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Biomedical subjects

A B Atkinson

Publications and source records attributed to A B Atkinson.

At least 55 records · Page 3Linked to original sources
PubMed1998

Effects of combination therapy with an angiotensin converting enzyme inhibitor and thiazide diuretic on insulin action in essential hypertension.

OBJECTIVE: To determine whether combination of an angiotensin converting enzyme inhibitor with a high dose of thiazide diuretic avoids adverse metabolic consequences of thiazide diuretics. DESIGN: Double-blind randomized crossover study of two 12-week treatment periods with captopril (up to 100 mg/day) either alone or in combination with 5 mg bendrofluazide given after a 6-week placebo run-in period. Treatment periods were separated by a 6-week placebo washout period. SETTING: Outpatient clinics in greater Belfast. PATIENTS: Fifteen white non-diabetic essential hypertensives (seven male) aged < 65 years recruited from general practices in greater Belfast. MAIN OUTCOME MEASURES: Systolic and diastolic blood pressures and peripheral and hepatic insulin action. RESULTS: Two patients failed to complete the study. Blood pressure was lowered (139/89+/-18/7 mmHg combination versus 160/97+/-21/7 mmHg captopril; P < 0.001). Fasting insulin level was raised (7.9+/-3.6 mU/l combination versus 6.2+/-3.2 mU/l baseline; P < 0.001). There were no differences between treatments for glucose, urate, cholesterol and triglyceride levels. Serum potassium level was lowered (3.8+/-0.4 mmol/l combination versus 4.2+/-0.4 mmol/l captopril, P < 0.05). Postabsorptive endogenous glucose production was raised (10.8+/-1.7 micromol/kg per min combination versus 10.0+/-1.5 micromol/kg per min captopril; P < 0.01) and was greater than baseline (9.7+/-2.1 micromol/kg per min, P < 0.05). Suppression of glucose production by insulin was similar with both treatments. Exogenous glucose infusion rates required to maintain euglycaemia did not differ (32.4+/-7.6 micromol/kg per min captopril, 32.7+/-6.2 micromol/kg per min combination, 31.5+/-7.2 micromol/kg per min baseline). CONCLUSIONS: Combination therapy increased glucose production (compared with captopril alone), indicating hepatic insulin resistance. It cannot be assumed that combined preparations with angiotensin converting enzyme inhibitors will ameliorate adverse effects of high doses of thiazide diuretics on insulin action.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Captopril does not improve insulin action in essential hypertension: a double-blind placebo-controlled study.

OBJECTIVE: To compare the effect of captopril with that of placebo on peripheral and hepatic insulin action in essential hypertension, in light of evidence that insulin resistance is associated with cardiovascular risk. DESIGN: Randomized, double-blind, placebo-controlled, crossover trial, with 8 week treatment periods of captopril and placebo preceded and separated by 6 weeks of placebo. SETTING: Belfast teaching hospital. PATIENTS: Eighteen Caucasian nondiabetic patients (10 males), aged under 65 years, with essential hypertension, recruited from general practices in the greater Belfast area. INTERVENTIONS: Captopril at 50 mg twice a day or placebo twice a day for two 8 week treatment periods. MAIN OUTCOME MEASURES: Peripheral and hepatic insulin sensitivity assessed by glucose clamps. RESULTS: Fourteen patients completed the study. Mean (+/- SEM) levels of fasting glucose, fasting insulin and postabsorptive hepatic glucose production were similar after captopril and placebo (5.4+/-0.1 versus 5.4+/-0.1 mmol/l, 10.6+/-2.2 versus 9.5+/-1.1 mU/l, 11.2+/-0.6 versus 11.0+/-0.5 mmol/kg per min, respectively). During hyperinsulinaemia, hepatic glucose production was suppressed to comparable levels after both treatments (4.8+/-0.6 versus 4.3+/-0.6 mmol/kg per min) and exogenous glucose infusion rates required to maintain euglycaemia were also similar (30.0+/-2.6 versus 30.3+/-2.6 mmol/kg per min). CONCLUSION: Captopril therapy in uncomplicated essential hypertension has no effect on peripheral or hepatic insulin sensitivity.

Antihypertensive Agents↗
PubMed1997

Macrovascular disease and hyperglycaemia: 10-year survival analysis in Type 2 diabetes mellitus: the Belfast Diet Study.

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.

Adult↗
PubMed1997

Insulin action and hepatic glucose cycling in Cushing's syndrome.

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.

3-Hydroxybutyric Acid↗
PubMed1997

Skeletal muscle blood flow is not a determinant of insulin resistance in essential hypertension.

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.

Blood Flow Velocity↗
PubMed1997

Expression of the apoptosis-suppressing gene BCL-2 in pheochromocytoma is associated with the expression of C-MYC.

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.

Adolescent↗
PubMed1997

Treatment of diabetic ketoacidosis using normalization of blood 3-hydroxybutyrate concentration as the endpoint of emergency management. A randomized controlled study.

OBJECTIVE: To compare the efficacy of an extended insulin regimen using correction of hyperketonemia as endpoint with a more conventional regimen in the treatment of diabetic ketoacidosis. RESEARCH DESIGN AND METHODS: A total of 22 patients admitted to a Belfast teaching hospital with clinical and biochemical features of diabetic ketoacidosis (pH < 7.25 and/or bicarbonate < 16 mmol/l) were randomized to either conventional or extended insulin regimens. In the conventional regimen, insulin was administered at 5 U/h until near-normoglycemia (blood glucose < or = 10 mmol/l) and then administered at a reduced rate until clinical recovery. In the extended regimen, administration of insulin at 5 U/h was continued beyond attainment of normoglycemia, until resolution of hyperketonemia (3-hydroxybutyrate < 0.5 mmol/l). Main outcome measures were 3-hydroxybutyrate and bicarbonate levels during the 24 h after attainment of near-normoglycemia. RESULTS: After near-normoglycemia, correction of hyperketonemia was achieved earlier with the extended treatment (5.9 +/- 0.8 vs. 21.8 +/- 3.4 h, P = 0.0004 [mean +/- SD]). The area under the curve of 3-hydroxybutyrate against time for 24 h after near-normoglycemia was reduced with the extended treatment (24.9 +/- 3.8 vs. 55.9 +/- 6.7 mmol.l-1.h-1, P = 0.001). These differences remained statistically significant after adjustment for higher baseline levels of 3-hydroxybutyrate at near-normoglycemia in the extended treatment group. Bicarbonate levels at 6 and 12 h after near-normoglycemia were not significantly different between groups. CONCLUSIONS: The extended insulin regimen, which was easy to implement at ward level, produced a more rapid resolution of ketosis than the conventional regimen.

3-Hydroxybutyric Acid↗
PubMed1996

Assessment of cure after transsphenoidal surgery for Cushing's disease.

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.

Cushing Syndrome↗
PubMed1996

Flow cytometric analysis does not reliably differentiate benign from malignant phaeochromocytoma.

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.

Adult↗
PubMed1996

Expression of bcl-2 oncoprotein in pituitary tumours: comparison with c-myc.

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.

Adenoma↗
PubMed1996

Association between insulin secretory pulse frequency and peripheral insulin action in NIDDM and normal subjects.

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.

Activity Cycles↗
PubMed1996

Phaeochromocytoma in Northern Ireland: a 21 year review.

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.

Adrenal Gland Neoplasms↗
PubMed1995

A comparison of the effects of low- and conventional-dose thiazide diuretic on insulin action in hypertensive patients with NIDDM.

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)

Adult↗
PubMed1995

Prevalence of hypertension and albuminuria in a teaching hospital diabetes 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)

Adult↗
PubMed1995

Microalbuminuria as identified by a spot morning urine specimen in non-insulin-treated diabetes: an eight-year follow-up study.

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.

Albuminuria↗