1. The release of arginine vasopressin (AVP) after an osmotic stimulus and head-up tilt was assessed in diabetic subjects with and without autonomic neuropathy 2. Six diabetic subjects with (DAN +ve) and five without (DAN − ve) evidence of autonomic neuropathy and five normal subjects were infused with 5% (w/v) NaCl at a rate of 0.05 ml min −1 kg −1 body weight for 120 min. Blood pressure, heart rate and plasma AVP were measured over this period 3. Seven DAN +ve, six DAN −ve and six normal subjects were tilted head-up to 45° for 120 min. Blood pressure, heart rate and plasma AVP were measured during the study 4. Infusion of 5% (w/v) NaCl produced appropriate rises in plasma osmolality and plasma AVP levels which did not differ between the three groups, confirming the normal osmotic release of AVP in the diabetic subjects 5. During head-up tilt, there were no differences in AVP responses between the three groups, despite a major hypotensive stimulus in the DAN + ve group 6. We conclude that osmotic release of AVP is normal in diabetes, but that cardiovascular release of AVP is impaired in diabetic subjects with cardiovascular reflex evidence of autonomic neuropathy, reflecting an afferent defect.

1. Diurnal patterns of urine output and sodium and potassium excretion were studied in 10 diabetic patients with and 10 without autonomic neuropathy, and in 10 normal subjects. 2. The diurnal patterns of excretion in the diabetic patients with autonomic neuropathy differed significantly from the two other groups, as a smaller proportion of the 24 h output of urine, sodium and potassium was excreted during the day and a larger proportion was excreted at night. 3. Similar changes were noted in the diurnal patterns of urinary kallikrein excretion in diabetic patients with autonomic neuropathy, and urinary kallikrein output correlated significantly with urine volume but not with urinary sodium excretion. 4. The diurnal patterns of excretion of urinary prostaglandin E 2 and 6-keto-PGF 1α were not significantly different in diabetic patients with autonomic neuropathy. 5. Nocturia was a common complaint in this group, and the number of nocturnal voidings correlated with night urine volume. There was no evidence of premature bladder emptying. 6. The changes observed in the day/night urine output and sodium excretion could not be explained by glycosuria, insulin regimens, impaired renal function or abnormal diurnal prostaglandin excretion; their possible relevance to the diurnal changes of urinary kallikrein excretion is discussed.

1. Unexplained cardiorespiratory arrests have been reported in patients with diabetic autonomic neuropathy and these could be due to denervation of the carotid chemoreceptors. 2. We have studied the ventilatory response to transient hypoxia ( ) during exercise in 22 male diabetic patients, six with symptomatic and cardiovascular evidence to suggest diabetic autonomic neuropathy (DAN+) and 12 without these features (DAN−). 3. There was no difference in the ventilatory response to transient hypoxia between the different groups of diabetic patients ( in DAN+ patients = −0·9 ± 0·2 litre min −1 kPa −1 ; in DAN− patients = −1·2 ± 0·6 litres min −1 kPa −1 ) even allowing for differences in the level of exercise achieved (CO 2 production in DAN+ patients = 743 ± 103 ml/min; CO 2 production in DAN– patients = 800 ± 144 ml/min). These results fell within our normal range for ventilatory response to transient hypoxia at this level of exercise. 4. The heart rate response to transient hypoxia varied within the groups but was significantly ( P < 0·05) less in the patients with established diabetic autonomic neuropathy. 5. We conclude that the peripheral chemoreceptors are intact in diabetic autonomic neuropathy and that other mechanisms must be implicated in the unexpected cardiorespiratory arrests seen in these patients. 1. Unexplained cardiorespiratory arrests have been reported in patients with diabetic autonomic neuropathy and these could be due to denervation of the carotid chemoreceptors. 2. We have studied the ventilatory response to transient hypoxia ( ) during exercise in 22 male diabetic patients, six with symptomatic and cardiovascular evidence to suggest diabetic autonomic neuropathy (DAN+) and 12 without these features (DAN−). 3. There was no difference in the ventilatory response to transient hypoxia between the different groups of diabetic patients ( in DAN+ patients = −0·9 ± 0·2 litre min −1 kPa −1 ; in DAN− patients = −1·2 ± 0·6 litres min −1 kPa −1 ) even allowing for differences in the level of exercise achieved (CO 2 production in DAN+ patients = 743 ± 103 ml/min; CO 2 production in DAN– patients = 800 ± 144 ml/min). These results fell within our normal range for ventilatory response to transient hypoxia at this level of exercise. 4. The heart rate response to transient hypoxia varied within the groups but was significantly ( P < 0·05) less in the patients with established diabetic autonomic neuropathy. 5. We conclude that the peripheral chemoreceptors are intact in diabetic autonomic neuropathy and that other mechanisms must be implicated in the unexpected cardiorespiratory arrests seen in these patients. 1. Unexplained cardiorespiratory arrests have been reported in patients with diabetic autonomic neuropathy and these could be due to denervation of the carotid chemoreceptors. 2. We have studied the ventilatory response to transient hypoxia ( ) during exercise in 22 male diabetic patients, six with symptomatic and cardiovascular evidence to suggest diabetic autonomic neuropathy (DAN+) and 12 without these features (DAN−). 3. There was no difference in the ventilatory response to transient hypoxia between the different groups of diabetic patients ( in DAN+ patients = −0·9 ± 0·2 litre min −1 kPa −1 ; in DAN− patients = −1·2 ± 0·6 litres min −1 kPa −1 ) even allowing for differences in the level of exercise achieved (CO 2 production in DAN+ patients = 743 ± 103 ml/min; CO 2 production in DAN– patients = 800 ± 144 ml/min). These results fell within our normal range for ventilatory response to transient hypoxia at this level of exercise. 4. The heart rate response to transient hypoxia varied within the groups but was significantly ( P < 0·05) less in the patients with established diabetic autonomic neuropathy. 5. We conclude that the peripheral chemoreceptors are intact in diabetic autonomic neuropathy and that other mechanisms must be implicated in the unexpected cardiorespiratory arrests seen in these patients.

1. The initial heart rate response to lying down was analysed in 18 younger (23–36 years) and 10 older (48–67 years) normal subjects, and consisted of an immediate shortening of the R—R interval reaching a maximum around the third or fourth beat after lying, followed by a lengthening beyond the resting value to reach a steady level around beats 25–30. In six diabetic patients with autonomic neuropathy, no cardiac acceleration occurred and the deceleration was markedly diminished. 2. In eight young normal subjects the pattern of response was altered by atropine, which abolished the initial shortening of the R—R interval over the first 10 beats. Thereafter slow but steady lengthening of the R—R interval occurred. With additional propranolol the later part of the response was further attenuated. Propranolol alone did not affect the normal pattern of response. 3. Six young normal subjects performed short periods of muscular exercise, lying, sitting and standing, and the heart rate patterns were compared with that after lying down. After both manoeuvres R—R interval shortened and then lengthened back to the resting level within 10–15 beats. Thereafter it remained steady after muscular exercise, but continued to lengthen after lying down. 4. In four young normal subjects, no initial R—R interval shortening occurred during fast or slow ‘passive’ tilting from the 80° head-up position to horizontal, whereas shortening was seen both with fast and slow ‘active’ lying down. 5. It is concluded that the immediate part of the heart rate response to lying down (during the first 10 beats) is under vagal control and the later part predominantly under sympathetic control. The first part of the response is probably due to a ‘muscle—heart’ reflex which occurs during the change in posture.

1. Forced expiratory flow rates and specific airways conductance were measured before and after the inhalation of the atropine-like drug ipratropium bromide in 11 diabetic patients with autonomic neuropathy and a control group of 11 diabetic patients without autonomic neuropathy. Respiratory muscle function was assessed by recording maximal inspiratory and expiratory mouth pressures. 2. There was no difference between the two groups of diabetic patients in airway calibre before ipratropium bromide or in maximal mouth pressures. 3. Bronchodilatation after ipratropium bromide was greater in the control group than in the autonomic neuropathy group of patients. 4. It is concluded that, despite the lack of clinical evidence of respiratory involvement, patients with diabetic autonomic neuropathy have reduced airway vagal tone.

1. The heart-rate response during sustained hand grip was studied in four normal subjects before and after intravenous atropine, propranolol and combined cardiac autonomic blockade with both drugs. The results suggest that the increase in heart rate during the first 30 s is due to parasympathetic withdrawal, whereas the further increase between 30 s and 180 s is probably mediated by a combination of parasympathetic withdrawal and sympathetic stimulation. 2. The increases in heart rate during each minute of sustained hand grip were compared in 26 normal subjects, 37 diabetic subjects without and 24 diabetic subjects with proven autonomic neuropathy. In the diabetic subjects with autonomic neuropathy the increase in heart rate during the first minute was impaired, whereas the increases during the second and third minutes were similar in all three groups. 3. The initial increase in heart rate over the first 30 s of hand grip and the later increase between 30 s and 180 s were compared in nine normal subjects, ten diabetic subjects without and six diabetic subjects with autonomic neuropathy. The increase during the first 30 s was impaired in the diabetic subjects with autonomic neuropathy, whereas the later phase of the response was similar in all three groups. 4. It is concluded that impairment of the heart-rate response to sustained hand grip in diabetic autonomic neuropathy is mainly due to impairment of the early parasympathetic phase, but that the presence of cardiac sympathetic damage can also be detected.

Clinical features of autonomic neuropathy include postural hypotension, sweating abnormalities, disturbance of body temperature regulation, gastric fullness and nausea, intermittent nocturnal diarrhoea, constipation, bladder problems and impotence. In diabetic patients, gustatory sweating and hypoglycaemic unawareness also sometimes occur (Johnson & Spalding, 1974). The onset of symptoms is usually insidious and permanent, but may occasionally be acute and reversible (Young, Asbury, Corbett & Adams, 1975). Autonomic dysfunction can arise from three main causes: first, those where the damage to the autonomic nervous system is isolated, as in primary postural hypotension (Bannister, Sever & Gross, 1977) and familial dysautonomia (Brunt & McKusick, 1970); secondly, those caused by toxic or pharmacological agents which interfere with autonomic reflexes; thirdly, those associated with systemic disease, of which diabetes mellitus is the most common. Other diseases which may cause autonomic dysfunction include amyloidosis, porphyria, tetanus, polyneuritis, tabes dorsalis, parkinsonism, chronic renal failure and alcoholism, and occasionally autonomic neuropathy has been associated with carcinoma of the bronchus or the pancreas (Johnson & Spalding, 1974). Although it is possible to localize lesions within the autonomic nervous system to afferent or efferent sympathetic or parasympathetic pathways (Johnson & Spalding, 1974; Moskowitz, 1977), many of the available tests are complex and invasive and often lack adequate control measurements (Young et al. , 1975). Because of the patchy nature of autonomic neuropathy, current interest has centred around the search for bedside tests that are ‘global’, reproducible and non-invasive. This review summarizes the present state of knowledge of simple tests of cardiovascular reflex function in the clinical evaluation of autonomic neuropathy, particularly in diabetic subjects.

1. The blood pressure and heart rate responses to static muscular exercise were measured in sixty normal subjects and 124 patients with diabetes mellitus, aged 25–54 years, during a standardized sustained handgrip test at 30% maximum voluntary contraction (MVC). 2. The normal range of the response was established. Females had a smaller blood pressure rise than males, and their MVC was lower. In the normal subjects there was a significant correlation between the size of the MVC and the height of the blood pressure response. The absolute muscle tension exerted should be taken into account in addition to the percentage MVC, when comparing responses to sustained exercise in different disease states. 3. The diabetic subjects showed a similar sex difference in their response. The mean diastolic blood pressure rises were smaller than in the control groups, both in males and females, but this was related to a smaller mean MVC. 4. Twenty-two of the diabetic subjects had an abnormally low response to sustained handgrip, which was not related to age, duration of diabetes, treatment or control of the disease. These diabetic subjects probably had damage of the autonomic fibres mediating the response. The findings would suggest that sustained handgrip is a useful and simple method of detecting involvement of the autonomic nervous system in diabetes.