The natural history of somatosensory and autonomic nerve dysfunction in relation to glycaemic control during the first 5 years after diagnosis of Type 1 (insulin-dependent) diabetes mellitus

Summary The natural evolution of neural dysfunction was studied prospectively over 5 years following diagnosis of Type 1 (insulin-dependent) diabetes in 32 patients aged 12–36 years. Motor and sensory nerve conduction velocities, heart rate variation at rest and during deep breathing, and pupillary function were measured at diagnosis and after 3,12, 24,48, and 60 months. Thermal and vibration sensation thresholds were determined after 24, 48, and 60 months of diabetes. Mean HbA₁ levels of months 3–60 within the normal range of <8.3% (7.3±0.2%) were observed in 13 patients (Group 1), while a mean HbA₁ of months 3–608.3% (10.0±0.3%) was found in 19 patients (Group 2). Mean nerve conduction was significantly diminished in Group 2 as compared with Group 1 in at least 4 out of 6 nerves tested during months 12–60 (p<0.05). Both tests of heart rate variation were significantly impaired in Group 2 as compared with Group 1 after 24 and 60 months (p<0.05), but no differences in pupillary function were observed between the groups. Thermal discrimination but not vibration perception thresholds on the foot were significantly higher in Group 2 than in Group 1 at 40 and 60 months (p<0.05). Abnormalities in nerve conduction, thermal discrimination, and heart rate variation, but not vibration perception threshold and the pupillary function tests were significantly more frequent in Group 2 than in Group 1 at 60 months (p<0.05). After 60 months, none of the patients of Group 1, but 6 and 4 patients of Group 2 developed subclinical or symptomatic neuropathy, respectively (p<0.05). These findings suggest that the evolution of subclinical and symptomatic neuropathy during the first 5 years after diagnosis of Type 1 diabetes may be predicted by poor glycaemic control and prevented by near-normoglycaemia.     

2型糖尿病患者听觉阈值与周围神经病变的关系分析

目的 通过比较无糖尿病的人群和2型糖尿病患者的纯音听阈值、振动觉阈值(VPT),了解2型糖尿病患者周围神经病变(DPN)与耳聋的关系.方法 测定173例研究对象的VPT及纯音听阈值,2型糖尿病患者同时测定感觉神经传导速度(SCV)和运动神经传导速度(MCV),将其分为对照组35例,无糖尿病神经病变组74例,糖尿病伴神经病变组64例.比较3组的基本情况、感音神经性耳聋(SNHL)发生率、纯音听阈值和VPT值,分析听阈值和神经传导速度的关系.结果 伴神经病变的糖尿病组SNHL发生率为29.69%,明显高于无糖尿病神经病变组(17.57%)和对照组(17.14%),且3组的年龄、糖尿病病程、HbA1c、糖化血清蛋白(GA)、空腹血糖、餐后2 h血糖、VPT和听阈值之间有显著性差异(均P＜0.05).不同VPT亚组的听阈值之间也存在明显差异(均P＜0.05).正中神经传导速度与1.00、2.00、4.00、8.00kHz听阈值呈明显负相关,logistic回归分析显示,年龄(回归系数=0.088,P＜0.01)是SNHL的独立危险因素,正中神经MCV(回归系数=-0.135,P=0.046)是影响SNHL的重要因素.结论 糖尿病患者易影响中高频听力,DPN患者常同时合并听力受损,年龄、正中神经MCV是影响SNHL的主要危险因素.

Abstract：

Objective In order to investigate the relationship between hearing loss and diabetic peripheral neuropathy( DPN ) via comparing the pure tone thresholds and vibration perception threshold(VPT) in type 2 diabetic patients and control person without diabetes. Methods 173 subjects including 138 type 2 diabetic patients(DM)and 35 non-diabetes controls were examined for VPT and hearing threshold. Nerve conducting velocity ( NCV )including sensory nerve conducting velocity( SCV )and motorial nerve conducting velocity( MCV )of diabetic patients were determined. The participants were divided into three groups: control group (n = 35 ), DM group without peripheral neuropathy( non-PN group, n = 74 ), and DM group complicated with peripheral neuropathy (PN group,n = 64 ). The clinical characteristics, biochemical parameters , the incidence of sensorineural hearing loss ( SNHL),pure tone threshold, and VPT were compared among three groups. At last, the relationship between hearing thresholds and NCV were analyzed. Results The incidence of hearing impairment of sensorineural type was 29.69% in PN group, which was significantly higher than that of non-PN group( 17.57% )and control group( 17. 14% ). There was significant differences in age, duration of diabetes, glycolated hemoglobin (HbA1c), glycolated serum albumin ( GA), Fasting blood glucose( FPG), 2h postprandial blood glucose( PPG), VPT, and hearing threshold among the three groups( all P＜0. 05 ). The value of hearing threshold increased significantly( all P＜0. 05 ) in 3 VPT subgroups with VPT≤ 15 V, VPT 16-25 V, and VPT ＞25 V. The Spearman correlation analysis showed median NCV was negatively correlated with hearing threshold on 1.00, 2.00, 4. 00, and 8. 00 kHz ( All P ＜ 0. 05 ). The logistic regression analysis indicated that the age( regression coefficient =0. 088, P＜0. 01 ) was the independent risk factor of SNHL, median nerve MCV ( regression coefficient = -0. 135, P = 0. 046 ) was the important influencing factor of SNHL. Conclusion Diabetic patients are more likely to suffer from impaired middle-frequency and high-frequency hearing, DPN in patients is often complicated with hearing impairment. Age and median nerve MCV were major risk factors of SNHL in diabetic patients.     

Pattern of myelinated fibre loss in the sural nerve in neuropathy related to Type 1 (insulin-dependent) diabetes

Summary Sural nerve biopsies were obtained from 17 diabetic patients with neuropathy. All patients except three had both a symmetric distal sensory and autonomic polyneuropathy related to Type 1 (insulin-dependent) diabetes mellitus; 3 patients had a purely sensory polyneuropathy. Mean age was 34.5 years (range 18–53 years). The biopsies were compared with specimens from an age-matched control series. Myelinated fibre loss in the diabetic nerves was found to be nonuniform. Although patchy fibre loss has been considered to favour a vascular basis, an identical pattern of nonuniform loss was observed in a series of sural nerve biopsies from patients with Type I hereditary motor and sensory neuropathy, a subgroup within the spectrum of peroneal muscular atrophy, mainly of autosomal dominant inheritance, and a condition in which a vascular causation can be discounted. Possible reasons for nonuniform fibre loss other than vascular disease are discussed.     

定量感觉测试在2型糖尿病小纤维神经病变诊断中的应用

糖尿病周围神经病变是2型糖尿病常见的慢性并发症之一,其中小纤维神经病变往往发生在2型糖尿病病程的早期阶段,如能早期诊断小纤维神经病变,及时采取干预措施,对延缓糖尿病周围神经病变的发展具有重要意义。定量感觉测试作为小纤维神经病变的诊断标准之一,因其无创、方便等优势便于被患者接受及在临床上广泛应用。本文主要从2型糖尿病患者...     

Exercise-induced conduction velocity increment: a marker of impaired peripheral nerve blood flow in diabetic neuropathy

Summary Severe microvascular disease exists at the stage of clinical diabetic neuropathy. A non-invasive test that will identify those diabetic subjects who will eventually develop neuropathy is essential for early intervention. Sural sensory conduction velocity was recorded (x 3) in 12 non-neuropathic diabetic subjects, 15 diabetic subjects with established neuropathy and 16 age-matched normal control subjects, before and after exercise to 80% age/sex predicted maximum heart rate. Fixed sural electrodes were used. Subcutaneous temperature was recorded by a needle thermocouple placed near the sural nerve. Sural sensory conduction velocity increased significantly after exercise in normal subjects (p<0.01, mean increase 5.07 m/s) and non-neuropathic diabetic subjects (p<0.02, mean increase 3.99 m/s) but not in neuropathic subjects (mean increase 0.99 m/s). Subcutaneous temperature rose significantly in normal subjects (p<0.01, mean increase 2.07°C) and non-neuropathic diabetic subjects (p<0.001, mean increase 2.52 °C) but not in neuropathic subjects (mean increase 0.15 °C). However, sural sensory conduction velocity increased by 1.2 m · s^–1. °C^–1 following direct warming of the limb in six neuropathic subjects which was comparable to that of normal and non-neuropathic subjects (1.49 and 1.48 m · s^–1. °C^–1). The impairment of exercise conduction increment in diabetic neuropathy suggests impaired nerve blood flow in diabetic neuropathy.     

Factor analysis of thermal and vibration thresholds in young patients with Type 1 diabetes mellitus.

AIMS: To identify factors that represent relationships among sets of interrelated thermal and vibration threshold variables and to find clinical correlates that are significantly associated with these factors. METHODS: Thermal and vibration perception thresholds were tested in the hands and feet of Type 1 diabetic patients treated in an outpatient clinic for juvenile-onset diabetes. Factor analysis was used to identify factors that represent relationships among sets of thermal and vibration threshold variables. RESULTS: One hundred and forty-eight patients (47.3% males, median current age 22.3 years and median duration of diabetes 11.4 years) were evaluated. Three factors explained 77% of the total variance: 'hand sensation' factor, underlying cold, warmth and vibration perception thresholds in the hand; 'foot sensation' factor, underlying the same sensory thresholds in the foot; and 'heat-related pain' factor, underlying heat pain perception threshold in both limbs. The 'foot sensation' factor was the only factor that significantly correlated with diabetes-related variables (e.g. duration and cumulative glycaemic control of the disease) and concurrent diabetic microangiopathy. Male sex was associated with higher values of the 'heat-related' factor, while the 'hand sensation' factor did not correlate with any of the study variables. CONCLUSIONS: The distribution of the various thermal and vibration threshold variables according to the three factors may point at length-dependent mechanism of axonal degeneration. Cold, warmth and vibration perception thresholds in the foot may be the only valuable psychophysical parameters in the evaluation of early sensory impairment associated with diabetes.     

Urinary albumin excretion rate is independently related to autonomic neuropathy in type 2 diabetes mellitus

OBJECTIVE: To evaluate if urinary albumin excretion rate (UAER) is independently related to subclinical autonomic neuropathy in type 2 diabetes. DESIGN: A controlled cross-sectional study. SETTING: Primary health care centre. SUBJECTS: Consecutive recently diagnosed (< 1 year) type 2 diabetic patients (group A, n = 150) and patients with long-standing (median 11 years) type 2 diabetes (group B, n = 146) chosen at random. A nondiabetic control group (group C, n = 150) matched for age and gender to group A. MAIN OUTCOME MEASURES: Neuropathy by cardiovascular reflex tests and UAER by nephelometry. METHODS: Univariate statistics in group A + B (t-test chi 2- or McNemars test) with Valsalva and breathing ratios as categorical grouping variables and the independent variables gender, smoking, systolic and diastolic blood pressure, fasting serum cholesterol, HDL cholesterol, triglycerides, haemoglobin A1c, glucagon stimulated C-peptide, fasting and postload 1 and 2 h blood glucose and serum insulin, UAER, coronary heart disease and congestive heart failure. Logistic regression analyses in group A + B with Valsalva and breathing ratios as dependent categorical variables and age, systolic blood pressure, congestive heart failure, coronary heart disease, fasting blood glucose, serum triglycerides and UAER as independent variables. RESULTS: Compared to nondiabetic subjects the diabetic patients of both groups were at increased risk of neuropathy as judged by the Valsalva ratio (P < 0.01). In known diabetic patients with a UAER > or = 30 mg 24-1 h neuropathy was more common than amongst their normoalbuminuric counterparts (Valsalva test P = 0.007, breathing test P = 0.02). In logistic regression analysis UAER independently explained abnormal Valsalva (P = 0.015) and breathing tests (P = 0.04) in the group A + B. CONCLUSIONS: UAER is independently related to subclinical autonomic neuropathy in type 2 diabetes.     

The influence of isolated small nerve fibre dysfunction on microvascular control in patients with diabetes mellitus.

AIM: The aim of the study was to investigate the influence of isolated small nerve fibre dysfunction on microvascular skin blood flow and transcutaneous oxygen tension in patients with diabetes mellitus. METHODS: Small nerve fibre dysfunction was assessed by the measurement of thermal and pain perception thresholds. Patients with evidence of large fibre disturbances as evaluated by means of vibration perception threshold were excluded from the study. Microvascular blood flow was investigated with laser-Doppler-fluxmetry (LDF) following stimulation with acetylcholine and mild thermal injury. RESULTS: Diabetic patients with small nerve fibre injury showed a significantly reduced increase in the laser-Doppler-flux signal following the application of acetylcholine compared with patients without neuropathy or healthy control subjects (2.8 arbitrary units (AU) (1.3-5.5) vs. 7.2 AU (4.1-25.5); P = 0.007 and vs. 8.5 AU (3.0-17.0), P = 0.02, respectively). The increase in LDF following thermal injury was also diminished in patients with small nerve fibre dysfunction compared with patients without neuropathy or the control group (29.8 AU (17.2-46.5) vs. 51.2 AU (29.5-93.5); P = 0.02 and vs. 54.6 AU (39.7-97.7); P = 0.004, respectively). In addition, they showed a significantly reduced transcutaneous oxygen tension compared with the other groups (42.9 mmHg (41.6-55.5) vs. 56.1 mmHg (49.2-60.8); P = 0.04 and vs. 59.0 mmHg (54.6-80.3), P = 0.03, respectively). CONCLUSIONS: Our study confirms an association between small nerve fibre injury and skin microvascular dysfunction. It further underlines the concept of neurovascular disturbances in the pathogenesis of neurotrophic foot ulceration. Diabet. Med. 18, 489-494 (2001)     

Increased urinary orosomucoid excretion is not related to impaired renal function in patients with type 2 diabetes

ObjectivesIncreased urinary orosomucoid excretion rate (UOER) independently predicted cardiovascular mortality in patients with type 2 diabetes at 5-years of follow-up. To further explore UOER in relation to local renal physiological phenomena, we studied renal glomerular and tubular functions in patients with type 2 diabetes and normal or increased UOER.MethodsWe performed a cross-sectional study of 40 patients with type 2 diabetes (normal UOER, n=16; increased UOER, n=24) who displayed no signs of cardiovascular disease and 21 healthy control persons. The renal clearance values of [⁵¹Cr]ethylenediaminetetraacetic acid ([⁵¹Cr]EDTA), lithium, orosomucoid, albumin, and sodium were measured.ResultsPatients with type 2 diabetes had normal glomerular filtration rate (GFR) measured by [⁵¹Cr]EDTA clearance. The clearance value of orosomucoid was highly increased in patients with increased UOER. The clearance values of albumin were similar in patients with increased UOER and in healthy controls. Investigations of renal tubular function revealed normal and similar levels of lithium clearance and proximal and distal reabsorption of sodium and water. Serum values of orosomucoid were higher in patients with increased UOER than in healthy controls (P<.001), but were still within reference limits, suggesting chronic low-grade inflammation. UOER was associated with increasing values of orosomucoid clearance (P<.0001) independently of serum orosomucoid.ConclusionsPatients with type 2 diabetes and increased UOER had normal GFR and showed no signs of renal glomerular or tubular dysfunction. We therefore hypothesize that increased levels of UOER may be caused by local renal production of orosomucoid due to chronic low-grade inflammation.     

Lipid-lowering therapy and peripheral sensory neuropathy in type 2 diabetes: the Fremantle Diabetes Study

Aims/hypothesis The aim of this study was to assess the relationships between lipid-lowering therapy and the prevalence and incidence of peripheral sensory neuropathy in type 2 diabetes mellitus. Methods We analysed data from an observational cohort study, the Fremantle Diabetes Study (FDS), specifically, (1) a cross-sectional sample comprising 1,237 FDS participants with type 2 diabetes mellitus, and (2) a longitudinal subgroup of 531 individuals who had attended six consecutive annual assessments. Neuropathy was identified using the clinical portion of the Michigan Neuropathy Screening Instrument. Results At entry, the cross-sectional sample had a mean ± SD age of 63.8 ± 11.3 years, 48.7% were men, median (interquartile range) diabetes duration was 4.0 (1.0–9.0) years, and 30.9% had peripheral neuropathy. Fibrates and statins were used by 3.5 and 6.8%, respectively. Multiple logistic regression analysis showed that older age, longer diabetes duration, central adiposity, increased height, higher fasting serum glucose, albuminuria and aboriginality were significant independent positive predictors of prevalent neuropathy, while systolic blood pressure and fibrate use (odds ratio 0.30, 95% CI 0.10–0.86; p = 0.025) were negatively associated. In the longitudinal subgroup, fibrate and statin use increased to 10.4 and 36.5%, respectively, over 5 years. In time-dependent Cox proportional hazards modelling, fibrate use [hazard ratio (HR) 0.52, 95% CI 0.27–0.98] and statin use (HR 0.65, 95% CI 0.46–0.93) were significant determinants of incident neuropathy (p ≤ 0.042). Conclusions/interpretation These preliminary observational data suggest that therapy with a statin or a fibrate may protect against the development of diabetic peripheral sensory neuropathy, but there is a need for additional confirmatory evidence, preferably from randomised clinical trials. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

High incidence of type 2 diabetes and increasing conversion rates from impaired fasting glucose and impaired glucose tolerance to diabetes in Mauritius

OBJECTIVE: To describe the incidence of different stages of glucose intolerance in a population from Mauritius followed over 11 years. RESEARCH DESIGN, METHODS AND SUBJECTS: Population-based surveys were undertaken in the multi-ethnic nation of Mauritius in 1987, 1992 and 1998 with 5083, 6616 and 6291 participants, respectively. Questionnaires, anthropometric measurements, and a 2-h 75-g oral glucose tolerance test were included. Three cohorts aged between 25 and 79 years with classifiable glucose tolerance data were identified; 3680 between 1987 and 1992, 4178 between 1992 and 1998, and 2631 between 1987 and 1998. Glucose tolerance was classified according to WHO 1999 criteria. RESULTS: The incidence rate of type 2 diabetes was higher between 1992 and 1998 than between 1987 and 1992. In men, the incidence was similar between cohorts (24.5 and 25.4 per 1000 person-years) whereas the incidence increased in women (23.3 and 16.4 per 1000 person-years). The incidence of diabetes peaked in the 45-54 year age group and then plateaued or fell. The incidences of impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) decreased in both men and women. Of normoglycaemic subjects at baseline, more women than men developed IGT and more men than women developed IFG. Of those labelled as IFG in 1987, 38% developed diabetes after 11 years. The corresponding figure for IGT was 46%. CONCLUSIONS: In this study, we report changes in incidence rates of glucose intolerance over a 11-year period. In particular, differences between men and women were observed. The increased incidence of IGT in women compared with men, and increased incidence of IFG in men compared with women was consistent with, and explains the sex biases seen in the prevalences of these states.     

Association between sarcopenia and the severity of diabetic polyneuropathy assessed by nerve conduction studies in Japanese patients with type 2 diabetes mellitus

Aims/IntroductionThis study examined the association between the severity of diabetic polyneuropathy (DPN) based on the Baba classification, and sarcopenia and its related factors.Materials and MethodsThe participants were 261 patients with type 2 diabetes mellitus. DPN was classified as stages 0–4 according to the Baba classification. Sarcopenia was diagnosed based on measurements of the skeletal mass index, grip strength and walking speed, using the Asia Working Group for Sarcopenia 2019 diagnostic criteria.ResultsThe median age of the participants was 67 years, the proportion of men was 58.6%, the median estimated duration of diabetes was 10 years and the median values for glycated hemoglobin were 10.3%. With regard to DPN, the prevalence of Baba classification stages 0–2 was 90.8% (n = 237), and that of stage 3 or 4 was 9.2% (n = 24). The prevalence of sarcopenia was 19.9%. A trend toward an increase in the frequency of slow walking speed was seen as the stage of DPN progressed. The frequencies of sarcopenia and slow walking speed were higher in the group with the Baba classification stages 3 and 4 than in the group with stages 0–2. On multiple logistic regression analyses, however, DPN was not significantly related to sarcopenia and walking speed.ConclusionsAlthough severe DPN might be related to sarcopenia, the frequency of severe DPN is low in the clinical setting, indicating that its contribution to sarcopenia is modest.     

Current perception thresholds: a new,quick, and reproducible method for the assessment of peripheral neuropathy in diabetes mellitus

Summary The Neurometer is a variable constant current sine wave stimulator, and has recently been proposed as a simple non-invasive and quantitative measure of peripheral nerve function. The device is portable and battery operated; assessment of upper and lower extremities takes only a few min, in contrast to conventional assessment techniques. In order to assess its potential in the quantification of diabetic neuropathy, detection thresholds for constant current electric sine wave stimulation were measured at three different frequencies in different sites in 31 healthy control subjects and 90 diabetic patients with and without neuropathy. The device provides good discrimination between neuropathic and non-neuropathic groups (p<0.001) and is quick and easy to use. Comparisons with results of conventional tests of nerve function show that high frequency detection thresholds correlate best with tests of large fibre function (r= 0.42–0.69, p<0.001), and low frequency detection thresholds correlate with tests of small fibre function (r=0.34–0.46, p<0.005). It is concluded that the device may be a simple and comprehensive way of assessing peripheral nerve function.