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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.

Two patients were treated with gastroenterostomy and vagotomy for intractable vomiting due to diabetic gastropathy. A morphometric examination of nerve fibres and capillaries in their resected abdominal vagi was performed and the results were compared with findings from two diabetic and two non-diabetic patients undergoing gastroenterostomy and vagotomy for duodenal ulceration. All four diabetic patients had pathological changes of a similar character: reduced myelinated fibre density, degeneration and regeneration of unmyelinated fibres, and capillary basement membrane thickening. Abnormalities were more pronounced in the two diabetic patients with gastropathy but intact and regenerating nerve fibres were still present. The findings support the view that vagal neuropathy could be a causal factor in diabetic gastropathy but imply that severe gastropathy with vomiting is not simply a consequence of autovagotomy. The morphological observations indicated that structural changes can occur in the autonomic nerves of diabetic patients who do not develop autonomic symptoms or have easily detectable abnormal autonomic physiology.

Endoneurial capillary abnormalities have been assessed quantitatively in sural nerve biopsies from diabetic patients with different syndromes of sensory polyneuropathy: chronic painful neuropathy, newly presenting painful neuropathy, and painless neuropathy associated with neurotrophic foot ulceration. Comparisons were made with age-matched nondiabetic control subjects. The diabetic groups showed no abnormality in capillary density or mean endoneurial area per fascicle. Compared with control subjects, all diabetic patients had an increase in mean capillary diameter, capillary wall thickness, and outer tunic (basement membrane and pericytes) thickness. The increase in wall thickness was most pronounced in patients with painless neuropathy (200%) and less marked in similar patients with painful neuropathy (100%). The pericyte volume fraction of the outer tunic was reduced in all diabetic patients, implying that basement membrane hypertrophy and reduplication were responsible for outer tunic thickening. There was evidence of endothelial cell hyperplasia rather than hypertrophy. There was a correlation between the degree of basement membrane thickening and the severity of myelinated fiber abnormality assessed neurophysiologically and morphologically. This study shows a link between the degree of endoneurial capillary basement membrane thickening, the type of neuropathology, and the clinical expression of neuropathy in diabetes mellitus.

The relationship between urinary sodium and dopamine excretion was investigated in 40 normal males and in 48 normotensive, Type 1 diabetic males, 11 with microalbuminuria and 37 with normal albumin excretion. In all three groups a significant correlation was demonstrated and the regression lines were similar. Thus, no evidence was found that a defect in dopamine mobilization contributes to the early renal pathophysiological changes of Type 1 diabetes.

An elevated peripheral leucocyte count is associated with an increased risk of myocardial infarction and progression of coronary artery disease. The aim of this study was to determine neutrophil count and activation, measured as an increase in plasma neutrophil elastase, in patients with stable ischaemic heart disease, insulin-dependent diabetes mellitus and essential hypertension compared with a comparable group of control subjects. Neutrophil count and neutrophil elastase were raised significantly for patients with ischaemic heart disease (p less than 0.005; p less than 0.002), diabetes mellitus (p less than 0.001; p less than 0.01) and hypertension (p less than 0.05; p less than 0.0001) respectively compared to the control subjects. Neutrophil elastase did not correlate with subject age or leucocyte count. This study confirms the association between leucocyte count and vascular disease, and is consistent with neutrophil activation contributing to the progression of vascular disease.

In diabetic subjects, polyol pathway activity might inhibit neutrophil function and cause nerve damage. The effects of ponalrestat, an aldose reductase inhibitor, were assessed on neutrophil intracellular killing of Escherichia coli and on autonomic function in diabetic subjects in a randomized double-blind, placebo-controlled, crossover trial. We studied 31 diabetic subjects with autonomic dysfunction and 21 age- and sex-matched control subjects. During two 12-wk treatment periods, the diabetic subjects took either 600 mg of ponalrestat or matching placebo once daily. Neutrophil killing of E. coli was measured by a microbiological assay technique. Kmax by neutrophils from the diabetic subjects was lower than in the control group (Kmax of diabetic subjects 54.5 ± 26.4 vs. control subjects 67.3 ± 16.3, P = 0.045). Ponalrestat significantly increased bacterial killing in the diabetic subjects (Kmax of ponalrestat 75.1 ± 16.5 vs. placebo 58.2 ± 20.8, P = 0.003) so that there was no longer any significant difference in Kmax between the control subjects and the diabetic subjects on active treatment. Ponalrestat had no significant effect on a range of standard cardiovascular autonomic nerve function tests. We conclude that neutrophil killing of E. coli is impaired in diabetic subjects with autonomic dysfunction. This is restored to normal by ponalrestat.

The cause of the neuropathic pain that is experienced by some patients with diabetic neuropathy remains to be established. Early neuropathological reports, based on comparisons between diabetic patients and non-diabetic control subjects, emphasised associations between pathological changes in specific classes of peripheral nerve fibre and the presence of pain. By making comparisons with more appropriate control subjects, namely diabetic patients without neuropathic pain, more recent studies have found that there are few clear morphological correlates for this type of pain. To investigate this further, we have conducted a detailed morphometric study of sural nerve biopsies from six diabetic patients, four with active acute painful neuropathy and two with recent remission from the same condition. Normal values for the neuropathological parameters were obtained from six non-diabetic control subjects. Teased fibre analysis showed that similar axonal and Schwann cell abnormalities were present in both groups of diabetic patients. Electron microscopical studies revealed that evidence of both myelinated and unmyelinated fibre degeneration and regeneration was also present in the nerves of all diabetic patients, irrespective of whether they had pain. Within the constraints of interpreting results from small numbers of patients, our observations suggested that remission from pain might be associated with a less abnormal axon/Schwann cell calibre ratio, more successful myelinated fibre regeneration and less active unmyelinated fibre regeneration. However, the inescapable finding of this study was, in fact, the similarity in the nerve fibre pathology in diabetic patients with active and remitting painful neuropathy. We conclude that the occurrence of nerve fibre degeneration and regeneration is in itself unlikely to be sufficient to account fully for diabetic neuropathic pain. However, it is conceivable that events occurring during certain stages in the pathological cycle of degeneration and regeneration create the necessary circumstances which lead to pain.

The level of expression of three monocyte cell surface receptors was studied in seven patients with Type 1 (insulin-dependent) diabetes admitted to hospital with ketoacidosis. After recovery of metabolic control the monocyte carbohydrate-binding ('lectin-like') receptors that recognize bacterial cell wall sugars and receptors for complement components were reduced in the patients compared with normal control subjects. This was in contrast to the expression of the receptor for the Fc portion of immunoglobulin which remained unaltered. Compared with the control subjects the level of 'lectin-like' receptors was reduced by 22.8 +/- 6.5% (p less than 0.05) on admission to hospital and 12.1 +/- 1.7% (p less than 0.001) 6 weeks later when metabolic control had been established. The expression of complement receptors was 33.8 +/- 8.1% (p less than 0.01) lower than normal subjects when the diabetic patients suffered from ketoacidosis and 8.6 +/- 1.6% (p less than 0.01) lower than control subjects when patients had recovered metabolic control. The increased susceptibility to infection seen in diabetic patients, and the high incidence of infection in patients with ketoacidosis, may be partially the result of these changes in monocyte recognition mechanisms.

We evaluated neuropathological abnormalities in sural nerve biopsies from 6 nondiabetic control subjects and 16 age-matched diabetic patients with different syndromes of sensory polyneuropathy (6 with chronic painful neuropathy [CPN], 4 with newly presenting painful neuropathy [NPN], and 6 with painless neuropathy associated with recurrent neurotrophic foot ulcers [RFU]). Although all but one of the evaluated features of myelinated and unmyelinated fiber pathology could be found in every diabetic patient, certain myelinated fiber abnormalities were associated with the clinical characteristics of the neuropathy. Thus, myelinated fiber density was severely reduced, “empty” Schwann tubes (an index of myelinated fiber degeneration) were increased, and early regeneration (bands of Bungner [BB], nonmyelinated axons) was pronounced in the RFU group. Progression from BB to regenerating myelinated fiber cluster (myelination and maturation) was more successful in patients with CPN and NPN than in those with RFU, and the finding of fibers with disproportionately large Schwann cells (cytoplasm and myelin) relative to axon caliber was exclusive to patients with neuropathic pain. We concluded that 1) unequal rates of successful fiber regeneration may cunderlie the apparent difference in the extent of myelinated fiber loss between painful and painless diabetic polyneuropathy; 2) myelinated and unmyelinated fiber degeneration and regeneration per se are probably not the cause of neuropathic pain in diabetic polyneuropathy, because each occurred in patients with RFU; and 3) axonal atrophy may be involved in neuropathic pain generation.

Plasma prolactin concentrations were compared in 7 insulin-dependent diabetics (IDD) without clinical evidence of microangiopathy and 6 non-diabetic controls matched for age and sex under basal conditions and in response to an i.v. infusion of arginine. Both groups exhibited a significant elevation in plasma prolactin concentration in response to the arginine infusion. There were no significant differences in basal prolactin concentrations nor in the prolactin response to the arginine infusion when comparing IDD and controls. Insulin-dependent diabetes is therefore not accompanied by a generalized hypothalamic disturbance and it seems likely that prolactin physiology is uninfluenced by the disorder of insulin-dependent diabetes under these circumstances.

Autonomic mechanisms underlying the initial heart rate response to standing were analyzed in nine normal subjects. The normal pattern of response was altered by atropine to a small and gradual R-R interval shortening over 30 beats, with no rebound R-R interval lengthening. With additional propranolol, R-R interval shortening was even less and confined to the first 15-20 beats, whereas propranolol alone did not affect the normal response pattern, showing that this is under vagal control with increased cardiac sympathetic activity occurring only if the vagus is blocked. The response was reproducible in 23 normal subjects. Heart rate variation during quiet standing was almost completely abolished by atropine, but unaffected by propranolol, confirming that it is also under vagal control. In four normal subjects no rebound R-R interval lengthening occurred during either "fast" or "slow" tilt, whereas it was present during both "slow" and "fast" standing. The rebound R-R interval lengthening is determined by the muscular activity involved in standing up, rather than by the speed of the maneuver.

Six normal subjects and 16 insulin-dependent diabetics with varying degrees of autonomic damage each had blood sampled for norepinephrine and pancreatic polypeptide for fifteen minutes after a mixed meal and intravenous (IV) edrophonium (Tensilon). The normal subjects showed a brisk but short-lived rise in norepinephrine after edrophonium (average maximum increase 70% between 2 and 6 minutes), as did most diabetics. However, diabetics with cardiovascular reflex evidence of sympathetic damage showed no rise in norepinephrine. Pancreatic polypeptide concentrations increased up to 400% above baseline after a mixed meal in both the normal and the diabetic group with normal cardiovascular reflexes. There was no significant rise in pancreatic polypeptide either in the diabetics with parasympathetic damage alone or in those with additional sympathetic damage. These results provide further evidence for the diffuse nature of the damage in diabetic autonomic neuropathy.

1. Twelve male diabetic patients inhaled nebulized histamine in doubling concentrations from 0.03 mg/ml to 32 mg/ml until they reached the maximum concentration or until their forced expiratory volume in 1 s (FEV1.0) fell by at least 20%. Six had evidence of severe autonomic neuropathy (DAN), while the other six did not. 2. More of the DAN group decreased their FEV1.0 on histamine inhalation by at least 20% (P < 0.02) and more of them decreased their maximal flow at 50% vital capacity by at least 20% than those in the group without DAN (P < 0.05). 3. The fall in FEV1.0 and in maximal flow at 50% of vital capacity was greater (P < 0.05) in the DAN group than in the group without DAN. 4. This suggests that diabetic patients with autonomic neuropathy have increased bronchial reactivity to histamine. This could either be due to differential damage of the respiratory autonomic nerves or, alternatively, to denervation hypersensitivity.

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.

The acute effect of inhibition of prostaglandin synthesis with indomethacin 50 mg by mouth on renal haemodynamics has been examined in 8 male Type 1 diabetic patients with elevated glomerular filtration rate who were free of diabetic complications. Renal plasma flow and glomerular filtration rate were measured by constant infusion of para-amino hippurate and polyfructosan, the patients being studied at normoglycaemia. Urinary excretion of prostaglandin E2 fell from 885 +/- 160 to 345 +/- 115 pg min-1, and excretion of 6-keto-prostaglandin F1 alpha fell from 489 +/- 77 to 283 +/- 50 pg min-1. There was no change in renal plasma flow or glomerular filtration rate following indomethacin. The results do not support the hypothesis that increased renal prostaglandin synthesis is a cause of hyperfiltration in diabetes mellitus.

Hypoglycemia is a serious problem in insulin-treated diabetic patients. In this study the efficacy of intravenous glucagon (1 mg) was compared with that of intravenous dextrose (25 g) in the treatment of hypoglycemia in insulin-treated patients attending an accident and emergency department. In addition, the prevailing glycemic control of these patients was compared with patients routinely attending a diabetic outpatient clinic. Both intravenous glucagon and dextrose were effective in the treatment of hypoglycemic coma. There was a difference in the glycemic profile after intravenous glucagon compared with intravenous dextrose, and recovery of a normal level of consciousness after glucagon was slower than after dextrose (6.5 vs. 4.0 min, respectively; P < .001), although the average duration of hypoglycemic coma was 1.4 h. The glucagon- and dextrose-treated groups had significantly lower HbA1 than comparable patients routinely attending the clinic (9.5 ± 0.8 vs. 12.0 ± 3.8%, respectively; P < .001). In view of the ease of administration and the small risk of vascular and extravascular complications, intravenous glucagon appears to be a useful alternative to intravenous dextrose in the treatment of severe hypoglycemia.

This study was designed to assess the density characteristics of platelets from controls (N = 10) and three groups of diabetics (N = 32) exhibiting various degrees of glycemic control. With continuous gradients of Percoll, platelets from controls and diabetics (N = 8) with an HbA1 less than or equal to 9% formed a band extending from 1.0625 g/ml to 1.0925 g/ml with a mean platelet density of 1.0775 g/ml. In the two groups of diabetics with HbA1 greater than or equal to 10%, there was an increase in the proportion of low-density platelets recovered on the gradients and the mean platelet density was reduced to 1.0750 g/ml (HbA1 = 10-13%) and 1.070 g/ml (HbA1 greater than or equal to 14%). All three groups of diabetics had normal levels of intraplatelet ATP/ADP and beta-thromboglobulin. It is unlikely that in vivo degranulation of platelets after activation was responsible for the altered density profiles. We propose that abnormal platelet subpopulations with low density but normal intraplatelet granule content were responsible for the changed density profiles.

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 E2 and 6-keto-PGF1α 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.

Twenty-nine diabetic patients (19 men, 10 women) aged 19–71 yr with newly developed painful polyneuropathy were studied prospectively for 12–18 mo. Pain remitted completely in 16 patients within 12 mo, but continued in the other 13 patients. At presentation, no differences were found in the type or prevalence of symptoms or neurophysiological measurements (electrophysiology and cardiovascular autonomic function tests) between the patients whose pain remitted and those whose pain continued. Most electrophysiological measurements improved slightly in remitting patients but deteriorated slightly in those whose pain continued to reveal a significant difference (P < .05) between the groups on final review. Similarly, abnormal autonomic nerve function improved slightly when pain remitted but worsened or persisted in patients whose pain continued, again revealing a significant difference between the groups (P < .05) on final review. We also observed that pain remission usually occurred if the onset of symptoms shortly followed some sudden metabolic change (e.g., rapid improvement in glycemic control, ketoacidosis, anorexia nervosa) when the duration of diabetes was relatively short or when considerable weight loss preceded the onset of pain. We suggest that remitting and chronic painful diabetic polyneuropathy have distinctive clinical features at presentation and detectable neurophysiological differences during their symptomatic evolution.

Insulin action and pharmacokinetics were compared, using the euglycaemic insulin clamp technique, in seven insulin-treated diabetics during the third trimester of pregnancy and one to three weeks post-partum. At an insulin infusion rate of 1 mU/kg/min, insulin mediated glucose disposal was significantly greater (p less than 0.02) following delivery (1.194 +/- 0.138 mmol/m2/min) than in pregnancy (0.761 +/- 0.072 mmol/m2/min) and the rate of decline in insulin mediated glucose disposal, at the end of the insulin infusion, was significantly greater (p less than 0.02) following delivery (24.78 +/- 4.22 mumol/m2/min2) than in pregnancy (15.17 +/- 2.00 mumol/m2/min2). The metabolic clearance rate, distribution space and pharmacological half-life of insulin were not significantly altered by pregnancy. These findings show that the third trimester of pregnancy is associated with steady state insulin resistance accompanied by a reduced rate of insulin deactivation, but normal insulin pharmacokinetics.

Fifty-one diabetic patients with mononeuropathies wereoneuropathy were studied to examine possible etiological factors, to determine the relationship with other diabetic complications, and to correlate with the presence and severity of background peripheral and autonomic neuropathy. The median, ulnar, and lateral popliteal nerves were most commonly affected and cranial neuropathy was relatively uncommon. When bilateral involvement of the same nerve was excluded, multiple mononeuropathies were found in only five patients. Median and ulnar mononeuropathy were gradual in onset and affected the dominant limb whereas other types of mononeuropathies were acute in onset with no predilection for either side. No consistent relationship was shown between the onset of mononeuropathy and age, sex, diabetic treatment, duration of diabetes, diabetic control, or other diabetic complications. In particular, there was no significant background peripheral and autonomic neuropathy, as assessed clinically and by objective tests, in almost one-half of the patients studied. It is concluded that diabetic mononeuropathy may occur independently of peripheral and autonomic neuropathy. It is possible, however, that a minimal degree of background damage, known to be present in all diabetic patients, may render them more susceptible than the general population to the various factors causing mononeuropathy.

The effect of long-term treatment with the aldose reductase inhibitor sorbinil (125 mg daily for 6 mo) was examined in 22 diabetic patients with subclinical abnormalities of nerve function. This was a placebo-controlled, double-blind crossover trial in which each of the two treatment periods lasted 6 mo. Peripheral nerve function was assessed electrophysiologically and by quantitative sensory testing; autonomie function was assessed by measurement of five cardiovascular reflexes and of mean heart rate from a 24-h ECG recording. Measurement of erythrocyte sorbitol concentrations demonstrated very significant inhibition of aldose reductase activity with sorbinil treatment, but no concomitant improvement in either peripheral or autonomie nerve function was observed.

A double-blind crossover study of fludrocortisone, 0.1 mg. twice daily, and placebo is reported in six diabetics with troublesome symptoms of postural hypotension due to autonomic neuropathy. During treatment with the active preparation there was an increase in the lying and tilted systolic blood pressure, a decrease in orthostatic tachycardia, and an increase in the total plasma volume and body weight, but with no change in plasma or urine osmolality. The symptoms of postural hypotension improved in four patients, while two patients with a low serum albumin developed ankle edema during treatment with fludrocortisone. It is concluded that fludrocortisone is effective in diabetics with symptomatic postural hypotension, but should be used with caution in patients with a low serum albumin.

Twenty-one normal subjects and 64 diabetics with varying severity of autonomic damage underwent 24-h ambulatory EKG monitoring. No diabetics had the “sick sinus syndrome,” and the frequency of arrhythmias was no higher than in the normal subjects. The diabetics had higher mean hourly heart rates, and with increasing autonomic damage there was reduction in diurnal heart rate variation. The mean waking and sleeping heart rates were higher in the diabetics. The maximum heart rates were not significantly different, but the minimum heart rates were significantly higher in the diabetics. These previously unrecognized abnormal 24-h heart rate patterns provide further evidence of damage to the heart rate-controlling mechanisms in diabetes mellitus.

Autonomic neuropathy is now well established as a relatively common and significant complication of diabetes mellitus. Its importance has been clarified in recent years during which the extent of autonomic control over all areas of body function has been defined. Using simple cardiovascular reflex tests, autonomic abnormalities can be demonstrated without any corresponding symptoms. The often stated concept of 'patchy' involvement in diabetic autonomic neuropathy should now be rejected as too should the view that autonomic neuropathy is either 'present' or 'absent' based on a single test result. When generalized and predominantly metabolic disturbances, as in diabetes, give rise to impaired nerve function, autonomic as well as somatic components of the nerve are affected. Where damage is severe this leads to the characteristic florid picture of symptomatic autonomic neuropathy with its particularly poor prognosis. For the physician in a busy clinic, much of the theoretical and experimental basis for autonomic neuropathy may not appear of direct relevance. However, he has now to be aware of the clinical implications of autonomic damage in the diabetic. This may have particular relevance in the care of the diabetic foot (see Chapter 10), the recognition of many of the vague symptoms associated with autonomic damage, the treatment of disabling features such as postural dizziness and nocturnal diarrhoea, and an awareness of the poor prognosis associated with symptomatic autonomic neuropathy. He will also need to be alert to the dangers of general anaesthesia in such patients, and the possibility of sudden unexpected deaths. Diabetic autonomic neuropathy causes widespread abnormalities, some of which are clinically apparent, some of which can be detected by sensitive tests, and others which have yet to be discovered. Inclusion of the neuropeptides and other hormones within the compass of autonomic control has opened up a whole new area of investigative interest, with many complex interrelationships which still need to be unravelled. This should lead to better understanding of the pathophysiological processes that cause damage to diabetic nerves. With so much research effort directed towards better glycaemic control and aldose reductase inhibitors (see Chapter 8), it may eventually be possible to reverse or prevent this potentially disabling and lethal complication of diabetes.

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.

Heart rate variation during three periods of single deep breaths and three periods of repeated deep breathing at 6 breaths/min was compared in 14 normal and 40 diabetic subjects. There were no differences between the two methods in either normals or diabetics, but the coefficient of variation was significantly smaller using the repeated deep breaths method. When the 6 periods of breathing were analysed separately, no 'training' effect could be detected. The first breath of the repeated deep breaths consistently produced the largest heart rate variation in 29% of the normals and 17% of the diabetics. We conclude that there is no advantage in using the single deep breath method to assess cardiac parasympathetic function in diabetics over the currently used 6 repeated deep breaths/min.

The clinical features and peripheral somatic and autonomic nerve function were studied in 10 diabetic subjects (nine men, one woman; mean age 59 yr, range 41–68 yr; mean duration of diabetes 20 yr, range 8 mo to 33 yr) with generalized small muscle wasting of the hands. Five patients were insulindependent and five non-insulin-dependent. Nine had retinopathy (two proiiferative, seven background), five nephropathy, two ischemic heart disease, and seven peripheral vascular disease. Nine patients Jiad clinical evidence of sensory peripheral neuropathy and absent reflexes in the lower limbs. Eight patients had distal sensory impairment and/or absent reflexes in the upper limbs. Seven had two or more symptoms of autonomic neuropathy. Nerve conduction measurements in the median, ulnar, and lateral popliteal nerves showed that all patients had moderate to severe polyneuropathy affecting both motor and sensory fibers. Nine had one or more abnormal cardiovascular autonomic function tests. Electromyography of affected muscles in the hands showed changes of chronic partial denervation and collateral reinnervation in all cases.

A double-blind, randomized, placebo-controlled cross-over trial of the aldose reductase inhibitor sorbinil was undertaken in 15 patients (age 35-68 yr) with chronic painful diabetic neuropathy. Treatment was evaluated by subjective pain responses, clinical examination, vibration perception threshold, motor and sensory nerve electrophysiology, and cardiovascular reflex tests of autonomic nerve function. Among the many measurements, only pain, tendon reflex scores, and sural sensory potential amplitude improved significantly during sorbinil administration, while scores of clinical sensory examination deteriorated. Four patients experienced an idiosyncratic reaction that rapidly recovered on discontinuing the drug. This study suggests that aldose reductase inhibitor treatment with suggests that aldose reductase inhibitor treatment with sorbinil may have an effect on symptomatic diabetic neuropathy in man.

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.

Lung volumes were measured by spirometry and helium-dilution technique in 28 young adult men with insulin-dependent diabetes mellitus (IDDM) of long duration and compared with 16 age- and height-matched adult men without diabetes. Reduced values for forced expiratory volume at 1 s, vital capacity, functional residual capacity, total lung capacity, residual volume, and single-breath carbon monoxide transfer factor were found for the IDDM patients compared to the control subjects. The results are consistent with reduced lung volumes in IDDM patients and did not correlate with the presence or absence of mild cheiroarthropathy but may relate to duration of diabetes.

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 plasma beta-thromboglobulin (βTG) content was measured in 56 diabetic patients with known complications of this disease, including neuropathy, retinopathy, and ischemie skin lesions. Although two patients were found to have elevated levels beyond the normal range, there was no significant difference between the diabetic group as a whole and the group of 35 controls. The significance of these findings with regard to the proposed contribution of small-vessel platelet sequestration in the pathogenesis of late complications of diabetes mellitus is discussed.

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.

In a group of 541 white diabetic men aged 20–59 yr attending one clinic it was found that 91 (15%) drank heavily, while a further 39 (7%) had frank alcoholism. The prevalence of symptomatic peripheral neuropathy was much higher in the 120 men who drank excessively. It is considered important, therefore, when treating diabetic patients with peripheral neuropathy not to assume that the diabetes itself is the cause in all cases. The alcoholic intake of the patient should be ascertained and, if excessive, it should be pointed out to the patient that this may well be the predominant factor causing symptoms.

Peripheral and autonomic nerve function was assessed at intervals over a 3-month period in seven diabetics after ketoacidosis. There was marked improvement in motor conduction velocity and terminal latency of both ulnar and common peroneal nerves in all patients. Five had one or more abnormal autonomic function tests but there were no consistent changes during the same period. It is postulated that peripheral nerves may be more susceptible to acute metabolic damage than autonomic fibres.

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.

Skin wrinkling, which may be dependent on peripheral autonomic innervation, was assessed in 100 normal and 42 diabetic subjects using a temperature-controlled water bath with immersion of the hands for 30 min. Markedly decreased skin wrinkling was observed in diabetic subjects and in manual workers, but did not correlate with cardiovascular tests of autonomic function, control, type or duration of diabetes, or diabetic complications. The cause of decreased skin wrinkling in people with diabetes is unexplained.

This study assessed the effect of the time interval between insulin injection and breakfast in determining subsequent postprandial glycaemic control and also whether this differed between highly purified porcine insulin and human insulin (crb) in six diabetic patients (age range 24-36 years, duration of diabetes greater than 10 years) usually treated with twice daily Actrapid MC and Monotard MC and with stable insulin requirements and diabetic control. On separate mornings each patient was given, after an overnight fast, their usual dose of either Actrapid MC and Monotard MC or Humulin S and Humulin Zn injected 5, 20, or 40 min before a standard breakfast. The postprandial glycaemic profile was not significantly different at any of the three time intervals with Actrapid MC and Monotard MC. However, with the human insulin the profile was significantly better at the 40 min interval than at the 5 min interval (p less than 0.05) and this was also better than any of the profiles with the porcine insulin, there being a significant difference between the two types of insulin (p less than 0.05). These findings suggest that the time interval between insulin injection and breakfast may be more important with human insulin than with porcine insulin.

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.

The vascular responses to the Valsalva manœuvre and sustained handgrip were measured in thirty-seven diabetics with signs and symptoms suggestive of autonomic neuropathy. The Valsalva manœuvre was abnormal in twenty-three (62%) and the handgrip was abnormal in fifteen (41%) of the patients. There was a significant correlation between the results of the two tests. The responses to the two tests were less abnormal in the fifteen patients with impotence alone, and only when this symptom was associated with other clinical features of diabetic autonomic neuropathy could it be reliably attributed to this disorder. Of the fourteen patients with postural hypotension, all had abnormal Valsalva responses, and eight had reduced handgrip responses. Motor-nerve-conduction studies showed that patients with these abnormal vascular reflexes had evidence of greater peripheral-nerve damage in their legs than those patients with normal responses. It is concluded that both the Valsalva and handgrip tests are useful in providing an objective assessment of the integrity of the autonomic nervous system in diabetes mellitus.

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.

Skin thickness is primarily determined by collagen content and is increased in insulin-dependent diabetes mellitus (IDDM). We measured skin thickness in 66 IDDM patients aged 24–38 yr and investigated whether it correlated with long-term glycemic control and the presence of certain diabetic complications. With univariate analysis, skin thickness was increased and significantly related to duration of diabetes (P < .001), previous glycemic control (P < .001), retinopathy (P < .001), cheiroarthropathy (P < .001), and vibrationperception threshold (P < .05). There was a negative correlation between forced expiratory volume at 1 s (P < .05) and vital capacity (P < .05) with duration of diabetes. Neither skin thickness nor ankle arteriomedial wall calcification correlated with abnormal autonomic function tests. When corrected for duration of diabetes, there was a weak correlation between skin thickness and glycemic control (P < .05) but no correlation with retinopathy, cheiroarthropathy, and vibration-perception threshold. This study confirms that there are widespread connective tissue changes in diabetes mellitus, although the biochemistry needs further elucidation.

The relative value of fructosamine as an alternative to glycosylated hemoglobin (HbA1) and other measures of glycemic control was assessed in 100 insulin-dependent (IDDM) and 104 non-insulin-dependent (NIDDM) diabetic patients. We measured HbA1 (by electrophoretic and affinity methods), plasma glucose, glycosylated plasma proteins, and fructosamine in blood taken at a single clinic visit. The values were compared both by correlation analysis and by considering whether the various indices of glycemic control placed the patients in the same clinical decision categories as they were in by the HbA1 (affinity) result. Fructosamine correlated moderately well with HbA1 (affinity; r = .8) and placed 71% of IDDM and 72% of NIDDM patients in the same clinical category of good, moderate, or poor control. Differences can probably be partly attributed to the different periods over which HbA1 and fructosamine reflect average glycemia and partly to imprecision.

The effect of nitroglycerin on heart rate and systolic blood pressure was compared in 5 normal subjects, 12 diabetic subjects without autonomic neuropathy, and 5 diabetic subjects with autonomic neuropathy. The magnitude and time course of the increase in heart rate and the decrease in systolic blood pressure after nitroglycerin were similar in the normal and diabetic subjects without autonomic neuropathy, whereas a lesser increase in heart rate and a greater decrease in systolic blood pressure occurred in the diabetic subjects with autonomic neuropathy. It is therefore suggested that caution should be exercised when prescribing vasodilator drugs in diabetic patients, particularly those with autonomic neuropathy.

Type 1 diabetics receiving once (Group 1, n = 72) and twice (Group 2, n = 48) daily subcutaneous injections of conventional beef insulin were compared, on a cross-sectional basis, in respect of insulin antibody binding by serum and total glycosylated haemoglobin (HbA1). Patients in Group 1 had higher insulin antibody binding (25.2 ± 15.8% vs 17.0 ± 13.9%; p < 0.01) and higher HbA1 levels (12.5 ± 2.0% vs 11.0 ± 1.8%; p < 0.001) than patients in Group 2. An inverse correlation ( τ = –0.28, p < 0.01) was observed between HbA1 and insulin antibody binding in C-peptide non-secretors of Group 1 but not in Group 1 C-peptide secretors, nor in C-peptide secretors and/or non-secretors of Group 2. It is suggested that in Type 1 diabetics who receive a single daily insulin injection and who have no endogenous insulin secretion, insulin antibodies may aid glycaemic control by prolonging insulin action.