Peripheral polyneuropathy in type 2 diabetes mellitus and impaired glucose tolerance. Correlations between morphology, neurophysiology, and clinical findings

Diabetic peripheral polyneuropathy (PN) is a common and serious complication of diabetes. The prevalence of PN is rising with the global burden of type 2 diabetes. The causal mechanisms of PN are not fully understood, but both vascular and metabolic factors play a role. New methods of investigating PN need to be correlated with standard methods in well-defined, population-based cohorts. Objectives: The overall aim was to investigate endoneurial microvascular abnormalities of the sural nerve and intraepidermal nerve fiber loss in type 2 diabetes and impaired glucose tolerance (IGT), in relation to glucose dysmetabolism, and clinical and neurophysiological measures of PN. Methods: Subjects were recruited from a prospective, population-based study of males from Malmö, Sweden (6956 responders). From this cohort, 182 individuals in three groups were identified, [69 with type 2 diabetes, 51 IGT, and 62 normal glucose tolerance (NGT)], matched for age, height, and body mass index (BMI). Endoneurial microangiopathy and myelinated nerve fiber density (MNFD) were assessed in 30 sural nerve biopsies (from 10 men with type 2 diabetes, 10 IGT, and 10 NGT). Intraepidermal nerve fibers (IENF) were assessed in skin biopsies from the distal leg in 86 subjects (50 men with type 2 diabetes, 15 IGT, and 21 NGT) and graded as absent IENF, low (1–3 IENF/section), or high (> 4 IENF/section) counts of IENF. The subjects underwent oral glucose tolerance test, clinical examination (Total Neuropathy Score; combined Neuropathy Symptom Score and Neuropathy Disability Score), and neurophysiological tests (nerve conduction and quantitative sensory testing) at baseline and at follow-up (6–10 years later). Vibrotactile sense of the index (median nerve) and little fingers (ulnar nerve) was assessed in 58 subjects (23 type 2 diabetes, 7 IGT, 28 NGT) with persistent glucose tolerance for 15 years. Results: Increased endoneurial capillary density was linked to current diabetes and future progression from IGT to diabetes. Decreased capillary luminal area was associated with deterioration of glucose tolerance. Increased basement membrane area was related to clinical PN. A low baseline sural nerve MNFD (< 4700 fibers/mm2) was associated with future progression of neurophysiological dysfunction in the peroneal and median nerves. MNFD correlated negatively with BMI. Absence of IENF was related to low sural nerve amplitude and conduction velocity, and high cold perception threshold. Vibrotactile sense was impaired in the index and particularly the little finger of diabetic subjects, mainly at high frequencies (250–500 Hz). IGT did not affect vibrotactile sense. Conclusions: Sural nerve endoneurial microangiopathy is related to glucose dysmetabolism and clinical PN. MNFD may predict future nerve dysfunction. Obesity may be a risk factor for PN. IENF count correlates with neurophysiological measures of PN. Vibrotactile sense is impaired in the fingers, particularly innervated by the ulnar nerve at high frequencies, in patients with type 2 diabetes but not those with IGT

Hand disorders, hand function, and activities of daily living in elderly men with type 2 diabetes.

AIMS/HYPOTHESIS: This study aimed to examine hand disorders, symptoms, overall hand function, activities of daily living (ADLs), and life satisfaction in elderly men with type 2 diabetes mellitus (DM), impaired glucose tolerance (IGT), and normal glucose tolerance (NGT). METHODS: Subjects were interviewed and evaluated with a battery of clinical and laboratory tests, including hand assessment, and a questionnaire. RESULTS: HbA1c differed between groups (highest in DM, especially in long-term DM). Limited joint motion (LJM), for example, prayer sign and Dupuytren's contracture, was most common in individuals with DM, followed by individuals with IGT, as compared to those with NGT. Vibrotactile sense was impaired symmetrically in the index and little fingers in DM. However, there were no differences for sensibility, dexterity, grip strength, and cold intolerance between groups. Individuals with long-term (>15 years) DM were more affected regarding sensibility and ADL than individuals with short-term DM, who had more sleep disturbances. ADL difficulties were less among IGT subjects. Vibrotactile sense showed correlations with Semmes-Weinstein monofilament test and static two-point discrimination. CONCLUSIONS/INTERPRETATION: Dupuytren's contracture and impaired vibrotactile sense in finger pulps occurred in patients with DM but not in those with IGT, although LJM occurred in both IGT and DM patients. A longer duration of DM was associated with more severe neuropathy and ADL difficulties. Life satisfaction was high, and hand disorders did not have a significant impact on ADL

Vibrotactile sense in median and ulnar nerve innervated fingers of men with Type 2 diabetes, normal or impaired glucose tolerance.

Aims To investigate vibrotactile sense (large fibre neuropathy) at different frequencies in index and little fingers (median and ulnar nerves, respectively) of subjects with diabetes, or impaired (IGT) or normal glucose tolerance (NGT). Methods Vibration thresholds (tactilometry at seven frequencies (8, 16, 32, 64, 125, 250 and 500 Hz)) and median nerve function (electrophysiology) were examined in men (age 73.4 +/- 0.12 years; n = 58, mean +/- sd) with persistent NGT (n = 28) or IGT (n = 7) or with Type 2 diabetes mellitus (T2DM) (n = 23) for > 15 years. Results HbA(1c) was increased and vibrotactile sense (sensibility index) was impaired in index and little fingers in men with T2DM. Vibration thresholds were particularly increased at 16, 250 and 500 Hz in the little finger (ulnar nerve). T2DM subjects showed electrophysiological (gold standard) signs of neuropathy in the median nerve. Although subjects with persistent IGT had higher HbA(1c), vibrotactile sensation and electrophysiology remained normal. HbA(1c) did not correlate with vibrotactile sense or electrophysiology, but the latter two correlated with respect to Z-score (sign of neuropathy) in forearm (NGT) and at wrist level (NGT and DM). Conclusions Vibration thresholds are increased in the finger pulps in T2DM subjects, particularly at specific frequencies in ulnar nerve innervated finger pulps. Neuropathy is not present in IGT. Tactilometry, with a multi-frequency approach, is a sensitive technique to screen for large fibre neuropathy in T2DM. Frequency-related changes may mirror dysfunction of various receptors

Evaluation of small nerve fiber dysfunction in type 2 diabetes.

To access publisher's full text version of this article click on the hyperlink belowOBJECTIVES: To assess potential correlations between intraepidermal nerve fiber densities (IENFD), graded with light microscopy, and clinical measures of peripheral neuropathy in elderly male subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes (T2DM), respectively. MATERIALS AND METHODS: IENFD was assessed in thin sections of skin biopsies from distal leg in 86 men (71-77 years); 24 NGT, 15 IGT, and 47 T2DM. Biopsies were immunohistochemically stained for protein gene product (PGP) 9.5, and intraepidermal nerve fibers (IENF) were quantified manually by light microscopy. IENFD was compared between groups with different glucose tolerance and related to neurophysiological tests, including nerve conduction study (NCS; sural and peroneal nerve), quantitative sensory testing (QST), and clinical examination (Total Neuropathy Score; Neuropathy Symptom Score and Neuropathy Disability Score). RESULTS: Absent IENF was seen in subjects with T2DM (n = 10; 21%) and IGT (n = 1; 7%) but not in NGT. IENFD correlated weakly negatively with HbA1c (r = -.268, P = .013) and Total Neuropathy Score (r = -.219, P = .042). Positive correlations were found between IENFD and sural nerve amplitude (r = .371, P = .001) as well as conduction velocity of both the sural (r = .241, P = .029) and peroneal nerve (r = .258, P = .018). Proportions of abnormal sural nerve amplitude became significantly higher with decreasing IENFD. No correlation was found with QST. Inter-rater reliability of IENFD assessment was good (ICC = 0.887). CONCLUSIONS: Signs of neuropathy are becoming more prevalent with decreasing IENFD. IENFD can be meaningfully evaluated in thin histopathological sections using the presented technique to detect neuropathy.Swedish Research Council Diabetes Association in Malmo Swedish Diabetes Foundation Skane University Hospital Lund-Malmo Lund University Region of Skan