm/s). PD patients underwent quantification of C-fibre density using skin biopsies and corneal confocal microscopy. All participants rated a stroking velocity of 3 cm/s as the most pleasant with significantly lower ratings for 0.3 and 30 cm/s. There was a significant positive correlation between C-fibre density and pleasantness ratings at 3 and 30 cm/s but not 0.3 cm/s. Mean pleasantness ratings were consistently higher in PD patients compared to control subjects across all three velocities. This study shows that perceived pleasantness to gentle touch correlates significantly with C-fibre density in PD. The higher perceived pleasantness in PD patients compared to controls suggests central sensitisation to peripheral inputs, which may have been enhanced by dopamine therapy.

AIM: To quantify muscle strength and size in subjects with impaired glucose tolerance (IGT) in relation to intramuscular non-contractile tissue, the severity of neuropathy and vitamin D level. METHODS: A total of 20 subjects with impaired glucose tolerance and 20 control subjects underwent assessment of strength and size of knee extensor, flexor and ankle plantar and dorsi-flexor muscles, as well as quantification of intramuscular non-contractile tissue and detailed assessment of neuropathy and serum 25-hydroxy vitamin D levels. RESULTS: In subjects with impaired glucose tolerance, proximal knee extensor strength (P=0.17) and volume (P=0.77), and knee flexor volume (P=0.97) did not differ from those in control subjects. Ankle plantar flexor strength was significantly lower (P=0.04) in the subjects with impaired glucose tolerance, with no difference in ankle plantar flexor (P=0.62) or dorsiflexor volume (P=0.06) between groups. Intramuscular non-contractile tissue level was significantly higher in the ankle plantar flexors and dorsiflexors (P=0.03) of subjects with impaired glucose tolerance compared with control subjects, and it correlated with the severity of neuropathy. Ankle plantar flexor muscle strength correlated significantly with corneal nerve fibre density (r= 0.53; P=0.01), a sensitive measure of small fibre neuropathy, and was significantly lower in subjects with vitamin D deficiency (P=0.02). CONCLUSIONS: People with impaired glucose tolerance have a significant reduction in distal but not proximal leg muscle strength, which is not associated with muscle atrophy, but with increased distal intramuscular non-contractile tissue, small fibre neuropathy and vitamin D deficiency. This article is protected by copyright. All rights reserved.

OBJECTIVE: Muscle weakness and atrophy of the lower limbs may develop in patients with diabetes, increasing their risk of falls. The underlying basis of these abnormalities has not been fully explained. The aim of this study was to objectively quantify muscle strength and size in patients with type 2 diabetes mellitus (T2DM) in relation to the severity of neuropathy, intramuscular noncontractile tissue (IMNCT), and vitamin D deficiency. RESEARCH DESIGN AND METHODS: Twenty patients with T2DM and 20 healthy control subjects were matched by age, sex, and BMI. Strength and size of knee extensor, flexor, and ankle plantar and dorsiflexor muscles were assessed in relation to the severity of diabetic sensorimotor polyneuropathy (DSPN), amount of IMNCT, and serum 25-hydroxy vitamin D (25OHD) levels. RESULTS: Compared with control subjects, patients with T2DM had significantly reduced knee extensor strength (P = 0.003) and reduced muscle volume of both knee extensors (P = 0.045) and flexors (P = 0.019). Ankle plantar flexor strength was also significantly reduced (P = 0.001) but without a reduction in ankle plantar flexor (P = 0.23) and dorsiflexor (P = 0.45) muscle volumes. IMNCT was significantly increased in the ankle plantar (P = 0.006) and dorsiflexors (P = 0.005). Patients with DSPN had significantly less knee extensor strength than those without (P = 0.02) but showed no difference in knee extensor volume (P = 0.38) and ankle plantar flexor strength (P = 0.21) or volume (P = 0.96). In patients with <25 nmol/L versus >25 nmol/L 25OHD, no significant differences were found for knee extensor strength and volume (P = 0.32 vs. 0.18) and ankle plantar flexors (P = 0.58 vs. 0.12). CONCLUSIONS: Patients with T2DM have a significant reduction in proximal and distal leg muscle strength and a proximal but not distal reduction in muscle volume possibly due to greater intramuscular fat accumulation in distal muscles. Proximal but not distal muscle strength is related to the severit

OBJECTIVE: Muscle weakness and atrophy of the lower limbs may develop in patients with diabetes, increasing their risk of falls. The underlying basis of these abnormalities has not been fully explained. The aim of this study was to objectively quantify muscle strength and size in patients with type 2 diabetes mellitus (T2DM) in relation to the severity of neuropathy, intramuscular noncontractile tissue (IMNCT), and vitamin D deficiency. RESEARCH DESIGN AND METHODS: Twenty patients with T2DM and 20 healthy control subjects were matched by age, sex, and BMI. Strength and size of knee extensor, flexor, and ankle plantar and dorsiflexor muscles were assessed in relation to the severity of diabetic sensorimotor polyneuropathy (DSPN), amount of IMNCT, and serum 25-hydroxy vitamin D (25OHD) levels. RESULTS: Compared with control subjects, patients with T2DM had significantly reduced knee extensor strength (P = 0.003) and reduced muscle volume of both knee extensors (P = 0.045) and flexors (P = 0.019). Ankle plantar flexor strength was also significantly reduced (P = 0.001) but without a reduction in ankle plantar flexor (P = 0.23) and dorsiflexor (P = 0.45) muscle volumes. IMNCT was significantly increased in the ankle plantar (P = 0.006) and dorsiflexors (P = 0.005). Patients with DSPN had significantly less knee extensor strength than those without (P = 0.02) but showed no difference in knee extensor volume (P = 0.38) and ankle plantar flexor strength (P = 0.21) or volume (P = 0.96). In patients with <25 nmol/L versus >25 nmol/L 25OHD, no significant differences were found for knee extensor strength and volume (P = 0.32 vs. 0.18) and ankle plantar flexors (P = 0.58 vs. 0.12). CONCLUSIONS: Patients with T2DM have a significant reduction in proximal and distal leg muscle strength and a proximal but not distal reduction in muscle volume possibly due to greater intramuscular fat accumulation in distal muscles. Proximal but not distal muscle strength is related to the severit