Assessment of neuropathy subtypes in type 1 diabetes.

INTRODUCTION: Diabetic polyneuropathy (DPN), a common complication of diabetes, can manifest as small, large, or mixed fiber neuropathy (SFN, LFN, and MFN, respectively), depending on the type of fibers involved. Despite evidence indicating small fiber involvement prior to large fiber involvement in type 1 diabetes mellitus (T1DM)-associated DPN, no evidence has been produced to determine the more prevalent subtype. We aim to determine the more prevalent type of nerve fiber damage-SFN, LFN, and MFN-in T1DM-associated DPN, both with and without pain. RESEARCH DESIGN AND METHODS: In this cross-sectional study, participants (n=216) were divided into controls; T1DM; T1DM with non-painful DPN (NP-DPN); and T1DM with painful DPN (P-DPN). DPN was further subgrouped based on neuropathy severity. The more prevalent type of fiber damage was determined applying small and large fiber-specific tests and three diagnostic models: model 1 (≥1 abnormal test); model 2 (≥2 abnormal tests); and model 3 (≥3 abnormal tests). RESULTS: MFN showed the highest prevalence in T1DM-associated DPN. No differences in neuropathy subtype were found between NP-DPN and P-DPN. DPN, with prevalent SFN plateaus between models 2 and 3. All models showed increased prevalence of MFN according to DPN severity. Model 3 showed increased DPN with prevalent LFN in early neuropathy. DPN with prevalent SFN demonstrated a similar, but non-significant pattern. CONCLUSIONS: DPN primarily manifests as MFN in T1DM, with no differentiation between NP-DPN and P-DPN. Additionally, we propose model 2 as an initial criterion for diagnosing DPN with a more prevalent SFN subtype in T1DM. Lastly, the study suggests that in mild stages of DPN, one type of nerve fiber (either small or large) is more susceptible to damage.

Contemporary prevalence of diabetic neuropathies in individuals with type 1 and type 2 diabetes in a Danish tertiary outpatient clinic.

BACKGROUND: Population-based prevalence estimates of distal symmetric polyneuropathy (DPN) and diabetic autonomic neuropathy (DAN) are scares. Here we present neuropathy estimates and describe their overlap in a large cohort of people with type 1 and type 2 diabetes. METHODS: In a large population of outpatient participants, DPN was assessed using vibration perception threshold, sural nerve function, touch, pain and thermal sensation. Definite DPN was defined by the Toronto Consensus Criteria. Painful DPN was defined by Douleur Neuropathique 4 Questions. DAN measures were: cardiovascular reflex tests, electrochemical skin conductance, and gastroparesis cardinal symptom index. RESULTS: We included 822 individuals with type 1 (mean age (±SD) 54 ± 16 years, median [IQR] diabetes duration 26 [15-40] years) and 899 with type 2 diabetes (mean age 67 ± 11 years, median diabetes duration 16 [11-22] years). Definite DPN was prevalent in 54 % and 68 %, and painful DPN was in 5 % and 15 % of type 1 and type 2 participants, respectively. The prevalence of DAN varied between 6 and 39 % for type 1 and 9-49 % for type 2 diabetes. DPN without other neuropathy was present in 45 % with T1D and 50 % with T2D. CONCLUSION: The prevalence of DPN and DAN was high. DPN and DAN co-existed in only 50 % of cases.

Gastrointestinal symptom burden in diabetic autonomic and peripheral neuropathy - A Danes cohort study.

OBJECTIVE: We investigated associations between gastrointestinal symptoms - evaluated as a combined weighted symptom score (CWSS) - Diabetic autonomic neuropathy (DAN), and distal symmetrical polyneuropathy (DSPN) in type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: Cross-sectional study in a tertiary outpatient clinic. CWSS was calculated based on questionnaires: gastroparesis composite symptom index (GCSI) and gastrointestinal symptom rating score (GSRS). DAN and DSPN were addressed using the composite autonomic symptom score 31 (COMPASS-31) questionnaire, cardiac autonomic reflex tests (CARTs), electrochemical skin conductance (ESC), vibration perception threshold (VPT), Michigan Neuropathy Screening Instrument (MNSI), pain- and thermal sensation. Analyses were adjusted for age, sex, diabetes duration, smoking, LDL-cholesterol, HbA1C and systolic blood pressure. Type 1 and type 2 diabetes were evaluated separately. RESULTS: We included 566 with type 1 diabetes and 377 with type 2 diabetes. Mean ± SD age was 58 ± 15 years and 565 (59.9 %) were women. A high CWSS was present in 143 (25 %) with type 1 and 142 (38 %) with type 2 diabetes. The odds of DAN by COMPASS-31 (p < 0.001) were higher in the high score group. For type 1 diabetes, odds of cardiac autonomic neuropathy were higher in the high CWSS group. The odds of DSPN by VPT and MNSI in type 1 diabetes, and by ESC, VPT and pain sensation in type 2 diabetes were higher in the high CWSS group. CONCLUSIONS: A high symptom score was associated with neuropathy by COMPASS-31 and vibration perception. Gastrointestinal symptom burden associated inconsistently with other neuropathy tests between diabetes types.

Structural changes in Schwann cells and nerve fibres in type 1 diabetes: relationship with diabetic polyneuropathy.

AIMS/HYPOTHESIS: Our aim was to investigate structural changes of cutaneous Schwann cells (SCs), including nociceptive Schwann cells (nSCs) and axons, in individuals with diabetic polyneuropathy. We also aimed to investigate the relationship between these changes and peripheral neuropathic symptoms in type 1 diabetes. METHODS: Skin biopsies (3 mm) taken from carefully phenotyped participants with type 1 diabetes without polyneuropathy (T1D, n=25), type 1 diabetes with painless diabetic polyneuropathy (T1DPN, n=30) and type 1 diabetes with painful diabetic polyneuropathy (P-T1DPN, n=27), and from healthy control individuals (n=25) were immunostained with relevant antibodies to visualise SCs and nerve fibres. Stereological methods were used to quantify the expression of cutaneous SCs and nerve fibres. RESULTS: There was a difference in the number density of nSCs not abutting to nerve fibres between the groups (p=0.004) but not in the number density of nSCs abutting to nerve fibres, nor in solitary or total subepidermal SC soma number density. The overall dermal SC expression (measured by dermal SC area fraction and subepidermal SC process density) and peripheral nerve fibre expression (measured by intraepidermal nerve fibre density, dermal nerve fibre area fraction and subepidermal nerve fibre density) differed between the groups (all p<0.05): significant differences were seen in participants with T1DPN and P-T1DPN compared with those without diabetic polyneuropathy (healthy control and T1D groups) (all p<0.05). No difference was found between participants in the T1DPN and P-T1DPN group, nor between participants in the T1D and healthy control group (all p>0.05). Correlational analysis showed that cutaneous SC processes and nerve fibres were highly associated, and they were weakly negatively correlated with different neuropathy measures. CONCLUSIONS/INTERPRETATION: Cutaneous SC processes and nerves, but not SC soma, are degenerated and interdependent in individuals with diabetic polyneuropathy. However, an increase in structurally damaged nSCs was seen in individuals with diabetic polyneuropathy. Furthermore, dermal SC processes and nerve fibres correlate weakly with clinical measures of neuropathy and may play a partial role in the pathophysiology of diabetic polyneuropathy in type 1 diabetes.

Declining Incidence Rates of Distal Symmetric Polyneuropathy in People With Type 1 and Type 2 Diabetes in Denmark, With Indications of Distinct Patterns in Type 1 Diabetes.

OBJECTIVE: It is not known if incidence rates for diabetic distal symmetric polyneuropathy (DSPN) are decreasing, as they are for other diabetic complications. Here, we investigated incidence rates of DSPN in type 1 and type 2 diabetes in a large population-based study. RESEARCH DESIGN AND METHODS: In the period 1996 to 2018, 19,342 individuals were identified at a Danish tertiary diabetes center. Vibration perception threshold was assessed by biothesiometry and repeated throughout the study. Exclusion of prevalent DSPN cases or missing data left data on 9,473 individuals for analysis of DSPN using a cutoff of >25 V and on 2,783 individuals for analysis using an age-, sex-, and height-specific cutoff. Poisson regression analysis was used to model incidence rates of DSPN for both cutoff types and separately for diabetes types. Covariates were sex, age, diabetes duration, and calendar time. RESULTS: Incidence rates (95% CI) of DSPN decreased from 1996 to 2018 (e.g., from 4.78 [3.60-6.33]/100 person-years [PY] to 1.15 [0.91-1.47]/100 PY for 40-year-old men with type 1 diabetes and from 16.54 [11.80-23.18]/100 PY to 8.02 [6.63-9.69]/100 PY for 60-year-old men with type 2 diabetes, when using >25 V as the cutoff value). Analyses using age-, sex-, and height-specific cutoff values demonstrated similar incidence patterns by calendar time without sex differences. For type 1 diabetes, decreasing incidence rates were seen with older age. CONCLUSIONS: Incidence rates for DSPN are declining in type 1 and type 2 diabetes, possibly due to improved diabetes treatment. This causality remains to be explored. Distinct age-related patterns indicate that the pathophysiology of DSPN may differ between diabetes types.

Distal symmetrical polyneuropathy is present in all individuals with diabetes and foot ulcers - and does not associate with healing time.

We estimated the occurrence of diabetic neuropathy using six different diagnostic modalities in individuals with newly diagnosed diabetic foot ulcers (DFUs) and assessed the association with DFU healing time. All individuals with DFU had distal symmetrical polyneuropathy. Presence of neuropathy did not associate with ulcer healing time (p ≥ 0.12).

Lower Blood Oxygen Saturation is Associated With Microvascular Complications in Individuals With Type 1 Diabetes.

CONTEXT: Blood oxygen saturation (SpO2) is lower in type 1 diabetes (T1D) compared with nondiabetic controls. Hypoxia (low tissue oxygenation) is thought to be a risk factor for progression of diabetic complications, but it is unknown whether hypoxemia (low SpO2) is associated with diabetic complications. OBJECTIVE: To test if hypoxemia is associated with presence of diabetic complications in T1D. DESIGN, SETTING, AND METHODS: Cross-sectional study in persons with T1D divided by a previously suggested threshold in low (<96%) and high (≥96%) SpO2, measured in the supine position with pulse oximetry. Complications included albuminuria (2 of 3 consecutive measurements ≥30 mg/g), any diabetic retinopathy, neuropathy, and history of cardiovascular disease (CVD). Odds ratios were adjusted for age, diabetes duration, sex, smoking, physical activity, body mass index, systolic blood pressure, and blood hemoglobin. RESULTS: We included 659 persons, 23 (3.5%) with low and 636 (96.5%) with high SpO2. In total, 151 (23%) had albuminuria, 233 (36%) had retinopathy, 231 (35%) had neuropathy, and 72 (11%) had CVD. The adjusted odds ratio (95% CI, P value) for low vs high SpO2 was 3.4 (1.3-8.7, P = 0.01) for albuminuria, 2.8 (1.0-7.5, P = 0.04) for retinopathy, 5.8 (1.8-18.6, P < 0.01) for neuropathy, and nonsignificant for CVD (0.6 [0.2-2.4, P = 0.51]). CONCLUSIONS: SpO2 below 96% was associated with increased presence of albuminuria, retinopathy, and neuropathy in T1D, but not with CVD. Whether hypoxemia could be a target of intervention to prevent progression in microvascular disease in type 1 diabetes should be investigated.