What Is in the Field for Genetics and Epigenetics of Diabetic Neuropathy: The Role of MicroRNAs.

Despite the high prevalence of diabetic neuropathy, its early start, and its impact on quality of life and mortality, unresolved clinical issues persist in the field regarding its screening implementation, the understanding of its mechanisms, and the search for valid biomarkers, as well as disease-modifying treatment. Genetics may address these needs by providing genetic biomarkers of susceptibility, giving insights into pathogenesis, and shedding light on how to select possible responders to treatment. After a brief summary of recent studies on the genetics of diabetic neuropathy, the current review focused mainly on microRNAs (miRNAs), including the authors' results in this field. It summarized the findings of animal and human studies that associate miRNAs with diabetic neuropathy and explored the possible pathogenetic meanings of these associations, in particular regarding miR-128a, miR-155a, and miR-499a, as well as their application for diabetic neuropathy screening. Moreover, from a genetic perspective, it examined new findings of polymorphisms of miRNA genes in diabetic neuropathy. It considered in more depth the pathogenetic implications for diabetic neuropathy of the polymorphism of MIR499A and the related changes in the downstream action of miR-499a, showing how epigenetic and genetic studies may provide insight into pathogenetic mechanisms like mitochondrial dysfunction. Finally, the concept and the data of genotype-phenotype association for polymorphism of miRNA genes were described. In conclusion, although at a very preliminary stage, the findings linking the genetics and epigenetics of miRNAs might contribute to the identification of exploratory risk biomarkers, a comprehensive definition of susceptibility to specific pathogenetic mechanisms, and the development of mechanism-based treatment of diabetic neuropathy, thus addressing the goals of genetic studies.

Validation of the Composite Autonomic Symptom Score 31 (COMPASS 31) for the assessment of symptoms of autonomic neuropathy in people with diabetes.

AIM: To validate the Composite Autonomic Symptom Score (COMPASS) 31, in its Italian version, for the diagnosis of diabetic cardiovascular autonomic neuropathy in a clinic-based, single-centre study. METHODS: A total of 73 participants with diabetes (age 55 ± 14 years) completed the COMPASS 31 questionnaire before undergoing cardiovascular autonomic neuropathy and diabetic polyneuropathy assessment according to cardiovascular reflex tests, neuropathic symptoms and signs, and vibration and thermal thresholds. RESULTS: The COMPASS 31 total weighted score differed between participants with and without cardiovascular autonomic neuropathy (29.9 ± 19.5 vs 16.1 ± 14.7; P = 0.003) and with and without diabetic polyneuropathy (28.9 ± 19.1 vs 12.7 ± 11.3; P < 0.0001). It was related to cardiovascular reflex tests score (rho = 0.38, P = 0.0013) as well as diabetic polyneuropathy symptoms (rho=0.61, P < 0.0001) and signs scores (rho = 0.49, P < 0.0001). Receiver-operating curve analysis showed a fair diagnostic accuracy of total score for cardiovascular autonomic neuropathy (area under the curve 0.748 ± 0.068, 95% CI 0.599-0.861) and diabetic polyneuropathy (area under the curve 0.742 ± 0.061, 95% CI 0.611-0.845). The best score thresholds were 16 for early cardiovascular autonomic neuropathy (sensitivity 75.0%, specificity 64.9%, positive predictive value 37.5% and negative predictive value 90.2%), and 17 for both confirmed cardiovascular autonomic neuropathy and diabetic polyneuropathy (sensitivity 70.0% and 65.5%, respectively; specificity 66.7% and 79.5%, respectively; positive predictive value 25.0% and 67.9%, respectively; and negative predictive value 93.0% and 77.8%, respectively). COMPASS 31 had a good internal consistency according to Cronbach's α coefficient of 0.73. CONCLUSIONS: COMPASS 31 can represent a valid, easy-to-use, quantitative assessment tool for autonomic symptoms in diabetic neuropathy, with a fair diagnostic accuracy for both cardiovascular autonomic neuropathy and diabetic polyneuropathy.

Frequency-modulated electromagnetic neural stimulation (FREMS) as a treatment for symptomatic diabetic neuropathy: results from a double-blind, randomised, multicentre, long-term, placebo-controlled clinical trial.

AIMS/HYPOTHESIS: The aim was to evaluate the efficacy and safety of transcutaneous frequency-modulated electromagnetic neural stimulation (frequency rhythmic electrical modulation system, FREMS) as a treatment for symptomatic peripheral neuropathy in patients with diabetes mellitus. METHODS: This was a double-blind, randomised, multicentre, parallel-group study of three series, each of ten treatment sessions of FREMS or placebo administered within 3 weeks, 3 months apart, with an overall follow-up of about 51 weeks. The primary endpoint was the change in nerve conduction velocity (NCV) of deep peroneal, tibial and sural nerves. Secondary endpoints included the effects of treatment on pain, tactile, thermal and vibration sensations. Patients eligible to participate were aged 18-75 years with diabetes for ≥ 1 year, HbA(1c) <11.0% (97 mmol/mol), with symptomatic diabetic polyneuropathy at the lower extremities (i.e. abnormal amplitude, latency or NCV of either tibial, deep peroneal or sural nerve, but with an evocable potential and measurable NCV of the sural nerve), a Michigan Diabetes Neuropathy Score ≥ 7 and on a stable dose of medications for diabetic neuropathy in the month prior to enrolment. Data were collected in an outpatient setting. Participants were allocated to the FREMS or placebo arm (1:1 ratio) according to a sequence generated by a computer random number generator, without block or stratification factors. Investigators digitised patients' date of birth and site number into an interactive voice recording system to obtain the assigned treatment. Participants, investigators conducting the trial, or people assessing the outcomes were blinded to group assignment. RESULTS: Patients (n = 110) with symptomatic neuropathy were randomised to FREMS (n = 54) or placebo (n = 56). In the intention-to-treat population (50 FREMS, 51 placebo), changes in NCV of the three examined nerves were not different between FREMS and placebo (deep peroneal [means ± SE]: 0.74 ± 0.71 vs 0.06 ± 1.38 m/s; tibial: 2.08 ± 0.84 vs 0.61 ± 0.43 m/s; and sural: 0.80 ± 1.08 vs -0.91 ± 1.13 m/s; FREMS vs placebo, respectively). FREMS induced a significant reduction in day and night pain as measured by a visual analogue scale immediately after each treatment session, although this beneficial effect was no longer measurable 3 months after treatment. Compared with the placebo group, in the FREMS group the cold sensation threshold was significantly improved, while non-significant differences were observed in the vibration and warm sensation thresholds. No relevant side effects were recorded during the study. CONCLUSIONS/INTERPRETATION: FREMS proved to be a safe treatment for symptomatic diabetic neuropathy, with immediate, although transient, reduction in pain, and no effect on NCV. TRIAL REGISTRATION: ClinicalTrials.gov NCT01628627. FUNDING: The clinical trial was sponsored by Lorenz Biotech (Medolla, Italy), lately Lorenz Lifetech (Ozzano dell'Emilia, Italy).

A simple new non-invasive sweat indicator test for the diagnosis of diabetic neuropathy.

A simple non-invasive indicator test (Neuropad(®)) has been developed for the assessment of sweating and, hence, cholinergic innervation in the diabetic foot. The present review summarizes current knowledge on this diagnostic test. The diagnostic ability of this test is based on a colour change from blue to pink at 10 min, with excellent reproducibility, which lends itself to patient self-examination. It has a high sensitivity (65.1-100%) and negative predictive value (63-100%), with moderate specificity (32-78.5%) and positive predictive value (23.3-93.2%) for the diagnosis of diabetic peripheral neuropathy. It also has moderate to high sensitivity (59.1-89%) and negative predictive value (64.7-91%), but low to moderate specificity (27-78%) and positive predictive value (24-48.6%) for the diagnosis of diabetic cardiac autonomic neuropathy. There are some data to suggest that Neuropad can detect early diabetic neuropathy, but this needs further evaluation. It remains to be established whether this test can predict foot ulceration and amputation, thereby contributing to the identification of high-risk patients.

Validation of DN4 as a screening tool for neuropathic pain in painful diabetic polyneuropathy.

AIMS: DN4 (Douleur Neuropathique en 4 Questions) is a screening tool for neuropathic pain consisting of interview questions (DN4-interview) and physical tests. It has not formally been validated in diabetes. We evaluated the validity and diagnostic accuracy of DN4 and DN4-interview in identifying neuropathic pain of painful diabetic polyneuropathy. METHODS: In 158 patients with diabetes, the presence of diabetic polyneuropathy and neuropathic pain was assessed using scoring system for symptoms and signs, quantitative sensory testing, nerve conduction studies, pain history, numerical rating scale, and Short-Form McGill Pain Questionnaire. Painful diabetic polyneuropathy was defined as the presence of diabetic polyneuropathy plus chronic neuropathic pain in the same area as neuropathic deficits. A blinded investigator performed DN4. RESULTS: The DN4 score was significantly related to all the neurological and electrophysiological measurements and to Short-Form McGill Pain Questionnaire (ρ = 0.58, P < 0.0001). DN4 and DN4-interview scores showed a high diagnostic accuracy for painful diabetic polyneuropathy with areas under the receiver operating characteristic curve of 0.94 and 0.93, respectively. At the cut-off of 4, DN4 displayed sensitivity of 80%, specificity of 92%, positive predictive value (PPV) of 82%, negative predictive value (NPV) of 91%, and likelihood ratio for a positive result (LR(+) ) of 9.6. At the cut-off of 3, DN4-interview showed sensitivity and specificity of 84%, PPV of 71%, NPV of 92%, and LR(+) of 5.3. CONCLUSIONS: This is the first validation study of DN4 for painful diabetic polyneuropathy, which supports its usefulness as both a screening tool for neuropathic pain in diabetes and a reliable component of the diagnostic work up for painful diabetic polyneuropathy.

Recommendations for the use of cardiovascular tests in diagnosing diabetic autonomic neuropathy.

Despite its prevalence, clinical and prognostic impact, diabetic autonomic neuropathy, is widely under-diagnosed. The need for training and expertise to perform the cardiovascular tests (usually the task of diabetologists) is one possible reason. The availability of computer-assisted systems has allowed a wider diffusion of testing, but has also highlighted the need for an adequate knowledge of physiopathological backgrounds for their correct application and interpretation. The recommendations presented here were developed by the Neuropathy Study Group of the Italian Society of Diabetology and then endorsed by the Italian Association for the Study of Neurovegetative System, to promote the widespread adoption of good clinical practice in diabetic cardiovascular autonomic testing by outlining main evidence-based aspects, i.e. which tests, how to perform them, adequate interpretation of the results and their diagnostic use, confounding conditions that can impact on tests reliability. Therefore, these recommendations include the essential aspects of the physiopathological substrate of the tests, the controversial points in their analysis, their diagnostic characteristics, as well as safety. Detailed information is given on the physiological (age, weight, body position, resting heart rate and blood pressure, respiratory pattern, exercise, meals, acute blood glucose changes) and pathophysiological confounding factors, with emphasis on the effects of drugs. Instructions on how to perform the tests and interpret their results are also considered together with indications of candidate patients and periodicity of testing. A patient instruction sheet on why and how to perform the tests is included. Finally, the specific requirements for computerized systems to perform and evaluate cardiovascular tests are provided.

Neuropad as a diagnostic tool for diabetic autonomic and sensorimotor neuropathy.

AIMS: The aim of the present study was to determine the diagnostic accuracy of the Neuropad sudomotor test for diabetic cardiovascular autonomic neuropathy (CAN) and diabetic polyneuropathy (DPN), the latter assessed using a multi-level diagnostic approach. METHODS: In 51 diabetic patients, CAN, symptoms and signs of DPN, vibration perception threshold (VPT), cold (CTT) and warm thermal perception thresholds (WTT) were measured. Neuropad response was determined as normal (complete colour change) or abnormal (absent or incomplete colour change). The time until the complete colour change (CCC time) was recorded. RESULTS: CCC time showed significant correlations with all the neurological parameters, the strongest of which were with Valsalva ratio (rho = -0.64, P < 0.0001), symptoms of DPN (rho = 0.66, P < 0.0001), postural hypotension (rho = 0.54, P = 0.0001) and CTT (rho = -0.54, P = 0.0001). CCC time showed moderate diagnostic accuracy for both CAN and DPN: the areas under the receiver operating characteristic (ROC) curves were 0.71 and 0.76, respectively. The diagnostic characteristics of three cut-off values of CCC time, identified by ROC analysis (i.e. 10, 15 and 18 min), were analysed. Compared with 10 min, the 15-min cut-off value provided better specificity (from 27% to 52% and from 31% to 62% for CAN and DPN, respectively) and a better likelihood ratio for negative result (from 0.67 to 0.34 and from 0.58 to 0.33) without lowering sensitivity (from 82% to 82% and from 85% to 80%). CONCLUSIONS: Neuropad is a reliable diagnostic tool for both CAN and DPN, albeit of only moderate accuracy. Extending the observation period to 15 min provides greater diagnostic usefulness.

Usefulness of ambulatory blood pressure monitoring in predicting the presence of autonomic neuropathy in type I diabetic patients.

This study investigated whether nondipping (defined as a day-night change in blood pressure (BP)

Validation of the nerve axon reflex for the assessment of small nerve fibre dysfunction.

OBJECTIVE: To validate nerve-axon reflex-related vasodilatation as an objective method to evaluate C-nociceptive fibre function by comparing it with the standard diagnostic criteria. METHODS: Neuropathy was evaluated in 41 patients with diabetes (26 men and 15 women) without peripheral vascular disease by assessing the Neuropathy Symptom Score, the Neuropathy Disability Score (NDS), the vibration perception threshold (VPT), the heat detection threshold (HDT), nerve conduction parameters and standard cardiovascular tests. The neurovascular response to 1% acetylcholine (Ach) iontophoresis was measured at the forearm and at both feet by laser flowmetry. An age-matched and sex-matched control group of 10 healthy people was also included. RESULTS: Significant correlations were observed between the neurovascular response at the foot and HDT (r(s) = -0.658; p<0.0001), NDS (r(s) = -0.665; p<0.0001), VPT (r(s) = -0.548; p = 0.0005), tibial nerve conduction velocity (r(s) = 0.631; p = 0.0002), sural nerve amplitude (r(s) = 0.581; p = 0.0002) and autonomic function tests. According to the NDS, in patients with diabetes who had mild, moderate or severe neuropathy, a significantly lower neurovascular response was seen at the foot than in patients without neuropathy and controls. A neurovascular response <50% was found to be highly sensitive (90%), with a good specificity (74%), in identifying patients with diabetic neuropathy. CONCLUSION: Small-fibre dysfunction can be diagnosed reliably with neurovascular response assessment. This response is already reduced in the early stages of peripheral neuropathy, supporting the hypothesis that small-fibre impairment is an early event in the natural history of diabetic neuropathy.

Does autonomic neuropathy play a role in erythropoietin regulation in non-proteinuric Type 2 diabetic patients?

AIMS: Erythropoietin (EPO)-deficient anaemia has been described in Type 1 diabetic patients with both severe autonomic neuropathy (AN) and proteinuria. This study was aimed at distinguishing between the effects of AN and nephropathy on haemoglobin and EPO levels in Type 2 diabetic patients at an early stage of diabetic nephropathy. METHODS: In 64 Type 2 diabetic patients (age 52 +/- 10 years, duration 10 +/- 9 years) without overt nephropathy and other causes of anaemia or EPO deficit, we assessed cardiovascular tests of AN, 24-h blood pressure (BP) monitoring, urinary albumin excretion rate (UAE), a full blood count, and serum EPO. RESULTS: Although the Type 2 diabetic patients with AN did not show differences in haemoglobin and EPO when compared with patients without AN, the presence of haemoglobin < 13 g/dl was associated with the presence of AN (chi(2)= 3.9, P < 0.05) and of postural hypotension (chi(2)= 7.8, P < 0.05). In a multiple regression analysis including as independent variables gender, body mass index, duration of diabetes, smoking, creatinine, 24-h UAE, 24-h diastolic BP, ferritin, erythrocyte sedimentation rate, and autonomic score, we found that the only variables independently related to haematocrit were autonomic score, ferritin and erythrocyte sedimentation rate. Finally, the physiological inverse relationship between EPO and haemoglobin present in a control group of 42 non-diabetic non-anaemic subjects was completely lost in Type 2 diabetic patients. The slopes of the regression lines between EPO and haemoglobin of the control subjects and the Type 2 diabetic patients were significantly different (t = 14.4, P < 0.0001). CONCLUSIONS: This study documents an early abnormality of EPO regulation in Type 2 diabetes before clinical nephropathy and points to a contributory role of AN in EPO dysregulation.

Factors determining the 24-h blood pressure profile in normotensive patients with type 1 and type 2 diabetes.

Some controversy still exists about factors involved in the abnormal circadian pattern of blood pressure (BP) in diabetes, while prognostic value of non-dipping condition is being increasingly recognised. This study was aimed at evaluating the relative influence of autonomic neuropathy (AN) and albumin excretion on 24-h BP profile in type 1 and type 2 diabetes. We measured AN cardiovascular tests, 24-h ambulatory BP, and urinary albumin excretion rate (UAE) in 47 type 1 and 34 type 2 normotensive non-proteinuric diabetic patients. In type 1 diabetic patients day-night differences (Delta) in systolic and diastolic BP were lower in those with AN than in those without (3 +/- 9 vs 10 +/- 6%, P < 0.01, and 8 +/- 9 vs 16 +/- 6%, P < 0.001), and in univariate regression analysis they were inversely related to both autonomic score, index of degree of AN (r = -0.61, P < 0.001 and r = -0.65, P < 0.001), and to 24-h UAE (r = -0.39, P < 0.01 and r = -0.46, P < 0.001). In type 1 diabetic patients AN was also associated with lower nocturnal decrease in UAE (patients with AN vs without AN: -37 +/- 214 vs 49 +/- 37%, P < 0.05), and with a stronger relationship between simultaneous 24-h UAE and 24-h BP (for systolic BP patients with AN vs without AN: r = 0.62, P < 0.01 vs r = 0.28, NS). In type 2 diabetic patients Delta systolic BP was reduced in patients with AN compared to those without (4 +/- 7 vs 10 +/- 4%, P < 0.01), and it was related only to autonomic score (r = -0.42, P < 0.01). Using a stepwise regression analysis, in type 1 diabetic patients autonomic score was the variable of primary importance for Delta BP, while in type 2 diabetic patients it was the unique determinant not only of Delta systolic BP but also of 24-h systolic BP. In conclusion, AN is the pivotal factor of blunted nocturnal fall in BP in both type 1 and type 2 diabetic patients. In type 1 diabetic patients AN is associated with attenuated circadian pattern of albuminuria and with a steeper relationship between albuminuria and BP, in type 2 diabetic patients AN is the only factor related to elevated 24-h BP levels. Longitudinal studies are needed to establish the potential role of autonomic dysfunction as a progression promoter for nephropathy and hypertension in type 1 and type 2 diabetes respectively.

Assessment of sympathetic innervation of the heart in diabetes mellitus using 123I-MIBG.

Radio-labeled metaiodobenzylguanidine (MIBG) is considered an established sympathetic neuron imaging agent capable of scintigraphically visualizing the organs richly innervated by the sympathetic nervous system. Its clinical applications now include cardiac and pulmonary adrenergic imaging. The quantitative determination of global and/or regional abnormalities of MIBG heart uptake has been demonstrated to be very useful in several clinical settings representing one of the major determinants of adverse prognosis. The presence and the severity of autonomic neuropathy are known as important prognostic factors in patients with diabetes. MIBG scintigraphy is able to non-invasively assess and characterize the adrenergic abnormalities of the cardiac innervation also in these patients. In order to evaluate whether 123I-MIBG is able to reveal abnormalities of myocardial adrenergic function in different groups of diabetic patients, we performed 123I-MIBG scintigraphy in control subjects and in normotensive Type 1 diabetic patients with and without autonomic neuropathy (N+ and N- patients), selected according to results of cardiovascular reflex tests. Regional abnormalities of adrenergic innervation were revealed in 10% of control subjects, in 70% of N- patients and in 100% of N+ patients. The finding of a higher than expected prevalence of MIBG regional abnormalities in patients without signs or symptoms of autonomic neuropathy allows to hypothesize that cardiac autonomic nervous damage occurs earlier than previously known in diabetic patients whose cardiovascular tests are still completely normal.

Diagnosis of cardiovascular autonomic neuropathy in diabetes.

The utility of standard cardiovascular tests for diagnosis of cardiac autonomic neuropathy in diabetes has been well documented. Attention must be paid to standardizing the procedure with regard to time of day, metabolic status, distance from meal and insulin, coffee and smoking avoidance, and patient's collaboration. In the presence of cardiovascular disease or drugs affecting the cardiovascular or autonomic nervous system, some caution is needed in interpreting the results. More recent reflex tests, which evaluate mainly sympathetic or baroreflex activity, despite their ability to detect early autonomic involvement, lack sufficient standardization and still need to be proved as valid alternatives. Of the different methods of measuring heart rate variability, spectral analysis has a greater ability to differentiate vagal and sympathetic modulation of heart rate than do time-domain methods. However, since these latter methods are easier and more widely available, they can be used as a screening approach. Twenty-four-hour evaluation of heart rate variability provides data on the circadian rhythm of sympathovagal activity, which can be affected earlier than and differently from cardiovascular reflex tests. Information obtained could have prognostic implications in terms of cardiovascular morbidity and mortality and offer therapeutic opportunities. However, a wide consensus on many technical aspects of both time-domain and frequency-domain methods is needed. Furthermore, large prospective studies in the diabetic population to assess the prognostic value of 24-h heart rate variability parameters on cardiovascular morbidity and mortality are lacking. Recently, I123 meta-iodobenzylguanidine (MIBG) scintigraphy has documented abnormalities of sympathetic myocardial innervation also in newly diagnosed IDDM. The meaning of this finding, whether it is an expression of functional or structural defects, needs to be clarified. Preliminary data point to a possible pathogenetic meaning of the known association between autonomic neuropathy and other diabetic complications. This area of investigation could provide useful insights into the complex and multifactorial pathogenesis of diabetic complications.

Autonomic neuropathy: clinical and instrumental findings.

The development of sensitive techniques evaluating functions under autonomic control has allowed the early detection of widespread abnormalities in diabetes mellitus. However, despite a high frequency of functional abnormalities, an overt clinical syndrome develops slowly and is quite rare. Characteristic clinical features, more recent methods for evaluating autonomic function, diagnostic procedures, and main instrumental findings in a diabetic population are reported. Emphasis is given to more promising techniques evaluating autonomic control of the cardiovascular system, such as myocardial scintigraphy and assessment of 24-h blood pressure and heart rate variability. The clinical meaning of the number of functional abnormalities observed in diabetic patients is considered. While the role of autonomic neuropathy in the pathogenesis of gastrointestinal motor disorders, hypoglycaemia unawareness or diabetic impotence needs to be revised, the importance of autonomic-related sweating and blood flow abnormalities in the pathogenesis of diabetic foot lesions is now better documented. Moreover, growing evidence of the importance of autonomic control of cardiovascular system, together with cardiovascular dysfunction linked to diabetic autonomic neuropathy, supports the hypothesis of a possible role of autonomic neuropathy in the increased cardiovascular morbidity and mortality observed in diabetic patients.

Autonomic neuropathy and cardiovascular risk factors in insulin-dependent and non insulin-dependent diabetes.

In 97 IDDM and 64 NIDDM patients aged under 65 years, we evaluated the relationship between autonomic neuropathy (AN) and retinopathy, nephropathy, glycemic control and cardiovascular risk factors. Diabetes duration and HbA1 were significantly higher and body mass index was significantly lower in IDDM patients with AN compared to those without. In NIDDM only age was significantly higher in neuropathic patients. AN was associated with retinopathy in both IDDM (chi2 = 10, P < 0.03) and NIDDM patients (chi2 = 14, P < 0.007), while only in IDDM albumin excretion was significantly higher in patients with AN. Blood pressure (BP) was significantly higher in both IDDM and NIDDM patients with AN compared to those without. There were no differences in smoking and serum lipids between patients with and those without AN. We performed a multiple regression analysis using autonomic score, index of cardiovascular tests impairment, as the dependent variable and age, diabetes duration, body mass index, HbA1, albumin excretion, cholesterolemia, triglyceridemia, systolic BP, and retinopathy as independent variables. With this model in IDDM autonomic score was only related to body mass index (r = -0.29, P < 0.05), to HbA1 (r = 0.46, P < 0.001), and to systolic BP (r = 0.24, P < 0.05), while in NIDDM it was only related to systolic BP (r = 0.54, P < 0.001). In conclusion, AN was related to age in NIDDM, and to diabetes duration and glycemic control in IDDM. AN was associated with retinopathy, with nephropathy (only in IDDM), and with BP levels, but not with dyslipidemia, smoking, or obesity. Excess mortality rate observed in diabetic AN cannot be referred to an association with cardiovascular risk factors.

Twenty-four-hour pattern of blood pressure and spectral analysis of heart rate variability in diabetic patients with various degrees of autonomic neuropathy. Comparison to standard cardiovascular tests.

We performed four cardiovascular tests of autonomic function (deep breathing, lying to standing, Valsalva manoeuvre, postural hypotension) and simultaneous 24h recordings of blood pressure (BP) and ECG in 35 normotensive diabetic subjects. Autoregressive power spectrum analysis of RR interval variability was applied to 24h ECG recordings to obtain for day and night periods power of low- (0.03-0.15 Hz, LF) and high-frequency (0.18- 0.40 Hz, HF) components, relative markers of sympathetic and vagal activity respectively, and their ratio (LF/HF), assumed as index of sympathovagal balance. Eighteen patients showed normal cardiovascular tests, 6 patients one abnormal heart rate test, 5 patients two abnormal heart rate tests, and 6 patients also abnormal postural hypotension test. In diabetic patients with increasing degree of autonomic neuropathy, there was a progressive reduction of day-night change in systolic BP (p < 0.01), of LF during the day (p < 0.01), of HF during the night (p < 0.04), of day-night change in HF (p < 0.02), and of day-night change in HF/LF (p < 0.03). Day-night change in systolic BP was related to postural hypotension (p < 0.001) and to deep breathing (p < 0.01). Day LF was related to lying to standing (p < 0.001), to postural hypotension (p < 0.005) and to deep breathing (p < 0.007). Night HF was related to deep breathing (p < 0.0002) and to lying to standing (p < 0.02). Day-night change in HF/LF was slightly related to deep breathing, lying to standing, and to postural hypotension (p < 0.04). In a multiple regression analysis including age, diabetes duration, and cardiovascular tests as independent variables, day-night change in BP and day LF were only related to postural hypotension, whereas night HF was related to deep breathing. In conclusion, in diabetic patients with increasing autonomic damage, there is a progressive impairment of nocturnal fall of BP and of sympathetic activity during the day, blunted nocturnal increase of vagal activity and lower circadian variation in sympathovagal balance. The significant but not very close correlation of day-night pattern of BP and sympathovagal activity to standard cardiovascular reflex tests, supports the independent usefulness of 24h BP monitoring and spectral analysis of heart rate variability in diabetic neuropathy.

Relationship between autonomic neuropathy, 24-h blood pressure profile, and nephropathy in normotensive IDDM patients.

OBJECTIVE: To evaluate the relationship between autonomic neuropathy, nephropathy, and 24-h blood pressure (BP) pattern in insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: We studied 30 normotensive IDDM patients without overt nephropathy, divided into two groups and matched for age, duration of diabetes, and HbA1, according to the presence of cardiovascular autonomic neuropathy. We simultaneously measured 24-h BP and urinary albumin excretion rate (UAE) on urine collections timed overnight and at 2-h intervals during the day. RESULTS: Mean day and night systolic and diastolic BP values did not significantly differ between the groups. Mean night albuminuria was significantly higher in patients with autonomic neuropathy than in those without (61.4 +/- 104.6 [mean +/- SD] vs. 16 +/- 25.2 micrograms/min, P < 0.04). The percentages day-night changes in systolic BP, diastolic BP, and UAE were significantly lower in neuropathic patients (systolic BP: 2.4 +/- 7.7 vs. 9.6 +/- 4.2%, P < 0.001; diastolic BP: 8.4 +/- 6.9 vs. 15.5 +/- 5.4%, P < 0.002; UAE: -8 +/- 99.4 vs. 49.3 +/- 29.4%, P < 0.02) and were inversely related to autonomic score, index of autonomic neuropathy degree (r = -0.54, P < 0.002; r = -0.58, P < 0.001; and r = -0.53, P < 0.005, respectively). In patients with autonomic neuropathy, 2-h day periods and day and night UAE were more strongly related, respectively, to mean 2-h day periods (r = 0.58, P < 0.0001), day systolic BP (r = 0.67, P < 0.04), and night systolic BP (r = 0.69, P < 0.04) than in patients without autonomic neuropathy (2-h day periods: r = 0.32, P < 0.001; day: r = 0.37, NS; night: r = 0.35, NS). CONCLUSIONS: Autonomic neuropathy in IDDM patients is associated with reduced nocturnal falls in BP and UAE and with a stronger relationship of UAE to systolic BP. We suggest a pathogenetic role of autonomic neuropathy in the development of diabetic nephropathy through changes in nocturnal glomerular function and by enhanced kidney vulnerability to hemodynamic effects of BP.

Relationship between the circadian rhythms of blood pressure and sympathovagal balance in diabetic autonomic neuropathy.

In diabetic autonomic neuropathy, abnormal circadian patterns of blood pressure and sympathovagal balance with reduced fall of blood pressure and prevalence of sympathetic activity during the night have been described. To correlate the abnormalities of blood pressure to those of sympathovagal balance, we simultaneously performed 24-h noninvasive monitoring of blood pressure and ECG in 25 diabetic patients (45.6 +/- 13.6 yr of age with a 17.6 +/- 9.1 yr duration of diabetes) with various degrees of cardiovascular reflex impairment. Autoregressive power spectrum analysis of RR interval variability was applied to 24-h ECG recordings to obtain for day and night periods the mean power of low- (0.03-0.15 Hz) and high-frequency (0.18-0.40 Hz) components, which are relative markers of sympathetic and vagal activity, respectively, and their ratio (low frequency/high frequency), assumed as index of sympathovagal balance. Diabetic patients showed a lower percentage of day-night change in systolic blood pressure (9 +/- 5.48 vs. 11.6 +/- 4.78%, P < 0.037), a lower day low frequency (5.9 +/- 0.81 vs. 6.62 +/- 0.73 In-ms2, P < 0.001), a lower night high frequency (6.06 +/- 0.71 vs. 6.52 +/- 0.85 In-ms2, P < 0.05), a lower day low frequency:high frequency ratio (1.82 +/- 1.77 vs. 3.05 +/- 1.82, P < 0.01), and a lower percentage of day-night change in low-frequency:high frequency ratio (-13.4 +/- 109.9 vs. 28.7 +/- 29.7%, P < 0.05), when compared with control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)