A comparative study of once daily insulin injection regimes in the treatment of elderly diabetics.

A randomised crossover trial of Insulatard, Lentard and Mixtard insulins as once daily therapy was undertaken in 10 diabetics who had been on long term insulin and in 7 patients who were poorly controlled on oral hypoglycaemic agents and had not previously received insulin. The glycaemic control of those patients with prior insulin therapy was very similar under these 3 insulin regimes. In patients previously on oral hypoglycaemic agents the mean (+/- SEM) blood glucose (10.0 +/- 0.8 mmol/l), log "M" value (1.78 +/- 0.10) and area under the glucose curve (192 +/- 16 mmol . hr/l) were all lower on Insulatard than when on Lentard (13.0 +/- 0.9, 2.03 +/- 0.08 and 258 +/- 17 respectively; p less than 0.05 in each case). Mixtard values were intermediate (11.2 +/- 1.3, 1.83 +/- 0.19 and 258 +/- 17). Furthermore blood glucose values were within the physiological range of 3-7 mmol/l in 20% of patients on Insulatard, in 16% on Mixtard but in only 2% on Lentard. Significant hypoglycaemia (blood glucose less than 3 mmol/l) in both groups of patients was noted more commonly with Mixtard (7 episodes) than with Lentard (3 episodes) or Insulatard (2 episodes). There was no significant difference in the free insulin levels between these insulin regimes but mean log total insulin levels were higher (p less than 0.005) when the patients were taking Lentard (2.33 +/- 0.13) in comparison with both Insulatard (1.99 +/- 0.14) and Mixtard (1.92 +/- 0.13). The mean insulin binding rose 4.9% during Lentard treatment and fell slightly by 0.6% on Insulatard and 0.9% on Mixtard (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The prevalence of autonomic neuropathy in insulin-dependent diabetes mellitus: a controlled study based on heart rate variability.

Autonomic function was investigated by tests of heart rate variation in 506 unselected insulin-dependent diabetics aged 12 to 85 years. Heart rate variability was measured by a computerised technique during rest and in response to a single deep breath, the Valsalva manoeuvre and standing. Changes in heart rate were compared with age-related normal ranges derived from 310 non-diabetic control subjects aged 18 to 87 years. Heart rate responses were found to be below the 5th centile control value in 13 to 23 per cent of diabetics. Impaired heart rate variability occurred more frequently in response to a single deep breath than to the other procedures. Results from all four procedures were combined in each subject to give an 'autonomic score', varying from 0 to 4. This score was greater than 1 in only five of 310 (1.6 per cent) non-diabetic control subjects. A score of 2 or more was therefore defined as abnormal and indicative of cardiac autonomic denervation. Abnormal autonomic scores were found in 84 diabetics (16.6 per cent). In diabetic subjects the autonomic score correlated most closely with heart rate variability at rest and in response to a single deep breath. Abnormal autonomic scores correlated significantly with duration of diabetes (p less than 0.0001) but not with age (p = 0.06). The frequency of abnormal autonomic scores was greatest in diabetics aged 40 to 49 years (24.5 per cent) and those with diabetes of 20 or more years duration (30.7 per cent).

Abnormal circadian rhythm of melatonin in diabetic autonomic neuropathy.

The circadian rhythm of melatonin secretion from the pineal body is entrained to the light-dark cycle and is controlled via sympathetic fibres originating from the superior cervical ganglia. We have therefore examined plasma melatonin profiles in diabetics with and without evidence of autonomic neuropathy and in normal matched controls. The physiological increase in nocturnal plasma melatonin concentration was not observed in diabetics neuropaths. There was no consistent pattern in the diabetics without neuropathy; only three out of the eight subjects in this group had a sustained nocturnal increase in melatonin. Normal diurnal variation of plasma cortisol was present in all groups of subjects. The present study shows that diabetic patients with evidence of autonomic neuropathy lack the normal circadian changes of plasma melatonin concentration. This provides confirmation for the control of pineal function via the sympathetic nervous system in man. The impaired melatonin profiles observed in diabetic patients without apparent autonomic neuropathy suggest that a subclinical state of sympathetic denervation may exist in this group of diabetics.

Hypoglycemia during adrenergic beta-blockade: evidence against mediation via a deficiency of lactate for gluconeogenesis.

Acute hypoglycemia was induced using intravenous inulin in three groups of normal volunteers: (1) seventeen control subjects, (2) six subjects under beta-adrenergic blockade with propranolol, and (3) eight subjects given propranolol plus sodium lactate as an exogenous substrate for gluconeogenesis. Under propranolol blockade the recovery from hypoglycemia was significantly impaired. This impairment was not prevented by the infusion of sodium lactate despite the production of an adequate elevation of blood lactate concentrations. These findings suggest that the impaired recovery from hypoglycemia during beta-adrenergic blockade is not mediated via a deficiency of lactate as substrate for hepatic gluconeogenesis.

Glycosylation of maternal hair and cord skin during pregnancy in diabetic and non-diabetic women.

A study of 15 insulin-dependent diabetics (IDD), 4 gestational diabetics (GDM), and 21 non-diabetic women was undertaken to assess non-enzymatic glycosylation in maternal hair, cord skin, and cord blood. Glycosylation of maternal hair was stable from tip to root in controls. In the IDD group, levels were highest at the tip, but were significantly lower in the middle and scalp segment (p less than 0.01), both tip and middle segments were higher than control values (p less than 0.01). In contrast, only the scalp segment of hair from the GDM group had a higher than normal level of glycosylation (p less than 0.01). Cord skin and cord blood glycosylation were significantly increased in the IDD group compared with normal (0.100 +/- 0.002 vs 0.074 +/- 0.008 mumol fructosamine/100 mg, p less than 0.01, and 0.160 +/- 0.002 vs 0.14 +/- 0.008, p less than 0.05, mean +/- S.E.M.), respectively. Only cord skin glycosylation was increased in the GDM group (0.116 +/- 0.003, p less than 0.01). Thus near normal glycaemic control of maternal insulin-dependent diabetes during pregnancy was associated with small but significant increases in cord skin glycosylation and a fall towards normal in maternal hair glycosylation which may provide a useful retrospective index of diabetic control.

Factitious diabetic instability.

Factitious diabetic instability is described in four patients. In three the predominant problem was recurrent hypoglycaemia. The fourth presented with apparent insulin resistance and episodes of ketoacidosis. The methods used to make the diagnosis are described, and the factors which contribute to this type of diabetic instability are discussed.

Multifocal idiopathic fibrosis presenting as facial pain and trismus.

An unusual case of idiopathic sclerosing fibrosis is described in which there was involvement of the face, neck, mediastinum and lungs with sparing of the thyroid and retroperitoneal tissues. In contrast to previous cases, facial pain and limitation of jaw movements were the presenting complaints and major causes of disability. Prednisolone treatment failed to arrest the disease.

Effect of renal function on renal responsiveness to parathyroid hormone in primary hyperparathyroidism and chronic renal failure.

The effect of renal function on the cyclic AMP (cAMP) response to exogenous parathyroid hormone (PTH) was examined in patients with chronic renal failure (n = 22) and primary hyperparathyroidism (n = 19). In the patients with chronic renal failure there was marked resistance to the effect of exogenous PTH. In primary hyperparathyroidism the cAMP responses were variable; most of the patients with an abnormally small response having impaired renal function. After parathyroidectomy, responsiveness improved to varying degrees. In three patients repeatedly tested up to several months after parathyroidectomy, the recovery of responsiveness was a gradual process which began within days but did not, however, return to normal. Thus, there was an irreversible component to the resistance to PTH in these patients. A strong negative correlation between plasma creatinine and the cAMP response to PTH (P less than 0.001) was found in a group of patients, some with treated primary hyperparathyroidism and some with chronic renal failure. Thus, renal impairment is an important, but probably not the sole, contributory factor involved in the irreversible resistance to the action of PTH in hyperparathyroidism.

Clinical and neurophysiological studies with the aldose reductase inhibitor, sorbinil, in symptomatic diabetic neuropathy.

The effect of sorbinil (200 mg daily for 4 weeks) was examined in 13 patients, mean age 59.7 years (range 42-72 years), with symptomatic diabetic neuropathy of mean duration 6 year (range 1-18 years). In this double-blind, placebo-controlled crossover trial, studies were made of motor, sensory and autonomic nerve function, severity of painful symptoms and duration of sleep. One patient was withdrawn because of an adverse reaction to sorbinil. In the other 12, constant mean values for glycosylated haemoglobin A1 between 11% and 12% indicated stable though not ideal diabetic control throughout the study. Example values for nerve conduction velocity on placebo and active treatment were: 44.3 +/- 5.9 and 44.8 +/- 5.1 metres/s (mean +/- SD) for median motor nerve, 38.4 +/- 8.2 and 37.2 +/- 7.7 metres/s for median sensory nerve. Thus there was no significant effect of sorbinil on conduction velocity in these or any other of the motor and sensory nerves tested. Abnormal autonomic function was not improved by sorbinil. Subjective pain scores on a 10 cm visual analogue scale were 4.2 +/- 2.4 on placebo and 4.3 +/- 2.4 after sorbinil. Duration of sleep on placebo and active treatment was 6.1 +/- 1.6 and 6.2 +/- 1.7 h/night, respectively. We were not able to detect any beneficial effect of sorbinil on painful diabetic neuropathy in our patients.

Papilloedema in diabetes: an ischaemic optic mononeuropathy.

Five diabetic patients had acute visual impairment due to papilloedema, which was bilateral in two patients. The clinical features and subsequent course were compatible with ischaemic optic mononeuropathy presumed to result from ischaemia in a posterior ciliary artery. This cause should always be considered in the differential diagnosis of papilloedema in a diabetic patient to avoid the instigation of inappropriate and invasive investigations. In general the condition has a good prognosis.

Reversible resistance to the renal action of parathyroid hormone in human vitamin D deficiency.

1. The response to exogenous parathyroid hormone (PTH) was tested in normal subjects and patients with osteomalacia due to vitamin D deficiency; 200 MRC units of bovine PTH were administered intravenously. 2. The rise in plasma adenosine 3':5'-cyclic monophosphate (cyclic AMP) and the increase in urinary excretion of cyclic AMP were reduced in the patients with vitamin D deficiency. After treatment with vitamin D the responses returned to normal. 3. It is suggested that this reversible resistance is due to the secondary hyperparathyroidism associated with vitamin D deficiency.

Effect of water deionisers on 'fracturing osteodystrophy' and dialysis encephalopathy in Plymouth.

In the Plymouth area, 95 patients with end-stage renal failure have undergone haemodialysis for 6 months or longer. Of the 47 patients beginning dialysis between 1967 and 1973, when water deionisers were not used routinely, a bone disease with multiple fractures, 'fracturing osteodystrophy', occurred in 18 patients and dialysis encephalopathy in 10. Of the 48 patients first dialysing between 1974 and 1979, when water deionisers used commonly, fracturing osteodystrophy occurred in only one and dialysis encephalopathy also in only one. Duration of dialysis without a water deioniser appeared to be the most important factor in the development of these two conditions. The use of water deionisers usually led to healing of fractures in patients with fracturing osteodystrophy and also led to improvement in 4 of the 11 patients with dialysis encephalopathy. Neither condition has occurred in any patient using a water deioniser from the first dialysis. Water deionisers, therefore, appeared to be effective in both the treatment and prevention of fracturing osteodystrophy and dialysis encephalopathy.

Studies of circulating parathyroid hormone in man using a homologous amino-terminal specific immunoradiometric assay.

Circulating immunoreactive parathyroid hormone (PTH) was measured by a homologous, amino-terminal, specific, immunoradiometric assay in man. In forty-two healthy subjects the concentrations ranged between < 40 pg/ml and 120 pg/ml. No hormone could be detected in the sera of eleven patients with hypoparathyroidism, but the concentrations were clearly elevated in six patients with pseudohypoparathyroidism (range 190-1120 pg/ml). In thirty-five patients with primary hyperparathyroidism the mean (+/- SEM) concentration was 283.4 +/- 42.4 pg/ml (range 100-1350 pg/ml). A significant positive correlation was demonstrated between immunoassayable hormone and serum calcium concentrations in these patients. In nine patients PTH concentrations were measured before and after parathyroidectomy. In all of them they were elevated pre-operatively but fell to the normal range after parathyroidectomy. The disappearance of exogenously administered synthetic human PTH (1-34) from the circulation of two normal subjects was rapid with an apparent plasma half-disappearance time (t1/2) between 2 and 3 min; the metabolic clearance rate was 12.9 and 9.0 ml. kg-1 . min-1 respectively. Similarly, the disappearance of endogenous, amino-terminal, immunoreactive PTH from the circulation of two patients with primary hyperparathyroidism after parathyroidectomy was rapid; the apparent t1/2 was approximately 3 min. Homologous amino-terminal specific immunoassays for PTH can thus be useful for the study of both the acute, and chronic, changes of circulating hormone in man and represent an improvement over heterologous unselected assay systems.

1, 25-dihydroxycholecalciferol in the pathogenesis of the hypercalcaemia of sarcoidosis.

A 36-year-old man with sarcoidosis had four episodes of hypercalcaemia in seven years, all of them during the summer months. Measurement over three years showed that hypercalcaemia was associated with small seasonal increases in serum-25-hydroxycholecalciferol within the normal range. These changes could be mimicked by the administration of 3000 units of vitamin D3 daily. Serum 1, 25-dihydroxycholecalciferol concentrations ranged between 26--62 pg/ml when serum calcium was normal, but were strikingly high, up to 137 pg/ml, when the patient was hypercalcaemic. These studies show for the first time that hypercalcaemia in sarcoidosis is associated with abnormally high circulating concentrations of 1, 25-dihydroxycholecalciferol, probably as a result of overproduction of this, the hormonal form of vitamin D.

Studies of hypoparathyroidism and pseudohypoparathyroidism.

Twenty eight hypocalcaemic patients were studied, 14 with primary hypoparathyroidism, nine with pseudohypoparathyroidism and two with hypo-hyperparathyroidism, to characterized the essential features of these disorders. Like tetany, which was present in 12 of the patients, epilepsy was a common symptom, occurring in 13, seven of whom had received anticonvulsants for two to eight years before hypocalcaemia was detected. Differentiation between primary and pseudohypoparathyroidism could not be made with certainty on clinical grounds but confident distinction could be made by measurement of endogenous parathyroid hormone concentrations and by testing for renal resistance to exogenous parathyroid hormone. This was achieved by measurement of the plasma and, in some patients, the urinary cyclic AMP response to an intravenous injection of highly purified bovine parathyroid hormone. These investigations were also valuable in the assessment of the other three hypocalcaemic patients in whom a diagnosis of parathyroid dysfunction would otherwise have been made. In 10 of the patients synthetic 1 alpha-hydroxylated forms of vitamin D were used to establish and maintain normocalcaemia, though their use required careful monitoring.