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Biomedical subjects

J R Petrie

Publications and source records attributed to J R Petrie.

At least 37 records · Page 2Linked to original sources
PubMed1999

Insulin-mediated vasodilation and glucose uptake are functionally linked in humans.

Intra-arterial infusion of insulin in physiological doses causes forearm vasodilation which is augmented by co-infusion of D-glucose, leading us to speculate that local insulin-mediated vasodilation may depend on insulin-mediated glucose uptake. We have examined the relationship between whole-body insulin sensitivity and forearm vasodilation in response to local infusion of insulin/glucose, thus avoiding any confounding effects of sympathetic stimulation on peripheral blood flow. Eighteen healthy, normotensive male volunteers (age, 26+/-5.4 years) attended on two separate occasions for measurement of: (1) whole-body insulin sensitivity with use of the hyperinsulinemic euglycemic clamp; (2) forearm vasodilation in response to an intra-arterial infusion of insulin/glucose with use of bilateral venous occlusion plethysmography. Insulin-mediated glucose uptake (M) for the group (mean+/-SD) was 10.0+/-2.2 mg. kg-1. min-1, and the percentage change in forearm blood flow ratio (%FBFR) for the group (median, interquartile range) was 28.2% (13.6, 48.6). In univariate analysis, M was significantly correlated with %FBFR (rs=0.60, P<0.05), but not with body mass index (BMI) (rs=-0. 42), age (r=-0.39) or mean arterial pressure (r=0.13). In multiple regression analysis, %FBFR remained a significant independent predictor of M (R2 (adj)=0.48, t=3.23, P<0.01) in a model involving BMI, age, and blood pressure. These data support the concept of a significant functional relationship between insulin's metabolic and vascular actions, possibly at an endothelial level.

Adult↗
PubMed1999

The effect of estradiol and a combined estradiol/progestagen preparation on insulin sensitivity in healthy postmenopausal women.

Abnormalities of carbohydrate metabolism and insulin sensitivity have been reported in estrogen deficiency. Estrogen replacement appears to result in an improvement in these parameters, although progestagens may antagonize these effects. We have examined the effects of transdermal estradiol and oral norethisterone on insulin sensitivity using the hyperinsulinemic euglycemic clamp method by performing a randomized, double blind, placebo-controlled study in 22 healthy women after a surgically induced menopause. After baseline measurements, subjects were randomized to receive either transdermal 17beta-estradiol (50 microg) or matching placebo patches for 6 weeks. The subjects were then further randomized to receive either estradiol in combination with oral norethisterone (1 mg) or a matching oral placebo preparation, crossing over after 6 weeks, with assessment of insulin sensitivity at the end of each treatment. No significant increase in insulin sensitivity was observed after 6 weeks of transdermal 17beta-estradiol treatment (95% confidence interval, -0.54, 1.86; P = 0.27). Addition of norethisterone for a further 6 weeks had no detectable effect on insulin sensitivity (95% confidence interval, -1.65, 1.10; P = 0.65). The results of this study using transdermal estradiol do not support previous reports that unopposed estrogens exert potentially beneficial effects on insulin sensitivity and suggest that the addition of an oral progestagen confers no clinically important risk or benefit. It is therefore unlikely that effects on insulin sensitivity contribute appreciably to the cardioprotective benefits attributed to hormone replacement therapy.

Administration, Cutaneous↗
PubMed1998

The atherogenic lipoprotein phenotype and vascular endothelial dysfunction.

There is accumulating evidence that elevated plasma triglycerides and related abnormalities constitute an independent cardiovascular risk factor. Although the pathogenetic basis for the apparent relationship between elevated triglyceride-rich lipoproteins and CAD is still uncertain, evidence is accumulating to suggest that endothelial dysfunction is involved. There is evidence to suggest that triglyceride-rich particles may be directly damaging to the endothelium; this may be principally via oxidative mechanisms. Triglyceride-rich particles can cross the endothelial barrier and enter the arterial wall, thus placing them in a position to promote direct endothelial damage. These particles stimulate endothelial expression of adhesion molecules and the prothrombotic factor PAI-1. By reducing LDL size and HDL cholesterol concentrations, thereby further increasing the endothelial oxidative burden, triglyceride-rich particles may indirectly promote endothelial dysfunction. In addition, free fatty acids, which are the major substrates for endogenous synthesis of triglyceride-rich particles, are also potentially damaging to the endothelium. This occurs via oxidative stress, by facilitating transfer of LDL across the endothelium, and by enhancing toxicity of triglyceride-rich particles. Finally, there is recent strong evidence to suggest that increased postprandial circulating concentrations of triglyceride-rich particles and remnant particles may be deleterious to the endothelium.

Animals↗
PubMed1998

How reproducible is bilateral forearm plethysmography?

AIMS: In studies using strain-gauge forearm plethysmography to measure changes in forearm blood flow (FBF) during intra-arterial infusions of vasoactive substances, measurements are often made in both arms simultaneously and the change in ratio of the infused and control arms used to express responses. However, the reproducibility of bilateral plethysmography in this setting has not been addressed in published studies. The unilateral technique remains in use, and forearm vascular resistance (FVR), an alternative method of expressing responses, is used by some investigators. We have assessed: (a) the intra-subject variability of bilateral FBF measurements (FBF ratios) at rest, after unilateral forearm exercise, and during intra-arterial infusions of vasoconstrictor substances; (b) whether bilateral plethysmography is more reproducible than unilateral plethysmography; and (c) the reproducibility of FVR (unilateral and bilateral). METHODS: Study 1 Nine healthy subjects attended 3 study days, 1 week apart. FBF was measured at rest and after 2 min of standardized unilateral forearm exercise; between-day intra-subject variability was expressed as coefficients of variation (CV) calculated using two-way analysis of variance (ANOVA). Study 2 Five healthy subjects attended 2 study days when FBF was measured during incremental infusions of noradrenaline (15, 30, 150, 300 pmol min[-1]) and angiotensin II (1, 5, 10, 50 pmol min[-1]); for each individual subject at each dose intra-subject variability was assessed using the difference between responses (percentage change from baseline) on days 1 and 2. RESULTS: Study 1 At rest, intra-subject variability (CV) of baseline FBF ratios was 19% compared with 31% (left) and 39% (right) for unilateral FBF measurements. After ipsilateral exercise, unilateral FBF measurements were more reproducible (32 vs 17%) than FBF ratios; by 20 min after exercise, the previous pattern had been re-established (19 vs 27%). Intra-subject variability (CV) of baseline FVR ratio and post-exercise FVR was 14%. Study 2 Inter-quartile ranges of the differences between responses on days 1 and 2 (FBF ratios vs FBF) were: angiotensin II 14 vs 18%; noradrenaline 16 vs 27%. CONCLUSIONS: FBF ratios are more reproducible than unilateral FBF measurements at rest (CV 19% vs 39%) and for measuring responses to intra-arterial infusions of vasoconstrictor substances. FVR may have a small reproducibility advantage. Non-experimental stimuli can cause significant and misleading changes in measured responses if unilateral measurements are used; it is therefore recommended that responses to intra-arterial infusions should be measured using bilateral forearm plethysmography with the results expressed as FBF ratios.

Angiotensin II↗
PubMed1998

Dietary sodium restriction impairs insulin sensitivity in noninsulin-dependent diabetes mellitus.

Dietary sodium restriction has a variety of effects on metabolism, including activation of the renin-angiotensin system. Angiotensin II has complex metabolic and cardiovascular effects, and these may be relevant to the effects of both nonpharmacological and pharmacological interventions in noninsulin-dependent diabetes mellitus (NIDDM). We have assessed the effect of dietary sodium restriction on insulin sensitivity and endogenous glucose production in eight normotensive patients with diet-controlled NIDDM who underwent hyperinsulinemic clamp studies in a randomized, double-blind, placebo-controlled cross-over protocol after two 4-day periods on sodium replete (160 mmol/day) and sodium deplete (40 mmol/day) diets. Mean +/- SD 24-h urinary sodium was 197 +/- 76.0 mmol (replete) and 67 +/- 19.5 mmol (deplete), P = 0.03. Insulin sensitivity was 42.0 +/- 11.3 mumol/kg.min (replete) and 37.0 +/- 11.6 mumol/kg.min (deplete), P = 0.04 (a reduction of 12%). Blood pressure was 130 +/- 21/78 +/- 11 mmHg (replete) and 128 +/- 12/73 +/- 10 mmHg (deplete). Dietary sodium restriction may result in a decrease in peripheral insulin sensitivity in normotensive patients with NIDDM, possibly via an elevation in prevailing angiotensin II concentrations.

Aged↗
PubMed1998

The vasodilating effect of insulin is dependent on local glucose uptake: a double blind, placebo-controlled study.

During systemic hyperinsulinemia in man, skeletal muscle vasodilation has consistently been demonstrated. However, most studies that have examined the vascular effect of local hyperinsulinemia have reported either no effect or only weak vasodilation, and all of these have been open in design. The present studies were designed in a double blind, placebo-controlled manner to evaluate the direct (local) vascular effect of insulin alone and in association with physiological concentrations of D-glucose. Forearm blood flow was measured in 17 healthy male volunteers by bilateral venous occlusion forearm plethysmography. Brachial artery infusions of 1 mU/min insulin, 5 mU/min insulin, or vehicle were administered for 90 min on 3 separate study days in random order. The higher dose of insulin was associated with weak (20%) vasodilation compared with placebo (F = 5.75 and P < 0.01, by ANOVA). When this protocol was repeated with intraarterial coinfusion of D-glucose, significant augmentation of the vascular effect was demonstrated (47% vasodilation). No augmentation of insulin-mediated vasodilation was observed with coinfusion of L-glucose, the metabolically inactive stereoisomer. These data suggest that local uptake of D-glucose by insulin-sensitive tissues is an important determinant of insulin-mediated vasodilation.

Adult↗
PubMed1997

Specific insulin assays, insulin sensitivity and blood pressure.

Serum insulin concentrations have been used as markers of insulin resistance in population studies examining the relationship between insulin resistance and blood pressure, but the relationship is variable among studies. We hypothesized that differences in cross-reactivity of insulin assays with proinsulin and its split/des-amino products might account for the variation. We therefore examined fasting and post-glucose load serum insulin concentrations (determined by both specific and conventional assays), insulin sensitivity (measured by the euglycaemic clamp technique), and blood pressure, in a group of 56 diabetic (NIDDM) and non-diabetic subjects. Insulin concentrations as measured by the two methods were highly correlated (r = 0.97, p < 0.0001), and the relationships among serum insulin concentrations, insulin sensitivity and blood pressure were independent of assay method; for example, in non-diabetic subjects the univariate correlation between log10AUC insulin and insulin sensitivity index was similar with both methods [r = -0.81 vs. r = -0.82, p < 0.0001 (specific vs. conventional assay)]. Discrepancies between studies in the relationship between serum insulin concentrations and blood pressure are unlikely to be due to cross-reactivity of conventional insulin assays with proinsulin-like molecules.

Adult↗
PubMed1997

The euglycaemic hyperinsulinaemic clamp: an evaluation of current methodology.

1. The recognition of the role of insulin resistance in disease states and the recent development of new drugs that modify insulin-dependent metabolism has led to increased use of the euglycaemic hyperinsulinaemic clamp to measure in vivo insulin sensitivity, but several key aspects of the technique are poorly documented in the literature. 2. We have evaluated the reproducibility and intersubject variation of measurements of insulin sensitivity in groups of insulin-sensitive and insulin-resistant subjects and assessed the effects of hand warning on haemodynamic and metabolic responses. 3. Subjects participated in one of two protocols: (i) 18 healthy male volunteers and 18 patients with hypertension and glucose intolerance were clamped on two occasions, 1 week apart with measurements of insulin sensitivity (M) derived after 120 and 180 min of hyperinsulinaemia; and (ii) six healthy volunteers were clamped on one occasion with simultaneous sampling of antecubital and 'arterialized' (dorsal hand) venous blood for comparison of plasma glucose concentrations and oxygen saturation and a further six volunteers were clamped on two occasions with and without the use of hand warming. 4. Measurements of M derived after 120 min (M120) and 180 min (M180) of hyperinsulinaemia were reproducible: the coefficients of repeatability (mg/kg per min) of M120 and M180 were 1.0 and 0.9 for volunteers and 1.0 and 1.0 for the patient group, respectively. The intersubject variation in insulin stimulus was high: coefficients of variation for M180 were 22% for volunteers compared with 38% for the patient group. In volunteers compared with the patient group, hand warming significantly increased venous oxygen saturations (95 +/- 2 vs 79 +/- 18%, respectively) and glucose concentrations (5.2 +/- 0.2 vs 4.5 +/- 0.4 mmol/L, respectively) and measurements of M were significantly higher using arterialized compared with antecubital venous blood. However, local hand warming was associated with systemic vasodilatation: blood pressure decreased (e.g. 6 mmHg diastolic; P < 0.05) with a compensatory increase in heart rate (8 b.p.m.). 5. In conclusion, clamps of 120 and 180 min duration yielded measurements of M that were reproducible. The technique is much more robust when used in the context of a crossover design because of the significant (20-40%) intersubject variation in M, even among apparently homogeneous male volunteers. Hand warming effectively arterializes venous blood and gives significantly higher M values, but induces systemic vasodilation, which may confound measurements of M.

Adult↗
PubMed1997

Insulin and lipid metabolism: new developments in drug therapy.

Current treatments for non-insulin-dependent diabetes mellitus (NIDDM) remain far from ideal. The presence of both hyperinsulinaemia and resistance to insulin action in NIDDM challenges the rationale of treatments which primarily boost insulin secretion. Novel therapeutic strategies focus mainly on increasing peripheral sensitivity to endogenous insulin, an approach which has the potential not only to treat, but also to prevent NIDDM in high-risk individuals. The most promising new agents are the thiazolidinedione derivatives, in particular troglitazone. Thiazolidinediones are ligands for a specific subtype of the peroxisome proliferator activated receptor (PPAR), and decrease plasma glucose levels in both obesity and NIDDM, while at the same time reducing circulating insulin and free fatty acid levels. The current development status of these agents is reviewed, along with an assessment of their potential in the prevention and treatment of diverse pathophysiological states characterised by insulin resistance, including atherosclerosis and polycystic ovarian disease. Reference is made to the current status of other experimental agents including hydantoin derivatives, (3)-adrenoceptor agonists, and inhibitors of lipolysis.

Journal Article↗
PubMed1996

Endothelial nitric oxide production and insulin sensitivity. A physiological link with implications for pathogenesis of cardiovascular disease.

BACKGROUND: Insulin sensitivity varies up to threefold in apparently healthy individuals, but the mechanism for this is unknown. We have examined the hypothesis that vascular endothelial nitric oxide production and insulin sensitivity are directly related in humans. METHODS AND RESULTS: Nineteen healthy male subjects were studied on 3 separate days 1 week apart during which time they underwent measurement of insulin sensitivity by the euglycemic hyperinsulinemic clamp technique (soluble insulin 1.5 mU . kg-1 . min-1) and measurement of in vivo basal and stimulated endothelial nitric oxide production by forearm venous occlusion plethysmography. There was a correlation between insulin sensitivity and forearm vasoconstrictor responses to NG-monomethyl-L-arginine, the substrate inhibitor of nitric oxide synthase (r = .52, P < .05). No correlations were observed between insulin sensitivity and noradrenaline, acetylcholine, or sodium nitroprusside responses. CONCLUSIONS: Endothelial nitric oxide synthesis and insulin sensitivity are positively related in healthy humans, which suggests a direct physiological link.

Acetylcholine↗
PubMed1996

Potential confounding effect of hand-warming on the measurement of insulin sensitivity.

1. Hand-warming is employed during metabolic studies to "arterialize' venous blood, but also has systemic haemodynamic effects. Study 1 aimed to determine if hand-warming affects the value for whole-body insulin sensitivity derived from the hyperinsulinaemic euglycaemic clamp technique. Study 2 was designed to assess the effect of hand-warming on contralateral forearm blood flow. 2. In study 1, eight healthy male subjects attended for four modified euglycaemic clamp studies, during which the right hand was placed in a heated-air hand box (55 degrees C), and the glucose infusion rate was adjusted according to blood samples from a cannula in either an ipsilateral dorsal hand vein or a contralateral antecubital vein with the box switched either on or off. In study 2, five healthy subjects attended two study days when the effect of 2 h of hand-warming (or control) on contralateral forewarm blood flow was measured. 3. Study 1; when clamps were performed according to samples taken from the contralateral antecubital vein, insulin sensitivity values were significantly lower during box-on versus box-off clamps (mean +/- SD 10.2 +/- 3.0 versus 13.0 +/- 3.8 mg min-1 kg-1, P < 0.05, 95% confidence interval -0.2, -5.3). When clamps were performed according to samples taken from the ipsilateral hand, there was no difference in insulin sensitivity during box-on versus box-off clamps (9.2 +/- 2.1 versus 9.0 +/- 1.7 mg min-1 kg-1, P not significant, 95% confidence interval -0.5, +0.9). There was a mean increase in heart rate of 6 beats/min in the box-on conditions (P < 0.05, analysis of variance). Study 2; forearm blood flow in the contralateral arm during hand-warming was significantly higher than in the control condition (P < 0.05, analysis of variance), although heart rate was similar on both study days. 4. Hand-warming had a detectable effect on insulin sensitivity when clamps were performed according to samples withdrawn from the contralateral arm, but no measurable effect when clamps were performed in the conventional manner. In addition, hand-warming increased heart rate during hyperinsulinaemia and contralateral FBF under basal conditions. These findings raise concern about unwanted (potentially confounding) systemic haemodynamic effects of hand-warming on the measurement of insulin sensitivity and insulin-mediated vasodilation.

Blood Glucose↗
PubMed1995

Haemodynamics, cardiac conduction and pharmacokinetics of mibefradil (Ro 40-5967), a novel calcium antagonist.

OBJECTIVES: Mibefradil (Ro40-5967) is a chemically novel non-dihydropyridine calcium antagonist. In this phase II study we compared its acute and chronic effects on blood pressure, heart rate and atrioventricular conduction (electrocardiographic PQ interval) with those of verapamil and diltiazem. PATIENTS AND METHODS: After a 4-week placebo run-in, 18 patients with mild to moderate essential hypertension were given single doses of mibefradil (150 mg), slow-release (SR) verapamil (240 mg), diltiazem (240 mg) and placebo at weekly intervals; pharmacokinetics and the effects on blood pressure, heart rate and PQ interval were studied on four 10-h study days. Seventeen of the same patients subsequently underwent 4 weeks of treatment with either mibefradil (100 mg daily; n = 10) or verapamil SR (240 mg daily; n = 7), and on the last day, they attended a further 10-h study day. Two studies were conducted: an acute, single-dose, double-blind, randomly allocated, placebo-controlled, crossover study and a chronic, open-label, randomly allocated, parallel-group study. RESULTS: Mibefradil was well tolerated. In the acute study, the antihypertensive effect (difference from placebo) of mibefradil 150 mg was of slower onset than that of verapamil or diltiazem, but comparable blood pressure reductions had been achieved by 6 h. The mean +/- SD maximal PQ prolongation (difference from placebo) was 15.6 +/- 16.1 ms, compared with 44.0 +/- 22.6 ms for verapamil and 56.0 +/- 48.9 ms for diltiazem (P<0.05 mibefradil versus verapamil; P<0.01 mibefradil versus diltiazem). In the chronic study there were no significant differences during steady-state conditions between mibefradil at 100 mg and verapamil SR at 240 mg in their effects on blood pressure, PQ and heart rate. The mean +/- SD elimination half-life (t1/2) of mibefradil under steady-state conditions was 26.8 +/- 5.5 h (versus an apparent t1/2 of 16.9 +/- 11.1 h for verapamil SR, P<0.05). CONCLUSIONS: Mibefradil is a well-tolerated and efficacious antihypertensive agent well suited to single daily dosing because of its intrinsic long plasma half-life. The effects on both blood pressure and PQ interval are of more gradual onset than those of unmodified verapamil and diltiazem after single doses.

Adolescent↗