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Biomedical subjects

A H Barnett

Publications and source records attributed to A H Barnett.

At least 19 recordsLinked to original sources
PubMed2006

Type 2 diabetes and cardiovascular risk in the UK south Asian community.

A popular hypothesis for the greater prevalence of type 2 diabetes and cardiovascular disease in UK south Asians is that they have an increased susceptibility of developing insulin resistance in response to certain environmental factors, including obesity and adoption of a sedentary lifestyle. Insulin resistance is postulated as a central feature of the metabolic syndrome, culminating in type 2 diabetes, atherosclerotic vascular disease and CHD; a pathway potentially accelerated by migration/urbanisation. We describe and compare the prevalence of type 2 diabetes, cardiovascular disease and their associated risk factors in UK south Asian and white Caucasian populations to determine possible reasons for the increased preponderance of these diseases in south Asians, and highlight key evidence for optimal risk factor management. Finally, we describe a UK community-based programme that attempts to reduce the morbidity and mortality from type 2 diabetes and cardiovascular disease in south Asians through a new approach to management.

Adult↗
PubMed2006

Relationship of serum adiponectin and resistin to glucose intolerance and fat topography in South-Asians.

OBJECTIVES: South-Asians have lower adiponectin levels compared to Caucasians. It was not clear however, if this intrinsic feature is related to aspects of glucose metabolism. This study aims to determine the relationship between body fat distribution and adipocytokine in South-Asian subjects by measuring serum adipocytokines, adiposity, insulinemia, and glucose tolerance levels. METHODS: In this cross-sectional study, 150 South-Asians (80 males, 70 females) were included, 60 had NGT (Control group, Age 51.33 +/- 11.5, BMI 27 +/- 2.3), 60 had IGT (Age 57.7 +/- 12.5, BMI 27.2 +/- 2.7), 30 had type 2 DM (Age 49.5 +/- 10.9, BMI 28 +/- 1.7). Measures of adiposity, adipocytokines and other metabolic parameters were determined. Parameters were measured using the following: a) Plasma glucose by glucose oxidase method b) CRP by immunoturbidimetric method (Roche/Hitachi analyser) c) insulin by Medgenix INS-ELISA immunoenzymetric assay by Biosource (Belgium) d) Leptin, Adiponectin by radioimmunoassay kits by Linco Research (St. Charles MO) e) Resistin by immunoassay kits by Phoenix Pharmaceuticals INC (530 Harbor Boulevard, Belmont CA 94002, USA). RESULTS: Adiponectin concentrations were highest in NGT, decreased in IGT and lowest in DMT2, (both p < 0.01). Leptin was significantly higher in DMT2 than IGT and NGT p = 0.02 and 0.04 respectively. There was a significant positive relationships between log adiponectin and 2-hr insulin values, p = 0.028 and history of hypertensions and a ischemic heart disease p = 0.008 with R = 0.65. There was a significant inverse correlation between log adiponectin and resistin, p < 0.01. CONCLUSION: Resistin levels had an inverse correlation with adiponectin levels, indicating an inverse relationship between pro-inflammatory cytokines and adiponectin. Adiponectin levels were related to glucose tolerance.

Adiponectin↗
PubMed2006

How well do rapid-acting insulins work in obese individuals?

Diabetes has reached epidemic proportions worldwide and most individuals with type 2 diabetes are obese. Therefore, there is a pressing need to carefully evaluate the impact of obesity on the efficacy of all diabetes therapies. Previously, obesity has been shown to adversely affect the efficacy of oral antidiabetic drugs; however, less is known about the impact of obesity on the properties of insulin and its analogues. As patients near target HbA1c, the more postprandial hyperglycaemia contributes to overall glycaemic control; thus, mealtime insulin, often supplied by a rapid-acting insulin analogue (RAI), becomes of increasing importance. As glycaemic targets set by professional bodies become lower and poor glycaemic control becomes increasingly less acceptable, earlier addition of RAIs to patients' treatment regimens may be required to meet these targets. However, in clinical practice, multiple barriers have challenged the acceptance and effective use of insulin therapy, including concern that it may cause weight gain. RAIs should ideally maintain their rapid-acting pharmacokinetic (PK) and pharmacodynamic (PD) profiles, irrespective of subcutaneous body fat, skin thickness and body mass index, in order to effectively meet intensive treatment goals. For example, initial PK/PD data with insulin glulisine in obese individuals suggest that this RAI may maintain its rapid-acting profile better than insulin lispro in the first 2 hours post-injection. However, data are preliminary and a thorough analysis of the impact of obesity on all RAIs in type 2 diabetes is warranted. This review focuses on the potential impact of obesity on RAIs and presents an overview of investigations in this area.

Blood Glucose↗
PubMed2006

Inhaled insulin: new technology, new possibilities.

The prevalence of diabetes is reaching epidemic proportions with an increasing need for new therapies. Several new therapies are in development and amongst these is inhaled insulin. Inhaled insulin is a novel way of delivering insulin and has been shown to have an efficacy comparable to subcutaneous insulin in patients with both type 1 and type 2 diabetes. Several inhaled insulin delivery systems are currently in development and the first of these, Exubera has recently been granted license in Europe and in the USA. In this article we review the efficacy and safety profile of Exubera and discuss its potential place in the management of diabetes.

Administration, Cutaneous↗
PubMed2005

Serum high molecular weight complex of adiponectin correlates better with glucose tolerance than total serum adiponectin in Indo-Asian males.

AIMS/HYPOTHESIS: It is well established that total systemic adiponectin is reduced in type 2 diabetic subjects. To date most studies have been concerned with the singular full-length protein or proteolytically cleaved globular domain. It is, however, apparent that the native protein circulates in serum as a lower molecular weight hexamer and as larger multimeric structures of high molecular weight (HMW). In this study we address the clinical significance of each form of the protein with respect to glucose tolerance. METHODS: Serum was obtained from 34 Indo-Asian male subjects (BMI 26.5+/-3.1; age 52.15+/-10.14 years) who had undertaken a 2-h oral glucose tolerance test. An aliquot of serum was fractionated using velocity sedimentation followed by reducing SDS-PAGE. Western blots were probed for adiponectin, and HMW adiponectin as a percentage of total adiponectin (percentage of higher molecular weight adiponectin [S(A)] index) was calculated from densitometry readings. Total adiponectin was measured using ELISA; leptin, insulin and IL-6 were determined using ELISA. RESULTS: Analysis of the cohort demonstrated that total adiponectin (r = 0.625, p = 0.0001), fasting insulin (r = -0.354, p = 0.040) and age (r = 0.567, p = 0.0001) correlated with S(A). S(A) showed a tighter, inverse correlation with 2-h glucose levels (r = -0.58, p = 0.0003) than total adiponectin (r = -0.38, p = 0.0001). CONCLUSIONS/INTERPRETATION: This study demonstrates the importance of the S(A) index as a better determinant of glucose intolerance than measurements of total adiponectin. Our findings suggest that HMW adiponectin is the active form of the protein.

Adiponectin↗
PubMed2005

Preventing renal complications in diabetic patients: the Diabetics Exposed to Telmisartan And enalaprIL (DETAIL) study.

Diabetic nephropathy is characterised by hypertension and persistent proteinuria. If ineffectively controlled, a progressive decline in renal function can result in end-stage renal disease. Patients with diabetic nephropathy are also at greatly increased risk of cardiovascular disease. Angiotensin-converting enzyme (ACE) inhibitors display additional renoprotective effects beyond systemic blood pressure lowering, perhaps due to reduction in intraglomerular pressure by inhibition of angiotensin II activity. In type 2 diabetics, ACE inhibitors have variable effects, with some studies showing a reduction in microalbuminuria, prevention of the progression to macroalbuminuria and maintenance of renal function. Randomised studies have demonstrated that angiotensin II receptor blockers (ARBs), as well as controlling systemic blood pressure, delay progression of proteinuria in patients with diabetic nephropathy. Telmisartan has a number of features that may make it particularly suitable for the treatment of diabetic nephropathy. In addition to its long duration of action and almost exclusive faecal excretion, its high lipophilicity should assist in tissue penetration. The Diabetics Exposed to Telmisartan And enalaprIL (DETAIL) study was designed to compare the long-term renal outcome of treatment with telmisartan 40.80 mg versus enalapril 10.20 mg (with titration to the higher dose after 4 weeks) in patients with type 2 diabetes, mild-to-moderate hypertension and albuminuria. The primary endpoint is the change in glomerular filtration rate after 5 years' randomised treatment. Secondary endpoints are annual changes in glomerular filtration rate, serum creatinine and urinary albumin excretion, as well as incidences of end-stage renal disease, cardiovascular events, all-cause mortality and adverse events. The groundbreaking DETAIL study revealed that telmisartan conferred comparable renoprotection to enalapril and was associated with a low incidence of mortality.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

The TGF-beta 1 gene codon 10 polymorphism contributes to the genetic predisposition to nephropathy in Type 1 diabetes.

AIMS: We hypothesize that transforming growth factor-beta (TGF-beta), a multifunctional growth factor which plays a key role in the development of tissue fibrosis, may be involved in the pathophysiology of diabetic nephropathy. Our aim was to examine three polymorphisms within the TGF-beta 1 gene, in codons 10, 25 and 263, for association with nephropathy in Type 1 diabetes. METHODS: We conducted a large case-control study using cases with Type 1 diabetes and clinical nephropathy. Controls were Type 1 diabetic subjects who have been injecting insulin for at least 50 years and have extremely low risk of nephropathy. Genotyping was by polymerase chain reaction with sequence-specific primers. RESULTS: There was a significant difference in the frequency of the TGF-beta 1 codon 10 genotypes in the diabetic nephropathy group (n = 420) when compared with the controls (n = 410, P = 0.007). There were no significant differences when the frequencies of the TGF-beta1 codons 25 and 263 genotypes in the diabetic nephropathy group were compared with the control group. CONCLUSIONS: In our study the TGF-beta 1 codon 10 polymorphism is associated with nephropathy in Type 1 diabetes and variation in this gene may contribute to the genetic predisposition to this complication in Type 1 diabetes.

Adult↗
PubMed2005

Introduction: the role of the thiazolidinediones in the cardiovascular risk management of type 2 diabetes.

SCOPE: This article serves as an introductory overview to this supplement which covers type 2 diabetes as an atherosclerotic disease, the evidence base for treatment of the various vascular risk factors, and provides a detailed appraisal of the potential for thiazolidinediones to play a major role in overall diabetes management, not just for glycaemia, but also from the point of view of cardio vascular disease. CONCLUSION: We are clearly entering into an extremely interesting time in the management of type 2 diabetes. The thiazolidinediones have the potential to target a fundamental defect in type 2 diabetes as well as to improve CV risk in this extremely high risk group of patients. Time will tell whether the obvious potential of these agents will result in dramatically improved clinical outcomes.

Cardiovascular Agents↗
PubMed2004

Modest weight loss and reduction in waist circumference after medical treatment are associated with favorable changes in serum adipocytokines.

Modest weight loss if maintained is associated with significant metabolic benefits and reduction in cardiovascular risk. Adipose tissue secretes cytokines believed to contribute to the pathogenesis of insulin resistance and cardiovascular risk. We therefore observed the effect of modest weight loss on serum adipocytokines and their relationship with changes in anthropometric and metabolic parameters within a period of 6 months in the setting of a routine obesity hospital clinic after various medical treatments. In this prospective, nonrandomized, nonblinded observational study, patients were first given treatment (sibutramine or orlistat) as decided by the treating clinician and then allocated into 1 of 2 groups according to the treatment prescribed. The first group included 21 Caucasian nondiabetic female subjects, with a mean (+/-SD) age of 43 +/- 11 years and a mean body mass index (BMI) of 46 +/- 8.6 kg/m(2); subjects were treated with sibutramine 10 or 15 mg/d for weight loss. The second group included 20 Caucasian nondiabetic female subjects, mean age 42 +/- 9 years and mean BMI 45.2 +/- 5.2 kg/m(2); orlistat was introduced after 1 month on a low-fat (</=30%) diet in this group. Blood pressure and anthropometric measurements were performed before and after weight loss by a single observer. Serum glucose, insulin, lipid profile, C-reactive protein (CRP), resistin, leptin, and adiponectin were measured before and after weight loss on a fasting sample. After 6 months, the sibutramine group had a modest mean weight loss of 5.4% (P =.0001), and waist circumference was reduced by 4.5 +/- 1.4 cm. There was a decrease in serum resistin, leptin, and CRP levels, and a rise in serum adiponectin (P <.05). Change (%) (Delta) in BMI (DeltaBMI%) was associated with Deltainsulin(%) (P =.02, r = 0.53) and Deltaleptin(%) (P =.01, r = 0.58). Change in waist was associated with Deltainsulin(%) (P =.005, r = 0.75) and Deltaresistin(%) (P =.03, r = -0.55). The orlistat-treated group had a mean weight loss of 2.5%. Although this group did not show significant change in metabolic parameters, surprisingly there was a greater decrease of resistin (P =.02) associated with comparable (%) increase in adiponectin and (%) reduction of waist circumference and CRP. We conclude that modest weight loss (>5%) after medical treatment in a routine obesity hospital clinic is associated with improvements in insulin sensitivity and lipid profile. Modest weight loss is also associated with potentially favourably changes in serum adipocytokines, particularly in a rise of serum adiponectin. Reduction of waist circumference is associated with a change in serum resistin.

Abdomen↗
PubMed2004

Exubera inhaled insulin: a review.

The focus of this review is inhaled insulin, specifically Exubera, which represents a novel prandial insulin delivery method. Fear of hypoglycaemia and the reluctance of patients to use multiple daily injection regimens is a major barrier to achieving good glycaemic control in patients with type 1 and type 2 diabetes. Inhaled insulin has been developed to provide more physiological prandial insulin replacement than regular human insulin in patients with diabetes, with the advantage of non-invasive delivery. Good glycaemic control, comparable to modern subcutaneously administered insulin preparations, has already been demonstrated, and no unexpected safety concerns have been reported with inhaled insulin. The development of such insulin delivery technologies that are better tailored to patients' needs may improve patient compliance, thereby facilitating the attainment of treatment targets. This review summarises the studies available and discusses the potential implications to patients of needle-free insulin administration.

Administration, Inhalation↗
PubMed2004

A placebo-controlled crossover study comparing the effects of nateglinide and glibenclamide on postprandial hyperglycaemia and hyperinsulinaemia in patients with type 2 diabetes.

AIM: This was a randomized, double blind, three period crossover study. The objective was to compare glucose, insulin and C-peptide 24 h profiles in patients with type 2 diabetes mellitus after dosing with nateglinide (given preprandially before three test meals), glibenclamide (administered once before breakfast) or placebo (given before three test meals). METHODS: Fourteen patients underwent screening followed within 3 weeks by three treatment periods of 1 day, each separated by 7 days. Dosing followed a six-sequence balanced, two 3 x 3-replicated Latin square. RESULTS: Mean peak serum insulin levels were lower after nateglinide (115 mU/l) than after glibenclamide (145 mU/l.h; p = 0.017) but higher than after placebo (79 mU/l; p = 0.001). However, peak insulin levels were reached earlier after nateglinide [mean time to peak (tmax) 1.7 h] compared to glibenclamide (mean tmax 2.1 h, p = 0.06). Total insulin exposure over the day was higher after glibenclamide compared with that following nateglinide (1216 vs. 1067 mU/l.h; p = 0.009). Similar findings were seen with serum C-peptide. Despite this, mean peak plasma glucose concentrations were lower following nateglinide (11.4 mmol/l from a baseline of 8.3 mmol/l) compared with glibenclamide (13.2 mmol/l from a baseline of 8.5 mmol/l; p = 0.001) and placebo (14.0 mmol/l from a baseline of 8.0 mmol/L; p < 0.001). CONCLUSIONS: Nateglinide improves early prandial measures of insulin and glucose response to a standard meal, more so than glibenclamide, in people with type 2 diabetes.

Aged↗
PubMed2004

Evidence for a Type 1 diabetes-specific mechanism for the insulin gene-associated IDDM2 locus rather than a general influence on autoimmunity.

AIMS: The Type 1 diabetes susceptibility locus, IDDM2, has been mapped to a variable number of tandem repeats (VNTR) region 5' upstream of the insulin (INS) and insulin-like growth factor (IGF2) genes on chromosome 11p15. The function of the VNTR is uncertain; however, it may influence the thymic expression of the insulin gene and affect the development of immune self-tolerance. The aim of this study was to investigate whether the INS VNTR region is a Type 1 diabetes-specific locus or acting as a general autoimmunity gene. METHODS: We genotyped the INS-IGF2 VNTR [using the surrogate INS-23 HphI single nucleotide polymorphism (SNP)] in 823 Graves' disease (GD)/multiple sclerosis (MS) families, 1433 GD/MS patients and 837 healthy control subjects. RESULTS: We found no evidence of excess transmission of the allele associated with Type 1 diabetes to individuals affected by GD or MS within the families. Analysis of the case-control dataset showed no genotypic or allelic difference between the two populations. CONCLUSIONS: These data suggest that the INS-IGF2 VNTR is acting as a Type 1 diabetes-specific susceptibility gene rather than as an influence on general autoimmunity.

Alleles↗
PubMed2004

Clustering of autoimmune disease in parents of siblings from the Type 1 diabetes Warren repository.

AIMS: Autoimmune disorders co-exist in the same individuals and in families, implying a shared aetiology. The aim of this study was to compare the prevalence of the common autoimmune diseases in the parents of siblings from the Type 1 diabetes Warren repository with the general population. METHODS: Between 1989 and 1996, 505 British families with at least two siblings affected by Type 1 diabetes were recruited. Clinical information was collected regarding the presence of autoimmune disease in the parents and the prevalence of disease in the parents was compared with that expected in the general population. RESULTS: The prevalence of autoimmune disease in the parents was significantly higher in the repository compared with that expected in the general population [P-value = 1.98 x 10(-5) (female), P-value = 1.1 x 10(-8) (male)]. Type 1 diabetes was recorded in 63/1010 (6.2%) parents with a marked paternal preponderance (9.5 vs. 3%P = 0.002). Other autoimmune diseases affected 27% of parents with diabetes and 13.2% of parents without diabetes (P < 0.01). CONCLUSION: These data confirm the importance of family history as a significant risk factor for the development of Type 1 diabetes and support the hypothesis that the common autoimmune diseases share at least some aetiological mechanisms.

Adult↗
PubMed2004

Evaluation of delivery of enhanced diabetes care to patients of South Asian ethnicity: the United Kingdom Asian Diabetes Study (UKADS).

AIMS: We tested the hypothesis that enhanced care for diabetes, tailored to the needs of the South Asian community with Type 2 diabetes, would improve risk factors for diabetic vascular complications and ultimately reduce morbidity and mortality. PATIENTS AND METHODS: The study was a cluster randomized controlled trial (RCT) with general practice the unit of randomization. Six West Midlands general practices with a high proportion of South Asian patients were randomized to 'enhanced care' using Asian link workers and extra community diabetes specialist nurse sessions (intervention) or continued standard practice care (control). RESULTS: Of 401 patients recruited to the study, 361 (90%), comprising 178 from Coventry and 183 from Birmingham were eligible and included in the analyses. The mean age at baseline (standard deviation, SD) was 58.9 (11.7 years) with median (interquartile range; IQR) duration of diabetes 6.5 (3-11) years. At one year follow-up there was a significant difference in reduction of systolic (4.6 mmHg, P = 0.035) and diastolic blood pressure (3.4 mmHg, P = 0.003) and total cholesterol (0.4 mmol/l, P = 0.005), comparing the intervention and control groups. After adjusting for baseline measurement and age, only differential reduction in diastolic blood pressure remained significant. There was no significant change in HbA(1c) and no difference between the groups. CONCLUSIONS: Using link workers and extra community diabetes specialist nurse input together with treatment protocols in primary care might prove a useful strategy in working towards NSF targets for diabetes management. In this study, small reductions in blood pressure and cholesterol were achieved. Improvement in glycaemic control may require longer and possibly different strategies. Further research is required to evaluate fully the effectiveness, including the costs and longer term sustainability of culturally sensitive initiatives.

Aged↗
PubMed2004

A comparison of foetal and labour outcomes in Caucasian and Afro-Caribbean women with diabetes in pregnancy.

Materno-foetal complications have an increased prevalence in pregnancies complicated by diabetes. Ethnicity and cultural background may further affect these outcomes. In this study, we compared labour and foetal outcomes in Afro-Caribbean and Caucasian women with diabetes in pregnancy, using the Birmingham computerised database of diabetes in pregnancy. A retrospective analysis, covering the period 1990-2002, was employed. Foetal outcomes included early foetal loss, neonatal and perinatal mortality, congenital malformations and infant size at delivery. Labour outcomes assessed were mode and time of delivery. Overall, Afro-Caribbean women achieve similar results to Caucasian women. No significant differences were seen in foetal outcomes between the two cohorts or between diabetic subtypes. Afro-Caribbean women were more likely to have a vaginal delivery, but present later for their first antenatal visit compared with Caucasian women. Variations in culture or access to health care may account for these differences. An awareness of the specific needs of ethnic minorities is essential to ensure that this encouraging trend continues.

Adult↗
PubMed2004

The role of cilostazol in the treatment of intermittent claudication.

This paper represents a review, by experts, of current opinion and information on intermittent claudication (IC) and the role that cilostazol plays in its treatment. IC is a common and debilitating condition that has a significant adverse impact on health-related quality of life (HR-QoL). It is currently under-recognised as a powerful marker of increased cardiovascular (CV) risk. The clinical priority is secondary prevention -- sometimes referred to as best medical therapy aimed at reducing CV risk. However, the priority for most patients (often overlooked by clinicians) is symptom relief: an increase in walking distance leading to an improvement in HR-QoL. The symptoms of IC may be improved by exercise, pharmacotherapy, and when these are unsuitable or unsuccessful, endovascular or surgical intervention. Cilostazol is indicated for the improvement of maximal and pain-free walking distance in patients with IC who do not have rest pain or tissue necrosis. In clinical trials, cilostazol improved symptoms both objectively and subjectively, and also improved HR-QoL. Cilostazol is usually well tolerated, with adverse events being generally mild to moderate in intensity, and transient or resolved after symptomatic treatment (e.g. non-prescription analgesics). Such events only infrequently require permanent drug withdrawal. There are no interactions with other drugs commonly prescribed in patients with IC, such as statins and anti-platelet agents. Cilostazol also has a range of potentially beneficial effects that may in the future be proven to decrease CV risk and modify the underlying process of atherosclerosis. Cilostazol represents the best evidence-based pharmacological therapy available for the symptoms of IC and should be the first-line treatment for symptom improvement in appropriate patients. Based on the available treatment strategies, the paper presents a suggested algorithm for the management of IC highlighting the role of cilostazol.

Algorithms↗
PubMed2004

11beta-hydroxysteroid dehydrogenase type 1 activity in lean and obese males with type 2 diabetes mellitus.

Glucocorticoids play an important role in the pathogenesis of obesity and insulin resistance. Impaired conversion of cortisone (E) to cortisol (F) by the type 1 isoenzyme of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) in obesity may represent a protective mechanism preventing ongoing weight gain and glucose intolerance. We have studied glucocorticoid metabolism in 33 male subjects with type 2 diabetes mellitus [age, 44.2 +/- 13 yr; body mass index (BMI), 31.1 +/- 7.5 kg/m(2) (mean +/- sd)] and 38 normal controls (age, 41.4 +/- 14 yr; BMI, 38.2 +/- 12.8 kg/m(2)). Circulating F:E ratios were elevated in the diabetic group and correlated with serum cholesterol and homeostasis model assessment-S. There was no difference in 11beta-HSD1 activity between diabetic subjects and controls. In addition, 11beta-HSD1 activity was unaffected by BMI in diabetic subjects. However, in control subjects, increasing BMI was associated with a reduction in the urinary tetrahydrocortisol+5alpha-tetrahydrocortisol:tetrahydrocortisone ratio (P < 0.05) indicative of impaired 11beta-HSD1 activity. The degree of inhibition correlated tightly with visceral fat mass. Changes in 11beta-HSD1 activity could not be explained by circulating levels of adipocytokines. Impaired E to F metabolism in obesity may help preserve insulin sensitivity and prevent diabetes mellitus. Failure to down-regulate 11beta-HSD1 activity in patients with diabetes may potentiate dyslipidemia, insulin resistance, and obesity. Inhibition of 11beta-HSD1 may therefore represent a therapeutic strategy in patients with type 2 diabetes mellitus and obesity.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗