Papers by Anthony Barnett
Objectives: South-Asians have lower adiponectin levels compared to Caucasians. It was not clear h... more 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.
Practical Diabetes International, 2006
The Journal of Clinical Endocrinology & Metabolism, 2003
Resistin, an adipocyte secreted factor, has been suggested to link obesity with type 2 diabetes i... more Resistin, an adipocyte secreted factor, has been suggested to link obesity with type 2 diabetes in rodent models, but its relevance to human diabetes remains uncertain. Although previous studies have suggested a role for this adipocytokine as a pathogenic factor, its functional effects, regulation by insulin, and alteration of serum resistin concentration by diabetes status remain to be elucidated. Therefore, the aims of this study were to analyze serum resistin concentrations in type 2 diabetic subjects; to determine the in vitro effects of insulin and rosiglitazone (RSG) on the regulation of resistin, and to examine the functional effects of recombinant human resistin on glucose and lipid metabolism in vitro. Serum concentrations of resistin were analyzed in 45 type 2 diabetic subjects and 34 nondiabetic subjects. Subcutaneous human adipocytes were incubated in vitro with insulin, RSG, and insulin in combination with RSG to examine effects on resistin secretion. Serum resistin was increased by approximately 20% in type 2 diabetic subjects compared with nondiabetic subjects P ؍ 0.004) correlating with C-reactive protein. No other parameters, including adiposity and fasting insulin levels, correlated with serum resistin in this cohort. However, in vitro, insulin stimulated resistin protein secretion in a concentration-dependent manner in adipocytes [control, 1215 ؎ 87 pg/ml (mean ؎ SEM); 1 nM insulin, 1414.0 ؎ 89 pg/ml; 1 M insulin, 1797 ؎ 107 pg/ml (P < 0.001)]. RSG (10 nM) reduced the insulin-mediated rise in resistin protein secretion (1 nM insulin plus RSG, 971 ؎ 35 pg/ml; insulin, 1 M insulin plus RSG, 1019 ؎ 28 pg/ml; P < 0.01 vs. insulin alone). Glucose uptake was reduced after treatment with 10 ng/ml recombinant resistin and higher concentrations (P < 0.05). Our in vitro studies demonstrated a small, but significant, reduction in glucose uptake with human recombinant resistin in differentiated preadipocytes. In human abdominal sc adipocytes, RSG blocks the insulin-mediated release of resistin secretion in vitro. In conclusion, elevated serum resistin in human diabetes reflects the subclinical inflammation prevalent in type 2 diabetes. Our in vitro studies suggest a modest effect of resistin in reducing glucose uptake, and suppression of resistin expression may contribute to the insulin-sensitizing and glucose-lowering actions of the thiazolidinediones. (J Clin Endocrinol Metab 88: 6098 -6106, 2003)
The Journal of Clinical Endocrinology & Metabolism, 2001
The gender-specific differences in body fat distribution suggest that sex steroids play an import... more The gender-specific differences in body fat distribution suggest that sex steroids play an important role in regulating body fat distribution. Sex steroids may regulate adipose tissue mass by altering adipocyte number and size. The effects of various sex steroids on in vitro proliferation of preadipocytes from both sc and omental fat depots was investigated in men and women. Abdominal sc and omental preadipocytes from men (n ؍ 14) and women (8 premenopausal and 7 postmenopausal) were cultured in the presence of 17-E2 (10 ؊7 -10 ؊9 M), estrone (10 ؊7 -10 ؊9 M), or dehydrotestosterone (DHT) (10 ؊7 -10 ؊9 M), and the rate of proliferation was measured over time (1-96 h) by DNA accumulation assays (micromoles per g) and [ 3 H]thymidine incorporation (disintegrations per min). In sc preadipocytes the rate of proliferation was increased between 24 -48 h with E2 (10 ؊7 M) in both men (P ؍ 0.028) and women (P ؍ 0.017). Subcutaneous preadipocytes from women were more responsive to E2 in stimulating proliferation than those from men (women vs. men, DNA assay, 24 h, P ؍ 0.014). In omental preadipocytes the increase in the rate of prolifera-tion occurred at 24 h with E2 (10 ؊7 M) in women (P ؍ 0.034) and at 48 h in men (P ؍ 0.031). Gender appeared to influence the rate of proliferation by E2 in omental preadipocytes, with maximal stimulation of proliferation at 48 h in preadipocytes from women treated with E2 (10 ؊7 M; p ؍ 0.007) compared with 72 h in preadipocyte cells from men (P ؍ 0.048), as shown by DNA assay. Both estrone and the androgen DHT had no significant gender-or site-specific effect on the rate of proliferation at any time point. All DNA content data were further validated by thymidine incorporation analysis. In summary, E2 stimulates the rate of proliferation of preadipocytes in a dose-dependent manner, with significant gender-and sitespecific differences. Neither estrone nor DHT affected adipocyte mass through proliferation of preadipocytes in this study. In conclusion, E2 may act as an important local factor influencing the proliferation of preadipocytes that may affect fat cell number in a depot-and gender-specific pattern in human abdominal sc and omental adipose tissue. (J Clin Endocrinol Metab 86: 5045-5051, 2001)
The Journal of Clinical Endocrinology & Metabolism, 2012
Context: After failure of metformin monotherapy, many second-line, glucose-lowering therapies are... more Context: After failure of metformin monotherapy, many second-line, glucose-lowering therapies are available to treat people with type 2 diabetes.
Diabetes, Obesity and Metabolism, 2008
Aim: To determine if therapeutic management programmes for type 2 diabetes that include self-moni... more Aim: To determine if therapeutic management programmes for type 2 diabetes that include self-monitoring of blood glucose (SMBG) result in greater reductions in glycated haemoglobin (HbA1c) compared with programmes without SMBG in non-insulin requiring patients. Methods: Multicentre, randomized, parallel-group trial. A total of 610 patients were randomized to SMBG or non-SMBG groups. Patients in both groups received the same oral antidiabetic therapy using a gliclazide modified release (MR)-based regimen for 27 weeks. The primary efficacy end-point was the difference between groups in HbA1c at the end of observation. Results: A total of 610 patients were randomized: 311 to the SMBG group and 299 to the non-SMBG group. HbA1c decreased from 8.12 to 6.95% in the SMBG group and from 8.12 to 7.20% in the non-SMBG group; between-group difference was 0.25% (95% CI: 0.06, 1.03; p ¼ 0.0097). Symptoms suggestive of mild to moderate hypoglycaemia was the most commonly reported adverse event, reported by 27 (8.7%) and 21 (7.0%) patients in the SMBG and non-SMBG groups, respectively; the incidence of symptomatic hypoglycaemia was lower in the SMBG group. Conclusion: In patients with type 2 diabetes, the application of SMBG as an adjunct to oral antidiabetic agent therapy results in further reductions in HbA1c.
Current Medical Research and Opinion, 2008
To compare associations between anteroposterior (AP) diameter or sagittal abdominal diameter - a ... more To compare associations between anteroposterior (AP) diameter or sagittal abdominal diameter - a measure of total central fat, and visceral fat alone with the metabolic syndrome as defined by ATPIII criteria. Twenty-four Caucasian male with type 2 diabetes and 24 non-diabetic Caucasian male subjects [body mass index (BMI) (+/-SD): 32.23 +/- 7.52 kg/m(2), age (+/-SD): 51.35 +/- 13.80 years] were studied by magnetic resonance imaging (MRI) scan to measure central fat at L4-L5 level. The visceral and total central adipose tissue was calculated in cm(2) and total sagittal MRI diameter and visceral sagittal MRI diameters in cm. Components of the ATPIII definition of the metabolic syndrome and circulating adipocytokine concentrations were also measured. MRI total sagittal abdominal diameter was positively associated with waist circumference in controls (r=0.62, p=0.007) and in diabetic subjects (r=0.81, p&lt;0.001). Binary logistic regression analysis showed that MRI-calculated total sagittal diameter (r=0.61, p=0.002) was a more significant predictor of the adverse metabolic profile of the metabolic syndrome than MRI-assessed visceral fat. Receiver operating characteristic curves revealed that MRI-calculated total sagittal diameter most effectively identified subjects with the metabolic syndrome. MRI-calculated total sagittal abdominal diameter is a non-validated MRI method that predicts the adverse metabolic profile of the ATPIII definition of the metabolic syndrome. Antero-posterior fat is a dimension of central fat that seems to be more closely associated with cardiovascular risk compared to visceral fat.
Current Medical Research and Opinion, 2008
Evidence for a link between periodontal disease and several systemic diseases is growing rapidly.... more Evidence for a link between periodontal disease and several systemic diseases is growing rapidly. The infectious and inflammatory burden of chronic periodontitis is thought to have an important systemic impact. Current evidence suggests that periodontitis is associated with an increased likelihood of coronary heart disease and may influence the severity of diabetes. This paper represents a UK and Ireland cross-specialty consensus review, undertaken by a group of physicians and dentists. The consensus group reviewed published evidence (PubMed search for review and original articles), focusing on the past 5 years, on the contributory role of periodontal disease to overall health. In particular, evidence relating to a role for periodontal disease in cardiovascular disease and in diabetes was considered. Initial studies of large epidemiological data sets have sought to find links between periodontitis and systemic disease outcomes, but a causal relationship still needs to be demonstrated between periodontal disease, cardiovascular disease and diabetes through prospective studies. There is a need for prospective studies assessing the association between periodontal disease and patients at particular risk of cardiovascular events which will allow assessment of both cardiovascular disease clinical endpoints and surrogate markers of cardiovascular risk. Of note, periodontal disease is also often more severe in subjects with diabetes mellitus, a group at already increased risk for cardiovascular events. While further research is needed to define the population-attributable risk of periodontal disease to both cardiovascular diseases and to diabetes control and progression, health education to encourage better oral health should be considered as part of current healthy lifestyle messages designed to reduce the increasing health burden of obesity, cardiovascular disease and diabetes.
Clinical Drug Investigation, 2013
Achievement of glycemic control is an important objective in the management of type 2 diabetes me... more Achievement of glycemic control is an important objective in the management of type 2 diabetes mellitus (T2DM). The objective of this study was to evaluate the safety and efficacy of the dipeptidyl peptidase-4 inhibitor saxagliptin versus placebo as add-on therapy in patients with T2DM inadequately controlled with insulin alone or insulin plus metformin. This was a long-term (28-week) extension of a short-term (24-week), randomized, double-blind, parallel-group trial of saxagliptin 5 mg once daily versus placebo as add-on therapy to open-label insulin or insulin plus metformin therapy totaling 52 weeks of treatment. In contrast with the goal of maintaining a stable insulin dosage during the short-term phase, during the extension phase the insulin dosage was flexible and adjusted as deemed appropriate by the investigator. The study was conducted in a clinical practice setting, including family practice and hospital sites. Patients with T2DM aged 18-78 years with glycated hemoglobin (HbA1c) 7.5-11 % on a stable insulin regimen (30-150 U/day with or without metformin) for ≥8 weeks at screening were included in the study. Patients were stratified by metformin use and randomly assigned 2:1 to oral saxagliptin 5 mg (n = 304) or placebo (n = 151) once daily. All patients who completed the initial 24 weeks of treatment were eligible to participate in the 28-week extension, regardless of whether they had required rescue treatment. The main outcome measure was change in HbA1c from baseline to week 52. In general, the outcomes achieved at week 24 were sustained to week 52. Adjusted mean change from baseline HbA1c at week 52 was greater with saxagliptin (-0.75 %) versus placebo (-0.38 %); the adjusted between-group difference was -0.37 % (95 % CI -0.55 to -0.19); between-group differences were similar in patients treated with metformin (-0.37 % [95 % CI -0.59 to -0.15]) and without metformin (-0.37 % [95 % CI -0.69 to -0.04]). At week 52, a greater proportion of patients receiving saxagliptin achieved HbA1c &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;7 % than those receiving placebo (21.3 vs. 8.7 %; between-group difference 12.6 % [95 % CI 6.1-19.1]). The increase from baseline in mean total daily insulin dose at week 52 was numerically smaller with saxagliptin (5.67 vs 6.67 U with placebo; difference, -1.01 U [95 % CI -3.24 to 1.22]). During the 52-week study period, the proportion of patients reporting ≥1 adverse event (AE) was 66.4 % with saxagliptin and 71.5 % with placebo, the majority being mild or moderate in intensity. The most common AEs (≥5 % with saxagliptin or placebo) were urinary tract infection, nasopharyngitis, upper respiratory tract infection, headache, influenza, and pain in extremity; the incidence of each AE was similar between treatment groups. In the saxagliptin and placebo groups, the incidence of reported hypoglycemia was 22.7 and 26.5 %, respectively; the incidence of confirmed hypoglycemia (fingerstick glucose ≤50 mg/dL [≤2.77 mmol/L] with characteristic symptoms) was 7.6 and 6.6 %, respectively. Adjusted mean change from baseline body weight was +0.8 kg with saxagliptin and +0.5 kg with placebo. Saxagliptin 5 mg once daily as add-on to insulin, with or without concomitant metformin, produced a durable improvement in glycemic control and was well tolerated over 52 weeks of treatment.
Across the world, the prevalence of diabetes is increasing rapidly, and in the UK this is of part... more Across the world, the prevalence of diabetes is increasing rapidly, and in the UK this is of particular concern in South Asian groups. Given the centrality of diabetes self-management to both policy and practice, it follows that research in this area, in particular to identify ...
Diabetes, obesity & metabolism, 2014
To investigate individual patient data from a comprehensive trials programme to evaluate the safe... more To investigate individual patient data from a comprehensive trials programme to evaluate the safety and efficacy of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin across a range of glucose-lowering regimens in a large elderly population with type 2 diabetes mellitus (T2DM). Data were pooled from individuals aged ≥ 65 years, who participated in seven phase III, placebo-controlled clinical trials of linagliptin (24-52 weeks). Safety was assessed by incidence and severity of adverse events (AEs) with a focus on hypoglycaemia. The primary efficacy endpoint was change in glycated haemoglobin (HbA1c). In total, 841 subjects received linagliptin 5 mg once a day and 490 received placebo. At baseline, the population had a mean ± s.d. age of 71.0 ± 4.6 years and a mean HbA1c concentration of 8.0 ± 0.8%; 63.5% of subjects received ≥ 2 antidiabetes drugs. Overall AEs and drug-related AEs were experienced by similar proportions of patients (linagliptin 71.3, placebo 73.3; linagliptin 1...
OBJECTIVE — We examined the prevalence of different forms of diabetes in Hong Kong Chinese patien... more OBJECTIVE — We examined the prevalence of different forms of diabetes in Hong Kong Chinese patients with familial early-onset type 2 diabetes and compared their clinical features with patients with familial late-onset type 2 diabetes. RESEARCH DESIGN AND METHODS — A total of 145 young patients with early- onset diabetes (age and age at diagnosis #40 years) and a family
Diabetic Medicine, 2014
To investigate concordance with medication, as assessed at baseline and at 1- and 2-year follow-u... more To investigate concordance with medication, as assessed at baseline and at 1- and 2-year follow-up, and to examine factors associated with non-concordance in a UK-resident South-Asian population. Data from the UK Asian Diabetes Study were analysed. Concordance with medications was assessed and recorded at three time points during the study. Multiple logistic regression was used to investigate the factors associated with non-concordance; the associations of baseline factors with year 1 concordance and baseline plus year 1 factors with year 2 concordance. Data for 403 patients from seven practices participating in the UK Asian Diabetes Study were analysed. The numbers of patients who were non-concordant were: 63 (16%) at baseline; 101 (25%) at year 1; and 122 (30%) at year 2. The baseline-measured variables that were significantly associated with year 1 non-concordance included diabetes duration, history of cardiovascular disease, components of the EuroQol quality of life questionnaire, the EQ-5D score, and number of medications prescribed. In multivariable analyses, the most important determinant of year 1 non-concordance was baseline non-concordance: odds ratio 13.6 (95% confidence limits 4.7, 39.9). Number of medications prescribed for blood pressure control was also significant: odds ratio 1.8 (95% confidence limits 1.4, 2.4). Similar results were observed for year 2 non-concordance. Non-concordance with medications was common and more likely in people prescribed more medications. The current target-driven management of risk factor levels may lead to increasing numbers and doses of medications. Considering the high cost of medications and the implications of poor health behaviours on morbidity and mortality, further investigation of prescribing behaviours and the factors affecting patient concordance are required.
The extreme obesity of the obese (ob/ob) mouse is attributable to mutations in the gene encoding ... more The extreme obesity of the obese (ob/ob) mouse is attributable to mutations in the gene encoding leptin, an adipocyte-specific secreted protein which has profound effects on appetite and energy expenditure. We know of no equivalent evidence regarding leptin&amp;amp;amp;amp;amp;amp;amp;amp;#39;s role in the control of fat mass in humans. We have examined two severely obese children who are members of the same highly consanguineous pedigree. Their serum leptin levels were very low despite their markedly elevated fat mass and, in both, a homozygous frame-shift mutation involving the deletion of a single guanine nucleotide in codon 133 of the gene for leptin was found. The severe obesity found in these congenitally leptin-deficient subjects provides the first genetic evidence that leptin is an important regulator of energy balance in humans.
Objectives: South-Asians have lower adiponectin levels compared to Caucasians. It was not clear h... more 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.
Current Diabetes Reports, 2007
Human Immunology, 1995
The association of MS with the HLA class II loci DR and DQ was investigated in subjects of Shangh... more The association of MS with the HLA class II loci DR and DQ was investigated in subjects of Shanghai Chinese and British Caucasian origin. Our aim was to determine whether common alleles predispose to the disease in both races. In the Caucasian population MS was significantly positively associated with the putative haplotype DRBl∗1501, DQA1∗0102, DQB1∗0602. In contrast, HLA class II
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Papers by Anthony Barnett