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SUMMARYNon-diabetic individuals who are non-secretors of blood group antigens are prone to superficial infections by Candida albicans. In this study, 216 patients with diabetes mellitus who were denture wearers were examined for the presence or absence of denture stomatitis. There was an overall trend for non-secretors to be prone to denture stomatitis compared with secretors. Stepwise linear discriminant analysis was used to dissect the contribution of secretor status and other variables to the development of the disease. Secretor status was found to be a contributory factor among patients with non-insulin dependent diabetes but not among those with insulin-dependent diabetes. The possible reasons for this are discussed.

QT intervals were measured over RR intervals ranging from 500 ms to 1000 ms in 13 normal male subjects, 13 male diabetic subjects without and 13 with autonomic neuropathy. There was a close linear relationship between QT and RR in all subjects. The slope of the regression line was significantly greater in the autonomic neuropathy group than the normal group. Thirty-two male diabetic subjects with varying degrees of autonomic dysfunction had repeat QT measurements 3 (range 2-6) years later. QT and QTC lengthened significantly at the second visit, unrelated to age or time between recordings, but which corresponded with changes in autonomic function. Of 71 male diabetic subjects under 60 years followed for 3 years, 13 had died, 8 unexpectedly. Of those with autonomic neuropathy. QT and QTC were significantly longer in those who subsequently died, despite similar ages and duration of diabetes. We conclude that QT/RR interval relationships are altered in diabetic autonomic neuropathy, and that changes in QT length with time parallel changes in autonomic function. There may be an association between QT interval prolongation and the risk of dying unexpectedly in diabetic autonomic neuropathy.

The progression of subclinical polyneuropathy over 2.5 years has been studied in a representative group of 75 young patients with Type 1 (insulin-dependent) diabetes (initial age 16-19 years). The relationships between changes in nerve function, glycaemic control and concurrently developing microvascular complications (retinopathy, microproteinuria) were investigated. Deterioration of motor, sensory and autonomic nerve function, retinopathy and microproteinuria was related to poor glycaemic control. In addition, there was an association between developing neural and microvascular complications which was not diminished when their common relationship to hyperglycaemia was taken into account. These findings suggest that, although poor glycaemic control is an essential permissive factor in the early development of diabetic polyneuropathy, other influences, shared with microvascular complications, must also be important.

Five different methods of analysing R-R interval (heart rate) variation were compared, using a computer technique, in 61 diabetics with a wide range of responses to autonomic function testing. Two methods differentiated best between the diabetics with and without autonomic damage: (1) the standard deviation of the mean R-R interval recorded for 5 min during quiet breathing with the subject either sitting or standing; (2) the difference between the maximum and minimum heart rates recorded over 1 min during deep breathing at six breaths per minute, again with the subject either sitting or standing. For routine clinical usage we conclude that recording the heart rate for 1 min on an ECG, while the subject sits and breaths deeply at six breaths per minute, and then measuring the difference between the maximum and minimum heart rate, is the most practical method currently available. For research purposes either this method or the standard deviation method during quiet breathing for 5 min, should be used.

In a five year prospective study clinical features associated with the development and progress of retinopathy were sought in 296 randomly selected diabetic men aged 20-59. None had ophthalmoscopically detectable retinopathy initially, but during follow up 66 developed the condition (47 background, 10 exudative, 9 proliferative). Linear logistic analyses (two tailed tests) showed that the initial features independently predictive of retinopathy were duration of diabetes, poor glycaemic control, impotence, and--unexpectedly--heavy alcohol consumption. Poor glycaemic control in the interim and proteinuria at review were also associated with the development of retinopathy. No relation was found with smoking or obesity. Glycaemic control and alcohol consumption were therefore the only aetiologically relevant associations identified. The development of severe retinopathy (exudative and proliferative) showed a particular association with heavy alcohol consumption, occurring in nine of the 70 heavy drinkers (13%) compared with 10 (4.4%) of the rest. Alcohol consumption may be an important independent factor associated predictively with sight threatening diabetic retinopathy.

The immediate heart-rate response to standing was measured in 22 normal controls and 25 patients with diabetes, 15 of whom had autonomic neuropathy. The response in the controls and patients without autonomic neuropathy was characteristic and consistent, with tachycardia maximal at around the 15th beat and relative bradycardia maximal at around the 30th beat. The diabetics with autonomic neuropathy, however, showed a flat response. In three controls the response was abolished with intravenous atropine but not with propranolol, showing that it is mediated through the vagus. A simplified test using routine ECGs and measuring the R-R interval at beats 15 and 30 with a ruler is easily performed as an outpatient procedure and may be used as a measure of autonomic function in diabetes.

Summary We describe two insulin-dependent diabetic females who presented with severe hypoglycaemia associated with atrial fibrillation which reverted to sinus rhythm after intravenous dextrose. Atrial fibrillation has not previously been reported as a complication of hypoglycaemia in insulin-dependent diabetic patients.

Concentrations of total glycosylated haemoglobins (Hb A1) were measured in 40 diabetics at diagnosis and at monthly intervals after treatment with chlorpropamide, insulin, or diet alone was begun. The mean Hb A1 concentration at presentation in 16 patients treated with chlorpropamide was significantly higher than that in 12 patients treated with insulin, and the duration of glycaemic symptoms was much longer in the chlorpropamide-treated group. In contrast, the mean plasma glucose concentration was similar in both groups. The mean concentrations of Hb A1 and plasma glucose at diagnosis in the 12 patients treated by diet alone were lower than those in the other two groups, and most of these patients were free of symptoms. Treatment quickly relieved symptoms and lowered plasma glucose in all patients. The Hb A1 concentration fell significantly with treatment such that after two months there was no significant difference between the three groups, although results remained above the normal range. These findings support the theory that the Hb A1 concentration reflects the blood glucose control over the previous one to two months and suggest that the duration of hyperglycaemia may be important in determining the Hb A1 concentration as well as the absolute blood glucose concentration.

In order to investigate whether the ability of peripheral blood monocytes to bind bacteria is impaired in diabetes, we studied carbohydrate-binding ("lectin-like") receptors and the receptor for the Fc portion of immunoglobulin on monocytes from 25 male Type 1 (insulin-dependent) diabetic patients and 10 age-matched healthy control subjects. Peripheral blood monocytes from the diabetic patients expressed lower levels of "lectin-like" receptors compared to the control subjects, whereas the expression of the receptor for the Fc portion of immunoglobulin was similar in both populations. There was no correlation between the degree of "lectin-like" binding activity and plasma glucose concentration or glycaemic control. Recognition of unopsonized bacteria by the "lectin-like" receptor is impaired in Type 1 diabetes; this may affect the efficient elimination of potential pathogens.

Sexual responsiveness in 82 Type 1 (insulin-dependent) diabetic women was compared with that of 47 normal control subjects, using an interview method for rating various aspects of sexual response, and attitude questionnaires. The diabetic women were questioned about symptoms of autonomic neuropathy, and cardiovascular autonomic nerve function tests were performed. There were differences between the two groups in the reports of vaginal lubrication, but in most other respects the groups were similar. The diabetic women were not less orgasmic, and reported significantly fewer unpleasant feelings during sexual intercourse. They saw themselves and their husbands as less 'potent' than did the normal subjects. The possible enhancing effect of diabetes on the marriage of some diabetic women possibly counteracted the relatively mild physiological deficits involved. There was very little difference in sexual response between women with and without symptomatic autonomic neuropathy.

Twenty patients were changed from a single daily injection of beef insulin (a mixture of soluble and protamine zinc insulin) to two daily injections (mixtures of soluble and isophane insulins). This was associated with a reduction, one month later, in the concentration of glycosylated haemoglobin (HbA1) and in the degree of late evening glycosuria. A reduction was shown 6 months later in antibody binding of beef and pork insulin by serum. Subsequent conversion to a twice daily regime of highly purified pork insulin was not associated with further improvement in diabetic control, but was associated after 1 month with a reduction in daily insulin dose, and after 5 months with a further reduction in antibody binding of beef and pork insulin by serum. Patients failing to show a C-peptide response to intravenous glucagon had a fall in HbA1 after conversion from a once to a twice daily insulin regime, which correlated inversely with insulin antibody binding estimated at the beginning of the study.

This review attempts to outline the present understanding of diabetic autonomic neuropathy. The clinical features have been increasingly recognised but knowledge of the localization and morphology of the lesions and their pathogenesis remains fragmentary. A metabolic causation as postulated in somatic nerves accords best with clinical observations. Most bodily systems, particularly the cardiovascular, gastrointestinal and urogenital, are involved with added disturbances of thermoregulatory function and pupillary reflexes. Possible effects on neuroendocrine and peptidergic secretion and respiratory control await definition. Current interest centres around the development of a new generation of tests of autonomic nerve function that are simple, non-invasive, reproducible and allow precision in diagnosis and accurate quantitation. Most are based on cardiovascular reflexes and abnormality in them is assumed to reflect autonomic damage elsewhere. Probably no single test suffices and a battery of tests reflecting both parasympathetic and sympathetic function is preferable. Little is known of the natural history. The prevalence may be greater than previously suspected and although symptoms are mild in the majority, a few develop florid features. The relation of control and duration of diabetes to the onset and progression of autonomic neuropathy is not clearly established. Once tests of autonomic function become abnormal they usually remain abnormal. Symptomatic autonomic neuropathy carries a greatly increased mortality rate possibly due to indirect mechanisms such as renal failure and direct mechanisms such as cardio-respiratory arrest. Improved treatment of some of the more disabling symptoms has been possible in recent years.

Sixteen insulin dependent diabetics of long standing, with undetectable fasting plasma C peptide concentrations, and eight non-diabetic controls were each infused intravenously with biosynthetic human and highly purified beef insulin (1 mU/kg/min) while euglycaemia was maintained by a Biostator. No difference was observed between the two insulins in respect of insulin pharmacokinetics or biological action. The diabetics showed appreciable insulin resistance, manifested by a 40% reduction in the rate of insulin mediated glucose disposal, which was unrelated to the presence of insulin antibodies. Insulin binding antibodies, however, increased insulin's clearance rate and distribution space and prolonged its pharmacological and biological half lives. The rate at which insulin action was lost, after an intravenous infusion, was more rapid in diabetics without insulin antibody binding than in controls. In respect of their influence on insulin pharmacokinetics, moderate concentrations of insulin antibodies may be of positive advantage to all diabetics without endogenous insulin secretion and are not responsible for the insulin resistance of type 1 diabetes.

Gastric emptying was studied in 12 diabetic patients, six with and six without objective evidence of autonomic neuropathy and in 20 non-diabetic controls, using a double isotope scinti-scanning technique which differentiated between solid and liquid emptying. Three patients with autonomic neuropathy exhibited gastric stasis, although this was detected by conventional radiology in only one. Neither the patients with stasis nor those without exhibited abnormally rapid early gastric emptying. In patients without stasis, the normal differentiation between solid and liquid emptying was impaired, suggesting an abnormality of antral peristalsis not attributable to vagal denervation. Both intravenous and oral metoclopramide produced symptomatic improvement in two patients with gastric stasis and restored their gastric emptying to normal.

Testicular sensation was examined in 32 male diabetics with symptoms suggestive of autonomic neuropathy to evaluate its usefulness as a clinical sign in this condition. Vascular reflex responses to the Valsalva manoeuvre and sustained handgrip and blood pressure fall on standing were measured as objective tests of autonomic involvement. Absent or diminished testicular sensation correlated well both with the clinical features of autonomic neuropathy, except where impotence occurred alone, and with abnormal vascular reflexes. Most patients with impotence alone had normal testicular sensation and normal vascular reflexes. It is concluded that this sign is useful in diabetics with impotence, the presence of intact testicular sensation indicating that the impotence is unlikely to be due to autonomic neuropathy.