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An association exists between hyperaldosteronism, hypertension and impaired insulin action. Eplerenone is a selective mineralocorticoid receptor antagonist; however, little is known about its effects on insulin action. The aim of this study was to determine the effect of eplerenone on insulin action in hypertensive adults, using the hyperinsulinaemic euglycaemic clamp. A randomised, controlled, double-blind, crossover design was employed. After a 6-week washout period, hypertensive, non-diabetic patients were treated with either eplerenone 25 mg twice daily or doxazosin 2 mg twice daily for 12 weeks. After each treatment period, insulin action was assessed by a hyperinsulinaemic euglycaemic clamp, with isotope dilution methodology. After washout, treatment groups were crossed over. Fifteen patients completed the study. There were no differences in fasting glucose, or fasting insulin between treatment with eplerenone or doxazosin. The measure of overall insulin sensitivity, exogenous glucose infusion rates during the last 30 min of the clamp, was similar with both treatments; 23.4 (3.9) μmol kg(-1) min(-1) after eplerenone and 23.3 (3.6) μmol kg(-1) min(-1) after doxazosin (P=0.83). Isotopically determined fasting endogenous glucose production rates were similar after both treatments (eplerenone 9.4 (0.6) μmol kg(-1) min(-1) vs doxazosin 10.6 (0.7) μmol kg(-1) min(-1)). There was a trend for lower endogenous glucose production rates during hyperinsulinaemia following eplerenone compared with doxazosin (2.0 (0.8) μmol kg(-1) min(-1) vs 4.1 (0.9) μmol kg(-1) min(-1)). There was no difference in insulin stimulated peripheral glucose utilisation rates after treatment with eplerenone or doxazosin (25.4 (3.6) μmol kg(-1) min(-1) vs 27.0 (3.9) μmol kg(-1) min(-1)). This study gives reassuring evidence of the neutral effect of eplerenone on insulin action in hypertensive, non-diabetic patients.

Concern exists regarding adverse metabolic effects of antihypertensive agents. In the United States, diuretics are recommended first-line but additional agents, usually angiotensin-converting enzyme (ACE) inhibitors, are often required to meet blood pressure targets. We have previously shown that the combination of low-dose diuretic with an ACE inhibitor has detrimental effects on insulin action compared with ACE inhibitor alone in hypertensive type 2 diabetic patients. Our aim was to establish whether similar effects occur in nondiabetic hypertensive patients using this combination. A randomized double-blind placebo-controlled crossover design was used. After a 6-week run-in, when regular antihypertensive medications were withdrawn and placebo substituted, patients received captopril 50 mg twice daily with either bendroflumethiazide 1.25 mg (CB) or placebo (CP) for 12 weeks with a 6-week wash-out between treatments. Insulin action was assessed by hyperinsulinemic euglycemic clamp after the 6-week run-in and at the end of each treatment period. There were no differences between treatments in fasting glucose or insulin concentrations. Glucose infusion rates required to maintain euglycemia were the same with each treatment (CP 22.1±2.2 vs CB 22.2±2.2 μmol/kg per minute). There was no difference in endogenous glucose production in the basal state (CP 8.9±0.5 vs CB 9.5±0.7 μmol/kg per minute; P=0.23) or during hyperinsulinemia (CP 2.2±0.6 vs CB 1.5±0.3 μmol/kg per minute; P=0.30). In contrast to the situation in type 2 diabetes mellitus, ACE inhibitor combined with low-dose thiazide diuretic does not adversely affect insulin action when compared with ACE inhibitor alone in nondiabetic hypertensive patients.

Objective: Addition of dehydroepiandrosterone sulphate (DHEAS) to standard pituitary replacement may improve quality of life and glucose metabolism. Conflicting results from the previous work probably relate to differences in populations studied and assessment techniques used. We examined the effects of DHEAS on insulin action and the quality of life in female patients with hypopituitary hypoadrenalism., Design: Randomized, double-blind, placebo-controlled, crossover design was used. Patients received either DHEAS 50 mg daily or placebo for 12 weeks., Patients: Fourteen hypopituitary females on stable standard replacement therapy and with low DHEAS were enrolled., Measurements: Insulin action by euglycaemic hyperinsulinaemic clamp and extensive quality of life parameters were assessed after each treatment., Results: Serum DHEAS (DHEAS 5·4 ± 0·8 vs placebo <0·8 ± 0·0 μm; P < 0·001) and androstenedione (DHEAS 4·1 ± 0·8 vs placebo 1·3 ± 0·2 nm; P < 0·05) rose to within the normal range after DHEAS 50 mg daily. There were no differences between treatments in testosterone, sex hormone-binding globulin (SHBG) or IGF-1. Quality of life measures were unchanged after DHEAS. There were no differences between treatments in fasting glucose, serum insulin, HbA1c or in insulin action (glucose infusion rates required to maintain euglycaemia; DHEAS 21·9 ± 2·5 vs placebo 24·5 ± 2·1 μmol/kg/min; P = 0·4). Triglyceride concentrations were lower following DHEAS (DHEAS 1·24 ± 0·18 vs placebo 1·41 ± 0·19 mm; P < 0·05) but other lipid parameters remained unchanged., Conclusion: There were no differences compared with placebo in quality of life or insulin action after DHEAS replacement therapy for 12 weeks. These results do not provide evidence for the addition of DHEAS to standard hypopituitary replacement therapy., (© 2012 Blackwell Publishing Ltd.)

Aim: Disordered insulin pulsatility is associated with insulin resistant states including Type 2 diabetes. However, whether abnormal basal insulin pulses play a role in the pathogenesis of insulin resistance or are simply an associated feature remains undetermined. We investigated this relationship further by studying the effect of overnight (10 h) pulsatile insulin infusion on subsequent insulin sensitivity., Methods: We studied 17 Type 2 diabetic patients who underwent one of two protocols. In protocol A (10 patients) on two separate nights we infused insulin 0.1 mU/kg/min either in a constant infusion or in pulses every 13 min. Octreotide (0.43 microg/kg/h) was given to suppress endogenous insulin secretion and physiological replacement of glucagon (30 ng/kg/h) administered. Insulin sensitivity was measured using a hyperinsulinaemic euglycaemic clamp (2 mU/kg/min) next morning. In protocol B (seven patients), we employed the same experimental procedure but used a basal insulin infusion rate of 0.09 mU/kg/min in 7-min or 13-min pulses., Results: Appropriate pulse patterns were confirmed in each protocol. In protocol A, after overnight infusions, glucose infusion rates required to maintain euglycaemia at steady state hyperinsulinaemia were similar (33.9 +/- 5.2 vs. 31.2 +/- 4.1 micromol/kg/min; P = NS). In protocol B, after overnight infusions the glucose infusion rates required during hyperinsulinaemia were significantly lower during 7-min pulses (39.9 +/- 5.7 vs. 44.7 +/- 5.6 micromol/kg/min; P < 0.05)., Conclusion: There was no demonstrable priming effect derived from overnight pulsatile insulin compared with constant insulin infusion on subsequent insulin sensitivity in Type 2 diabetic subjects. The failure of 7-min pulses to exhibit an advantageous effect over 13-min pulses raises questions about the natural frequency of basal insulin pulses and their biological effect.

Background and Aims: Endothelial dysfunction, insulin resistance and oxidative stress are believed to be central and associated mechanisms in atherogenesis. We aimed to determine the effect of the antioxidant vitamin E on endothelial function, insulin action and cardiovascular risk markers in young healthy adult offspring of parents with Type 2 diabetes., Methods: Healthy, glucose-tolerant adults (18-38 years), 14 (12 male/2 female) with at least one parent with Type 2 diabetes, and 14 (12 male/2 female) subjects with no family history of diabetes (controls) were studied. Insulin action was assessed by euglycaemic hyperinsulinaemic clamp (1 mU/kg/min). Endothelial function was assessed by forearm blood flow (FBF) responses to intra-brachial artery infusions of acetylcholine (ACh) (endothelium-dependent vasodilation), sodium nitroprusside (SNP) (endothelium-independent vasodilation) and N(G)-monomethyl L-arginine (LNMMA) (nitric oxide synthase inhibition). Thirteen offspring (18-38 years, 11 male/2 female, BMI < 30 kg/m2) completed a randomized, double-blind, crossover trial (12 weeks vitamin E 800 IU/day or placebo, 6-week washout)., Results: Exogenous glucose infusion rates to maintain euglycaemia were positively associated with response to acetylcholine in offspring (r = 0.61, P < 0.05), and were linked with triglycerides. Vitamin E had no effect on endothelial function, insulin action or cardiovascular risk markers in healthy adult offspring of parents with Type 2 diabetes., Conclusions: Our results support a positive association between insulin action and endothelial-dependent vasodilation in young healthy adult offspring of parents with Type 2 diabetes, but indicate no effect of vitamin E on these parameters.

The optimal means of assessing the integrity of the hypothalamic-pituitary-adrenal (HPA) axis after pituitary surgery remains controversial. We compared low-dose (1 micro g iv) and standard-dose (250 micro g im) corticotropin tests performed 1 and 4-6 wk after pituitary surgery with an insulin hypoglycemia test performed at 4-6 wk. Forty-one patients (21 male and 20 female; median age, 52 yr; range, 23-73 yr) who had undergone pituitary surgery were studied (Cushing's disease excluded). Twenty-two of the 41 patients had normal cortisol responses to all tests both at 1 and 4-6 wk after surgery. Eight patients had subnormal cortisol responses to all tests. Of the 11 patients with discrepant results, seven had subnormal responses only after the low-dose corticotropin test; the remaining four patients had borderline responses to one or more tests. At 4-6 wk after surgery, subjects with a 30-min serum cortisol after standard-dose corticotropin of less than 350 nmol/liter (12.7 micro g/dl) consistently had a subnormal response to hypoglycemia, and those with a serum cortisol greater than 650 nmol/liter (23.6 micro g/dl) had a normal response to hypoglycemia. Definitive testing of the HPA axis using the standard-dose corticotropin test can be carried out provided it is performed at least 4 wk after pituitary surgery. A 30-min cortisol level greater than 650 nmol/liter (23.6 micro g/dl) indicates adequacy of the HPA axis, and a level of less than 350 nmol/liter (12.7 micro g/dl) indicates ACTH deficiency. No further testing is then required. An intermediate level of 350-650 nmol/liter (12.7-23.6 micro g/dl) warrants further assessment using the insulin hypoglycemia test.

Essential hypertension is associated with impairment of both endothelial function and insulin action, and this has provided rationale for the use of antihypertensive agents that are at least neutral, if not beneficial, in these areas. This study examines the effect of the alpha-adrenergic blocker, doxazosin, on endothelial function and insulin action. Sixteen patients with essential hypertension were recruited with 13 (3 men/10 women; median age, 55 years; range, 38 to 65 years) completing the study. A double-blind, placebo-controlled crossover study design was used. After a 6-week placebo run-in, there were two 12-week treatment periods of either placebo or doxazosin, separated by a 6-week wash out period. Subjects were studied at the end of each treatment period with endothelial function assessed by forearm plethysmography and insulin action by the hyperinsulinemic clamp technique. Blood pressure was significantly lowered by doxazosin (doxazosin 144 +/-3/86 +/- 2 mm Hg; placebo 159 +/- 3/96 +/- 1 mm Hg, P <.005 for both systolic and diastolic pressure; mean +/- SEM). Baseline forearm blood flow (FBF) was unchanged (doxazosin 4.9 +/- 0.9; placebo 4.0 +/- 0.7 mL x 100 mL(-1) x min(-1), P >.05), however, FBF responses (area under dose response curve, percentage change in infused:control arm ratio) to acetylcholine (endothelium-dependent vasodilation) were improved by doxazosin (doxazosin 58.6 +/- 11.7 standard units [SU]; placebo 22.1 +/- 7.0 SU, P =.03) with responses to sodium nitroprusside (endothelium-independent vasodilation) unchanged (doxazosin 40.3 +/- 5.5 SU; placebo 46.3 +/- 8.1 SU, P >.05). Exogenous glucose infusion rates to maintain euglycemia during hyperinsulinemia were not significantly different (doxazosin 30.4 +/- 0.9; placebo 32.3 +/- 1.0 micromol x kg(-1) min(-1), P >.05). Suppression of postabsorptive endogenous glucose production by insulin was also unchanged by treatment (doxazosin 65.6% +/- 7.5% suppression; placebo 68.3% +/- 11.2% suppression, P >.05). Doxazosin has a neutral effect on both peripheral and hepatic insulin action, but improves endothelium-dependent vasodilation. These results indicate that doxazosin can be used safely in patients with insulin resistance, while its positive effect on endothelial function may lessen the subsequent incidence of atherosclerosis.

Insulin is normally secreted in man in regular pulses every 5 to 15 minutes. Disordered pulsation has been demonstrated in several insulin-resistant states and it is unclear whether this represents a primary beta-cell defect contributing to impairment of peripheral insulin action or rather is a consequence of insulin resistance. Basal or near basal insulin administration by pulsatile infusion augments hypoglycemic effect and improves insulin-mediated glucose uptake compared with insulin by continuous infusion. To date no study has examined whether normal basal insulin pulsatility is required to preserve subsequent insulin sensitivity during hyperinsulinemia. We studied the effect of overnight pulsatile versus continuous basal insulin on a subsequent hyperinsulinemic euglycemic clamp. Nineteen normal volunteers (male:female ratio, 17:2; mean age +/- SEM, 26.1 +/- 2.3 years) were studied on 2 occasions each. Endogenous insulin secretion was inhibited by octreotide (0.43 microg kg(-1). h(-1)) and replaced overnight at 5.4 mU kg(-1). h(-1) either by continuous infusion or in 2-minute pulses every 13 minutes (n = 10) or every 7 minutes (n = 9). Glucagon was replaced at physiological concentration by continuous infusion (30 ng. kg(-1). h(-1)). Venous plasma glucose overnight was not significantly different between the pulsatile and continuous protocols. After discontinuing the overnight insulin infusion, insulin action was assessed during a hyperinsulinemic euglycemic clamp (1 mU kg(-1). h(-1)). Glucose infusion rates at steady-state during the hyperinsulinemic clamp were similar between continuous and both frequencies of pulsatile infusion (continuous 44.6 +/- 4.3 micromol. kg(-1). min(-1) v 13-minute pulsatile 41.7 +/- 5.9 micromol. kg(-1). min(-1), P =.27; continuous 34.6 +/- 2.5 micromol. kg(-1) min(-1) v 7-minute pulsatile 41.4 +/- 3.2 micromol. kg(-1). min(-1), P =.08). We conclude that overnight pulsatile compared with continuous insulin administration has no different effect on subsequent peripheral insulin-mediated glucose uptake. A priming effect cannot therefore explain the previously demonstrated association between endogenous insulin pulse frequency and peripheral insulin action.

Objective: Hypercortisolism is associated with impaired glucose tolerance and insulin resistance. For many years hydrocortisone 30 mg was the standard total daily replacement dose in adult hypopituitarism. The use of this conventional dose has now been shown to result in mild biochemical hypercortisolism and might contribute to the increased cardiovascular risk reported in hypopituitarism. The use of lower doses of hydrocortisone replacement therapy might prevent some of the adverse metabolic effects seen with conventional doses., Patients: In a randomized crossover study we assessed peripheral and hepatic insulin action in 15 ACTH-deficient patients with normal glucose tolerance on two occasions while receiving either a low-dose oral hydrocortisone replacement (LOR) therapy (15 mg at 0800, 5 mg at 1700) or a physiological hydrocortisone infusion (PHI), which achieved physiological serum cortisol concentrations., Results: Exogenous glucose infusion rates required to maintain euglycaemia were similar for the LOR and the PHI protocols (26.2 +/- 0.4 vs. 23.8 +/- 0.6 micromol/kg/min, respectively). Endogenous glucose production was also similar (12.0 +/- 2.5 vs. 11.6 +/- 2.4 micromol/kg/min, respectively) and in the post-absorptive state suppressed to a similar extent following insulin (4.5 +/- 2.0 vs. 5.1 +/- 3.1 micromol/kg/min)., Conclusion: Hydrocortisone replacement therapy at a dose of 15 mg with breakfast, 5 mg with evening meal does not increase peripheral or hepatic insulin resistance when compared to a hydrocortisone infusion designed to simulate physiological serum cortisol concentrations.

There is controversy about the effect of replacement GH on insulin action in adult hypopituitary patients. GH replacement calculated from weight leads to unacceptable side effects in some patients. Recent studies suggest it should be individually titrated in adults using serum IGF-I levels. We have assessed the effect of titrated GH replacement on peripheral and hepatic insulin action in 13 adult-onset hypopituitary patients (8 males and 5 females; ages 47 +/- 10 yr, mean duration of hypopituitarism 6 yr) with confirmed GH deficiency (GHD; maximum GH <5 mU/liter during insulin induced hypoglycemia), ACTH deficiency, and normal glucose tolerance. All patients were on stable hydrocortisone replacement (15 mg with breakfast, 5 mg with evening meal) for at least 2 months before the trial. Insulin action was assessed by the euglycemic hyperinsulinemic glucose clamp technique (1 mU/kg x min) before and after 6 months of GH therapy. GH was started at 0.8 IU sc daily and titrated monthly until the serum IGF-I increased to within 1-2 SD of the mean of normal age-matched controls. Body mass index did not change significantly during the 6 months of GH therapy. Fasting plasma glucose and HbA1c increased significantly after 6 months (5.2 +/- 0.0 vs. 5.5 +/- 0.0 mmol/liter, P < 0.0001, and 4.5 +/- 0.1 vs. 4.7 +/- 0.1%, P < 0.0005, respectively). There was no increase in fasting serum insulin (51.6 +/- 10.2 vs. 60.0 +/- 10.2 pmol/liter, P = 0.12). Exogenous glucose infusion rates required to maintain euglycemia were similar after GH (23.0 +/- 0.4 vs. 21.1 +/- 0.3 micromol/kg x min, P = 0.6). Endogenous glucose production in the fasting state was also unchanged following GH (11.8 +/- 0.7 vs.12.3 +/- 0.9 micromol/kg x min, P = 0.5) and suppressed to a similar extent following insulin (4.4 +/- 0.8 vs. 5.5 +/- 0.8 micromol/kg x min, P = 0.3). In summary, GH therapy for 6 months, with serum IGF-I maintained in the upper physiological range, increased fasting plasma glucose and HbA1c. There was no effect on peripheral or hepatic insulin sensitivity. Patients receiving GH therapy require long-term monitoring of glucose tolerance.

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.

Polycystic ovary syndrome (PCOS) is associated with abnormalities of insulin action and insulin secretion. Ethinyl oestradiol/cyproterone acetate is a common agent used to treat the symptoms of PCOS, but its effects on insulin action and insulin pulsatility have not been examined. We investigated the relationship between insulin action and insulin secretion in 11 patients with PCOS, at diagnosis and after 3 months of treatment with ethinyl oestradiol/cyproterone acetate, and in 13 controls. Insulin action was assessed using the euglycaemic hyperinsulinaemic clamp (2 mU/kg/min for 2 h). Insulin pulsatility was examined over 90 min by 2 min sampling. Short-term insulin pulses were identified using PULSAR. Treatment with ethinyl oestradiol/cyproterone acetate resulted in significant reductions in testosterone (3.3+/-0.7 vs. 1.9+/-0.2 nmol/l, p<0.05), free androgen index (10.2+/-0.7 vs. 1.2+/-0.2, p<0.05) and LH/FSH ratio (2.6+/-0.5 vs. 1.0+/-0.2, p<0.05). During hyperinsulinaemic clamps, the glucose infusion rate (GIR) required to maintain euglycaemia was lower in PCOS compared to controls (33.6+/-2.7 vs. 45.1+/-3.5 micromol/kg/min, p<0.05) but similar in PCOS before and after treatment (33.6+/-2.8 vs. 33.6+/-2.7 micromol/kg/min, p=0.9). Numbers of pulses identified in PCOS and controls were similar and unaltered by ethinyl oestradiol/cyproterone acetate. There was no correlation between GIR and frequency of insulin pulses in PCOS before or after treatment (r=0.2, p=0.6; post r=-0.5, p=0.1) unlike controls (r=-0.6, p=0.04). Despite considerable improvement in androgen profile, treatment with ethinyl oestradiol/cyproterone acetate did not alter insulin action in PCOS, and this insulin resistance does not appear to be determined by insulin pulse frequency.

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.

Objective: Studies in normal humans and in patients with type 2 diabetes mellitus have demonstrated a close inverse relationship between peripheral insulin sensitivity and the frequency of short-term insulin secretory pulses in the systemic circulation. Our objective was to study this relationship in essential hypertension., Design: Study of insulin sensitivity and insulin pulse characteristics in hypertensive subjects and normotensive controls using well-established techniques., Methods: Twelve subjects with essential hypertension and 12 age- and sex-matched normotensive controls were recruited. Insulin action was measured using the glucose clamp technique combined with isotope dilution methodology. Insulin pulsatility in the peripheral circulation was assessed by sampling every 2 min for 90 min after an overnight fast Pulses were identified using the computer program Pulsar., Results: Insulin sensitivity index (glucose infusion rate/ serum insulin) was lower in the hypertensive patients (P= 0.01) and fasting insulin was increased (P= 0.008) compared to controls. The frequency and amplitude of insulin pulses were similar in the two groups. Insulin pulse frequency and insulin sensitivity were inversely related in the normotensive group (r= -0.68, P= 0.015), but not in the hypertensive group (r= -0.23, P= 0.48). Insulin clearance was reduced in the hypertensive group (P= 0.03), and was inversely related to insulin pulse frequency in the two groups combined (r = -0.51, P= 0.01)., Conclusions: Insulin action was not related to insulin pulse frequency in essential hypertension, in contrast to the situation in normal man.

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.

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.

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.

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.

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.

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 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.

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.

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.

Increased activity of the hepatic glucose-glucose 6-phosphate (G/G-6-P) cycle is associated with hepatic and peripheral insulin resistance in acromegaly. To determine whether a similar association occurs after short-term growth hormone (GH) elevation within the physiological range, two-step euglycemic hyperinsulinemic clamps were performed in normal human males after 12-h GH (2.2 ng.kg-1 x h-1) and control infusions. G/G-6-P cycle activity and endogenous glucose production (EGP) were determined by [2-3H]- and [6-3H]-glucose using labeled exogenous glucose infusions and selective enzymatic detritiation. GH increased levels of circulating lipid intermediates despite a twofold increase in basal insulin (P < 0.005), but plasma glucose, EGP, and G/G-6-P cycle activity were unchanged. GH impaired insulin suppression of EGP and lipid intermediates and impaired insulin stimulation of glucose disposal, but G/G-6-P cycle activity was unchanged. We conclude that increased activity of the G/G-6-P cycle does not contribute to the hepatic insulin resistance induced by GH under these conditions but that changes in fatty acid metabolism may be partly responsible for the impairment in hepatic and peripheral insulin action.

Peripheral insulin resistance is a feature of essential hypertension, but there is little information about hepatic insulin sensitivity. To investigate peripheral and hepatic insulin sensitivity and activity of the hepatic glucose/glucose 6-phosphate (G/G6P) substrate cycle in essential hypertension, euglycemic glucose clamps were performed in eight untreated patients and eight matched controls at insulin infusion rates of 0.2 and 1.0 mU.kg-1.min-1. A simultaneous infusion of (2(3)H)- and (6(3)H)glucose, combined with a selective detritiation procedure, was used to determine glucose turnover, the difference being G/G6P cycle activity. Endogenous hepatic glucose production (EGP) determined with (6(3)H)glucose was similar in hypertensive and control groups in the postabsorptive state (11.0 +/- 0.3 v 10.9 +/- 0.3 mumol.kg-1.min-1) and with the 0.2 mU insulin infusion (4.9 +/- 0.5 v 4.0 +/- 0.8 mumol.kg-1.min-1). With the 1.0 mU insulin infusion, glucose disappearance determined with (6(3)H)glucose was lower in the hypertensive group (21.8 +/- 2.4 v 29.9 +/- 2.4 mumol.kg-1.min-1, P less than .001). G/G6P cycle activity was similar both in the postabsorptive state (2.2 +/- 0.4 v 2.7 +/- 0.4 mumol.kg-1.min-1) and during insulin infusion (0.2 mU, 2.5 +/- 0.3 v 2.9 +/- 0.4; 1.0 mU, 4.7 +/- 0.3 v 5.3 +/- 1.1 mumol.kg-1.min-1 for hypertensive and control groups, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

To examine the effects of physiological insulin concentrations on the renin-angiotensin and sympathetic nervous systems, healthy volunteers were studied by the euglycaemic glucose clamp technique with sequential 60 min 0.5 and 1.0 mU kg-1 min-1 insulin infusions and, subsequently, by a control infusion simulating clamp conditions. Plasma renin activity increased from 0.8 +/- 0.1 ng ml-1 h-1 basally to 1.0 +/- 0.2 ng ml-1 h-1 during the 0.5 mU infusion to 1.4 +/- 0.1 ng ml-1 h-1 during the 1 mU infusion but did not change during control infusion (0.9 +/- 0.3 ng ml-1h-1 to 0.9 +/- 0.2 ng ml-1h-1 to 1.0 +/- 0.1 ng ml-1h-1) (P less than 0.001 insulin vs. control by ANOVAR). Plasma angiotensin II increased during insulin (21.2 +/- 1.8 to 25.2 +/- 2.3 to 29.3 +/- 2.4 pg ml-1) but not during control infusion (24.0 +/- 2.8 to 23.6 +/- 2.6 to 23.5 +/- 2.5 pg ml-1) (P less than 0.001 insulin vs. control). Serum aldosterone did not change significantly during either infusion (insulin: 239 +/- 89 pmol l-1 to 237 +/- 50 pmol l-1 to 231 +/- 97 pmol l-1, control: 222 +/- 79 to 237 +/- 50 to 213 +/- 97 pmol l-1). Plasma noradrenaline increased to a greater extent during insulin (1.03 +/- 0.2 to 1.14 +/- 0.8 to 1.27 +/- 0.17 nmol l-1) than control infusion (0.86 +/- 0.09 to 0.97 +/- 0.09 to 0.99 +/- 0.09 nmol 1-1 (P less than 0.01 insulin vs. control). Changes in mean systolic blood pressure during insulin infusion were significantly different from control (+ 3 vs. -4 mmHg, P less than 0.001). In conclusion acute hyperinsulinaemia within the physiological range increases circulating hormones of the renin-angiotensin and sympathetic nervous systems and also increases systolic blood pressure.

Objective: To determine whether rates of road traffic accidents were higher in diabetics treated with insulin than in non-diabetic subjects., Design: Controlled, five year retrospective survey., Setting: Diabetic, dermatology, and gastroenterology outpatient clinics., Patients: 596 Diabetics treated with insulin (354 drivers) aged 18-65 attending two clinics and 476 non-diabetic outpatients (302 drivers)., Main Outcome Measures: Rates of accidents in diabetic and non-diabetic subjects., Results: A self completed questionnaire was used to record age, sex, driving state, and rates of accidents and convictions for motoring offences among diabetic and non-diabetic volunteers. For the diabetic volunteers further information was obtained on treatment, experience of hypoglycaemia, and declaration of disability to the Driving and Vehicle Licensing Centre and their insurance company. Accident rates were similar (81 (23%) diabetic and 76 (25%) non-diabetic drivers had had accidents in the previous five years). A total of 103 diabetic drivers had recognised hypoglycaemic symptoms while driving during the previous year. Only 12 reported that hypoglycaemia had ever caused an accident. Overall, 249 had declared their diabetes to an insurance company. Of these, 107 had been required to pay an increased premium, but there was no excess of accidents in this group., Conclusions: Diabetic drivers treated with insulin and attending clinics have no more accidents than non-diabetic subjects and may be penalised unfairly by insurance companies.

Sixteen patients with clinically active acromegaly were investigated; four of these had insulin-independent diabetes mellitus. Those acromegalic subjects who were not diabetic exhibited excessive insulin responses to glucose and arginine stimulation. By contrast, plasma glucagon concentrations in these patients did not differ significantly from those in control subjects. Acromegalic patients who also had insulin-independent diabetes had a markedly reduced insulin response to glucose stimulation, while arginine-induced insulin secretion was relatively well preserved. Although there was a tendency for plasma glucagon concentrations to be higher in the diabetic than in the nondiabetic group of acromegalic subjects, this difference did not achieve statistical significance either in the basal state or during the glucose amd arginine infusion tests.