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Our objective was to determine whether Type 1 diabetic patients with microalbuminuria are less sensitive to the effects of insulin on glucose metabolism and skeletal muscle blood flow, compared to those with normal albumin excretion, after careful matching for confounding variables. We recruited 10 normotensive Type 1 diabetic patients with microalbuminuria and 11 with normoalbuminuria matched for age, sex, body mass index, duration of diabetes and HbA(1c). Peripheral and hepatic insulin action was assessed using a two-step euglycaemic hyperinsulinaemic clamp (2 h at 0.4 mU x kg(-1) x min(-1), 2 h at 2.0 mU x kg(-1) x min(-1)) combined with isotope dilution methodology. Skeletal muscle blood flow was determined by venous occlusion plethysmography. During the clamps, glucose infusion rates required to maintain euglycaemia were similar in the microalbuminuric subjects and controls (step 1, 8.2+/-1.4 (SE) vs 9.2+/-1.3 micromol x kg(-1) x min(-1): step 2, 30.9+/-2.7 vs 32.0+/-3.8 micromol x kg(-1) x min(-1)), as was hepatic glucose production basally and at steady state in step 1. In step 2, hepatic glucose production was lower in the microalbuminuric group (2.9+/-0.9 vs 6.4+/-0.7 micromol x kg(-1) x min(-1), P=0.005). During step 2, skeletal muscle blood flow increased significantly above baseline in the normoalbuminuric group (4.1+/-0.5 vs 3.2+/-0.4 ml x 100-ml(-1) x min(-1), P=0.01) but not in the microalbuminuric group (2.4+/-0.3 vs 2.3+/-0.4 ml x 100-ml(-1) x min(-1)). In conclusion, microalbuminuria in Type 1 diabetes was found to be associated with impairment of insulin-mediated skeletal muscle blood flow, but not with insulin resistance.

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.

Objectives: To estimate the economic efficiency of tight blood pressure control, with angiotensin converting enzyme inhibitors or beta blockers, compared with less tight control in hypertensive patients with type 2 diabetes. Design: Cost effectiveness analysis incorporating within trial analysis and estimation of impact on life expectancy through use of the within trial hazards of reaching a defined clinical end point. Use of resources driven by trial protocol and use of resources in standard clinical practice were both considered. Setting: 20 hospital based clinics in England, Scotland, and Northern Ireland. Subjects: 1148 hypertensive patients with type 2 diabetes from UK prospective diabetes study randomised to tight control of blood pressure (n=758) or less tight control (n=390). Main outcome measure: Cost effectiveness ratios based on (a) use of healthcare resources associated with tight control and less tight control and treatment of complications and (b) within trial time free from diabetes related end points, and life years gained. Results: Based on use of resources driven by trial protocol, the incremental cost effectiveness of tight control compared with less tight control was cost saving. Based on use of resources in standard clinical practice, incremental cost per extra year free from end points amounted to £1049 (costs and effects discounted at 6% per year) and £434 (costs discounted at 6% per year and effects not discounted). The incremental cost per life year gained was £720 (costs and effects discounted at 6% per year) and £291 (costs discounted at 6% per year and effects not discounted). Conclusions: Tight control of blood pressure in hypertensive patients with type 2 diabetes substantially reduced the cost of complications, increased the interval without complications and survival, and had a cost effectiveness ratio that compares favourably with many accepted healthcare programmes.

Hypertension is linked to the development of nephropathy in Type 1 diabetes. Total exchangeable sodium is elevated in patients with Type 1 diabetes in good metabolic control, and correlates with blood pressure. Atrial natriuretic factor has been shown to have effects on sodium and blood pressure homeostasis in man. Basal and NaCl-stimulated plasma atrial natriuretic factor was therefore studied in 33 patients with Type 1 diabetes. Seventeen had no evidence of nephropathy, 11 had incipient nephropathy (albumin excretion rate 20-199 micrograms min-1) and five had overt nephropathy. Seventeen age- and sex-matched normal control subjects were also studied. Subjects fasted from 2200 h, rose at 0745 h and remained ambulant until 0945 h. After 15 min supine, 2 l 0.15 mmol l-1 NaCl was infused over 4 h. Basal erect (0945 h) plasma atrial natriuretic factor was 4.2 +/- 0.5, 3.5 +/- 0.4, 2.5 +/- 0.2, and 2.5 +/- 0.3 pmol l-1 in the control, non-nephropathic, incipient-nephropathic, and overt nephropathic diabetic groups, respectively (all NS). Levels in all groups increased in response to NaCl infusion, and the responses were not different between groups. Urinary sodium excretion for 12 h before NaCl infusion was not different between groups, but during the 12 h after the start of the infusion was significantly (p less than 0.05) less in the Type 1 diabetic group without nephropathy than in the control group. These results suggest that atrial natriuretic factor does not play a major role in the development of changes in sodium balance which are associated with Type 1 diabetes and nephropathy.

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.

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.

Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant syndrome of unknown aetiology characterized by lifelong elevation in serum calcium concentration and low urinary calcium excretion. These features suggest that the causal gene is important for maintenance of extracellular calcium homeostasis by the parathyroid gland and kidney. To identify the chromosomal location of FHH gene(s), we clinically evaluated 114 individuals in four unrelated affected families and performed linkage analyses. The disease gene mapped to the long arm of chromosome 3 in each family (combined maximum multipoint lod score = 20.67). We suggest that this is the predominant FHH locus and anticipate that identification of the FHH gene will improve our understanding of the molecular basis for physiologic and pathologic regulation of calcium.

There is little information available concerning the presence or absence of a normal variation in the circulating concentration of atrial natriuretic homone throughout a 24 h period. We have examined this in 8 normal subjects (aged 23–35 years) on a fixed 120 mmol Na+ diet. Circulating levels of ANH, plasma renin activity, serum aldosterone and serum cortisol were determined two-hourly during 24 h in a supine position. There was a significant change in the concentration of each of these four hormones during the study period (P< 0.05). ANH: peak 8.5 (22.00 h), nadir 4.0 (12.00 h) (pmol/l); PRA: peak 1.7 (04.00 h), nadir 0.8 (22.00 h) (μg · l−1 · h−1); aldosterone: peak 350 (14.00 h), nadir 143 (22.00 h) (pmol/l); cortisol: peak 346 (08.00 h), nadir 51 (22.00 h) (nmol/l). Peak plasma ANH occurred at 22.00 h and with the exception of times 20.00 h and 10.00 h this value was significantly higher than all the other time means (P< 0.05). The only other significant differences were between plasma ANH at 20.00 h and 06.00 h, 08.00 h, 12.00 h and 14.00 h, respectively (P< 0.05). From midnight until 18.00 h, there was no significant difference between any of the time means. There was a peak in PRA at 04.00 h, while peak serum aldosterone and serum cortisol occurred at 14.00 h and 08.00 h, respectively. This study suggests that ANH may display a diurnal rhythm. Our findings provide further physiological evidence that plasma ANH and PRA may have a reciprocal relationship.

In October 2002, a workshop was held in Ancona, Italy, to reach a Consensus on the management of Cushing's syndrome. The workshop was organized by the University of Ancona and sponsored by the Pituitary Society, the European Neuroendocrine Association, and the Italian Society of Endocrinology. Invited international participants included almost 50 leading endocrinologists with specific expertise in the management of Cushing's syndrome. The consensus statement on diagnostic criteria and the diagnosis and treatment of complications of this syndrome reached at the workshop is hereby summarized.