Impaired Gastric Myoelectrical Activity in Patients with Chronic Renal Failure

Dysmotility and delayed emptying of the stomachhave been reported in patients with chronic renalfailure (CRF). The aim of this study was to investigatewhether gastric myoelectrical activity was impaired in patients with CRF using electrogastrography.The electrogastrogram (EGG) was recorded in 24symptomatic patients with CRF (15 with diabetes) and 12normal subjects. Two 30-min EGG recordings before and after a test meal were analyzed using spectralanalysis methods. It was found that patients with CRFshowed a significantly lower percentage of normal 2-4cpm slow waves in both fasting and fed states in comparison with healthy controls (in fastingstate: 88.9 ± 2.5% vs 67.4 ± 6.6%/63.27.0%, P < 0.01; in fed state: 89.6 ± 1.8% vs64.6 ± 6.2%/62.0 ± 8.3%, P < 0.01;controls vs diabetic patients/nondiabetic patients). Both patient groups showed a significantlyhigher prevalence of the abnormal EGG, which was definedas the percentage of 2-4 cpm slow waves lower than 70%(fasting state: 8% vs 60%/56%, P < 0.01/0.05; fed state: 0% vs 53%/56%, P < 0.005/0.002;controls vs diabetic patients/nondiabetic patients). Nosignificant difference was observed in the regularity ofthe gastric slow waves between the two patient groups. The healthy controls showed a significantincrease in the dominant power and frequency of the EGGafter the test meal. However, this increase was absentin the two patient groups. It was concluded that patients with chronic renal failure haveabnormal gastric myoelectrical activity, includingimpaired regularity of the gastric slow wave and afailed increase in the power of the EGG at 3 cpm.Electrogastrography is an attractive noninvasive method for thestudy of gastric motility in patients with severechronic renal failure.     

Effects of epalrestat,an aldose reductase inhibitor,on diabetic neuropathy and gastroparesis

OBJECTIVE: Diabetic patients with severe autonomic nervous disorder show delayed gastric emptying accompanied by diabetic gastroparesis, which decreases the electric activity of the stomach associated with gastric motility. It is reported that epalrestat, an aldose reductase inhibitor, is useful for treating diabetic neuropathy. Therefore, we evaluated whether this drug improves the decreased gastric motility in diabetic patients. METHODS: The present study evaluated the electrogastrograms (EGG) and autonomic nervous activity in 15 healthy volunteers (N group), and in 15 diabetic patients before and after the administration of epalrestat (DM group). Autonomic nervous activity was evaluated by spectral analysis of heart rate variability. The EGGs were recorded before and after oral administration of epalrestat (3 months or more) in the DM group. RESULTS: The dominant frequency of EGG was 3 cycles/min (cpm) in the N group. However, these 3 cpm waves disappeared with bradygastria, and postprandial increases in the peak powers of EGG were not observed in the DM group. Both the amplitude of 3 cpm waves and the postprandial peak powers were significantly increased after the administration of epalrestat. The parameters of autonomic nervous activities (LF power, HF power, and the LF/HF ratio) were significantly lower in the DM group before the administration of epalrestat than in the N group. However, these parameters were improved after the administration of epalrestat. CONCLUSION: Since gastroparesis is a form of diabetic dysautonomia, complication by gastroparesis may influence blood sugar control and the absorbance of oral antidiabetics. Epalrestat significantly increased the amplitude of 3 cpm waves on EGG and improved the spectral analytical parameters of heart rate variability. These findings suggest that epalrestat is useful for the treatment of diabetic gastroparesis.     

Gastric myoelectrical activity in diabetics with and without diabetic autonomic neuropathy

BACKGROUND/AIMS: The effects of diabetes mellitus on gastric myoelectrical activity has not been fully investigated. The aim of the present study was to investigate the pattern of gastric myoelectrical activity in noninsulin dependent diabetics, detected by electrogastrography in an attempt to clarify the relation between diabetic autonomic neuropathy and gastric myoelectrical abnormalities, if any. METHODOLOGY: The study was carried out on 34 noninsulin dependent diabetes (7 males, 27 females). Their age ranged from 35-60 years with mean age of 51.5 +/- 3.5 years. The EGG was recorded for 30 min in both the fasting and postprandial states, using an ambulatory EGG recording device (Digitrapper EGG, Synectics Medical). The adaptive spectral analysis method was used to assess the normality of the EGG. The EGG was defined as abnormal if: the percentage of normal slow waves (2.5-3.7 cycles/min) was below 70% during either the baseline or postprandial recording or there was a decrease in EGG peak power after the meal, or both. RESULTS: EGG abnormalities were detected in 13 patients (38.2%); 1 had tachygastria, 1 had bradygastria, 7 had dysrhythmias, and 4 had decreased EGG peak power after the meal. All diabetic patients with abnormal EGG suffer autonomic neuropathy. CONCLUSIONS: These results suggest that gastric myoelectrical abnormalities occur in a high proportion of noninsulin dependent diabetics and these abnormalities predominate in those patients with autonomic neuropathy.     

Helicobacter pylori prevalence in diabetic patients and its relationship with dyspepsia and autonomic neuropathy

AIMS: We evaluated the prevalence of Helicobacter pylori (HP) in Type 2 diabetic patients and its relationship with dyspeptic symptoms and complications of diabetes. MATERIALS AND METHODS: Seventy-eight Type 2 diabetic patients (54 females, 24 males, mean age: 51.9 +/- 10.6 yr) and 71 non-diabetic control subjects were involved in the study. Patients were questioned for dyspeptic symptoms. Cardiovascular autonomic neuropathy, nephropathy and retinopathy were investigated in diabetic patients. Upper gastrointestinal tract endoscopy was performed for all patients and gastric biopsies were obtained and searched for HP. RESULTS: Helicobacter pylori prevalence was significantly higher in diabetic patients than in control subjects (75.6 vs 46%, p < 0.05). No differences were found between women and men with regard to HP infection status in diabetic patients. There was no relation between HP and diabetic complications, nephropathy and retinopathy. Helicobacter pylori prevalence was significantly higher in diabetic patients with cardiovascular autonomic neuropathy than in diabetic patients without cardiovascular autonomic neuropathy (90.6 vs 44.0%, p < 0.02). Forty-seven subjects with diabetes had symptoms of dyspepsia (60.3%) and the prevalence of HP was higher in these patients (p < 0.002). CONCLUSION: There is a high prevalence of HP infection in diabetic patients and it is correlated with dyspeptic symptoms. Diabetic subjects complicated with cardiovascular autonomic neuropathy and dyspepsia are at high risk of HP infection and should be carefully investigated and considered for eradication therapy.     

Gastric Dysrhythmias and Delayed Gastric Emptying in Patients with Functional Dyspepsia

An association between dyspepsia, gastricmotility disorders, and myoelectrical abnormalities hasbeen noted. The objective of the present study was toinvestigate both antral myoelectrical activity and gastric emptying in patients with functionaldyspepsia (FD). Electrogastrography (EGG) was performedin 25 adult patients with FD, which had been evaluatedby score. After an overnight fast, for 1 hr in the pre- and postprandial state (370 kcalliquid-solid test meal) the following EGG parameterswere determined: dominant frequency [DF (cpm)], DF (%)in the normal range (2-4 cpm), bradygastria (<2 cpm), tachygastria (4-10 cpm), dominant frequencyinstability coefficient (DFIC), and postprandial tofasting power ratio (PR). The data were correlated toresults obtained in 20 age- and gender-matched controls. In addition, in 17 consecutive patients the EGGdata were compared to the gastric retention ofradionuclides after 60 min (liquid-solid phase labeledwith ^99mTc colloid). Patients with FDrevealed a preprandial increase in tachygastria compared to controls(P < 0.001). Of 17 FD, seven patients exhibiteddelayed gastric emptying (t60 retention >68%). Thesepatients showed significantly more pre- and postprandial tachygastrias than patients with normal gastricemptying (P < 0.05). The dyspeptic symptology and H.pylori status did not correlate with EGG andradioscintigraphy. Patients with FD frequently revealimpaired gastric emptying and increased tachygastria,which may have pathophysiological significance in someof these patients.     

Mental arithmetic stress as a test for evaluation of diabetic sympathetic autonomic neuropathy

The effects of a 1-min mental arithmetic stress test on heart rate change were studied in 72 Type 1 diabetic patients, 36 without and 36 with diabetic autonomic neuropathy (mean age 33 and 44 yr, respectively), and in 80 matched normal subjects. Variation in hand skin temperature was also recorded in 25 normal subjects and 30 diabetic patients without and 32 with autonomic neuropathy. While mental arithmetic rapidly reduced skin temperature of normal volunteers and of patients without autonomic neuropathy, no effect was found in autonomic neuropath (a drop of 0.63 +/- 0.05 (+/- SE), 0.52 +/- 0.04 and 0.16 +/- 0.02 degrees C (p less than 0.001), respectively). In control subjects and in diabetic patients without and with autonomic neuropathy the heart rate increase was 22.9 +/- 6.8 (+/- SD), 21.4 +/- 8.4 and 7.0 +/- 3.7 beats min-1, respectively (p less than 0.001). The ratio between maximum mental arithmetic-induced heart rate and basal heart rate was 1.29 +/- 0.10, 1.24 +/- 0.10 and 1.07 +/- 0.05 (p less than 0.001) for healthy subjects, non-neuropathic patients, and neuropathic patients. Cut-off values (the low normal limit for these variables) are proposed: skin temperature 0.23 degrees C, heart rate increase 11.6 beats min-1 and heart rate ratio 1.12. Anxiety state, blood glucose concentration (excluding hypoglycaemia), body position, basal heart rate, and age did not interfere with responses to mental arithmetic stress.     

Alteration of gastric myoelectrical and autonomic activities with audio stimulation in healthy humans

OBJECTIVE: Cold or emotional stress was reported to affect gastric myoelectrical activity. The aim of this study was to investigate the effects of music or noise on gastric myoelectrical activity and autonomic function in healthy volunteers. MATERIALS AND METHODS: The study was performed in 10 fasted healthy volunteers and included 30 min at baseline, 30 min of classical music via headphones and 30 min of loud household noises via headphones. The electrogastrogram (EGG) readings were recorded simultaneously with the electrocardiogram (ECG) recording. RESULTS: Both classical music and noise altered the regularity of gastric slow waves. The percentage of normal 2-4 cycles/min (cpm) waves was reduced from 77.9 +/- 4.7% at baseline to 66.9 +/- 5.4% during music (p < 0.006) and 67.7 +/-5.4% during noise (p < 0.05). The reduction was attributed to a significant increase in bradygastria (15.8 +/- 3.9% versus 9.8 +/- 2.6%, p < 0.04) with the music and a significant increase in arrhythmia (7.4 +/- 1.6% versus 2.0 +/- 1.1%, p < 0.02) with the noise. The dominant frequency and power of the EGG were, however, not altered with either music or noise. Neither music nor noise had any effect on the autonomic function assessed by the heart rate variability. CONCLUSIONS: Audio stimulation, with both music and noise, alters the rhythmicity of gastric slow waves. Classical music seems to increase bradygastria, whereas, household noise may increase arrhythmia. The effect of audio stimulation on the gastric slow wave does not seem to involve sympathetic or vagal efferent pathways assessed by the spectral analysis of heart rate variability.     

Standing to lying heart rate variation. A new simple test in the diagnosis of diabetic autonomic neuropathy

We have examined the immediate heart-rate response to standing to lying (S-L) in 83 male insulin-dependent diabetic subjects aged 40 +/- 11 years (mean +/-S.D.) who underwent five other cardiovascular autonomic tests. Using a specially devised scoring system, the patients were divided into 3 groups: 54 subjects without autonomic neuropathy; 17 'borderlines'; 12 with autonomic neuropathy. The results were compared with those of 50 sex and age matched controls. We evaluated: S-L1 = ratio between R-R mean before lying and R-R minimum over the first 5 beats after lying; S-L2 = ratio between R-R maximum between the 20th to 25th beat and R-R minimum over the first 5 beats after lying. In controls S-L1 was 1.23 +/- 0.098 (mean +/- S.D.), S-L2 1.56 +/- 0.2. In diabetic subjects without autonomic neuropathy S-L1 was 1.18 +/- 0.096 (p less than 0.01), S-L2 1.50 +/- 0.23. In the autonomic group S-L1 was 1.03 +/- 0.01 (p less than 0.001), S-L2 1.16 +/- 0.086 (p less than 0.001). We propose that the lowest normal and highest abnormal limits of S-L1 are 1.10 and 1.07, respectively, and that normal and highest abnormal limits of S-L2 are 1.23 and 1.41, respectively. We suggest the use of S-L1 as a pure parasympathetic test and S-L2 as a mixed but predominantly sympathetic test in the diagnosis of autonomic neuropathy.     

QT interval prolongation and sudden cardiac death in diabetic autonomic neuropathy

Alterations in cardiac sympathetic innervation may result in QT interval prolongation and predispose to sudden arrhythmias and death. Sudden cardiac death occurs in diabetic patients who have autonomic neuropathy, but the cause is uncertain. In 30 patients with insulin-dependent diabetes mellitus who had no evidence of ischemic heart disease, cardiac autonomic neuropathy, determined by clinical tests, was found in 17. The corrected QT interval (QTc), measured using Bazett's formula at rest and peak exercise, was prolonged (greater than 440 msec) in 12 of these patients at rest and in 15 at peak exercise. Prolonged QTc intervals were found only in patients who had definite cardiac autonomic neuropathy. As a group, the QTc interval (mean +/- SD) in the diabetic patients with cardiac autonomic neuropathy was prolonged compared to that in patients without cardiac autonomic neuropathy at rest (447 +/- 28 vs. 405 +/- 9 ms; P less than 0.0001) and peak exercise (468 +/- 23 vs. 402 +/- 23 ms; P less than 0.0001). There was a direct linear relationship between the extent of cardiac autonomic neuropathy and the QTc interval (r = 0.71; P less than 0.001). One of the patients with cardiac autonomic neuropathy and prolonged QTc intervals had a nonuniform loss of adrenergic neurons in his heart demonstrated by meta-iodobenzyl-guanidine scintigraphy, indicating sympathetic imbalance; he subsequently died unexpectedly. These data suggest that diabetic cardiac autonomic neuropathy may result in sympathetic imbalance and QTc interval prolongation, predisposing these patients to sudden arrhythmias and death.     

Circadian patterns of heart rate variability, fibrinolytic activity, and hemostatic factors in type I diabetes mellitus with cardiac autonomic neuropathy.

Diabetes mellitus is associated with a marked increase in the risk of coronary events but with an altered circadian distribution that demonstrates an absent morning peak and higher infarction rate during the evening hours. To elucidate the mechanism of this phenomenon, the circadian pattern of heart rate variability was evaluated in 22 type I diabetic patients with diabetic autonomic neuropathy in conjunction with circadian changes of fibrinolytic and hemostatic factors. The circadian pattern (6 A.M. to 10 P.M. vs 10 P.M. to 6 A.M.) of 3 indexes of parasympathetic tone was evaluated using 24-hour heart rate variability analysis. The high-frequency power (3.0 +/- 0.2 vs 3.3 +/- 0.2 ms2, p = 0.08) and the percentage of RR intervals with >50 ms variation (0.47 +/- 0.18 vs 0.69 +/- 0.33 ms, p = 0.52) demonstrated no significant circadian variation. The square root of mean squared differences of successive RR intervals showed a small but significant increase during nighttime (8.5 +/- 0.7 vs 9.7 +/- 1.1 ms, p = 0.02). Fibrinolytic activity was significantly lower at 8 A.M. than at 4 P.M. (166.4 +/- 12.5 to 200.2 +/- 9.3 mm2, p = 0.0003), but with a low amplitude. Plasminogen activator inhibitor 1 showed no circadian variation. Factor VII and fibrinogen demonstrated a significant reduction from 8 A.M. to 4 P.M., but both peak and nadir values were elevated. The von Willebrand factor was markedly elevated with no circadian variation. Thus, diabetic autonomic neuropathy is associated with a loss of both the nocturnal predominance of parasympathetic activity and a prothrombotic state that persists throughout the day. These abnormalities may attenuate the relative protection from coronary events during the afternoon and nighttime.     

QT dispersion in type 2 diabetic patients with altered diurnal blood pressure rhythm

BACKGROUND: QT dispersion (QTd) is a good prognostic marker in type 2 diabetic patients without previous cardiovascular disease. Diabetic patients with an attenuated decline in nocturnal blood pressure (non-dippers) have been shown to have increased risk of diabetic complications, vascular events and mortality. AIM: The aim of this study was to evaluate the relationship between diurnal blood pressure rhythm, QTd and microvascular complications in type 2 diabetic patients. METHODS: Cardiovascular autonomic function tests, 24-h ambulatory blood pressure monitoring and urinary albumin excretion measurements were performed in healthy controls (n = 25), normoalbuminuric (n = 34) and microalbuminuric (n = 23) type 2 diabetic patients. QTd was assessed manually from 12-lead surface electrocardiograms. RESULTS: Compared with the controls, both normoalbuminuric and microalbuminuric diabetic patients had increased QTd (59.11 +/- 15.86; 60.27 +/- 17.95 vs. 40.48 +/- 10.92, p < 0.001 and p < 0.001, respectively). Similarly, diabetic patients had increased QTd regardless of the presence of autonomic neuropathy. On the other hand, non-dipper diabetic patients had increased QTd compared with the controls and dipper diabetic patients (69.73 +/- 14.50 vs. 40.48 +/- 10.92; 47.84 +/- 9.62 ms, p < 0.001). There was a negative correlation between QTd and diurnal diastolic blood pressure change (r = -0.48, p < 0.0005). CONCLUSION: Patients with type 2 diabetes mellitus were found to have increased QT dispersion irrespective of the presence of diabetic autonomic neuropathy. However, QT dispersion in dipper diabetic patients was similar to the controls. This finding might point out that attenuated decline of nocturnal blood pressure could be a more sensitive marker for autonomic neuropathy.     

Dissociated sensory loss in diabetic autonomic neuropathy.

Aims: Clinical observation has led to the idea that there might be a distinctive form of selective sensory and autonomic neuropathy affecting patients with Type 1 diabetic mellitus with severe symptomatic autonomic neuropathy (Type 1-DAN) and this study was conducted to evaluate the presence of such a neuropathy in Type 1-DAN. METHODS: Nineteen Type 1 diabetic patients presenting for treatment of severe symptomatic autonomic neuropathy were examined (all had > or = 2 autonomic symptoms; age 39.3 +/- 10.2 years; duration of disease 25.6 +/- 10.5 years). For comparison, 19 Type 1 diabetic patients with neuropathic foot ulcers (age 44.5 +/- 6.6 years; duration of disease 26.7 +/- 9.2 years), 14 clinically uncomplicated Type 1 diabetic patients (age 39.9 +/- 5.6 years; duration of disease 22.9 +/- 9.3 years) and 16 non-diabetic healthy people as controls (age 39.3 +/- 10.7 years) were also examined. Results The large fibre modalities (light touch and vibration perception) were better preserved in the Type 1-DAN group than in the foot ulcer group. Thus, light touch sensation was normal in 11 out of 19 Type 1-DAN patients compared to only three out of 19 foot ulcer patients (P < 0.01), and vibration perception was 24.9 +/- 15.0 V and 40.5 +/- 7.9 V, respectively (P < 0.002) with some of the Type 1-DAN patients in the normal range. In contrast, the small fibre modalities, thermal perception and autonomic function, were grossly abnormal in both groups (hot thermal perception 14.1 +/- 2.5 degrees C and 12.6 +/- 3.7 degrees C; cold thermal perception 13.8 +/- 2.7 degrees C and 10.9 +/- 4. 7 degrees C; heart rate variation 2.9 +/- 1.5 beats/min and 4.8 +/- 4.0 beats/min, respectively). CONCLUSIONS: There is indeed a subgroup of Type 1 diabetic neuropathy patients who suffer from severe autonomic symptoms associated with a selective small fibre sensory and autonomic loss with relatively preserved large fibre sensory modalities.     

Fasting and postprandial small intestinal slow waves non-invasively measured in subjects with total gastrectomy

BACKGROUND AND AIM: Slow wave is essential to initiate gastrointestinal tract motility. Subjects with total gastrectomy (TG) provide an opportunity to study small intestinal slow wave in the absence of stomach interference. The aims of this study were to determine the origin of 3 cycles per min (cpm) slow wave recorded via electrogastrogram (EGG) and the characteristics of putative small intestinal slow waves in TG subjects. METHODS: Thirty-three subjects with TG (25 male, age: 44-83 years) were consecutively enrolled. In each subject, the myoelectricity-like signals of the gastrointestinal tract were recorded using 3-channel EGG. Fourier transform-based spectral analysis was performed to derive the EGG parameters including dominant frequency/power, % normal rhythm (2-4 cpm), and power ratio. RESULTS: Neither visual nor spectral analysis of the EGG revealed any waves at a frequency of about 3 cpm. The most frequently observed peaks in the power spectra of all subjects were those at approximately 1, approximately 6 and approximately 11 cpm with occurrences of 97%, 6.1% and 90.9%, respectively. Based on visual analysis of all recorded signals, the approximately 11 cpm signal was exactly rhythmically recorded rather than the approximately 1 cpm. The recorded approximately 11 cpm wave had a frequency of 10.9 +/- 1.0 cpm in the fasting state and 10.9 +/- 1.3 cpm in the fed state (NS), and a power of 31.5 +/- 3.2 dB in the fasting state and 35.2 +/- 3.8 dB in the fed state (P < 0.0001). None of other factors, including sex, age, and body mass index, had any impact on this approximately 11 cpm wave. CONCLUSIONS: Small intestinal slow wave can be recorded non-invasively using EGG via cutaneous electrodes in TG subjects. Sex, age and body mass index have no effect on the intestinal slow waves. The power rather than frequency of intestinal slow wave is increased after a solid meal.     

Cardiovascular autonomic neuropathy associated with carotid atherosclerosis in Type 2 diabetic patients.

AIMS: To clarify if cardiovascular autonomic neuropathy is associated with carotid artery atherosclerotic plaques in Type 2 diabetic patients. METHODS: Cardiovascular autonomic nerve function was related to carotid artery ultrasound in 61 Type 2 diabetic patients 5-6 years after diagnosis of diabetes. RESULTS: Cardiovascular autonomic neuropathy [abnormal age corrected expiration/inspiration (E/I) ratio or acceleration index (AI)] was found in 13/61 (21%) patients. Patients with cardiovascular autonomic neuropathy showed increased degree of stenosis in the common carotid artery (24.6 +/- 13.2% vs. 14.7 +/- 9.2%; P = 0.014) and a tendency towards a higher plaque score (4.0 +/- 1.7 vs. 3.2 +/- 1.6; P = 0.064). Controlled for age, AI correlated inversely with degree of stenosis (r = -0.39; P = 0.005), plaque score (r = -0.39; P = 0.005), and mean (r = -0.33; P = 0.018) and maximum (r = -0.39; P = 0.004) intima-media thickness in the common carotid artery. In contrast, E/I ratio correlated only slightly with mean intima-media thickness in the common carotid artery (r = -0.28; P = 0.049). CONCLUSIONS: Cardiovascular autonomic neuropathy was associated with carotid atherosclerosis in Type 2 diabetic patients. Abnormal E/I ratios reflect efferent structural damage to parasympathetic nerves whereas abnormal AI reflects afferent autonomic dysfunction possibly due to impaired baroreceptor sensitivity secondary to carotid atherosclerosis.     

Non-invasive assessment of gastrointestinal motility disorders in diabetic patients with and without cardiovascular signs of autonomic neuropathy.

Twenty six patients with insulin dependent diabetes mellitus underwent a gastric emptying test, a gall bladder contraction test, an orocaecal transit study, and a colon transit test. Eleven patients had signs of cardiovascular autonomic neuropathy, 15 patients were without signs of cardiovascular autonomic neuropathy. Mean gastric clearance of radioopaque markers ingested with a meal averaged 29.5 (2.3) markers per six hours in subjects without cardiovascular autonomic neuropathy compared with 17.8 (2.3) markers per six hours in patients with cardiovascular autonomic neuropathy (p < 0.02). Gall bladder emptying in response to graded CCK8 stimulation was impaired in five of 11 patients with cardiovascular autonomic neuropathy, whereas it was normal in the patients without cardiovascular autonomic neuropathy (p < 0.01). Oral caecal transit times were not significantly different in the two patient groups, whereas colonic transit was slower in the patients with cardiovascular autonomic neuropathy compared with the group without cardiovascular autonomic neuropathy (p < 0.02). There was no correlation between disturbed gastric clearance, impaired gall bladder contraction, and prolonged colonic transit time in the patients with cardiovascular autonomic neuropathy nor was there a correlation between any disturbed motor function and age or duration of diabetes. It is concluded that autonomic neuropathy can affect motor functions throughout the gastro-intestinal tract. Any disturbed motor function in the gut could therefore be one of the numerous expressions of diabetic neuropathy affecting the cardiovascular, the endocrine or the gastrointestinal system.     

Cardiac autonomic neuropathy and its correlation with QTc dispersion in type 2 diabetes

This study was conducted on 50 patients of diabetes mellitus type 2 and 20 healthy controls to correlate severity of diabetic cardiac autonomic neuropathy with QTc interval and QTc dispersion. Five standard cardiovascular response tests were carried out (i.e. Valsalva ratio, expiration-inspiration ratio, immediate heart rate response to standing, fall of systolic blood pressure on standing and sustained hand grip test) to determine the severity of cardiac autonomic neuropathy by scoring system. QTc dispersion was determined by subtracting heart rate-corrected minimum QTc interval (QTc min) from maximum QT interval (QTc max) from standard electrocardiogram. Severity of cardiac autonomic neuropathy strongly correlated with QTc dispersion (r = 0.760; p = 0.0001). Correlation of severity of cardiac autonomic neuropathy with QTc max and QTc mean was also found but weaker than with QTc dispersion (r = 0.663, r = 0.542, p = 0.0001 each) and no correlation was found with QTc min (r = 0.177; p = 0.17). This shows that QTc dispersion is a better predictor of cardiac autonomic neuropathy than any of above three QTc intervals. QTc max, QTc mean and QTc dispersion were significantly higher (p < 0.001) in diabetics with autonomic neuropathy (450 +/- 23, 423 +/- 22 and 57 +/- 12 msec; n = 30) than without neuropathy (407 +/- 14, 397 +/- 15 and 20 +/- 7 msec; n = 20) and control subjects (408 +/- 20, 399 +/- 19 and 19 +/- 7 msec; n = 20) but QTc min remained same in the three groups (393 +/- 21, 387 +/- 12, 388 +/- 19 msec, respectively) (p > 0.05). Correlation of QTc dispersion was stronger with QTc max (r = 0.781; p < 0.001) than QTc mean (r = 0.625; p = 0.001) but not with QTc min (r = 0.097; p = 1.0) which suggests that regional increase in QT interval due to regional autonomic denervation leads to increased QTc dispersion. Thus, QTc dispersion is a sensitive, non-invasive, simple and cost-effective predictor of cardiac dysautonomia.     

Decreased alpha 2-adrenergic receptors on platelet membranes from diabetic patients with autonomic neuropathy and orthostatic hypotension

Platelet adrenergic receptors were studied in normal subjects and diabetic patients with autonomic neuropathy to determine the relationship between adrenoreceptor status and orthostatic hypotension. The binding of [3H]clonidine and [3H]yohimbine to platelet membranes was measured in diabetic patients with autonomic neuropathy and orthostatic hypotension (n = 12) and without orthostatic hypotension (n = 11), diabetic patients without autonomic neuropathy (n = 12), and normal subjects (n = 9). Mean basal and standing plasma norepinephrine levels were not different in the four groups, and there was no relationship between orthostasis and norepinephrine responses. The diabetic patients with orthostatic hypotension had a significantly greater fall in mean blood pressure [31 +/- 2.8 (+/- SE) mm Hg] than any of the other three groups. Diabetic patients with diabetic autonomic neuropathy and orthostatic hypotension had a 30-40% decrease in number of platelet alpha 2-adrenergic receptors, as demonstrated by [3H]clonidine and [3H]yohimbine binding. The maximum number of binding sites for clonidine was 34 +/- 2.8 (+/- SE) fmol/mg protein in normal subjects, 27.4 +/- 3.4 in diabetic patients with neuropathy, 26 +/- 2.5 in diabetic patients with autonomic neuropathy without orthostatic hypotension, and 20.4 +/- 3.8 fmol/mg protein in diabetic patients with autonomic neuropathy with orthostatic hypotension (P less than 0.001). The maximum number of binding sites for yohimbine was 112 +/- 12.6 in normal subjects, 127 +/- 10 in diabetic patients without orthostatic hypotension, and 87 +/- 12.4 fmol/mg protein in patients with diabetic autonomic neuropathy with orthostatic hypotension (P less than 0.001). Reduced platelet alpha 2-receptors are associated with postural hypotension in diabetic autonomic neuropathy. If applicable to the postjunctional alpha 2-adrenergic receptor on sympathetic neurons, reduced vascular responses to changes in posture would be expected despite normal or enhanced norepinephrine secretion.     

Autonomic neuropathy in streptozotocin diabetic rats: effect of acetyl-L-carnitine

The present study was designed to characterize cardiac autonomic neuropathy in streptozotocin-induced (45 mg/kg i.v.) diabetic rat by analysis of heart rate variability (HRV), and to assess, in this model, the effects of treatment with acetyl-L-carnitine (ALC). Heart rate was reduced in diabetic rats (332+/-22 vs. 411+/-35 beat per min; P<0.0001). This bradycardia was partly reversed with ALC (369+/-52 beat per min; P<0.05 vs. untreated). Both time- and frequency-domain parameters of HRV were significantly reduced in diabetic rats. The reduction of spectral power was around 50% at high frequencies and about 70% at low frequencies, suggesting a decrease of parasympathetic activity. Low/high frequency ratio was significantly decreased in diabetic rats suggesting decreased sympathetic tone, while nonlinear analysis indicated a reduction of the chaotic complexity of heart rate dynamics in diabetic rats. Standard deviation of heart rate in ALC-treated rats was significantly higher than in untreated diabetic rats (P<0.0001). ALC counteracts the reduction of the power spectrum observed in diabetic animals (P<0.0005) normalizing the spectra profile. ALC restored chaotic complexity of heart rate dynamics. These results on the whole indicate that both sympathetic and parasympathetic cardiac tone were reduced significantly in diabetic rats and that ALC treatment prevents the development of autonomic neuropathy in streptozotocin-induced diabetes in rats.     

Hemodynamic effects of octreotide in patients with autonomic neuropathy

BACKGROUND. The somatostatin analogue, ectrootide, is being used to treat postprandial hypotension in patients with autonomic neuropathy. Although the therapeutic effect of the drug is presumably secondary to a splanchnic vasoconstrictor action, its effect on splanchnic hemodynamics has never been characterized in patients with autonomic neuropathy. Moreover, it is unknown whether octreotide acts on other vascular beds in this group of patients or whether it affects cardiac output. We, therefore, measured splanchnic, forearm, and systemic vascular resistance and cardiac output before and after administering octreotide (0.4 microgram/kg s.c.) to patients with idiopathic autonomic neuropathy and diabetic autonomic neuropathy. METHODS AND RESULTS. Splanchnic blood flow was determined from the clearance of indocyanine green in seven patients. We observed that octreotide decreased splanchnic blood flow (from 850 +/- 77 to 664 +/- 48 ml/min, p less than 0.005), increased mean blood pressure (from 97 +/- 6 to 115 +/- 3 mm Hg, p less than 0.005), and increased splanchnic vascular resistance (from 0.118 +/- 0.012 to 0.18 +/- 0.018 mm Hg/ml/min, p less than 0.005). Forearm blood flow was measured by plethysmography in 13 patients. Octreotide increased forearm vascular resistance in patients with idiopathic autonomic neuropathy (n = 8) from 19.1 +/- 1.0 to 27.2 +/- 3.8 mm Hg/ml/min/100 ml forearm volume (p less than 0.01) and from 25.2 +/- 3.9 to 41.0 +/- 6.8 mm Hg/ml/min/100 ml (p less than 0.01) in patients with diabetic autonomic neuropathy (n = 5). Cardiac output was measured by two-dimensional echocardiography. Octreotide administration increased cardiac output in five of six patients with idiopathic autonomic neuropathy (from 4.4 +/- 0.4 to 5.0 +/- 0.5 l/min, p less than 0.02) and five of five patients with diabetic autonomic neuropathy (from 3.8 +/- 0.4 to 5.1 +/- 0.4 l/min, p less than 0.02). Systemic vascular resistance increased in patients with idiopathic autonomic neuropathy from 21.2 +/- 2 to 24.9 +/- 2.6 (p less than 0.05) but did not change in patients with diabetic autonomic neuropathy. CONCLUSION. The pressor effect of octreotide in patients with autonomic neuropathy is associated with increased splanchnic and forearm vascular resistance and with increased cardiac output.     

Cell-mediated immunity and symptomatic diabetic autonomic neuropathy

T lymphocytes have been implicated in the nerve damage observed in allergic experimental neuritis and in idiopathic polyneuritis. Symptomatic autonomic neuropathy in long-standing Type 1 diabetes is a rare and unexplained complication, and some preliminary evidence has suggested a pathogenetic role for the immune system. We have measured levels of activated T lymphocytes in 18 Type 1 diabetic patients with symptomatic autonomic neuropathy and in 16 matched patients with uncomplicated Type 1 diabetes. Purified T lymphocytes from peripheral blood were stained with a fluorescein-labelled monoclonal antibody directed to the activation marker HLA-DR and counted under UV microscopy. Percent DR positive T lymphocytes were significantly raised in the patients with autonomic neuropathy when compared with long-standing uncomplicated diabetic patients (8.2 +/- 4.2 vs 4.9 +/- 3.3%, p less than 0.01). This finding lends support for a role of the immune system in the development of autonomic neuropathy.