Measurement of glucose metabolism and insulin secretion during normal pregnancy and pregnancy complicated by gestational diabetes.

Gestational diabetes affects 2-3% of pregnant women and is associated with foetal complications including macrosomia and an increased likelihood of developing diabetes in later life. We have therefore studied seven women with gestational diabetes and five control women both during the third trimester of pregnancy and again 2-3 months post-partum, using the minimal model analysis of the frequently sampled labelled ([6,6-2H2]-glucose) intravenous glucose tolerance test. Glucose tolerance (glucose Kd) was significantly reduced in the women with gestational diabetes compared with the normal pregnant women both in pregnancy (1.16 +/- 0.11 vs 1.78 +/- 0.23%/min; p < 0.05) and post-partum (1.47 +/- 0.22 vs 2.59 +/- 0.43%/min; p < 0.05) and increased significantly in the control women after delivery (p < 0.05). Glucose effectiveness was not significantly different between the women with gestational diabetes and the control group either during or after pregnancy. Insulin sensitivity was significantly lower during pregnancy than after delivery in the women with gestational diabetes (p < 0.05). There was no significant difference in basal insulin secretion in the two groups during pregnancy or post-partum. However, during pregnancy the control subjects significantly increased (p < 0.001) their insulin secretion over a period of 20 min in response to an intravenous glucose tolerance test (96.2 +/- 42.7 pmol/kg) compared with post-partum values (58.3 +/- 25.2 pmol/kg) while in the women with gestational diabetes insulin secretion was similar in pregnancy (65.5 +/- 9.3 pmol/kg) and after delivery (57.7 +/- 15.7 pmol/kg). These data suggest that the glucose intolerance in gestational diabetes compared to normal pregnancy is due to reduced insulin sensitivity and an impaired ability in gestational diabetes to increase insulin secretion in response to glucose.

A probabilistic approach to glucose prediction and insulin dose adjustment: description of metabolic model and pilot evaluation study.

A model of carbohydrate metabolism has been implemented as a causal probabilistic network, allowing explicit representation of the uncertainties involved in the prediction of 24-h blood glucose profiles in insulin-dependent diabetic subjects. The parameters of the model were based on experimental data from the literature describing insulin and carbohydrate absorption, renal loss of glucose, insulin-independent glucose utilisation and insulin-dependent glucose utilisation and production. The model can be adapted to the observed glucose metabolism in the individual patient and can be used to generate predicted 24-h blood glucose profiles. A penalty is assigned to each level of blood glucose, to indicate that high and low blood glucose levels are undesirable. The system can be asked to find the insulin doses that result in the most desirable 24-h blood glucose profile. In a series of 12 patients, the system predicted blood glucose with a mean error of 3.3 mmol/l. The insulin doses suggested by the system seemed reasonable and in several cases seemed more appropriate than the doses actually administered to the patients.

Leucine metabolism in patients with Cushing's syndrome before and after successful treatment.

OBJECTIVE: Results from studies on the effect of glucocorticosteroids on protein turnover in both rat and man have been conflicting. The aim of this study was to investigate the primary cause of muscle wasting in patients with Cushing's syndrome. DESIGN: Studies of whole body 1(-14)C-leucine turnover in patients with Cushing's syndrome before and after successful treatment, and in control subjects. PATIENTS: Eleven patients with Cushing's syndrome before and after (n = 5) treatment and 11 control subjects. MEASUREMENTS: Whole body 1(-14)C-leucine turnover to determine leucine metabolic clearance rate, leucine production rate, leucine oxidation rate and leucine incorporation into protein. RESULTS: Plasma leucine concentration (mean +/- SEM 100 +/- 6 mumol/l), leucine metabolic clearance rate (9.97 +/- 0.11 mumol/min/kg), leucine turnover (0.98 +/- 0.11 mumol/min/kg) and leucine incorporation into protein (0.71 +/- 0.09 mumol/min/kg) were all significantly reduced in patients with Cushing's syndrome compared with control subjects (122 +/- 6 mumol/l, P < 0.05; 13.61 +/- 1.27 mumol/min/kg, P < 0.05; 1.65 +/- 0.12 mumol/min/kg, P < 0.05; 1.46 +/- 0.10 mumol/min/kg, P < 0.001, respectively). Leucine oxidation rate was similar in the patients with Cushing's syndrome and control subjects. When leucine metabolism was expressed in terms of lean body mass (LBM) in five patients with Cushing's syndrome and 11 control subjects, leucine MCR, leucine turnover and leucine oxidation were not significantly different in the two groups. However, leucine incorporation into protein was significantly reduced (P < 0.001) in the patients with Cushing's syndrome (1.07 +/- 0.20 mumol/min/kg LBM) compared with control subjects (1.95 +/- 0.11 mumol/min/kg LBM). CONCLUSION: We conclude from these studies that the muscle wasting associated with Cushing's syndrome is primarily due to a reduction in protein synthesis.

Glucose turnover in type I diabetic subjects during exercise. Effect of selective and nonselective beta-blockade and insulin withdrawal.

OBJECTIVE: To assess the effect of selective beta 1-blockade (atenolol and betaxolol) and nonselective beta-blockade (propranolol) on glucose turnover in subjects with insulin-dependent (type I) diabetes mellitus during moderate exercise. RESEARCH DESIGN AND METHODS: Five subjects with type I diabetes were infused with insulin and then exercised for 1 h, after pretreatment with each of the three drugs or saline and, on a separate day, after withdrawal of insulin. Glucose turnover was measured using tritiated glucose. RESULTS: Plasma glucose, initially 9.2 +/- 0.5 mmol/L (mean +/- SE) when insulin infused and 14.0 +/- 0.8 when insulin was withdrawn, fell on exercise by 3.4 +/- 1.1 mmol/L (P < 0.05) saline, 4.0 +/- 0.8 mmol/L (P < 0.01) with betaxolol, 3.8 +/- 0.7 mmol/L (P < 0.01) with atenolol, 5.0 +/- 0.6 mmol/L (P < 0.005) with propranolol, and 1.7 +/- 1.0 mmol/L (NS) when insulin was withdrawn. Propranolol, but not the other beta-blockers, caused a significantly greater fall in glucose on exercise than during the control study. Glucose appearance rate (Ra) was similar basally and rose to an almost identical level in all five groups during exercise. Glucose disappearance rate (Rd) rose similarly during exercise, except after propranolol when the rise was significantly greater than with saline (P < 0.01). Failure of glucose to change significantly during exercise when insulin had been withdrawn was associated with the smallest rise in Rd and the highest nonesterified fatty acid concentrations. Propranolol and betaxolol, but not atenolol, reduced nonesterified fatty acids. CONCLUSIONS: We conclude that the greater fall in glucose on exercise after beta-blocking drugs is probably largely a direct effect of beta 2-blockade on muscle, increasing the exercise-induced rise in Rd glucose. This offers support to the use of beta 1-specific drugs, where beta-blockade is necessary in type I diabetes.

An integrated approach for the computer-assisted treatment of diabetic patients on insulin.

A prototype computer system has been developed to provide advice on the day-to-day adjustment of carbohydrate intake and insulin regimen in the insulin-dependent diabetic patient. The system also produces a 24-h simulation of the patient's blood glucose profile based on these adjustments. Advice is generated by a qualitative knowledge-based system which suggests what the next step in improving glycaemic control might be for a given patient, e.g. 'decrease morning short-acting insulin by 2 units'. The quantitative simulator module contains two different mathematical models. The first is a non-linear model in differential equation form which consists of a one-compartment glucose model linked to a model with free and bound insulin compartments. This physiological model is solved by a general-purpose simulation engine. The second is a linear systems model which uses a transfer function to describe the insulin input/blood glucose response relationship for individual diabetic patients. Results of a preliminary medical validation are presented.

Comparison of the real-time use of glycosylated haemoglobin and plasma fructosamine in the diabetic clinic.

The within-clinic use of glycosylated haemoglobin (HbA1) and plasma fructosamine results in assessing blood glucose control and clinical management was compared in 1030 diabetic patients. The physician initially reviewed the patient with one randomly allocated measure (HbA1 or fructosamine) and completed a questionnaire concerning perception of blood glucose control, alteration to diet, alteration to medication, referral for diabetes education, and follow-up interval. The patient was then re-assessed using the second measure and the questionnaire repeated. Discordance rates for the study end-points, judged as binary outcomes, were: blood glucose control 15%; alteration to diet 7%; alteration to medication 9%; referral for education 3%; follow-up interval 4%. A significantly greater number of patients were rated as poorly controlled with HbA1 than with fructosamine (p less than 0.001) and were, in consequence, more frequently recommended alteration to diet and medication, referral for education and shorter follow-up interval; the rate of discordance for at least one of the management decisions was 16%. Multifactorial analysis showed that discordant management was dependent on the reviewing physician (p less than 0.001) and a history of cardiovascular disease (p less than 0.01); but neither type of diabetes, nor presence of nephropathy or variant haemoglobins, nor plasma glucose concentration, significantly influenced the likelihood of a discordance. Replacing HbA1 with fructosamine in the diabetic clinic may result in significant differences in the physician's perception of blood glucose control and in the management of patients.

Glucose metabolism in patients with Cushing's syndrome.

Glucose intolerance, sometimes severe enough to cause frank diabetes mellitus, is a frequent feature of Cushing's syndrome. The primary cause of the hyperglycaemia, whether due to glucose over-production or under-utilization, remains unresolved. We therefore measured glucose turnover using an intravenous bolus of 3-3H glucose in 14 normoglycaemic patients with Cushing's syndrome and 14 control subjects. Seven of the patients with Cushing's syndrome were also restudied post-operatively. Plasma glucose concentrations were similar in all three groups whereas glucose metabolic clearance rate (MCR) (1.80 +/- 0.06 ml/min/kg) and glucose turnover rate (9.09 +/- 0.36 mumol/min/kg) were significantly reduced in patients with Cushing's syndrome compared to normal subjects (2.21 +/- 0.1; P less than 0.001; 10.90 +/- 0.50; P less than 0.01) and rose post-operatively to normal values (2.35 +/- 0.14 ml/min/kg; 11.07 +/- 0.48 mumol/min/kg). We conclude from these results that the hyperglycaemia sometimes found in Cushing's syndrome may be primarily due to decreased utilization rather than increased glucose production.

A comparison of CT and MRI in the assessment of the pituitary and parasellar region.

We have carried out a prospective study to compare high resolution thin slice, contrast-enhanced, axial computed tomography (CT) with unenhanced magnetic resonance imaging (MRI) at 1.5T in the assessment of the pituitary and parasellar region. Forty patients with suspected pituitary disease presenting to an endocrine unit were studied. MRI was superior to CT for the identification of the posterior pituitary and pituitary stalk and was better at showing the cystic nature of tumours. Visualization of the optic chiasm and assessment of displacement of the optic chiasm and the carotid arteries were also better with MRI. CT was equally good at showing cavernous sinus displacement or invasion, sphenoid sinus invasion and erosion of the floor of the sella turcica and was the only technique able to show calcification of the gland. More focal abnormalities were seen in the pituitary gland with CT than with unenhanced MRI, but there was a higher false positive rate for microadenoma detection with CT. All the scans were interpreted separately by three observers, two radiologists and one clinician. The percentage agreement between the observers for the identification of pituitary and parasellar structures was better for MRI than for CT and the clinician in particular found interpretation of the MR images easier. MRI thus not only gives more information overall than CT but it is a more reliable technique between different observers for the assessment of the pituitary and parasellar region.

Metabolic effects of an insulin-like factor causing hypoglycaemia in a patient with a haemangiopericytoma.

We have studied a patient with fasting hypoglycaemia and skin lesions (sign of Leser-Trélat) related to a retroperitoneal haemangiopericytoma in whom removal of the tumour resulted in immediate cure of hypoglycaemia. Before removal of the tumour, severe fasting hypoglycaemia was associated with undetectable insulin and C-peptide levels. She required 16.9 mumol/kg/min (10.4 g/h) of glucose intravenously to prevent hypoglycaemia and endogenous glucose production (measured using tritiated glucose) was suppressed to 1.3 mumol/kg/min while the whole-body glucose utilization rate was elevated at 18.2 mumol/kg/min. After removal of the tumour both endogenous glucose production rate and utilization rate returned to normal (11.5 mumol/kg/min). Resting energy expenditure, measured by indirect calorimetry, was markedly elevated at 2109 kcal/day (161% of predicted) and fell to 1205 (97% of predicted) after the tumour was removed. Glucose oxidation was also enhanced at 8.5 mumol/kg/min and fell to 3.3 mumol/kg/min after removal of the tumour. Other metabolites and hormones measured, and their response to oral glucose, were all consistent with the presence of a circulating substance with similar properties to insulin. We conclude that her hypoglycaemia resulted primarily from suppression of endogenous glucose production but also from enhanced glucose utilization. These effects were the result of a circulating growth factor sharing many metabolic effects with insulin, but with a much greater effect on resting energy expenditure and glucose oxidation.

Increased glucose carbon recycling in severely insulin deficient type 1 (insulin-dependent) diabetic subjects.

Six Type 1 (insulin-dependent) diabetic subjects were studied in order to determine the contribution of recycling of glucose carbon to the overproduction of glucose which is characteristic of the fasting hyperglycaemia produced by insulin withdrawal. The subjects were studied on two occasions, once after an overnight insulin infusion and once following 24 h of insulin withdrawal. The difference in turnover rates of 1-14C-glucose and 3-3H-glucose was used as a measure of glucose recycling. Insulin withdrawal caused a marked metabolic derangement with a rise in non-esterified fatty acids from 0.69 +/- 0.23 to 1.11 +/- 0.21 mmol/l (mean +/- SEM, p less than 0.05), total ketones from 0.27 +/- 0.06 to 2.06 +/- 0.51 mmol/l (p less than 0.01), cortisol from 341 +/- 43 to 479 +/- 31 nmol/l (p less than 0.05) and growth hormone from 1.1 +/- 0.3 to 19 +/- 5 mu/l (p less than 0.05). Glucose turnover rose from 13.8 +/- 2.3 mumol.kg-1.min-1 at a glucose of 6.9 +/- 0.7 mmol/l in the insulin infused study to 25.8 +/- 4.4 mumol.kg-1.min-1 (p less than 0.05) at a glucose of 16.4 +/- 0.7 mmol/l in the insulin withdrawn study. Recycling also rose from 3.0 +/- 0.4 mumol.kg-1.min-1 to 9.4 +/- 2.2 mumol.kg-1.min-1 (p less than 0.05) when insulin withdrawn, accounting for 23 +/- 3% and 36 +/- 3% of glucose turnover, respectively. We conclude that in the severely insulin deficient Type 1 diabetic subject recycling of glucose carbon is a major contributor to the excess glucose production.

Persistent abnormalities of the metabolism of an oral glucose load in insulin-treated type I diabetics.

We have compared disposal of an oral glucose load in 12 normal subjects and 10 c-peptide-negative, type I-diabetic subjects, who were treated with insulin (by overnight intravenous insulin infusion followed by a dose of subcutaneous insulin prior to the oral glucose load) to achieve a blood glucose profile that approximated the glucose intolerance commonly seen in insulin-treated diabetics. We used a combination of the dual-isotope and forearm techniques, together with whole-body indirect calorimetry, to quantify the various determinants of glucose tolerance. The diabetic subjects had impaired glucose tolerance in that, despite similar fasting plasma glucose levels (5.46 +/- 0.17 mmol/L v 5.35 +/- 0.10 mmol/L in the normal subjects), they had a higher peak glucose (14.3 +/- 1.2 mmol/L v 10.0 +/- 0.7 mmol/L P less than .01) and area under the glucose curve (2,483 +/- 197 mmol.min/L v 1,525 +/- 43 mmol.min/L P less than .001). Up to 120 minutes after the oral glucose load, the amount of glucose entering the systemic circulation exceeded that leaving by 14.6 +/- 2.3 g in the diabetics and only by 2.6 +/- 0.5 g in the normal subjects (P less than .001), accounting for the higher plasma glucose peak in the diabetics. Total systemic glucose appearance rates were significantly greater in the diabetics between 60 and 120 minutes, and endogenous glucose production suppressed more slowly in diabetics than in the normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Paraneoplastic rhinophyma and the Leser-Trélat sign.

A case of the Leser-Trélat sign associated with an underlying malignant haemangiopericytoma is described. In addition, the patient had profound hypoglycaemia and a rhinophyma-like nasal swelling which rapidly resolved post-operatively. The tumour appeared to be secreting a factor(s) which cross-reacted with both insulin receptors to induce hypoglycaemia and epidermal growth factor receptors inducing a profusion of eruptive seborrhoeic warts. It aslo had marked sebotrophic activity. The association of the Leser-Trélat sign with malignant haemangiopericytoma has not previously been described.

Cryptogenic tuberculosis as a preventable cause of end-stage renal failure.

A women with a history of urethral stenosis, not causing significant urinary tract obstruction but requiring dilation, presented at the age of 49 with renal failure (creatinine clearance of 16-20 ml/min). Investigations (including pyelography) directed to finding the cause of her renal failure were negative with the exception of renal biopsy which revealed granulomata, one of which showed caseation. Treatment with antituberculous drugs arrested the decline in glomerular filtration rate and was later associated with sustained improvement in renal function. Tuberculosis should always be considered as a possible cause of unexplained renal failure even if the classical pyelographic features of tuberculosis, i.e. calyceal distortion and calcification, are absent. Appropriate treatment may improve renal function and avert the need for renal replacement therapy.