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Chromogranin A (CgA), pancreastatin (PST), intervening-peptide (IP) and WE-14 antisera were employed to investigate the proteolysis of CgA in 50 pituitary adenomas. All non-functioning (NF) pituitary tumours (n = 28) exhibited CgA immunoreactivity. PST, IP and WE-14 immunostaining was observed in 85%, 89% and 67%, respectively. CgA, PST and IP immunostaining were comparable in the majority of NF tumours, while less intense WE-14 immunoreactivity was detected in a subpopulation of NF tumour cells. Approximately half of the functioning pituitary tumours expressed CgA immunoreactivity. Six of nine ACTH-secreting tumours displayed CgA and IP immunostaining; four of these tumours displayed PST immunoreactivity. WE-14 immunoreactivity was detected in one corticotroph tumour. Three of six growth hormone (GH) secreting tumours displayed CgA immunostaining, two exhibited PST and IP, and one exhibited WE-14 immunoreactivity. Clusters of WE-14 immunopositive cells were detected in one GH tumour. One of seven prolactinomas exhibited weak CgA immunostaining, while weak IP and WE-14 immunostaining was detected in an additional tumour. No PST immunostaining was detected in prolactinomas. Therefore CgA is a valuable marker of NF pituitary tumours, however it is a more sporadic marker of functioning adenomas. In general, the cellular pattern and intensities of CgA, PST and IP immunoreactivity were comparable in the majority of pituitary adenomas. In contrast, WE-14 immunostaining was observed in a subpopulation of tumour cells. The pathophysiological significance of the proteolysis of CgA to generate bioactive peptides in both NF and functioning pituitary adenomas remains to be established.

Objective: To compare the insulin hypoglycaemia test with the short overnight metyrapone test in the assessment of the hypothalamic-pituitary-adrenal (HPA) axis posthypophysectomy., Design: Prospective comparative study of the insulin hypoglycaemia test and the overnight metyrapone test in 32 patients 4-6 weeks after pituitary surgery., Subjects: Thirty-two patients with known pituitary disease. None with present or previous Cushing's syndrome., Outcome Measurements: Maximum serum cortisol achieved during insulin induced hypoglycaemia compared with 0900 hours serum 11-deoxycortisol level following a weight related oral dose of metyrapone at 0000 h., Results: One of the 32 patients required further surgery and was studied twice after each operation. Thirty-three results are therefore compared. Twenty-six of these had a normal cortisol response of 550 nmol/l or above leading to the cessation of replacement hydrocortisone. Six of these 26 patients however, failed the metyrapone test (11-deoxycortisol level less than 200 nmol/l). After 3-40 months (median 20 months) of follow-up off steroid therapy, no patient to date has displayed any clinical evidence of steroid deficiency. Of the seven patients who failed the insulin hypoglycaemia test, six also failed the metyrapone test., Conclusions: The overnight metyrapone test identified more patients with possible ACTH deficiency than the insulin hypoglycaemia test. Further follow-up of these patients is required before a final judgement can be made as to whether more subtle but clinically relevant ACTH deficiency can be detected by the metyrapone test. Our clinical follow-up to date would not support this.

To compare bilateral inferior petrosal sinus sampling (IPSS) with high dose dexamethasone (HDD) and CRH testing (using recently proposed stringent response criteria) in the differential diagnosis of ACTH-dependent Cushing's syndrome, we reviewed 53 consecutive cases. The main analysis was limited to 45 cases with confirmed diagnosis: 44 with pituitary dependency, proven by confirmatory histology and/or significant biochemical improvement after pituitary surgery, and 1 with ectopic ACTH syndrome. After HDD (2 mg every 6 h for 48 h), 21 of the 44 pituitary cases met the stringent more than 90% suppression criterion. Twenty-three of the 44 pituitary cases also underwent CRH testing; 16 of 23 met a stringent response criterion of a more than 50% serum cortisol rise. For HDD and CRH testing combined, 8 of 23 fulfilled both stringent criteria, 10 of 23 had discordant results, and 5 of 23 failed to fulfil either of the stringent criteria for pituitary dependency. IPSS was performed in all 44 of the proven pituitary cases; 36 had petrosal/peripheral ACTH ratios of 2.0 or more without CRH stimulation. Thus, in patients with proven pituitary disease, stringent response criteria to HDD and CRH testing were fulfilled by only 48% and 70%, respectively. IPSS, which gave direct evidence of pituitary ACTH secretion in 82% of the cases, is therefore considered necessary in a significant proportion of cases.

Objective: Low birth weight has been associated with hyperlipidemia, hypertension, diabetes, and coronary heart disease in adult life, but the precise mechanism is debated. The endothelium is thought to play a pivotal role in each of the above conditions with abnormalities being detectable before the development of overt disease. To investigate the possibility that endothelium has a role in mediating the excessive risk of adult vascular disease associated with low birth weight, endothelial function was assessed in young healthy adults who were either of low or normal birth weight at term., Research Design and Methods: Twelve low birth weight (2.2 +/- 0.05 kg, mean +/- SEM) subjects (six men/six women; age 28 +/- 0.2 years) and twelve age- and sex-matched normal birth weight (3.3 +/- 0.07 kg) control subjects were studied. The L-arginine-nitric oxide pathway was assessed in the forearm vascular bed by using venous occlusion plethysmography during intra-arterial brachial infusion of acetylcholine, sodium nitroprusside, norepinephrine, and NG-monomethyl-L-arginine (L-NMMA). Von Willebrand factor, a noninvasive marker of endothelial dysfunction, was also measured. Comparisons were made using Student's t test., Results: Von Willebrand factor was significantly elevated in low birth weight compared with normal birth weight subjects (136.9 +/- 12.7 vs. 95.6 +/- 9.5%; P = 0.016). The groups did not differ in the responses to acetylcholine (P = 0.76), sodium nitroprusside (P = 0.84), norepinephrine (P = 0.21), or L-NMMA (P = 0.35)., Conclusions: The finding of elevated von Willebrand factor in low birth weight subjects is suggestive of endothelial cell injury but does not appear to be associated with dysfunction of the L-arginine-nitric oxide pathway.

In primary hyperaldosteronism, it is important to distinguish between unilateral and bilateral disease, as management strategies differ. In the period 1983-95, we identified 34 patients with primary hyperaldosteronism. Following further investigations, a diagnosis of aldosterone-secreting adenoma was made in 17 patients, and surgery was performed. Computed tomography clearly localized an apparent adenoma (discrete adenoma=1 cm diameter; normal contralateral gland) in only 10 of these patients (59%); two of these 'adenomas' were subsequently shown to be hyperplastic glands without adenomas. Histological examination showed adrenal adenomas in the remaining 15 patients. An 'adenoma' also appeared to be clearly localized in 3/17 patients later classified as having bilateral adrenal hyperplasia by adrenal vein sampling. CT scanning, therefore clearly localizes adenomas in only 50% of histologically proven cases, and can also produce misleading results. Adrenal vein sampling results altered our management approach in one third of cases. On the basis of our detailed results we would recommend surgery if there is clear evidence of unilateral aldosterone secretion along with CT findings which may not be strictly localizing but are in keeping with the dominant side on adrenal vein sampling. The decision to refer for surgery in primary hyperaldosteronism can be difficult, and we would caution against too heavy a reliance on CT results when recommending adrenalectomy, and suggest that adrenal vein sampling should remain a routine part of the investigation of patients with primary hyperaldosteronism.

There is considerable evidence that endothelium-dependent nitric oxide (NO)-mediated vasodilatation in response to acetylcholine is impaired in essential hypertension, whereas the endothelium-independent response to sodium nitroprusside is normal. More limited data have suggested that there is also reduced vasoconstriction in response to N(G)-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of basal NO release. As it is not known whether endothelial dysfunction in hypertension, if indeed present, is a cause or consequence of the condition, we have studied the normotensive offspring of parents with essential hypertension. Both basal and stimulated vascular responses were examined in 12 normotensive offspring [mean age (+/-S.E.M.) 26.1+/-1.4 years] of parents with essential hypertension and compared with those in 12 age-matched offspring (mean age 25.6+/-1.1 years) of normotensive subjects. Forearm blood flow was measured simultaneously in both arms by venous occlusion plethysmography, both at baseline and during intra-arterial brachial infusion of increasing doses of acetylcholine, sodium nitroprusside, noradrenaline and L-NMMA. There were no significant differences between the groups in the responses to acetylcholine, sodium nitroprusside or noradrenaline. In contrast, the vasoconstrictor response to L-NMMA was significantly blunted in the offspring of hypertensive parents compared with that in the offspring of normotensive parents (P=0.005). Thus endothelial dysfunction, as demonstrated by impaired basal production of NO, is present in subjects at high risk of essential hypertension, and does not occur simply as a consequence of the condition.

Aims: It has been suggested that the adverse metabolic effects of antihypertensive therapy offset some of the benefits of blood pressure reduction. It has also been suggested that angiotensin converting enzyme (ACE) inhibitors reduce insulin resistance and that, if used together with thiazide diuretics, the adverse effects of thiazides on insulin sensitivity may be eliminated. We examined the effects on insulin sensitivity of captopril either alone or in combination with bendrofluazide in 11 hypertensive Type 2 diabetic patients., Methods: Insulin action was assessed using an isoglycaemic hyperinsulinaemic clamp in a double-blind, randomized, crossover study after a 6-week placebo run-in and following two 12-week treatment periods with captopril (C) (100 mg) alone or in combination with bendrofluazide (CB) (2.5 mg)., Results: Blood pressure was lower following CB compared to C (128/82 vs. 144/ 88 mmHg; P<0.005) and both were lower than baseline (162/101 mmHg; P < 0.001). CB resulted in a significant increase in fasting plasma glucose compared to C (9.7+/-0.8 vs. 8.5+/-0.6 mmol/; P < 0.05). Exogenous glucose infusion rates required to maintain isoglycaemia during hyperinsulinaemia were lower after CB compared to C (22.3+/-2.4 vs. 27.4+/-4.2 mol x kg(-1) x min(-1); P < 0.05). Suppression of endogenous glucose production was reduced after CB compared to baseline (4.0+/-0.6 vs. 2.4+/-0.5 mol x kg(-1) x min(-1); P< 0.05)., Conclusions: Combination of bendrofluazide with captopril lowered blood pressure but resulted in deleterious effects on insulin action compared to captopril alone.

We reviewed 31 patients in whom both bilateral inferior petrosal sinus sampling without CRH stimulation, and a CT scan of the lungs were done. Twenty-five had normal lung CT scans, of whom 23 had a higher inferior petrosal sinus: peripheral ACTH ratio > or = 1.5. After careful follow-up, none was subsequently shown to have ectopic ACTH syndrome. Six had abnormal lung CT scans, of whom two had ratios > or = 1.5. In these two patients, other investigations suggested pituitary disease, and pituitary surgery led to apparent cure. Of the remaining four patients, who had ratios < 1.5, two had incidental lung findings, and pituitary abnormalities were demonstrated at pituitary surgery. The third underwent bilateral adrenalectomy, and no evidence of ectopic ACTH syndrome has emerged as yet after 4 years follow-up. The fourth had a small-cell carcinoma of the lung, confirmed histologically. Our series suggests that whole-lung CT scanning is only necessary in cases of ACTH-dependent Cushing's syndrome where bilateral inferior petrosal sinus sampling has not demonstrated a significant increase in petrosal sinus ACTH levels as compared with the peripheral level. Thus, in our experience the test is now only necessary in those patients (approximately 25%) where the ratio is < or = 1.5.

Previous studies indicate that low dose bendrofluazide (1.25 mg/day) has no deleterious effect on insulin sensitivity in contrast to conventional doses. To evaluate the antihypertensive effect of 1.25 mg bendrofluazide across 24 h, we studied 12 subjects in a randomized, double blind, cross-over trial, comprising 8 weeks of either 1.25 mg/day bendrofluazide or placebo. Twenty-four-hour blood pressure averages were significantly lower after bendrofluazide compared with placebo (systolic 125 +/- 4 v 136 +/- 3 mm Hg, P < .005; diastolic: 78 +/- 2 v 85 +/- 2 mm Hg, P < .01). Trough:peak ratios were 0.67 +/- 0.07 for systolic and 0.72 +/- 0.15 for diastolic blood pressure reduction. In conclusion, 1.25 mg bendrofluazide daily produced a useful antihypertensive effect across the full 24-h period.

Aims: Familial aggregation of diabetes and nephropathy has been observed in several populations. Various interpretations have included underlying genetic mechanisms possibly mediated by a predisposition to hypertension. Endothelial dysfunction is now recognized as central to these conditions and offers a unifying mechanism to explain the disease aggregation. To test this hypothesis, we have examined endothelial function in healthy subjects at differing risks for diabetic nephropathy., Methods: Endothelial function was assessed in 12 healthy offspring (nine male (M)/three female (F); age 25.8+/-1.2 years, mean +/- SEM) of parents with Type 1 diabetes mellitus (DM) and end-stage renal disease compared with 12 control offspring (9 M/3 F; age 26.3+/-1.3 years) of parents with long duration (>20 years) Type 1 DM but without evidence of nephropathy. Forearm blood flow responses to brachial artery infusion of acetylcholine (endothelium-dependent), sodium nitroprusside (endothelium-independent), noradrenaline and the competitive inhibitor of basal nitric oxide release N(G)-monomethyl-L-arginine were assessed using venous occlusion plethysmography., Results: There were no significant differences between the groups in von Willebrand factor, fasting plasma glucose (4.2+/-0.1 vs. 4.0+/-0.2 mmol/l) or in 24-h ambulatory blood pressure. Similarly, the groups did not differ in vasodilation to acetylcholine (P = 0.75) and sodium nitroprusside (P = 0.79) or in vasoconstriction to noradrenaline (P = 0.45) and N(G)-monomethyl-L-arginine (P = 0.30)., Conclusion: These data do not support a role for endothelial dysfunction in the familial aggregation of diabetic nephropathy.

Objective: To study the reliability of the naloxone test in assessing the hypothalamic-pituitary-adrenal (HPA) axis in patients following transsphenoidal pituitary surgery, by comparison with the insulin stress test (IST). Also, to establish a normal range for the response to naloxone in healthy controls., Design: All patients had the IST performed, soluble insulin 0.1-0.3 U/kg (usually 0.15 U/kg) being administered intravenously, followed by venous sampling for plasma glucose and serum cortisol at 0, 15, 30, 45, 60, 75 and 90 minutes. Naloxone (125 micrograms/kg body weight) was similarly administered to all patients 6 days later, with sampling at -15, 0, 15, 30, 45, 60, 90 and 120 minutes for plasma glucose, serum cortisol and plasma ACTH. The naloxone test was also performed on control subjects using an identical protocol., Subjects: Twenty patients (11F/9M) aged 48.8 +/- 2.8 years (mean +/- SE) 4-6 weeks following transsphenoidal pituitary surgery. Twelve normal healthy control subjects (6F/6M) aged 31.5 +/- 3.0 years., Measurements: Serum cortisol was measured by radioimmunoassay and plasma ACTH by immunoradiometric assay., Results: Adequate hypoglycaemia (< or = 2.0 mmol/l) was achieved in all patients. Peak cortisol was > 550 nmol/l in 17 subjects (range: 572-867 nmol/l) and a subnormal response observed in 3 (peak cortisol 163-498 nmol/l). In the 17 patients with a normal cortisol response to hypoglycaemia the response to naloxone was extremely variable, with serum cortisol falling in 4 and an increment of < or = 100 nmol/l in 6 others. In the 3 patients who failed the IST, two responded to naloxone and one did not. In normal controls, 3 of the 12 had little or no response to naloxone., Conclusions: As the naloxone test fails to produce a response in all normal subjects it is impossible to define a 'normal' response. The numerous discrepancies with the IST in patients are further evidence of the test's lack of reliability in assessing the HPA-axis and it is consequently not a viable alternative to traditional dynamic methods such as the IST.

Objective: To compare the effects of monthly intra-muscular injections of a long acting preparation of octreotide, Sandostatin LAR, with multiple daily subcutaneous injections of octreotide and to study the interrelationships between mean 24 h growth hormone profile, serum total and free IGF-1 levels, 24 h urinary growth hormone levels and serum IGFBP-3., Design: Patients were assessed by 24 h GH profile off octreotide or any other GH modifying drug therapy; on subcutaneous octreotide (200-600 micrograms daily in divided doses for six weeks); and 28 days after the second of two injections of Sandostatin LAR (20 mg by intra-muscular injection) administered 28 days apart. Serum total and free IGF-1, serum IGFBP-3 and 24 h urinary GH were also measured on each occasion., Results: Sandostatin LAR was well tolerated. None of the patients reported any adverse effect and all completed the study uneventfully. Mean GH off treatment was 10.1 +/- 3.0 micrograms/l falling equally significantly (P < 0.05) during therapy with subcutaneous octreotide to 3.0 +/- 0.7 micrograms/l and Sandostatin LAR to 2.8 +/- 0.7 micrograms/l. Fasting 0900 h GH was significantly reduced (P < 0.05) on Sandostatin LAR (3.0 +/- 0.7 micrograms/l) compared with subcutaneous octreotide (5.1 +/- 1.2 micrograms/l). Mean total IGF-1 off treatment was 658.6 +/- 56.1 micrograms/l and was reduced to a comparable extent with subcutaneous octreotide and Sandostatin LAR (466.0 +/- 59.7 and 448.6 +/- 59.5 micrograms/l respectively; both P < 0.05). Free IGF-1 off treatment was 3.1 +/- 0.6 micrograms/l and was reduced equally by subcutaneous octreotide and Sandostatin LAR (1.2 +/- 0.2 and 1.2 +/- 0.2 micrograms/l; both P < 0.05). IGFBP-3 was reduced to a greater extent during Sandostatin LAR than during subcutaneous octreotide (4518.2 +/- 247.3 vs 5132.8 +/- 280.7 micrograms/l; P < 0.05). Twenty-four hour urinary GH excretion was reduced to a comparable extent with both therapies. Highly significant positive correlations were found between mean 24 h GH levels and free IGF-1 (r = 0.66, P < 0.0001) and 24 h urinary GH excretion (r = 0.94, P < 0.0001). The relationships between mean 24 h GH levels and total IGF-1 and IGFBP-3 although significant showed less powerful correlations., Conclusions: These results suggest that Sandostatin LAR is well tolerated and as effective as subcutaneous octreotide. In addition, urinary growth hormone and serum free IGF-1 may prove valuable for outpatient follow-up of acromegalic patients, as both correlate well with mean 24 h serum growth hormone levels.

A European multicentre, open-label 12-month study with Sandostatin LAR administered intramuscularly at 4-week intervals was initiated in 151 acromegalics responsive to octreotide. All patients received 3 injections of the 20 mg dose, following which the dose was adjusted to 10 mg in patients with mean 4-hour GH serum concentrations below 1 microgram/L (N: 29) and to 30 mg in patients with concentrations above 5 micrograms/L (N: 22). The GH level suppression was significant in the 20 mg dose group (p < 0.01) and for all 151 patients (p < 0.004), and was consistently maintained in all patients for the duration of the study. The suppression of the mean serum GH concentration to below 2.5 micrograms/L was recorded in 69.8% of patients at the endpoint treatment with Sandostatin LAR and 65.8% during prior treatment with Sandostatin s.c. A consistent suppression of serum IGF-I levels was also achieved. The number of patients with headache, fatigue, perspiration, joint pains and paresthesias had decreased significantly (p < 0.05) after the 6t]h injection of Sandostatin LAR vs. previous s.c. treatment. No patient discontinued the study because of drug-related adverse events. The most frequently reported adverse events were mild diarrhea, abdominal pain and flatulence. The local tolerability was very good. No impairment of safety hematology, biochemistry and thyroid function tests and no increased incidence of gallstone formation was recorded. Well tolerated and at least as efficacious as the s.c. formulation, Sandostatin LAR might become an alternative primary treatment to pituitary surgery and radiotherapy.

Secondary failure of plasma glucose control following initial successful response to diet therapy may be due to dietary indiscretion, or to progression of the intrinsic diabetic condition. We report a 10-year prospective natural history study of 432 newly diagnosed diabetic patients aged 40-69 years undertaken to assess the effect of intensive dietary management, where patients were transferred to insulin, or oral hypoglycaemic therapy (tolbutamide, metformin) by predetermined criteria of weight and plasma glucose. Secondary failure to diet therapy occurred in 41 patients in years 2-4, 67 patients in years 5-7, and 51 patients in years 8-10; 173 patients remained on diet alone until death or the end of the study. Continuation on diet alone was associated with a lower ongoing fasting plasma glucose, greater beta-cell function assessed by an oral glucose tolerance test at 6 months, and increasing age. The rate of rise of fasting plasma glucose was inversely related to the duration of successful dietary therapy, but mean weight remained constant in all groups while on diet alone. The ongoing fall in beta-cell function assessed by HOMA modelling closely mirrored the progressive rise in fasting plasma glucose: there was no change in mean insulin sensitivity in any of the groups.

The relationship between macrovascular disease and blood glucose control in long-term follow-up of Type 2 (non-insulin-dependent) diabetes mellitus is difficult to study because of the gradual rise in fasting plasma glucose due to ongoing beta-cell failure. We used time-dependent covariates in Cox's proportional hazards model to allow variables measured annually during a 10-year prospective follow-up to be related to risk of myocardial infarction or cerebrovascular accident. Data for 432 newly diagnosed diabetic patients were available, 112 of whom suffered myocardial infarction (fatal or non-fatal). Analysis of baseline measurements only gave relative hazards (95% CL) of 1.04 (0.99, 1.09) per mmol l(-1) increase in fasting plasma glucose, 1.43 (1.12, 1.83) per decade increase in age and 1.07 (0.98, 1.17) per 10 % increase in percentage of ideal weight. Analysis incorporating ongoing measurements gave corresponding figures of 1.07 (1.02, 1.12) for fasting plasma glucose, 1.64 (1.23, 2.20) for age and 1.06 (0.95, 1.18) for percentage of ideal weight. The risk of myocardial infarction while on insulin treatment 1.09 (0.58, 2.06) or oral agents 1.41 (0.86, 2.31) was not significantly elevated relative to dietary treatment. Baseline smoking status, systolic blood pressure, and previous myocardial infarction were also significant predictors of myocardial infarction. Similar relationships were found for cerebrovascular accident and total mortality. Increasing fasting plasma glucose is a significant independent predictor of macrovascular disease in diabetes.

Objective: Although it is well established that hypercortisolism causes insulin resistance, the mechanisms responsible for impaired insulin action in Cushing's syndrome are unclear. This study investigated the contribution of the glucose/glucose-6-phosphate substrate cycle (G/G6P)., Patients: Eight patients with Cushing's syndrome and seven control subjects were studied. All had normal fasting plasma glucose., Design: Insulin action was assessed using the euglycaemic glucose clamp at insulin infusion rates of 0.4 and 2.0 mU/kg/min combined with a simultaneous infusion of [2(3)H]- and [6(3)-H]-glucose. Glucose/ glucose-6-phosphate cycle activity was calculated as the difference in glucose turnover rates determined separately for [2(3)H]- and [6(3)H]-glucose by selective enzymatic detritiation., Measurements and Results: Exogenous glucose infusion rates required to maintain euglycaemia were significantly lower in Cushing's patients compared to controls, during the 0.4 mU/kg/min (7.8 +/- 1.2 vs 15.7 +/- 0.5 mumol/kg/min, P < 0.001) and the 2.0 mU/ kg/min insulin infusions (26.2 +/- 2.8 vs 51.5 +/- 3.5 mumol/ kg/min, P < 0.001). Endogenous glucose production was similar in both groups in the postabsorptive state (10.2 +/- 0.3 vs 10.8 +/- 0.4 mumol/kg/min, P = 0.50) and suppressed to a similar degree during hyperinsulinaemia. G/G6P cycle activity was markedly increased in the Cushing's group in the postabsorptive state (5.4 +/- 1.1 vs 2.0 +/- 0.5 mumol/kg/min, P = 0.028) and during the 0.4 mU/kg/min (3.2 +/- 0.6 vs 1.2 +/- 0.4 mumol/kg/min, P = 0.014) and 2.0 mU/kg/min insulin infusions (3.3 +/- 0.8 vs 1.1 +/- 0.5 mumol/kg/min, P = 0.049)., Conclusions: Patients with Cushing's syndrome show marked peripheral insulin resistance and enhanced hepatic G/G6P cycle activity. In the fasting state increased glucose/glucose-6-phosphate cycle activity may be a protective mechanism limiting hyperglycaemia. During hyperinsulinaemia G/G6P cycle activity was increased but insulin resistance was predominantly due to reduced peripheral glucose uptake.

It has become increasingly clear that deregulation of programmed cell death is a critical component in multistep tumorigenesis. Previous studies have demonstrated a high frequency of Bcl-2 expression in tumors arising from cells derived from the neural crest and in tumor cell lines of neural origin. The present investigation was undertaken to determine whether similar molecular events occur in human pheochromocytoma. With the aim of determining the potential role of apoptosis in the pathogenesis of this tumor, we assessed proto-oncogene Bcl-2 and c-myc protein products as well as Bcl-2 messenger RNA levels in a collection of such tumors. Western blot analysis revealed that such tumors expressed the 26 kDa Bcl-2 (5 of 8 cases) and the 64 kDa c-Myc (7 of 8 cases) proteins. Northern blot analysis detected the Bcl-2 transcripts in 6 of 8 tumors. Immunoperoxidase staining, using a monoclonal anti-Bcl-2 antibody, was positive in 18 (82%), including 5 malignant tumors, of the 22 specimens examined. This Bcl-2 immunoreactivity was seen in 14 of 18 (78%) sporadic tumors, including 2 that were extra-adrenal, and all familial tumors. Of the 22 tumor samples examined for c-Myc protein, 20 (91%) tumors were positive. Our results suggest that deregulation of programmed cell death may be a critical component in the multistep tumorigenesis of human pheochromocytoma. The genetic complementation of simultaneously deregulated Bcl-2 and c-myc may be implicated in this process.

Objective: To investigate the haemodynamic effects of insulin and their relationship to insulin resistance in essential hypertension., Design: Group comparison between patients with essential hypertension and normal controls., Setting: Outpatient clinics serving the greater Belfast area., Patients: Eleven patients with essential hypertension and eight age-, sex- and weight-matched control subjects were recruited. Administration of all antihypertensive agents to the hypertensive patients was stopped 6 weeks prior to the study., Methods: Leg blood flow was measured using venous occlusion plethysmography. Insulin action was assessed using the hyperinsulinaemic euglycaemic clamp technique., Results: The hypertensive subjects were insulin-resistant compared with the normal controls. Insulin infusion resulted in similar increases in calf blood flow in the two groups. There was no correlation between calf blood flow and measurements of insulin sensitivity in either group., Conclusions: Differences in whole-body glucose uptake in hypertensive and control subjects are not likely to be related to differences in insulin-induced stimulation of muscle blood flow.

Aims/background: Whereas the control of hormone secretion from pituitary adenomas has been studied in considerable detail, the molecular events underlying the development of these tumours are still poorly understood. Abnormalities of some oncogenes and tumour suppressor genes have been previously reported to occur at very low frequencies. The aim of the present study was to assess the possible expression of the bcl-2 oncoprotein and to compare it with that of c-myc in pituitary adenomas., Methods: Monoclonal antibodies were used, along with microwave antigen retrieval and the avidin-biotin immunohistochemical method, to investigate expression of the oncoproteins bcl-2 and c-myc in 30 primary pituitary tumours from five broad diagnostic groups and in five normal pituitaries., Results: Bcl-2 and c-myc immunoreactivities were detected in nine (30%) and eight (27%) tumour samples, respectively. Of the nine bcl-2 and eight c-myc positive tumours, seven were positive for both oncoproteins and included one of the four corticotrophinomas studied, four of seven prolactinomas, one of two somatotrophinomas, and one of four oncocytomas. All 13 null cell adenomas studied were negative for both bcl-2 and c-myc immunoreactivities., Conclusions: These results indicate that the bcl-2 and c-myc oncoproteins are expressed abnormally in over one quarter of pituitary tumours. Most these tumours co-expressed both oncoproteins. The genetic complementation of simultaneously deregulated bcl-2 and c-myc is implicated, through the regulation of apoptosis, in the pathogenesis of pituitary tumours.

Objective: To report our experience of 41 patients with phaeochromocytoma., Design: Retrospective study., Setting: Teaching hospital, United Kingdom., Subjects: Forty-one patients who presented with phaeochromocytoma 1970-1991., Interventions: Removal of tumour (n = 38)., Main Outcome Measures: Mortality, morbidity, and recurrence., Results: Thirty-four patients had sporadic tumours, five had the multiple endocrine neoplasia (MEN) type 2 syndrome, and two had non-MEN familial phaeochromocytoma. Thirty-six patients (88%) presented with symptoms of catecholamine excess, and 37 (90%) were hypertensive. The diagnosis was confirmed biochemically in 37. Tumours were located using computed tomography (n = 26), vascular studies (n = 11), and ultrasonography (n = 3). Thirty-eight patients had their tumours resected, of whom 10 (27%) developed complications. There were no postoperative deaths. Two patients were managed conservatively, and one died before diagnosis. Six patients developed recurrent tumours a mean of five years after the initial operation, and another patient had an inoperable tumour at initial diagnosis; four of these seven died from metastatic disease. Metaiodobenzylguanidine (MIBG) scans were positive in three of the patients who developed recurrences., Conclusions: Patients with phaeochromocytoma can now be operated on safely but prolonged follow-up is essential.

Abnormalities of both insulin secretion and insulin action occur in NIDDM. It is not clear, however, which is the primary defect. Recently, it has been suggested that the frequency of insulin pulses is an important factor regulating insulin action in normal humans. We examined the relationship between pulsatile insulin secretion and insulin action in eight NIDDM subjects and eight health matched control subjects. Insulin action was assessed prevailing fasting glucose levels before and after hype insulinemia (2-h insulin infusion at 2.0 mU / kg / min). Pulsatility of insulin was assessed by sampling every 2 min for 90 min after an overnight fast and identifying insulin pulses using the computer program Pulsar. Fasting plasma glucose and postabsorptive endogenous glucose production were both greater in diabetic subjects compared with control subjects (10.1 +/- 1.2 vs. 5.4 +/- 0.1 mmol/l, P < 0.01; 11.8 +/- 0.8 vs. 9.9 +/- 0.4 micromol / kg / min, P < 0.05). During the 2.0 mU insulin infusion, glucose clearance was lower in the diabetic subjects (3.6 +/- 0.7 vs. 6.9 +/- 0.5 ml / kg / min), P < 0.05), whereas endogenous glucose production was suppressed to a similar degree in both groups (4.5 +/- 0.8 vs. 3.6 +/- 0.7 micromol x kg(-1) x min(-1), NS). The frequency of insulin pulses and glucose clearance were negatively correlated in both diabetic subjects (r = -0.75, P < 0.05) and normal control subjects (r = -0.82, P < 0.01). This negative correlation was also present in both groups taken together (r = -0.72, P < 0.001). There was no correlation between insulin pulse frequency and endogenous glucose production either in the fasting state or during hyperinsulinemia. We concluded that the frequency of insulin pulses and peripheral insulin sensitivity are closely linked in NIDDM and normal subjects.

Background and Objective: The differentiation of benign from malignant phaeochromocytoma is difficult. We have examined whether the use of flow cytometric determination of nuclear DNA content would be useful as a predictor of malignant behaviour in patients with phaeochromocytoma as some previous studies had suggested that a diploid cytometric DNA pattern indicated benign disease., Design and Patients: DNA flow cytometry was performed on phaeochromocytoma tissue from 36 patients (19 female, 17 male; mean age at presentation 39.5 years). The results were correlated with clinical outcome after prolonged follow-up., Measurements: DNA histograms were constructed following nuclear suspension analysis., Results: Of 26 patients followed up for more than 5 years after initial removal of primary phaeochromocytoma, three have died from malignant recurrence. In these patients a diploid DNA cytometric pattern was observed in two and an aneuploid pattern in one. Twenty-one patients are still alive. DNA cytometry showed a diploid pattern in the one patient who developed recurrent phaeochromocytoma 4 years after removal of a primary tumour., Conclusion: In this study, three of nine patients with an apparently benign diploid cytometric pattern subsequently developed recurrent disease. Routine use of DNA flow cytometry did not reliably differentiate benign from malignant phaeochromocytoma. Prolonged clinical and biochemical follow-up is still necessary for all patients with this condition.

The best long-term results of transsphenoidal surgery appear to be in those patients who have unmeasurable serum cortisol levels in the immediate post-operative period. This appears to be due to isolated ACTH deficiency in the remaining normal pituitary gland. In our experience, however, long-term clinical remission may be possible with measurable serum cortisol levels post-operatively. The cortisol response to ACTH or CRF appears to provide no greater discrimination than basal measurements and is possibly less helpful than dexamethasone suppression. The prolonged clinical remission that we have seen in some patients with early measurable but low cortisol levels, together with the possible operative morbidity and partial success of repeat surgery, suggests careful assessment before a recommendation is made of an immediate second operation in these patients. The possibility of cyclical secretion of cortisol must be considered both pre and post-operatively. Finally, as experience with transsphenoidal surgery is still relatively short, all these patients need continuing endocrine follow-up in centres with adequate experience of the condition. For the individual patient we recommend that decisions regarding further therapy are based on 0800-0900 h serum cortisol levels, an index of cortisol production (serum cortisol day profiles or 24 hour urinary free cortisol), and the response to low dose dexamethasone suppression in the early post-operative period.

A number of factors suggest that abnormalities of the adrenal cortex are present in essential hypertension. To determine whether altered cortisol excretion exists in essential hypertension, we have measured urinary free cortisol and cortisol to creatinine ratios in early morning urine specimens for 14 consecutive days. We have established a reference range for these parameters in 26 normotensive subjects. We have also compared these values in nine normotensive subjects and nine patients with essential hypertension closely matched for age, sex and body mass index. In the 26 normotensive subjects, urinary free cortisol was 240 +/- 13 nmol/l (mean +/- s.e.m) and cortisol to creatinine ratio was 22 +/- l. In the nine hypertensive subjects, urinary free cortisol was 238 +/- 48 nmol/l and cortisol to creatinine ratio was 20 +/- 3. We have not demonstrated an abnormality of cortisol excretion in essential hypertension.

The pathogenesis of the hypertension associated with Cushing's syndrome is not completely understood. Sensitivity to pressor agents may play a role. We have investigated this possibility by measuring blood pressure (BP) during incrementally increasing infusions of the alpha-adrenergic agonist phenylephrine. Ten subjects (8 women: 2 men), aged 40 +/- 5 years (mean +/- s.e.m.) with Cushing's syndrome were studied. All had raised BP but none had received any anti-hypertensive treatment for at least 16 days before study. Ten age- (40 +/- 5 years) and sex-matched control subjects were also studied. At 13.30, 30 min after a light meal, subjects had an intravenous cannula inserted, ECG leads and a sphygomanometer cuff attached, and then rested supine in a quiet room for 30 min. Phenylephrine was then infused incrementally at intervals of 5 min. The doses used were 0.3, 0.6, 0.9, 1.35 and 2 micrograms/kg/min. Basal mean blood pressure (MAP) was 108 +/- 2 mm Hg (mean +/- s.e.m.) in patients and 74 +/- 3 mm Hg in controls (P < 0.05) and pulse rate was 75 +/- 5 and 68 +/- 3 beats/min (NS), respectively). MAP increased and pulse rate decreased linearly with time. The rate of rise of MAP was 1.7 +/- 0.4 mm Hg/min in subjects and 1.1 +/- 0.2 mm Hg/min in controls (NS). The rate of decrease of pulse was significantly more rapid in Cushing's subjects than in controls (1.4 +/- 0.2; 0.6 +/- 0.1 beats/min2; P < 0.05). The lack of any increased BP response to alpha-adrenergic stimulation suggests that altered sensitivity is not a major cause of the increased BP seen in patients with Cushing's syndrome.

In conventional doses, thiazide diuretics impair glucose tolerance and decrease insulin sensitivity, making them an unpopular choice for treating diabetic patients with hypertension. However, use of low-dose thiazide diuretics may avoid the adverse metabolic effects seen with conventional doses. In a double-blind, randomised crossover study we assessed peripheral and hepatic insulin action in 13 hypertensive non-insulin-dependent diabetic patients after a 6-week placebo run-in and following two 12-week treatment periods with either low (1.25 mg) or conventional (5.0mg) dose bendrofluazide. There were no differences between doses in their effects on systolic and diastolic blood pressure. Bendrofluazide 1.25 mg had significantly less effect on serum potassium, uric acid, fasting glucose and HbA1C concentrations than the 5.00 mg dose. Exogenous glucose infusion rates required to maintain euglycaemia were significantly different between doses (p < 0.05) with conventional-dose bendrofluazide worsening peripheral insulin resistance compared to baseline (23.8 +/- 2.9 vs 27.3 +/- 3.5 mumol.kg-1.min-1, p < 0.05) and low-dose bendrofluazide producing no change compared to baseline (26.8 +/- 3.6 vs 27.3 +/- 3.5 mumol.kg-1.min-1, p = NS). Postabsorptive endogenous glucose production was higher on treatment with bendrofluazide 5.0 mg compared to 1.25 mg (11.7 +/- 0.5 vs 10.2 +/- 0.3 mumol.kg-1.min-1, p < 0.05) and suppressed to a lesser extent following insulin (4.0 +/- 0.7 vs 2.0 +/- 0.4 mumol.kg-1.min-1, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

We report five novel mutations in the human Ca(2+)-sensing-receptor gene that cause familial hypocalciuric hypercalcemia (FHH) or neonatal severe hyperparathyroidism. Each gene defect is a missense mutation (228Arg-->Gln, 139Thr-->Met, 144Gly-->Glu, 63Arg-->Met, and 67Arg-->Cys) that encodes a nonconservative amino acid alteration. These mutations are each predicted to be in the Ca(2+)-sensing receptor's large extracellular domain. In three families with FHH linked to the Ca(2+)-sensing-receptor gene on chromosome 3 and in unrelated individuals probands with FHH, mutations were not detected in protein-coding sequences. On the basis of these data and previous analyses, we suggest that there are a wide range of mutations that cause FHH. Mutations that perturb the structure and function of the extracellular or transmembrane domains of the receptor and those that affect noncoding sequences of the Ca(2+)-sensing-receptor gene can cause FHH.

This study was designed to ascertain the long-term safety and efficacy profile of the somatostatin analogue octreotide as treatment of refractory acromegaly. Eight patients (aged 21-62 years) with persistent growth hormone (GH) elevation (duration 1-15 years) despite previous therapy were studied. Octreotide was given subcutaneously in increasing doses for the first year to a maximum of 500 micrograms three times daily. The dose then was reduced to 200 micrograms three times daily for the next 3 years. At annual assessments, 24-h GH profiles, insulin-like growth factor I (IGF-I) and a side-effect profile including gall-bladder ultrasound were studied. Oral glucose tolerance tests (75 g) were performed basally and after 6 months and 3 years of therapy. Haemoglobin A1 (HbA1) was also assessed. Side effects were recorded. Mean GH (+/- SEM) was 36.0 +/- 9 mU/l basally and was reduced significantly at all subsequent assessments on therapy (4-year mean, 9.4 +/- 2.1 mU/l). The IGF-I level also remained suppressed and was normalized in four of eight patients who remained on octreotide. Fasting plasma glucose and HbA1 were not changed by therapy but 2-h glucose was elevated after 6 months and 3 years (basal mean, 7.6 mmol/l (5.3-9.0 mmol/l); 3-year mean, 10.7 mmol/l (8.4-15.7 mmol/l); p < 0.05). Five patients developed gallstones and in three these had disappeared following 1 year of bile salt dissolution therapy. Octreotide continues to suppress serum GH and IGF-I long term without attenuation of effect. Gallstone formation is a major side effect.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied insulin and C-peptide levels in patients with non-insulin-dependent diabetes mellitus (NIDDM) during standard oral or intravenous glucose tolerance tests (GTT) at the time of diagnosis and after 3 months dietary therapy. On the second occasion they also had an 'augmented' GTT, in which slow intravenous infusion of glucose raised basal plasma glucose to a level similar to that at the time of diagnosis. Eight patients had oral tests, and seven patients intravenous tests. In both groups, dietary therapy significantly reduced fasting and peak plasma glucose (p < 0.05 for oral; p < 0.01 for intravenous GTT). Serum insulin levels during conventional oral GTT were not significantly different after dietary therapy compared to diagnosis, but were significantly higher during the 'augmented' oral GTT (p < 0.05). In those patients who underwent intravenous GTT, there was a significant increase in both the total amount of insulin secreted (0-60 min) and in first-phase insulin secretion (0-10 min) during the 'augmented' test compared to diagnosis (p < 0.01), but first-phase insulin secretion during the conventional intravenous GTT was unchanged. Serum C-peptide responses were also greater during 'augmented' tests (p < 0.05), similar in pattern to serum insulin. There is a relative deficiency in insulin secretion in untreated NIDDM, which can be reversed by dietary therapy. It is essential to study insulin and C-peptide secretion in controlled 'fasting' glucose conditions.

This study followed up a cohort of patients with microalbuminuria identified on a spot morning urine sample 8 years earlier and aimed to determine if a spot morning urinary albumin concentration was able to identify patients with non-insulin treated diabetes at increased risk of mortality and progression to nephropathy. In 1984, 47 of 216 patients chosen by random selection from our teaching hospital-based diabetes clinic were identified as having microalbuminuria (urinary albumin concentration 35-300 micrograms ml-1). Subjects were compared with an age-matched control group from the 1984 cohort who did not have microalbuminuria. Eight years later, 22 of 47 (46.8%) patients with microalbuminuria had died compared to 10 of 47 (21.3%) patients without albuminuria (p < 0.05). The majority of deaths were from cardiovascular disease (53.1%). Logistic regression showed microalbuminuria to be an independent predictor of mortality, not influenced by age, duration of diabetes, blood pressure, glycosylated haemoglobin or creatinine at the initial examination. Eight years later, in the group with initial microalbuminuria, eight still had microalbuminuria and five patients had developed nephropathy. In the group without albuminuria in 1984, only one patient had progressed to microalbuminuria and no patients to nephropathy. In conclusion, a spot urinary albumin concentration is of value in identifying patients with an increased risk of mortality or progression to nephropathy, and is simple to obtain at a clinic.

The prevalence of hypertension and its relationship to nephropathy were measured in a hospital-based diabetic clinic. Six hundred patients (300 insulin treated, 300 non-insulin treated) were randomly selected from a clinic population of 1054 insulin treated and 1039 non-insulin treated subjects. Eighty-three percent of patients with insulin treated diabetes and 72% of patients with non-insulin treated diabetes were studied. Blood pressure data from the Belfast MONICA project were used for the control group. In patients with insulin treated diabetes (age 25-64 years) the prevalence of a systolic blood pressure > 160 mmHg or a diastolic blood pressure > 95 mmHg or on treatment for hypertension (WHO criteria) was 19.1% in males (NS, vs. control group) and 17.8% in females (NS); the prevalence of a systolic blood pressure > 140 mmHg and diastolic blood pressure > 90 mmHg was 17.6% in males (NS, vs. control group) and 9.5% in females (NS). In patients with non-insulin treated diabetes (age 35-65 years) the prevalence of hypertension by WHO criteria (see above) was 26.8% in males (NS, vs. control group) and 28.9% in females (NS); the prevalence of a systolic blood pressure > 140 mmHg and diastolic blood pressure > 90 mmHg was 21.4% in males (NS, vs. control group) and 17.8% in females (NS).(ABSTRACT TRUNCATED AT 250 WORDS)

We describe a case of recurrent hypoglycaemia associated with a hepatoma. During hypoglycaemia serum insulin was undetectable. Plasma insulin-like growth factor II (IGF-II) was not elevated although 71% of plasma IGF-II was present as big IGF-II (molecular weight 11 kDa) which probably represents a non-glycated form of pro-IGF-II. The GH response to hypoglycaemia was impaired and plasma levels of both IGF-I and the GH-dependent IGF binding protein (IGFBP-3) were low. A recently described unextracted assay directed against the first 21 amino acids of the E-domain (E-21) of proinsulin-like growth factor-II (pro-IGF-II) allows direct plasma estimation (plasma E-21) of larger molecular forms of IGF-II without interference from normal IGF-II and IGF binding proteins. Basal values were grossly elevated (23.7 and 23.8 nmol/l). Treatment with GH led to an increase in the mean plasma glucose across 24 hours (4.25 +/- 0.21 mol/l (mean +/- SEM) before treatment, compared with 4.86 mmol/l +/- 0.17 following GH (P < 0.01)) and a reduction in hypoglycaemic attacks. The treatment was associated with a rise in IGFBP-3 and small increases in insulin like growth factors. Subsequent treatment with the somatostatin analogue octreotide did not produce a significant change in plasma glucose levels or insulin-like growth factors. Two courses of intrahepatic adriamycin restored elevated levels of E-21 to normal. Total IGF-II remained normal and IGF-I increased. GH treatment was successfully withdrawn with no effect on plasma glucose or growth factor levels. The patient remained free from hypoglycaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

The debate continues on how to screen for microalbuminuria in clinical practice in patients with insulin-dependent diabetes mellitus. Our study assesses the value of a spot morning urine specimen obtained at a clinic visit. In 1984, as part of a randomised survey of our diabetes clinic, 43 of 249 patients with insulin treated diabetes mellitus, were found to have microalbuminuria (urinary albumin concentration 35-300 ug ml-1) on a spot morning urine sample. These subjects were compared with an age-matched control group from the 1984 cohort who did not have microalbuminuria. Eight years later, in the group with microalbuminuria, 10 had died compared to six in the control group (p = 0.17) with 62.5% of all deaths being from cardiovascular disease. In the group with microalbuminuria, 10 of 27 still had incipient nephropathy while five had progressed to nephropathy. In the group without microalbuminuria only three of 33 patients had progressed to microalbuminuria while none had progressed to nephropathy. In conclusion a spot morning urine sample is a useful screening test to identify patients at risk of progression to nephropathy.

Objective: To see whether low dose thiazide diuretics given to patients with essential hypertension might avoid the adverse metabolic consequences seen with conventional doses., Design: Double blind randomised crossover study of two 12 week treatment periods with either low dose (1.25 mg) or conventional dose (5.0 mg) bendrofluazide given after a six week placebo run in period., Setting: Outpatient clinics serving the greater Belfast area., Subjects: 16 white non-diabetic patients (9 male) under 65 with essential hypertension recruited from general practices within the greater Belfast area., Main Outcome Measures: Systolic and diastolic blood pressure and peripheral and hepatic insulin action., Results: One man failed to complete the study. There were no differences between doses in their effects on systolic and diastolic blood pressure. Bendrofluazide 1.25 mg had substantially less effect on serum potassium concentration than the 5.0 mg dose. There were no intertreatment differences in fasting glucose, insulin, cholesterol, and triglyceride concentrations. Bendrofluazide 5.0 mg significantly increased postabsorptive endogenous glucose production compared with baseline (mean 10.9 (SD 1.2) v 10.0 (0.8) mumol/kg/min), whereas bendrofluazide 1.25 mg did not. Postabsorptive endogenous glucose production was significantly higher with bendrofluazide 5.0 mg compared with 1.25 mg (10.9 (1.2) v 9.9 (0.8) mumol/kg/min) but was suppressed to a similar extent after insulin (bendrofluazide 5.0 mg 2.8 (1.5) mumol/kg/min v bendrofluazide 1.25 mg 2.2 (1.5) mumol/kg/min). Exogenous glucose infusion rates required to maintain euglycaemia were not significantly different between doses and were similar to baseline., Conclusions: Bendrofluazide 1.25 mg is as effective as conventional doses but has less adverse metabolic effect. In contrast with conventional doses, low dose bendrofluazide has no effect on hepatic insulin action. There is no difference between low and conventional doses of bendrofluazide in their effect on peripheral insulin sensitivity.

Objective: To investigate the relationship between insulin and vascular risk factors in a healthy male population at high risk of ischaemic heart disease., Design: Computer-generated random number selection of subjects., Setting: A suburban general practice population (total practice population 4500) in Northern Ireland., Subjects: Four hundred male subjects, aged 35-65 years, were randomly selected with 273 responding., Intervention: At interview, each subject completed a questionnaire, had blood pressure measured and a 12-lead ECG recorded. The next morning, fasting blood samples were taken and a timed overnight urine collection for the albumin excretion rate was returned., Results: To exclude the confounding effects of other variables on insulin concentrations, a healthy nonobese, nondiabetic, normotensive group with no history of ischaemic heart disease, no family history of diabetes and not taking drugs was identified (n = 120). Within this group there was a significant correlation between insulin and triglyceride (r = 0.30; P < 0.05), high-density lipoprotein (HDL) cholesterol (r = 0.24; P < 0.05) and glucose (r = 0.30; P < 0.05). A group with higher insulin levels (n = 22) were compared to a group with lower insulin levels (n = 22). Serum triglyceride was higher (1.29 +/- 0.1 vs. 1.00 +/- 0.08 mmol L-1; P < 0.05), HDL cholesterol was lower (1.26 +/- 0.06 vs. 1.50 +/- 0.09 mmol L-1; P < 0.05) and plasma glucose higher (5.2 +/- 0.1 vs. 4.9 +/- 0.1 mmol L-1; P < 0.05) in the group with higher insulin levels., Conclusions: There is a relationship between insulin and triglyceride, HDL cholesterol and glucose but not blood pressure, cholesterol or low-density-lipoprotein (LDL) cholesterol in a healthy population at high risk of ischaemic heart disease.

Objective: Increasing dietary sodium intake increases blood pressure in some subjects with essential hypertension. Atrial natriuretic factor (ANF) has a potential role in modifying these changes. The purpose of this study was to observe the blood pressure and plasma ANF responses to low and high sodium diets in subjects with essential hypertension to see if the plasma ANF and blood pressure responses were related., Design: An in-patient study of subjects taking their normal diet (day 1), a 12 mmol sodium diet for 6 days and a 250 mmol diet for 6 days., Patients: Seven men with essential hypertension., Measurements: Continuous 24 hour urine collections were analysed for sodium excretion. Blood pressure was recorded at 0900, 1205 and 1700 h on days 1, 7 and 13. Blood was taken at 0900 h (fasting supine overnight) and at 1200 h (after 2 hours erect posture) on the above days for plasma ANF, plasma renin activity (PRA) and serum aldosterone., Results: Urinary sodium excretion was (mean +/- SEM) 11 +/- 1 mmol on day 5 of the low sodium diet, and 294 +/- 17 mmol during the fifth day of the high sodium diet. Plasma ANF (supine and erect) was significantly lower (2.8 +/- 0.6, 1.6 +/- 0.2 pmol/l) on the low sodium diet when compared to the high sodium diet (8.6 +/- 2.4, 5.0 +/- 1.6 pmol/l (P < 0.05)). Supine and erect PRA and serum aldosterone were significantly higher on the low compared to the high sodium diet. Blood pressure responses were heterogeneous rather than bimodal. Mean arterial blood pressure was 107 +/- 3 mmHg on the low sodium diet and 111 +/- 4 mmHg on the high sodium diet (P < 0.05). Changes of blood pressure did not correlate with the changes of plasma ANF., Conclusions: Failure of plasma atrial natriuretic factor to rise with increasing dietary sodium did not therefore determine the blood pressure response to the change in dietary sodium. No link was established between plasma atrial natriuretic factor response and sodium sensitivity.

Increased glucose/glucose-6-phosphate (G/G6P) substrate cycle activity may be an early marker of disordered hepatic glucose metabolism. To investigate the effects of glucocorticoids on G/G6P cycle activity and insulin resistance, we studied eight normal subjects using the euglycemic glucose clamp technique with high pressure liquid chromatography-purified [2(3)H]- and [6-3H]glucose tracers at insulin infusion rates of 0.4 and 2.0 mU/kg.min after 24-h cortisol (2 micrograms/kg.min) and saline infusions. Endogenous glucose production ([6-3H]glucose) was greater after cortisol than saline in the postabsorptive state (13.3 +/- 0.5 vs. 12.2 +/- 0.5 mumol/kg.min; P < 0.05) and during 0.4-mU insulin infusion (10.5 +/- 0.7 vs. 5.0 +/- 0.8 mumol/kg.min; P < 0.005). During 2.0-mU insulin infusion, endogenous glucose production was suppressed similarly (5.1 +/- 0.4 vs. 4.1 +/- 0.5 mumol/kg.min), but glucose disappearance was less after cortisol than saline (38.7 +/- 3.5 vs. 64.6 +/- 4.3 mumol/kg.min; P < 0.001). G/G6P cycle activity after cortisol and saline was similar in the postabsorptive state and during 0.4 mU insulin. During 2.0 mU insulin, cycle activity was greater after cortisol than saline (3.6 +/- 0.9 vs. 0.8 +/- 0.5 mumol/kg.min; P < 0.005). In conclusion, cortisol induces hepatic insulin resistance without significantly changing G/G6P cycle activity. At high glucose turnover rates, G/G6P cycle activity is increased by cortisol; however, reduced glucose disappearance is the main cause of impaired insulin action.

Objective: To examine the relationship between sensory modalities of neurological function and antecedent glycemic control in IDDM patients., Research Design and Methods: Examinations were conducted on 220 IDDM patients (age at onset < 25 yr, duration < 18 yr) for the presence or absence of the right or left ankle reflex and determination of vibration perception threshold at each medial malleolus and great toe using biothesiometry. These parameters were related to the concurrent HbA1 and to a mean of serial measurements (mean HbA1) over the previous 6 yr., Results: Ankle reflexes were absent in 39 (right ankle) and 41 (left ankle) patients, respectively. Mean (right + left) ankle and toe VPTs were 8.7 +/- 3.6 and 6.3 +/- 4.2 (mean +/- SD) (arbitrary units), respectively. Both the mean and concurrent HbA1 were significantly different in patients with absent ankle reflexes (11.6 +/- 1.9 and 12.2 +/- 2.8%, respectively) compared with present ankle reflexes (10.3 +/- 1.7, 10.3 +/- 2.1%) (P < 0.0001). Similarly, a present ankle reflex was related to mean HbA1 arbitrarily divided into groups < 10, 10-12, > 12% (P = 0.0009). In contrast, mean ankle VPT (8.0 +/- 2.2, 8.8 +/- 3.1, and 10.3 +/- 6.2) and toe VPT (5.5 +/- 2.2, 6.1 +/- 2.9, and 8.5 +/- 8.2) did not increase significantly with poor glycemic control (P > 0.05). Age, right ankle reflex, retinopathy, 24-h urinary albumin excretion rate, and erect systolic blood pressure were the only independent variables predicting the toe VPT using linear regression analysis., Conclusions: These findings support a role for glycemic control in neurological dysfunction in IDDM patients, but also suggest that other unknown factors may be involved.

Objective: We assessed the current role of bilateral adrenalectomy in the overall management strategy of hypercortisolism., Design: Retrospective review of case notes., Patients: Twenty-six patients (20F/6M); mean age 46 years (range 15-70 years), median duration of follow-up 5.25 years (0.6-19.1 years) who had undergone bilateral adrenalectomy at the Royal Victoria Hospital since 1972. Eighteen had had prior transsphenoidal surgery which did not control the hypercortisolism., Measurements: Morbidity, mortality, incidence of Nelson's syndrome., Results: Surgery was performed through bilateral postero-lateral incisions (20 patients) or a long epigastric incision (six patients). The mean combined weight of the adrenals at surgery was 11.2 g. Twenty patients received subcutaneous heparin and 18 antibiotic prophylaxis peri and post-operatively. There was no operative mortality. Minor complications included one post-operative wound infection and a small pneumothorax requiring drainage. Major complications occurred in two other patients, both with pre-existing invasive pituitary tumours and considered at high risk because of age and general debility. One patient had a massive pulmonary embolus and the other a subphrenic abscess post-operatively. This latter patient, the only mortality, died from an unrelated cause three years post-operatively. Six patients have subsequently undergone pituitary surgery and three have received external pituitary irradiation therapy for expanding tumours., Conclusions: Bilateral adrenalectomy, in experienced hands, is a relatively safe and useful management option in patients with hypercortisolism. Growth of a pituitary adenoma post-operatively is now the most worrying complication.

Objective: To determine if insulin resistance is present in normotensive adults at increased risk of developing hypertension., Design: Normotensive subjects with at least one hypertensive parent were paired with offspring of normotensive parents (controls), being matched for age, sex, social class, and physical activity., Setting: Outpatient clinic., Subjects: 30 paired subjects (16 men and 14 women) with and without a family history of hypertension, aged 18-32, with a body mass index < 25 kg/m2, with blood pressure < 130/85 mm Hg, and not taking drugs., Interventions: Euglycaemic glucose clamp (two hour infusion of insulin 1 mU/kg/min) and intravenous glucose tolerance test (injection of 100 ml 20% glucose)., Main Outcome Measures: Insulin mediated glucose disposal and insulin secretion., Results: The offspring of hypertensive parents had slightly higher blood pressure than did the controls (mean 117 (SD 6) v 108 (5) mm Hg systolic, p = 0.013; 76 (7) v 67 (6) mm Hg diastolic, p = 0.017). Their insulin mediated glucose disposal was lower than that of controls (29.5 (6.5) v 40.1 (8.6) mumol/kg/min, p = 0.002), but, after adjustment for blood pressure, the difference was not significant (difference 6.9 (95% confidence interval -1.5 to 15.3), p = 0.10). Insulin secretion in the first hour after injection of glucose was slightly but not significantly higher in the offspring of hypertensive patients (9320 (5484) v 6723 (3751) pmol.min/l). The two groups had similar concentrations of plasma glucose (5.2 (0.3) v 5.1 (0.4) mmol/l), serum cholesterol (4.4 (0.8) v 4.6 (0.8) mmol/l), serum triglyceride (0.89 (0.52) v 0.68 (0.27) mmol/l), and serum low density lipoprotein cholesterol (2.81 (0.65) v 2.79 (0.61) mmol/l). The offspring of hypertensive parents, however, had lower serum concentrations of high density lipoprotein cholesterol (1.24 (0.31) v 1.56 (0.35) mmol/l, p = 0.002) and higher serum concentrations of non-esterified fatty acids (0.7 (0.4) v 0.4 (0.4) mmol/l, p = 0.039)., Conclusions: Young normotensive subjects who are at increased risk of developing hypertension are insulin resistant.

Recent studies have suggested that microalbuminuria is relatively common (9.4%) in non-diabetic subjects and that it is an excellent marker for increased cardiovascular risk. In an attempt to assess the prevalence of microalbuminuria in Northern Ireland where there is a high incidence of coronary heart disease, we studied 400 males, age 35-65 years, chosen at random from a Belfast general practice. There was a 73% response rate (n = 273). Sixteen per cent of the population has ischaemic heart disease. Microalbuminuria was defined as an increased urinary albumin excretion rate of 20-200 ug min-1. Thirteen subjects (4.7%) had an albumin excretion rate of 20 ug min-1 or more. After exclusion of subjects with diabetes mellitus or renal diseases, the group with microalbuminuria (n = 8), was compared to those without microalbuminuria (n = 256). There was no significant difference in the incidence of ischaemic heart disease between the two groups, nor did the group with microalbuminuria have a more adverse profile of vascular risk factors, apart from serum triglyceride (1.8 +/- 0.2 v 1.3 +/- 0.0 mmol l-1, p < 0.05) and plasma glucose (5.5 +/- 0.3 v 5.1 +/- 0.3 mmol l-1, p < 0.05) levels. We conclude that in a general practice from an area at high risk of ischaemic heart disease, the prevalence of microalbuminuria was low. Contrary to previous reports, microalbuminuria was not helpful in predicting subjects at risk of ischaemic heart disease.

It has been suggested that increased glucose/glucose 6-phosphate substrate cycling impairs net hepatic glucose uptake in Type 2 (non-insulin-dependent) diabetes mellitus and contributes to hyperglycaemia. To investigate glucose/glucose 6-phosphate cycle activity and insulin action in Type 2 diabetes we studied eight patients and eight healthy control subjects, using the euglycaemic glucose clamp and isotope dilution techniques with purified [2-3H]- and [6-3H] glucose tracers, in the post-absorptive state and eight patients and five healthy control subjects during consecutive insulin infusions at rates of 0.4 and 2.0 mU.kg-1 x min-1. [2-3H]glucose and [6-3H]glucose radioactivity in plasma samples were determined using selective enzymatic detritiation, allowing calculation of glucose turnover rates for each isotope, the difference being glucose/glucose 6-phosphate cycling. Endogenous glucose production ([6-3H]glucose) was greater in diabetic than control subjects in the post-absorptive state (15.6 +/- 1.5 vs 11.3 +/- 0.4 mumol.kg-1 x min-1, p < 0.05) and during the 0.4 mU insulin infusion (10.1 +/- 1.3 vs 5.2 +/- 0.3 mumol.kg-1 x min-1, p < 0.01) indicating hepatic insulin resistance. Glucose/glucose 6-phosphate cycling was significantly greater in diabetic than in control subjects in the post-absorptive state (2.6 +/- 0.4 vs 1.6 +/- 0.2 mumol.kg-1 x min-1, p < 0.05) but not during the 0.4 mU insulin infusion (2.0 +/- 0.4 vs 2.0 +/- 0.3 mumol.kg-1 x min-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: We assessed the endocrine outcome after transsphenoidal surgery for Cushing's disease., Design: Five-year (mean) follow-up (range 1 month-12 years) of patients undergoing transsphenoidal surgery for Cushing's disease between 1977 and 1990; review of case notes, current clinical and biochemical assessment including 24-hour urinary free cortisol., Setting: Northern Ireland., Subjects: Forty-one patients (33F: 8M); mean age at diagnosis 39.1 years (9-72 years)., Main Outcome Measures: Measurements of early post-operative 0800 h serum cortisol and 24-hour urinary free cortisol at least 24 hours after withdrawal of oral hydrocortisone therapy. This was followed by low dose dexamethasone testing. Current 24-hour urinary free cortisol measurements. Retrospective definition of cure., Results: Twenty-seven patients were either cured or improved by surgery, 14 were considered definite failures. Of 19 patients cured, eight had unmeasurable early post-operative 0800 h serum cortisol levels while of 15 tested, 13 had complete suppression with dexamethasone and two suppressed normally but to still measurable levels (39 and 60 nmol/l respectively). Seventeen patients in total have subsequently had bilateral adrenalectomy of whom two have developed Nelson's syndrome. Seven of the 41 patients were shown to have definite cyclical cortisol secretion first diagnosed post-operatively in three patients. Hormone deficiency included TSH (5), LH/FSH (1), cortisol (1) and ADH (temporary in 7, permanent in 1). In all, seven patients had some type of permanent hormonal deficiency post-operatively., Conclusions: Transsphenoidal surgery offers a worthwhile cure rate without the necessity of life-long endocrine therapy. Post-operative endocrine assessment must be rigorous so that early further management can be planned in the significant percentage of patients in whom cure is not achieved. Early complete suppression on low dose dexamethasone testing is very suggestive of cure but repeated and long-term monitoring of 24-hour urinary free cortisol is advisable.