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S J Cleland

Publications and source records attributed to S J Cleland.

At least 19 recordsLinked to original sources
PubMed2007

Effects of low-dose continuous combined hormone replacement therapy on glucose homeostasis and markers of cardiovascular risk in women with type 2 diabetes.

BACKGROUND: Low-dose hormone replacement therapy (HRT) has attracted interest for the treatment of postmenopausal symptoms in diabetes because of concerns about increased risk of coronary heart disease (CHD) and stroke with conventional HRT containing conjugated equine oestrogens (CEEs) and medroxyprogesterone acetate (MPA). OBJECTIVES: We assessed the effects on glucose homeostasis and cardiovascular risk factors of continuous oral 17beta oestradiol (1 mg) and norethisterone (0.5 mg) in postmenopausal women with type 2 diabetes. DESIGN: Double-blind, randomized placebo-controlled trial. ASSESSMENTS: Hyperinsulinaemic isoglycaemic clamp and cardiovascular risk factors were assessed before and after 3 months of treatment. RESULTS: Twenty-eight women completed the study. HRT decreased fasting glucose compared with placebo [-9.4% with HRT vs.+2.3% for placebo, 95% confidence interval (CI) -23.2 to -0.3] and total cholesterol (-13.7 vs.+1.0%, 95% CI -22.4 to -3.1%) No significant effect was seen on metabolic clearance rate of glucose, glycated haemoglobin (HbA1c), triglycerides, high density lipoprotein (HDL)-cholesterol or C-reactive protein (CRP). CONCLUSIONS: In women with type 2 diabetes, low-dose HRT decreased fasting glucose and total cholesterol without detectable adverse effects on glucose clearance, triglycerides and CRP as reported with conventional HRT.

Blood Glucose↗
PubMed2006

Blunted response to systemic nitric oxide synthase inhibition in the cerebral circulation of patients with Type 2 diabetes.

AIMS: Diabetes is a major risk factor for stroke, but the mechanisms that impart the excess risk are unclear. Endothelial dysfunction, which has been demonstrated in the coronary and peripheral vasculature of diabetic patients, is an important early marker of vascular disease. However, the effect of diabetes on cerebrovascular endothelium has not been examined. We sought to investigate the effect of diabetes on basal cerebrovascular endothelial function as assessed by response to the nitric oxide synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA). METHODS: Fourteen men with Type 2 diabetes and 15 age-matched male control subjects were recruited. The participants had no clinically evident vascular disease and were taking no vasoactive or lipid-lowering medication. Each received a single 15-min intravenous infusion of L-NMMA (0.8 mol/kg/min). Cerebral blood flow was assessed by colour Doppler imaging of the internal carotid artery (ICA) at 10-min intervals for 20 min prior to and following the infusion. Middle cerebral artery velocity (MCAv) was assessed by transtemporal Doppler ultrasound at the same time points. RESULTS: L-NMMA produced a mean reduction in ICA flow area under curve (AUC) in the control group of 12.8 +/- 17.8% compared with a 2.1 +/- 21.7% reduction in the group with diabetes (P < 0.05), indicating blunted basal cerebrovascular response to NOS inhibition in the diabetic group. There was no significant change in MCAv following L-NMMA in either group. Mean +/- sd MAP rose 6.4 +/- 4.2 mmHg in the control group vs. 8.8 +/- 3.5 mmHg in the diabetic group [P = not significant (NS)]. No adverse event or symptom was reported. CONCLUSIONS: Response to NOS inhibition is impaired in the cerebral circulation of patients with diabetes. This observation is consistent with the elevated cerebrovascular risk reported in this population, and may represent a future therapeutic target in stroke prevention.

Adult↗
PubMed2004

Higher carotid-radial pulse wave velocity in healthy offspring of patients with Type 2 diabetes.

AIMS: To determine whether carotid-radial pulse wave velocity (crPWV), a simple non-invasive measurement of muscular artery structure and function, is increased in offspring of patients with Type 2 diabetes compared with well-matched controls with no family history of diabetes. Serum levels of intercellular adhesion molecule-1 (sICAM-1) were also examined. METHODS: Offspring (n = 19, M = 8) were recruited via contact with patients attending clinics. Controls (n = 19, M = 8) were recruited by advertisement. crPWV was measured using COMPLIOR. Blood pressure and heart rate were determined and fasting blood taken for measurement of metabolic and endothelial parameters. RESULTS: Offspring and controls were well matched [mean (sd)] for age [33.1 (9.6) vs. 32.8 (9.5) years], body mass index [24.8 (4.9) vs. 24.3 (3.4) kg/m2], waist circumference [78.3 (2.3) vs. 76.3 (2.5) cm], and systolic blood pressure [120 (9.3) vs. 119 (14.2) mmHg]. crPWV was 10% higher in the offspring [9.94 (1.3) m/s] compared with controls [9.01 (1.2) m/s, P = 0.02] despite similar pulse pressure [52 (10.5) vs. 53.5 (9.3) mmHg] and resting heart rate [71 (8.7) vs. 69 (14.0) beats/min]. They also showed a trend toward higher sICAM-1 [217 (55) vs. 188 (40) ng/ml, P = 0.07] concentrations which were also strongly correlated to crPWV in offspring (r = 0.63, P = 0.004). CONCLUSIONS: Vascular dysfunction in the form of increased muscular artery stiffness is present from an early stage in subjects at higher risk of developing diabetes. This may be secondary to impaired activation of endothelial signalling pathways in the context of inherited insulin resistance.

Adult↗
PubMed2003

Glucocorticoids and insulin sensitivity: dissociation of insulin's metabolic and vascular actions.

Insulin sensitivity in tissues such as a skeletal muscle and fat is closely correlated with insulin action in the vasculature, but the mechanism underlying this is unclear. We investigated the effect of dexamethasone on insulin-stimulated glucose disposal and vasodilation in healthy males to test the hypothesis that a reduction in glucose disposal would be accompanied by a reduction in insulin action in the vasculature. We performed a double-blind, placebo-controlled, cross-over trial comparing insulin sensitivity (measured by the euglycemic hyperinsulinemic clamp) and vascular insulin action (measured by small vessel wire myography) in young healthy males allocated to placebo or 1 mg dexamethasone twice daily for 6 d, each in random order. Six days of dexamethasone therapy was associated with a 30% (95% confidence interval, 19.1-40.0%) fall in insulin sensitivity. Despite this, there was no difference in insulin-mediated vasodilation between phases. Dexamethasone had no effect on circulating markers of endothelial function, such as D-dimer, von Willebrand factor, and tissue plasminogen activator. By short-term exposure to high dose dexamethasone we were able to differentially affect the metabolic and vascular actions of insulin. This implies that, using this model, there is physiological uncoupling of the effects of insulin in different tissues.

Acetylcholine↗
PubMed2000

Insulin action is associated with endothelial function in hypertension and type 2 diabetes.

A primary defect in the vascular action of insulin may be a key intermediate mechanism that links endothelial dysfunction with reduced insulin-mediated cellular glucose uptake in metabolic and cardiovascular disorders. The present study was designed to characterize more fully the relations between insulin action and endothelial function in male patients with essential hypertension (H, n=9) or type 2 diabetes (D, n=9) along with healthy control subjects (C) matched for age, body mass index, and lipid profile. They attended for measurement of whole-body insulin sensitivity (MCR) by the hyperinsulinemic clamp technique (day 1) and forearm vasoreactivity in response to intra-arterial infusions of insulin/glucose (day 2) and N(G)-monomethyl-L-arginine (L-NMMA) and norepinephrine (day 3) by bilateral venous-occlusion plethysmography. Results expressed as mean+/-SE MCR (mL/kg per minute) were 7.22+/-0. 99 (C), 6.32+/-0.78 (H), and 5.06+/-0.53 (D). Insulin/glucose-mediated vasodilation (IGMV) was 17.1+/-5.6% (C), 17. 2+/-5.5% (H), and 12.3+/-6.4% (D). L-NMMA vasoconstriction (LNV) was 37.9+/-5.1% (C), 37.5+/-2.3% (H), and 33.6+/-2.8% (D). There were no significant differences among groups for these parameters. Pooled correlation analyses revealed associations between MCR and IGMV (r=0. 46, P<0.05), MCR and LNV (r=0.44, P<0.05), and IGMV and LNV (r=0.52, P<0.01). This study supports functional coupling between insulin action (both metabolic and vascular) and basal endothelial nitric oxide production in humans.

Age Factors↗
PubMed2000

Endothelial dysfunction as a possible link between C-reactive protein levels and cardiovascular disease.

Low-grade chronic inflammation, characterized by elevated plasma concentrations of C-reactive protein (CRP), is associated with an increased risk of atherosclerotic cardiovascular disease. Endothelial cell activation is an early event in atherogenesis, and previous studies have reported correlations between indirect markers of endothelial cell activation and CRP concentration. Therefore, in the present study, we measured CRP concentration (and leptin concentration as an index of fat mass) in nine healthy subjects (mean age 53+/-8.1 years; body mass index 27+/-3.2 kg/m(2); mean arterial blood pressure 101+/-9.0 mmHg) undergoing measurement of basal endothelial nitric oxide (NO) synthesis using intra-brachial infusions of N(G)-monomethyl-L-arginine (L-NMMA; a substrate inhibitor of endothelial NO synthase) and noradrenaline (a non-specific control vasoconstrictor). In univariate analysis, CRP concentration was correlated with (i) the percentage decrease in forearm blood flow (FBF) during L-NMMA infusion (r=0.85, P=0.004); and (ii) the serum leptin concentration (r=0.65, P=0.05). In multivariate analysis, the relationship between CRP concentration and the FBF response to L-NMMA remained significant when age and leptin (t=2.65, P=0.045), age and BMI (t=3.69, P=0.014), or age and low-density-lipoprotein-cholesterol plus high-density-lipoprotein-cholesterol (t=3.37, P=0.044), were included in regression models. In contrast, the response of FBF to noradrenaline was not significantly related to CRP concentration. These data demonstrate for the first time a relationship between low-grade chronic inflammation and basal endothelial NO synthesis (measured using an invasive method), and support the notion that endothelial dysfunction is a critical intermediate phenotype in the relationship between inflammation and cardiovascular disease.

Adult↗
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↗
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↗
PubMedDate not supplied

Insulin as a vascular hormone: implications for the pathophysiology of cardiovascular disease.

1. Metabolic disorders, such as obesity and non-insulin-dependent diabetes mellitus, and cardiovascular disorders, such as essential hypertension, congestive cardiac failure and atherosclerosis, have two features in common, namely relative resistance to insulin-mediated glucose uptake and vascular endothelial dysfunction. 2. Significant increases in limb blood flow occur in response to systemic hyperinsulinaemia, although there is marked variation in the results due to a number of confounding factors, including activation of the sympathetic nervous system. Local hyperinsulinaemia has a less marked vasodilator action despite similar plasma concentrations, but this can be augmented by co-infusing D-glucose. 3. Insulin may stimulate endothelial nitric oxide production or may act directly on vascular smooth muscle via stimulation of the Na+-H+ exchanger and Na+/K+-ATPase, leading to hyperpolarization of the cell membrane and consequent closure of voltage-gated Ca2+ channels. 4. There is evidence both for and against the existence of a functional relationship between insulin-mediated glucose uptake (insulin sensitivity) and insulin-mediated vasodilation (which can be regarded as a surrogate measure for endothelial function). 5. If substrate delivery is the rate-limiting step for insulin-mediated glucose uptake (in other words, if skeletal muscle blood flow is a determinant of glucose uptake), then endothelial dysfunction, resulting in a relative inability of mediators, including insulin, to stimulate muscle blood flow, may be the underlying mechanism accounting for the association of atherosclerosis and other cardiovascular disorders with insulin resistance. 6. Glucose uptake may determine peripheral blood flow via stimulation of ATP-dependent ion pumps with consequent vasorelaxation. 7. A 'third factor' may cause both insulin resistance and endothelial dysfunction in cardiovascular disease. Candidates include skeletal muscle fibre type and capillary density, distribution of adiposity and endogenous corticosteroid production. 8. A complex interaction between endothelial dysfunction, abnormal skeletal muscle blood flow and reduced insulin-mediated glucose uptake may be central to the link between insulin resistance, blood pressure, impaired glucose tolerance and the risk of cardiovascular disease. An understanding of the primary mechanisms resulting in these phenotypes may reveal new therapeutic targets in metabolic and cardiovascular disease.

Cardiovascular Diseases↗