Search

BACKGROUND. Dietary sodium intake mismatches urinary sodium excretion over prolonged periods. Our aims were to localize and quantify electrostatically bound sodium within human skin using triple-quantum–filtered (TQF) protocols for MRI and magnetic resonance spectroscopy (MRS) and to explore dermal sodium in type 2 diabetes mellitus (T2D).\ud \ud METHODS. We recruited adult participants with T2D (n = 9) and euglycemic participants with no history of diabetes mellitus (n = 8). All had undergone lower limb amputations or abdominal skin reduction surgery for clinical purposes. We used 20 μm in-plane resolution 1H MRI to visualize anatomical skin regions ex vivo from skin biopsies taken intraoperatively, 23Na TQF MRI/MRS to explore distribution and quantification of freely dissolved and bound sodium, and inductively coupled plasma mass spectrometry to quantify sodium in selected skin samples.\ud \ud RESULTS. Human dermis has a preponderance (>90%) of bound sodium that colocalizes with the glycosaminoglycan (GAG) scaffold. Bound and free sodium have similar anatomical locations. T2D associates with a severely reduced dermal bound sodium capacity.\ud \ud CONCLUSION. We provide the first evidence to our knowledge for high levels of bound sodium within human dermis, colocating to the GAG scaffold, consistent with a dermal “third space repository” for sodium. T2D associates with diminished dermal electrostatic binding capacity for sodium.

Background Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight and increasing physical activity. Even modest weight loss can improve control of blood glucose. If drug treatment is necessary, the drug of first choice is metformin. However, some people cannot tolerate metformin, which causes diarrhoea in about 10%, and it cannot be used in people with renal impairment. This review appraises three of the newest class of drugs for monotherapy when metformin cannot be used, the sodium–glucose co-transporter 2 (SGLT2) inhibitors. Objective To review the clinical effectiveness and cost-effectiveness of dapagliflozin (Farxiga, Bristol-Myers Squibb, Luton, UK), canagliflozin (Invokana, Janssen, High Wycombe, UK) and empagliflozin (Jardiance, Boehringer Ingelheim, Ingelheim, Germany/Eli Lilly and Company, Indianapolis, IN, USA), in monotherapy in people who cannot take metformin. Sources MEDLINE (1946 to February 2015) and EMBASE (1974 to February 2015) for randomised controlled trials lasting 24 weeks or more. For adverse events, a wider range of studies was used. Three manufacturers provided submissions. Methods Systematic review and economic evaluation. A network meta-analysis was carried out involving the three SGLT2 inhibitors and key comparators. Critical appraisal of submissions from three manufacturers. Results We included three trials of dapagliflozin and two each for canagliflozin and empagliflozin. The trials were of good quality. The canagliflozin and dapagliflozin trials compared them with placebo, but the two empagliflozin trials included active comparators. All three drugs were shown to be effective in improving glycaemic control, promoting weight loss and lowering blood pressure (BP). Limitations There were no head-to-head trials of the different flozins, and no long-term data on cardiovascular outcomes in this group of patients. Most trials were against placebo. The trials were done in patient groups that were not always comparable, for example in baseline glycated haemoglobin or body mass index. Data on elderly patients were lacking. Conclusions Dapagliflozin, canagliflozin and empagliflozin are effective in improving glycaemic control, with added benefits of some reductions in BP and weight. Adverse effects are urinary and genital tract infections in a small proportion of users. In monotherapy, the three drugs do not appear cost-effective compared with gliclazide or pioglitazone, but may be competitive against sitagliptin (Januvia, Merck Sharp & Dohme Limited, Kenilworth, NJ, USA). Funding The National Institute for Health Research Health Technology Assessment programme.

Objective\ud \ud Thyroid status has been implicated in macrovascular disease both in patients with and without diabetes, however its effect on microvascular complications has not been explored. We assessed the prevalence and time to development of diabetic retinopathy in patients with type 2 diabetes with and without thyroxine treatment.\ud \ud Research design and methods \ud \ud The prevalence of retinopathy was determined, in a retrospective cohort study from a secondary care referral diabetes clinic patients with type 2 diabetes and coexisting treated hypothyroidism (THD; n=147) and duration matched controls without hypothyroidism (DM2; n=383). Using Kaplan-Meier survival analysis and Cox Proportional Hazards regression model we estimated the time to development of retinopathy in the two groups.\ud \ud Results \ud \ud Prevalence of retinopathy was 27.9% in THD group, as compared to 55.1% in the DM2 group (p

Objective Cardiac resynchronisation therapy (CRT) is an effective therapy for selected patients with heart failure (HF); however, a significant non-response rate exists. We examined current evidence on extracellular cardiac matrix (ECM) biomarkers in predicting response following CRT. Methods Complete literature review of PubMed, Ovid SP MEDLINE, Cochrane Library and TRIP, reference lists, international cardiology conferences and ongoing studies between December 1999 and December 2015 conducted according to prospectively registered study selection and analysis criteria (PROSPERO:CRD42016025864) was performed. All observational and randomised control trials (RCT) were included if they tested prespecified ECM biomarkers’ ability to predict CRT response. Risk of bias assessment and data extraction determined pooling of included studies was not feasible due to heterogeneity of the selected studies. Results A total of 217 studies were screened; six (five prospective cohort and one RCT substudy) were included in analysis with 415 participants in total. Study sizes varied (n=55–260), cohort characteristics contrasted (male: 67.8%–83.6%, ischaemic aetiology: 40.2%–70.3%) and CRT response definitions differed (three clinical/functional, three echocardiographic). Consistent observation in all ECM biomarker behaviour before and after CRT implantation was not observed between studies. Lower type I and type III collagen synthesis biomarkers (N-terminal propeptides of type I and III procollagens) expression demonstrated replicated ability to predict reverse left ventricular remodelling. Conclusion Collagen synthesis biomarkers offer the most potential as ECM biomarkers for predicting CRT response. Heterogeneity between these studies was large and limited the ability to pool and compare results numerically. Use of different response definitions was one of the biggest challenges.

OBJECTIVE To examine the global prevalence and major risk factors for diabetic retinopathy (DR) and vision-threatening diabetic retinopathy (VTDR) among people with diabetes. RESEARCH DESIGN AND METHODS A pooled analysis using individual participant data from population-based studies around the world was performed. A systematic literature review was conducted to identify all population-based studies in general populations or individuals with diabetes who had ascertained DR from retinal photographs. Studies provided data for DR end points, including any DR, proliferative DR, diabetic macular edema, and VTDR, and also major systemic risk factors. Pooled prevalence estimates were directly age-standardized to the 2010 World Diabetes Population aged 20–79 years. RESULTS A total of 35 studies (1980–2008) provided data from 22,896 individuals with diabetes. The overall prevalence was 34.6% (95% CI 34.5–34.8) for any DR, 6.96% (6.87–7.04) for proliferative DR, 6.81% (6.74–6.89) for diabetic macular edema, and 10.2% (10.1–10.3) for VTDR. All DR prevalence end points increased with diabetes duration, hemoglobin A1c, and blood pressure levels and were higher in people with type 1 compared with type 2 diabetes. CONCLUSIONS There are approximately 93 million people with DR, 17 million with proliferative DR, 21 million with diabetic macular edema, and 28 million with VTDR worldwide. Longer diabetes duration and poorer glycemic and blood pressure control are strongly associated with DR. These data highlight the substantial worldwide public health burden of DR and the importance of modifiable risk factors in its occurrence. This study is limited by data pooled from studies at different time points, with different methodologies and population characteristics.

OBJECTIVE To evaluate the changes in circulating endotoxin after a high–saturated fat meal to determine whether these effects depend on metabolic disease state. RESEARCH DESIGN AND METHODS Subjects (n = 54) were given a high-fat meal (75 g fat, 5 g carbohydrate, 6 g protein) after an overnight fast (nonobese control [NOC]: age 39.9 ± 11.8 years [mean ± SD], BMI 24.9 ± 3.2 kg/m2, n = 9; obese: age 43.8 ± 9.5 years, BMI 33.3 ± 2.5 kg/m2, n = 15; impaired glucose tolerance [IGT]: age 41.7 ± 11.3 years, BMI 32.0 ± 4.5 kg/m2, n = 12; type 2 diabetic: age 45.4 ± 10.1 years, BMI 30.3 ± 4.5 kg/m2, n = 18). Blood was collected before (0 h) and after the meal (1–4 h) for analysis. RESULTS Baseline endotoxin was significantly higher in the type 2 diabetic and IGT subjects than in NOC subjects, with baseline circulating endotoxin levels 60.6% higher in type 2 diabetic subjects than in NOC subjects (P < 0.05). Ingestion of a high-fat meal led to a significant rise in endotoxin levels in type 2 diabetic, IGT, and obese subjects over the 4-h time period (P < 0.05). These findings also showed that, at 4 h after a meal, type 2 diabetic subjects had higher circulating endotoxin levels (125.4%↑) than NOC subjects (P < 0.05). CONCLUSIONS These studies have highlighted that exposure to a high-fat meal elevates circulating endotoxin irrespective of metabolic state, as early as 1 h after a meal. However, this increase is substantial in IGT and type 2 diabetic subjects, suggesting that metabolic endotoxinemia is exacerbated after high fat intake. In conclusion, our data suggest that, in a compromised metabolic state such as type 2 diabetes, a continual snacking routine will cumulatively promote their condition more rapidly than in other individuals because of the greater exposure to endotoxin.

Aims - A common variant, rs9939609, in the FTO (fat mass and obesity) gene is associated with adiposity in Europeans, explaining its relationship with diabetes. However, data are inconsistent in South Asians. Our aim was to investigate the association of the FTO rs9939609 variant with obesity, obesity-related traits and Type 2 diabetes in South Asian individuals, and to use meta-analyses to attempt to clarify to what extent BMI influences the association of FTO variants with diabetes in South Asians. Methods - We analysed rs9939609 in two studies of Pakistani individuals: 1666 adults aged = 40 years from the Karachi population-based Control of Blood Pressure and Risk Attenuation (COBRA) study and 2745 individuals of Punjabi ancestry who were part of a Type 2 diabetes case–control study (UK Asian Diabetes Study/Diabetes Genetics in Pakistan; UKADS/DGP). The main outcomes were BMI, waist circumference and diabetes. Regression analyses were performed to determine associations between FTO alleles and outcomes. Summary estimates were combined in a meta-analysis of 8091 South Asian individuals (3919 patients with Type 2 diabetes and 4172 control subjects), including those from two previous studies. Results - In the 4411 Pakistani individuals from this study, the age-, sex- and diabetes-adjusted association of FTO variant rs9939609 with BMI was 0.45 (95% CI 0.24–0.67) kg/m2 per A-allele (P = 3.0 × 10-5) and with waist circumference was 0.88 (95% CI 0.36–1.41) cm per A-allele (P = 0.001). The A-allele (30% frequency) was also significantly associated with Type 2 diabetes [per A-allele odds ratio (95% CI) 1.18 (1.07–1.30); P = 0.0009]. A meta-analysis of four South Asian studies with 8091 subjects showed that the FTO A-allele predisposes to Type 2 diabetes [1.22 (95% CI 1.14–1.31); P = 1.07 × 10-8] even after adjusting for BMI [1.18 (95% CI 1.10–1.27); P = 1.02 × 10-5] or waist circumference [1.18 (95% CI 1.10–1.27); P = 3.97 × 10-5]. Conclusions - The strong association between FTO genotype and BMI and waist circumference in South Asians is similar to that observed in Europeans. In contrast, the strong association of FTO genotype with diabetes is only partly accounted for by BMI.

In diabetes, endothelial dysfunction and an altered retinal blood flow have been reported and precede overt macrovascular and microvascular disease. Furthermore, an association between postprandial hyperglycaemia, retinopathy and cardiovascular disease has been observed. Methods: Endothelial function and retinal vascular reactivity have been measured in baseline conditions in 10 healthy control subjects and 21 patients with Type 2 diabetes. In the patients with Type 2 diabetes, endothelial function and retinal vascular reactivity have been also measured every hour, for 4 h, during an oral glucose tolerance test. Endothelial function has been evaluated by measuring flow-mediated vasodilation of the brachial artery, while retinal vascular reactivity has been measured using a retinal vessel analyser, during a flicker. Results: At 1 and 2 h after glucose ingestion, endothelial function decreased (P < 0.05), while retinal vascular reactivity increased, even at 3 h (P < 0.05), vs. the baseline values. Conclusion : Our data highlight that acute hyperglycaemia impacts on endothelial function simultaneously at both macrovascular and at microvascular levels, inducing functional change, which could contribute towards explaining the clinical evidence of a strong association between postprandial hyperglycaemia, cardiovascular disease and retinopathy.

Recent genome-wide association (GWA) studies and subsequent replication studies have greatly increased the number of validated type 2 diabetes susceptibility variants, but most of these have been conducted in European populations. Despite the high prevalence of the disease in South Asians, studies investigating GWA-validated type 2 diabetes risk variants in this ethnic group are limited. We investigated 30 single nucleotide polymorphisms (SNPs), predominantly derived from recent GWA studies, to determine if and to what extent these variants affect type 2 diabetes risk in two Punjabi populations, originating predominantly from the District of Mirpur, Pakistan.Thirty SNPs were genotyped in 1,678 participants with type 2 diabetes and 1,584 normoglycaemic control participants from two populations; one resident in the UK and one indigenous to the District of Mirpur.SNPs in or near PPARG, TCF7L2, FTO, CDKN2A/2B, HHEX/IDE, IGF2BP2, SLC30A8, KCNQ1, JAZF1, IRS1, KLF14, CHCHD9 and DUSP9 displayed significant (p0.05) associations with type 2 diabetes, with similar effect sizes to those seen in European populations. A constructed genetic risk score was associated with type 2 diabetes (p = 5.46 × 10(-12)), BMI (p = 2.25 × 10(-4)) and age at onset of diabetes (p = 0.002).We have demonstrated that 13 variants confer an increased risk of type 2 diabetes in our Pakistani populations; to our knowledge this is the first time that SNPs in or near KCNQ1, JAZF1, IRS1, KLF14, CHCHD9 and DUSP9 have been significantly associated with the disease in South Asians. Large-scale studies and meta-analyses of South Asian populations are needed to further confirm the effect of these variants in this ethnic group.

OBJECTIVE To assess chemerin levels and regulation in sera and adipose tissue from women with polycystic ovary syndrome (PCOS) and matched control subjects. RESEARCH DESIGN AND METHODS Real-time RT-PCR and Western blotting were used to assess mRNA and protein expression of chemerin. Serum chemerin was measured by enzyme-linked immunosorbent assay. We investigated the in vivo effects of insulin on serum chemerin levels via a prolonged insulin-glucose infusion. Ex vivo effects of insulin, metformin, and steroid hormones on adipose tissue chemerin protein production and secretion into conditioned media were assessed by Western blotting and enzyme-linked immunosorbent assay, respectively. RESULTS Serum chemerin, subcutaneous, and omental adipose tissue chemerin were significantly higher in women with PCOS (n = 14; P < 0.05, P < 0.01). Hyperinsulinemic induction in human subjects significantly increased serum chemerin levels (n = 6; P < 0.05, P < 0.01). In adipose tissue explants, insulin significantly increased (n = 6; P < 0.05, P < 0.01) whereas metformin significantly decreased (n = 6; P < 0.05, P < 0.01) chemerin protein production and secretion into conditioned media, respectively. After 6 months of metformin treatment, there was a significant decrease in serum chemerin (n = 21; P < 0.01). Importantly, changes in homeostasis model assessment–insulin resistance were predictive of changes in serum chemerin (P = 0.046). CONCLUSIONS Serum and adipose tissue chemerin levels are increased in women with PCOS and are upregulated by insulin. Metformin treatment decreases serum chemerin in these women.

OBJECTIVE—The purpose of this study was to compare prevalence and risk factors for diabetic retinopathy among U.K. residents of South Asian or white European ethnicity. RESEARCH DESIGN AND METHODS—This was a community-based cross-sectional study involving 10 general practices; 1,035 patients with type 2 diabetes were studied: 421 of South Asian and 614 of white European ethnicity. Diabetic retinopathy, sight-threatening retinopathy, maculopathy, and previous laser photocoagulation therapy were assessed after grading of retinal photographs. Data were collected on risk factors including age, duration, and treatment of diabetes, blood pressures, serum total cholesterol, and A1C. RESULTS—Patients of South Asian ethnicity had significantly higher systolic (144 vs. 137 mmHg, P < 0.0001) and diastolic (84 vs. 74 mmHg, P < 0.0001) blood pressure, A1C (7.9 vs. 7.5%, P < 0.0001), and total cholesterol (4.5 vs. 4.2 mmol/l, P < 0.0001). Diabetic retinopathy was detected in 414 (40%) patients (189 South Asian [45%] versus 225 white European [37%]; P = 0.0078). Sight-threatening retinopathy was detected in 142 (14%) patients (68 South Asian [16%] versus 74 white European [12%]; P = 0.0597). After adjustment for confounders, there were significantly elevated risks of any retinopathy and maculopathy for South Asian versus white European patients. CONCLUSIONS—Patients of South Asian ethnicity had a significantly higher prevalence of diabetic retinopathy and maculopathy, with significantly elevated systolic and diastolic blood pressure, A1C, and total cholesterol; lower attained age; and younger age at diagnosis. Earlier onset of disease and higher levels of modifiable risk factors make early detection of diabetes, annual referral for retinal screening, and intensive risk factor control key elements in addressing this health inequality.

Maternal leptin affects placental growth hormone (GH), whereas ghrelin, a natural ligand of the growth-hormone-secretagogue receptor, modulates GH action. Both hormones may affect fetal growth, and dysregulation in diabetes may lead to fetal growth disturbances. The aim was to investigate changes in maternal ghrelin during pregnancy with diabetes and to establish reference leptin levels. Twelve healthy non-diabetic (ND) and 12 pregnant women with Type 1 diabetes (T1DM) were recruited. Age and body mass index (BMI) [ND: age 29.9 +/- 4.7 years (mean +/- sd), BMI 25.2 +/- 3.7 kg/m(2); T1DM: age 31 +/- 5.5 years, BMI 27 +/- 3.1 kg/m(2)] were similar in the groups. HbA(1c) in T1DM was 6.2 +/- 1.1% at 20 weeks, 6.3 +/- 1.1% at 30 weeks' gestation and 7.8 +/- 2.1% postpartum. Fasting plasma ghrelin, total leptin, free leptin (FL) and soluble leptin receptor (sOB-R) levels were measured at 20 and 30 weeks' gestation and postpartum and determined by radioimmunoassay. All pregnancies resulted in full-term singleton births with no differences in birth weight between groups [T1DM: 3.4 +/- 0.56 kg (mean +/- SE); ND: 3.6 +/- 0.3 kg, P = NS]. Ghrelin levels were lower in T1DM when corrected for age and mothers' weight (T1DM: 458 +/- 36 pg/ml and 432.9 +/- 26.6 pg/ml; ND: 562 +/- 52 pg/ml and 515.8 +/- 63 pg/ml at 20 and 30 weeks, respectively, P < 0.05). T1DM mothers had higher levels of sOB-R and FL levels declined at 30 weeks' gestation in T1DM (P = 0.04) but not in ND. In a population of pregnant women with expected changes in leptin levels as previously reported, ghrelin levels were lower in T1DM pregnancies at 20 and 30 weeks. This may have implications for fetal development and requires further study in diabetes, particularly in pregnancies that result in macrosomia. Diabet. Med. 25, 1400-1405 (2008).

Obesity and the metabolic syndrome are associated with insulin resistance, hyperinsulinemia and serious cardiovascular sequealae; of note, increased circulating levels of plasminogen activator inhibitor-1 (PAI-1) with the consequent hypo- fibrinolysis are the main hemostatic disorder linked to the metabolic syndrome (1). The metabolic syndrome is associated with visceral obesity. Adipose tissue (AT) produces several hormones and cytokines termedadipokinesthat regulate energy homeostasis, glucose and lipid metabolism and cardiovas- cular homeostasis (2), of which, PAI-1 is a prothrombotic adipokine (3). Recently, Varma et al. established thrombospondin-1 (TSP- 1) as a novel adipokine, preferentially produced by visceral AT and highly expressed in obese, insulin-resistant subjects (4). TSP-1, originally isolated from platelets, (5) has prothrombotic properties (6,7). Furthermore, Varma et al. observed that AT TSP-1 mRNA expression was positively associated with circulating PAI-1 levels and speculated that TSP-1 may mediate the elevation of PAI-1 that promotes a prothrombotic state (4). TSP-1 influences transforming growth factor-b activity whereas PAI-1 is a major downstream target of transforming growth factor-b; increased transforming growth factor-b activity is associated with obesity, insulin resistance and the metabolic syndrome (8-11). Therefore, we studied the effects of acute and chronic hyperinsulinemia on circulating TSP-1 as well as PAI-1 activity via a prolonged insulin-glucose infusion in healthy subjects. We also assessed the effects of insulin on TSP-1 protein production and secretion into conditioned media as well as the effects of insulin on PAI-1 protein production

Summary Background Delivery of high-quality, evidence-based health care to deprived sectors of the community is a major goal for society. We investigated the effectiveness of a culturally sensitive, enhanced care package in UK general practices for improvement of cardiovascular risk factors in patients of south Asian origin with type 2 diabetes. Methods In this cluster randomised controlled trial, 21 inner-city practices in the UK were assigned by simple randomisation to intervention (enhanced care including additional time with practice nurse and support from a link worker and diabetes-specialist nurse [nine practices; n=868]) or control (standard care [12 practices; n=618]) groups. All adult patients of south Asian origin with type 2 diabetes were eligible. Prescribing algorithms with clearly defined targets were provided for all practices. Primary outcomes were changes in blood pressure, total cholesterol, and glycaemic control (haemoglobin A 1c ) after 2 years. Analysis was by intention to treat. This trial is registered, number ISRCTN 38297969. Findings We recorded significant differences between treatment groups in diastolic blood pressure (1·91 [95% CI −2·88 to −0·94] mm Hg, p=0·0001) and mean arterial pressure (1·36 [−2·49 to −0·23] mm Hg, p=0·0180), after adjustment for confounders and clustering. We noted no significant differences between groups for total cholesterol (0·03 [−0·04 to 0·11] mmol/L), systolic blood pressure (−0·33 [−2·41 to 1·75] mm Hg), or HbA 1c (−0·15% [−0·33 to 0·03]). Economic analysis suggests that the nurse-led intervention was not cost effective (incremental cost-effectiveness ratio £28 933 per QALY gained). Across the whole study population over the 2 years of the trial, systolic blood pressure, diastolic blood pressure, and cholesterol decreased significantly by 4·9 (95% CI 4·0–5·9) mm Hg, 3·8 (3·2–4·4) mm Hg, and 0·45 (0·40–0·51) mmol/L, respectively, and we recorded a small and non-significant increase for haemoglobin A 1c (0·04% [−0·04 to 0·13]), p=0·290). Interpretation We recorded additional, although small, benefits from our culturally tailored care package that were greater than the secular changes achieved in the UK in recent years. Stricter targets in general practice and further measures to motivate patients are needed to achieve best possible health-care outcomes in south Asian patients with diabetes. Funding Pfizer, Sanofi-Aventis, Servier Laboratories UK, Merck Sharp & Dohme/Schering-Plough, Takeda UK, Roche, Merck Pharma, Daiichi-Sankyo UK, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Bristol-Myers Squibb, Solvay Health Care, and Assurance Medical Society UK.

OBJECTIVE—Polycystic ovary syndrome (PCOS) is associated with insulin resistance and obesity. Recent studies have shown that plasma omentin-1 levels decrease with obesity. Currently, no data exist on the relative expression and regulation of omentin-1 in adipose tissue of women with PCOS. The objective of this study was to assess mRNA and protein levels of omentin-1, including circulating omentin-1, in omental adipose tissue of women with PCOS and matched control subjects. Ex vivo and in vivo regulation of adipose tissue omentin-1 was also studied. RESEARCH DESIGN AND METHODS—Real-time RT-PCR and Western blotting were used to assess mRNA and protein expression of omentin-1. Plasma omentin-1 was measured by enzyme-linked immunosorbent assay. The effects of d-glucose, insulin, and gonadal and adrenal steroids on adipose tissue omentin-1 were analyzed ex vivo. The in vivo effects of insulin (hyperinsulinemia) on omentin-1 levels were also assessed by a prolonged insulin-glucose infusion. RESULTS—In addition to decreased plasma omentin-1 levels in women with PCOS (P < 0.05), compared with control subjects, there was significantly lower levels of omentin-1 mRNA (P < 0.01) and protein (P < 0.05) in omental adipose tissue of women with PCOS (P < 0.01). Furthermore, in omental adipose tissue explants, insulin and glucose significantly dose-dependently decreased omentin-1 mRNA expression, protein levels, and secretion into conditioned media (P < 0.05, P < 0.01). Also, hyperinsulinemic induction in healthy subjects significantly reduced plasma omentin-1 levels (P < 0.01). CONCLUSIONS—Our novel findings reveal that omentin-1 is downregulated by insulin and glucose. These may, in part, explain the decreased omentin-1 levels observed in our overweight women with PCOS.

Objective:\ud To predict the diabetes-related outcomes of people undertaking a type 2 Diabetes Self-Management Education (DSME) programme from their baseline data.\ud \ud Design:\ud A mixed-methods longitudinal experimental study. 6 practice nurses and 2 clinical academics undertook blind assessments of all baseline and process data to predict clinical, behavioural and psychological outcomes at 6 months post-DSME programme.\ud \ud Setting Primary care.\ud \ud Participants:\ud –31 people with type 2 diabetes who had not previously undertaken DSME.\ud \ud Intervention:\ud All participants undertook the Diabetes Manual 1:1 self-directed learning 12-week DSME programme supported by practice nurses trained as Diabetes Manual facilitators.\ud \ud Outcome variables: \ud Glycated haemoglobin (HbA1c), diabetes knowledge, physical activity, waist circumference, self-efficacy, diabetes distress, anxiety, depression, demographics, change talk and treatment satisfaction. These variables were chosen because they are known to influence self-management behaviour or to have been influenced by a DSME programme in empirical evidence.\ud \ud Results:\ud Baseline and 6-month follow-up data were available for 27 participants of which 13 (48%) were male, 22 (82%) white British, mean age 59 years and mean duration of type 2 diabetes 9.1 years. Significant reductions were found in HbA1c t(26)=2.35, p=0.03, and diabetes distress t(26)=2.30, p=0.03, and a significant increase in knowledge t(26)=−2.06, p=0.05 between baseline and 6 months. No significant changes were found in waist circumference, physical activity, anxiety, depression or self-efficacy. Accuracy of predictions varied little between clinical academics and practice nurses but greatly between outcome (0–100%). The median and mode accuracy of predicted outcome was 66.67%. Accuracy of prediction for the key outcome of HbA1c was 44.44%. Diabetes distress had the highest prediction accuracy (81.48%).\ud \ud Conclusions:\ud Clinicians in this small study were unable to identify individuals likely to achieve improvement in outcomes from DSME. DSME should be promoted to all patients with diabetes according to guidelines.

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.

Cardiovascular disease remains the biggest cause of morbidity and mortality in patients with type 2 diabetes.1 Individual drugs from two classes of glucose-lowering agents, glucagon-like peptide-1 (GLP-1)receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors, have been shown in recent clinical trials to improve cardiovascular outcomes in patients with type 2 diabetes at high risk of cardiovascular disease. These new data are reflected in guidelines from several professional associations, but not in the National Institute for Health and Care Excellence (NICE) guidelines in the UK.2 We believe that NICE and other national and international health authorities should respond rapidly to new data, particularly when there is potential to improve outcomes and save lives.

Attendance at diabetic retinopathy screening in minority ethnic groups, including the South Asian population, is known to be poor. We describe a cluster randomised controlled trial conducted in 10 general practitioner (GP) surgeries in Coventry, UK, during 2007 which aimed to evaluate the use of a Link Worker–delivered intervention to improve attendance. The intervention consisted of a simple telephone reminder with the main outcome measure being attendance at diabetic retinopathy screening. We found a statistically significant difference between mean attendance proportions for intervention (0.89) and control (0.74) practices: difference (95% confidence interval (CI)) 0.15 (0.04–0.27), t = 3.03, p = 0.0162; this difference remained significant when adjusted for previous year’s proportions. In this proof-of-concept study, in inner city Coventry, we demonstrated increased attendance at diabetic retinopathy screening by use of a simple Link Worker–implemented telephone call intervention. The use of Link Worker phone calls may be a useful tool to increase attendance for diabetic retinopathy screening in a group with high did-not-attend (DNA) rates and a high prevalence of diabetic retinopathy and visual impairment.

Aims: 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. Methods: 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. Results: 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. Conclusions: 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.

he revised draft type 2 diabetes guideline1 from the UK National Institute for Health and Care Excellence (NICE) were released in June, 2015, for further consultation. Some positive changes have been made since the first draft was published in January, 2015, especially with respect to patient preferences.2 However, we believe that the revised guideline remains unfit for purpose and is a missed opportunity to improve the lives of patients with type 2 diabetes. If sanctioned by NICE, the guideline will be confusing and unworkable in busy clinical practice. It might also diminish the international reputation of NICE and reduce the influence of UK practice on the global management of type 2 diabetes.

C CLARKE, CG BRENNAN, K RODGERS, RM DWYER, PPA SMYTH ENDOCRINE LABORATORY, DEPARTMENT OF MEDICINE AND THERAPEUTICS, UNIVERSITY COLLEGE DUBLIN, IRELAND he demonstration in extrathyroidal human tissues of the sodium iodide symporter (NIS) has raised the possibility that 1311, commonly used as a systemic therapeutic ablative agent in hyperthyroidism and thyroid cancer, might be applied in the treatment of tumours in other NISexpressing tissues such as human breast cancer. Thyroidal transport of 1311 is known to be proportional to circulating stable I and the aim of this study was to determine how stable I (KI) would effect such transport in human breast cancer cell lines MDA-MB-231, MCF-7 and in FRTL-5 thyroid cells. All cells were incubated with KI (01 00mM) for 72 hours after which 1Th I was added . Incubation and uptake of 'l by cells was counted every four hours. Timed efflux of '^I was measured every five minutes. KI in the incubation medium blocked 1251 uptake in a dose-dependent manner in the E receptor positive MCF7 cell line. The effect was less marked in the E receptor negative MDA-MB-231 with significant uptake being maintained even at an I concentration of 50mM. A similar blockade was seen in the FRTL-5 cells with maximum uptake blockade of 25mM I. The rate of efflux of 15I was similar in both MCF-7 and MDA-MB-231 cell lines with a tin of 35 and 40 minutes respectively. In contrast, efflux from the FRTL-5 cells was faster (tire=15 mins). As the human breast has a much lower avidity for I than the thyroid, control of dietary intake would assume even greater importance in radioactive iodine treatment of breast tumours or their metastases.

Objectives: To synthesise current evidence for the effects of exenatide and liraglutide on heart rate, blood pressure and body weight.\ud \ud Design: Meta-analysis of available data from randomised controlled trials comparing Glucagon-like peptide-1 (GLP-1) analogues with placebo, active antidiabetic drug therapy or lifestyle intervention.\ud \ud Participants: Patients with type 2 diabetes.\ud \ud Outcome measures: Weighted mean differences between trial arms for changes in heart rate, blood pressure and body weight, after a minimum of 12-week follow-up.\ud \ud Results: 32 trials were included. Overall, GLP-1 agonists increased the heart rate by 1.86 beats/min (bpm) (95% CI 0.85 to 2.87) versus placebo and 1.90 bpm (1.30 to 2.50) versus active control. This effect was more evident for liraglutide and exenatide long-acting release than for exenatide twice daily. GLP-1 agonists decreased systolic blood pressure by −1.79 mm Hg (−2.94 to −0.64) and −2.39 mm Hg (−3.35 to −1.42) compared to placebo and active control, respectively. Reduction in diastolic blood pressure failed to reach statistical significance (−0.54 mm Hg (−1.15 to 0.07) vs placebo and −0.50 mm Hg (−1.24 to 0.24) vs active control). Body weight decreased by −3.31 kg (−4.05 to −2.57) compared to active control, but by only −1.22 kg (−1.51 to −0.93) compared to placebo.\ud \ud Conclusions: GLP-1 analogues are associated with a small increase in heart rate and modest reductions in body weight and blood pressure. Mechanisms underlying the rise in heart rate require further investigation.

South Asians have a higher risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) than white Caucasians, for a given BMI. Premature biological ageing, assessed by reduction in telomere length (TL), may be mediated by factors resulting from altered metabolic profiles associated with obesity. We hypothesise that ethnicity and metabolic status represent detrimental factors contributing to premature biological ageing. Therefore we assessed TL in two South Asian, age and BMI-matched cohorts [T2DM (n=142) versus non-T2DM (n=76)] to determine the effects of BMI, gender, lipid and CVD profile on biological ageing. Genomic DNA was obtained from the UKADS cohort; biochemical and anthropometric data was collected and TL was measured by quantitative real-time PCR. Our findings indicated a gender-specific effect with reduced TL in T2DM men compared with non-T2DM men (P=0.006). Additionally, in T2DM men, TL was inversely correlated with triglycerides and total cholesterol (r=−0.419,P<0.01;r=−0.443,P<0.01). In summary, TL was reduced amongst South Asian T2DM men and correlated with triglycerides and total cholesterol. This study highlights enhanced biological ageing among South Asian, T2DM men, which appears to be tracked by changes in lipids and BMI, suggesting that raised lipids and BMI may directly contribute to premature ageing.

Objective - This study investigated and compared the prevalence of microalbuminuria and overt proteinuria and their determinants in a cohort of UK resident patients of white European or south Asian ethnicity with type 2 diabetes mellitus. Research design and methods - A total of 1978 patients, comprising 1486 of south Asian and 492 of white European ethnicity, in 25 general practices in Coventry and Birmingham inner city areas in England were studied in a cross-sectional study. Demographic and risk factor data were collected and presence of microalbuminuria and overt proteinuria assessed. Main outcome measures - Prevalences of microalbuminuria and overt proteinuria. Results - Urinary albumin:creatinine measurements were available for 1852 (94%) patients. The south Asian group had a lower prevalence of microalbuminuria, 19% vs. 23% and a higher prevalence of overt proteinuria, 8% vs. 3%, X2?=?15.85, 2df, P?=?0.0004. In multiple logistic regression models, adjusted for confounding factors, significantly increased risk for the south Asian vs. white European patients for overt proteinuria was shown; OR (95% CI) 2.17 (1.05, 4.49), P?=?0.0365. For microalbuminuria, an interaction effect for ethnicity and duration of diabetes suggested that risk for south Asian patients was lower in early years following diagnosis; OR for SA vs. WH at durations 0 and 1 year were 0.56 (0.37, 0.86) and 0.59 (0.39, 0.89) respectively. After 20 years’ duration, OR?=?1.40 (0.63, 3.08). Limitations - Comparability of ethnicity defined groups; statistical methods controlled for differences between groups, but residual confounding may remain. Analyses are based on a single measure of albumin:creatinine ratio. Conclusions - There were significant differences between ethnicity groups in risk factor profiles and microalbuminuria and overt proteinuria outcomes. Whilst south Asian patients had no excess risk of microalbuminuria, the risk of overt proteinuria was elevated significantly, which might be explained by faster progression of renal dysfunction in patients of south Asian ethnicity.

Background: The Meta-Analysis of Glucose and Insulin related traits Consortium (MAGIC) recently identified 16 loci robustly\ud associated with fasting glucose, some of which were also associated with type 2 diabetes. The purpose of our study was to\ud explore the role of these variants in South Asian populations of Punjabi ancestry, originating predominantly from the\ud District of Mirpur, Pakistan.\ud Methodology/Principal Findings: Sixteen single nucleotide polymorphisms (SNPs) were genotyped in 1678 subjects with\ud type 2 diabetes and 1584 normoglycaemic controls from two Punjabi populations; one resident in the UK and one\ud indigenous to the District of Mirpur. In the normoglycaemic controls investigated for fasting glucose associations, 12 of 16\ud SNPs displayed b values with the same direction of effect as that seen in European studies, although only the SLC30A8\ud rs11558471 SNP was nominally associated with fasting glucose (b = 0.063 [95% CI: 0.013, 0.113] p = 0.015). Of interest, the\ud MTNR1B rs10830963 SNP displayed a negative b value for fasting glucose in our study; this effect size was significantly lower\ud than that seen in Europeans (p = 1.2961024). In addition to previously reported type 2 diabetes risk variants in TCF7L2 and\ud SLC30A8, SNPs in ADCY5 (rs11708067) and GLIS3 (rs7034200) displayed evidence for association with type 2 diabetes, with\ud odds ratios of 1.23 (95% CI: 1.09, 1.39; p = 9.161024) and 1.16 (95% CI: 1.05, 1.29; p = 3.4961023) respectively.\ud Conclusions/Significance: Although only the SLC30A8 rs11558471 SNP was nominally associated with fasting glucose in our\ud study, the finding that 12 out of 16 SNPs displayed a direction of effect consistent with European studies suggests that a\ud number of these variants may contribute to fasting glucose variation in individuals of South Asian ancestry. We also provide\ud evidence for the first time in South Asians that alleles of SNPs in GLIS3 and ADCY5 may confer risk of type 2 diabetes.

To study the diurnal variation and the effect of insulin on adiponectin multimers and nuclear factor-kappaB (NF-κB) activity in human endothelial cells.We utilized a prolonged insulin-glucose infusion in six healthy human subjects. HMW and total adiponectin levels were higher in the morning and lower at night; NF-κB activities in serum treated human microvascular endothelial cells (HMEC-1) cells were lower in the morning and higher at night. Hyperinsulinemic induction significantly decreased HMW and total adiponectin levels but increased NF-κB activity in serum treated HMEC-1 cells (P0.05, P0.01). There were no significant changes to MMW and LMW adiponectin levels (P0.05).Circadian rhythm of HMW adiponectin and NF-κB activity are altered by hyperinsulinemia providing novel insights adiponectin and NF-κB biology, which may be pertinent to insulin resistant states, e.g. obesity and type 2 diabetes mellitus.

Background/Aim: People of south Asian origin have an excessive risk of morbidity and mortality from cardiovascular disease. We examined the effect of ethnicity on known risk factors and analysed the risk of cardiovascular events and mortality in UK south Asian and white Europeans patients with type 2 diabetes over a 2 year period. Methods: A total of 1486 south Asian (SA) and 492 white European (WE) subjects with type 2 diabetes were recruited from 25 general practices in Coventry and Birmingham, UK. Baseline data included clinical history, anthropometry and measurements of traditional risk factors-blood pressure, total cholesterol, HbA1c. Multiple linear regression models were used to examine ethnicity differences in individual risk factors. Ten-year cardiovascular risk was estimated using the Framingham and UKPDS equations. All subjects were followed up for 2 years. Cardiovascular events (CVD) and mortality between the two groups were compared. Trial registration number: ISRCTN 38297969. Findings: Significant differences were noted in risk profiles between both groups. After adjustment for clustering and confounding a significant ethnicity effect remained only for higher HbA1c (0.50 [0.22 to 0.77]; P=0.0004) and lower HDL (-0.09 [-0.17 to -0.01]; P=0.0266). Baseline CVD history was predictive of CVD events during follow-up for SA (P

A post-prandial increase in saturated fatty acids (SFAs) and glucose (Glc) activates an inflammatory response, which may be prolonged following restoration of physiological SFAs and Glc levels — a finding referred to as ‘metabolic memory'. This study examined chronic and oscillating SFAs and Glc on the inflammatory signalling pathway in human adipose tissue (AT) and adipocytes (Ads) and determined whether Ads are subject to “metabolic memory.” Abdominal (Abd) subcutaneous (Sc) explants and Ads were treated with chronic low glucose (L-Glc): 5.6 mM and high glucose (H-Glc): 17.5 mM, with low (0.2 mM) and high (2 mM) SFA for 48 h. Abd Sc explants and Ads were also exposed to the aforementioned treatment regimen for 12-h periods, with alternating rest periods of 12 h in L-Glc. Chronic treatment with L-Glc and high SFAs, H-Glc and high SFAs up-regulated key factors of the nuclear factor-κB (NFκB) pathway in Abd Sc AT and Ads (TLR4, NFκB; P

In a randomised cross-over study we compared human isophane insulin (Human InsulatardTM) with human crystalline insulin zinc suspension (Human UltratardTM) as longer-acting, night-time insulins given thrice daily soluble insulin in the management of diabetes. We studied 20 insulin-dependent patients aged 20–47 years. At the end of each 12-week study period, total daily insulin dose was 56.9 ± 3.9U with Human InsulatardTM and 59.4 ± 4.4U with Human UltratardTM (no significant difference). The amount of longer-acting insulin used was lower with Human InsulatardTM than with Human UltratardTM (23.3 ± 2.5 vs 29.0 ± 3.2U per day, p

Background Recent studies have implicated variants of the transcription factor 7-like 2 (TCF7L2) gene in genetic susceptibility to type 2 diabetes mellitus in several different populations. The aim of this study was to determine whether variants of this gene are also risk factors for type 2 diabetes development in a UK-resident South Asian cohort of Punjabi ancestry. Methods We genotyped four single nucleotide polymorphisms (SNPs) of TCF7L2 (rs7901695, rs7903146, rs11196205 and rs12255372) in 831 subjects with diabetes and 437 control subjects. Results The minor allele of each variant was significantly associated with type 2 diabetes; the greatest risk of developing the disease was conferred by rs7903146, with an allelic odds ratio (OR) of 1.31 (95% CI: 1.11 – 1.56, p = 1.96 × 10-3). For each variant, disease risk associated with homozygosity for the minor allele was greater than that for heterozygotes, with the exception of rs12255372. To determine the effect on the observed associations of including young control subjects in our data set, we reanalysed the data using subsets of the control group defined by different minimum age thresholds. Increasing the minimum age of our control subjects resulted in a corresponding increase in OR for all variants of the gene (p ≤ 1.04 × 10-7). Conclusion Our results support recent findings that TCF7L2 is an important genetic risk factor for the development of type 2 diabetes in multiple ethnic groups.

Thiazolidinediones cause sodium retention and edema by a direct effect on the kidneys. The aim of this study was to use the technique of head-out water immersion to investigate the effects of rosiglitazone on sodium and volume homeostasis in subjects with type 2 diabetes mellitus. The volume expansion response to water immersion was compared with the response on a non-immersion control day in 12 nondiabetic male subjects and 8 diet-controlled male type 2 diabetic subjects with hourly blood and urine sampling over a 4-h period. This was repeated after both groups had taken 4 mg of rosiglitazone daily for 7 days. Immersion produced a natriuresis in both groups ( P < 0.001). An impairment of this natriuresis was seen in the diabetic subjects ( P = 0.006). However, when rosiglitazone was taken, there was no significant difference in immersion-induced natriuresis compared with nondiabetic controls ( P = 0.2). There was an immersion-induced rise in atrial natriuretic peptide (ANP) and urinary cyclic guanosine monophosphate (cGMP), in the healthy subjects (ANP P = 0.001, cGMP P = 0.043), which was not seen in the diabetic subjects (ANP P = 0.51, cGMP P = 0.74). Rosiglitazone restored the immersion-induced increase in cGMP excretion and rise of ANP in the diabetic group (ANP P = 0.048, cGMP P = 0.009). This study confirms that type 2 diabetic subjects have an impaired natriuretic response to acute volume expansion, which appears to be enhanced rather than diminished by rosiglitazone. This may be related to its effects in increasing natriuretic peptides and restoring the impaired cGMP excretion to volume expansion.

“Common sense is not so common” – Voltaire (1694–1778) The latest NICE guidelines for the management of type 2 diabetes are now available for consultation. They contain sensible recommendations regarding lifestyle, patient education, monitoring and targets. Unfortunately, the pharmacotherapy section shows a distinct failure of common sense. The recommendations include using the insulin secretagogue repaglinide as a first-line agent, where metformin is not tolerated or contraindicated, or second-line in combination with metformin. Pioglitazone is recommended as the principal second-line therapy with metformin. The advice on glucagon-like peptide-1 receptor agonist (GLP-1ra) usage and assessment of efficacy and failure to recommend long acting analogue insulins over isophane are also major concerns. The recommendations appear to be based on meta- analyses and pharmacoeconomics, driven by an imperative on costs and failing to appreciate the “value” of the options under consideration. The cost to patients and the health service of the serious side-effects of these treatments is underestimated. Given the emphasis in these guidelines on the importance of lifestyle changes, including weight loss, plus an over-riding need to avoid hypoglycaemia, these pharmacotherapeutic recommendations appear paradoxical in the extreme. We believe that these recommendations, if enacted, will undermine seriously the reputation of NICE both nationally and internationally.

Aims/hypothesis Adiponectin is an adipocyte-derived secretory factor that is specifically produced in adipocytes. It exerts effects on energy homeostasis via peripheral and central mechanisms. However, it is not clear whether adiponectin crosses the blood–brain barrier in humans. In serum, adiponectin circulates in several different complexes, each of which has distinct functions. Here, we wanted to test whether adiponectin can be found in human cerebrospinal fluid (CSF) and whether specific adiponectin complexes are enriched in CSF compared with peripheral serum samples. We also wanted to establish whether there is a sex-related difference with regard to the distribution of adiponectin oligomers in CSF. Materials and methods We studied 22 subjects (11 men, 11 women) in this study. Their average BMI was 28.0± 4.7 kg/m 2 ; average age was 70±7 years. Results Analysis of total adiponectin revealed that adiponectin protein is present in human CSF at approximately 0.1% of serum concentration. The distribution of adiponectin oligomers differs considerably in CSF from that of serum within matched samples from the same patients. Only the adiponectin trimeric and low-molecular-mass hexameric complexes are found in CSF, with a bias towards the trimeric form in most patients. Male subjects have a higher CSF: serum ratio of total adiponectin (p

Microalbuminuria is more common in South Asian individuals compared to white Europeans. The aim of this study was to determine the relationship between blood pressure and microalbuminuria in a cohort of patients with type 2 diabetes in these two ethnic groups. These further data were analysed from 552 patients (311 South Asian patients and 241 white Europeans) who had microalbuminuria screening data collected. Prevalence of microalbuminuria was significantly higher in South Asian compared with white European patients (31% versus 20%, p=0.007). Among patients with normal, untreated blood pressure, the proportion who had microalbuminuria was three times higher among South Asian patients compared with the white European group (30.7% versus 10.1%, p=0.049, relative risk = 3.1 [1.0–9.5]). In addition, despite their higher cardiovascular risk, South Asian patients were less likely to be prescribed a statin or antihypertensive drug treatment. In conclusion, thresholds and targets for treatment of cardiovascular risk factors in South Asians may need to be lower than those for white Europeans, and targeted intervention will be required to achieve this.

Objectives: To review systematically the evidence on the performance of diagnostic tests used to identify infection in diabetic foot ulcers (DFUs) and of interventions to treat infected DFUs. To use estimates derived from the systematic reviews to create a decision analytic model in order to identify the most effective method of diagnosing and treating infection and to identify areas of research that would lead to large reductions in clinical uncertainty. Data sources: Electronic databases covering period from inception of the database to November 2002. Review methods: Selected studies were assessed against validated criteria and described in a narrative review. The structure of a decision analytic model was derived for two groups of patients in whom diagnostic tests were likely to be used. Results: Three studies that investigated the performance of diagnostic tests for infection on populations including people with DFUs found that there was no evidence that single items on a clinical examination checklist were reliable in identifying infection in DFUs, that wound swabs perform poorly against wound biopsies, and that semi-quantitative analysis of wound swabs may be a useful alternative to quantitative analysis. However, few people with DFUs were included, so it was not possible to tell whether diagnostic performance differs for DFUs relative to wounds of other aetiologies. Twenty-three studies investigated the effectiveness (n = 23) or cost-effectiveness ( n = 2) of antimicrobial agents for DFUs. Eight studied intravenous antibiotics, five oral antibiotics, four different topical agents such as dressings, four subcutaneous granulocyte colony stimulating factor (G-CSF), one evaluated oral and topical Ayurvedic preparations and one compared topical sugar versus antibiotics versus standard care. The majority of trials were underpowered and were too dissimilar to be pooled. There was no strong evidence for recommending any particular antimicrobial agent for the prevention of amputation, resolution of infection or ulcer healing. Topical pexiganan cream may be as effective as oral antibiotic treatment with ofloxacin for the resolution of local infection. Ampicillin and sulbactam were less costly than imipenem and cilastatin, a growth factor (G-CSF) was less costly than standard care and cadexomer iodine dressings may be less costly than daily dressings. A decision analytic model was derived for two groups of people, those for whom diagnostic testing would inform treatment people with ulcers which do not appear infected but whose ulcer is not progressing despite optimal concurrent treatment - and those in whom a first course of antibiotics ( prescribed empirically) have failed. There was insufficient information from the systematic reviews or interviews with experts to populate the model with transition probabilities for the sensitivity and specificity of diagnosis of infection in DFUs. Similarly, there was insufficient information on the probabilities of healing, amputation or death in the intervention studies for the two populations of interest. Therefore, we were unable to run the model to inform the most effective diagnostic and treatment strategy. Conclusions: The available evidence is too weak to be able to draw reliable implications for practice. This means that, in terms of diagnosis, infection in DFUs cannot be reliably identified using clinical assessment. This has implications for determining which patients need formal diagnostic testing for infection, on whether empirical treatment with antibiotics ( before the results of diagnostic tests are available) leads to better outcomes, and on identifying the optimal methods of diagnostic testing. With respect to treatment, it is not known whether treatment with systemic or local antibiotics leads to better outcomes or whether any particular agent is more effective. Limited evidence suggests that both G-CSF and cadexomer iodine dressings may be less expensive than 'standard' care, that ampicillin/ sulbactam may be less costly than imipenem/ cilastatin, and that an unlicensed cream ( pexiganan) may be as effective as oral ofloxacin. Further research is needed to ascertain the characteristics of infection in people with DFUs that influence healing and amputation outcomes, to determine whether detecting infection prior to treatment offers any benefit over empirical therapy, and to establish the most effective and cost-effective methods for detecting infection, as well as the relative effectiveness and cost-effectiveness of antimicrobial interventions for DFU infection.

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.

Background— Good screening performance of retinal photography and ophthalmoscopy together in screening for diabetic retinopathy in primary care have been reported. This study reanalysed the data to evaluate the screening performance of photography alone. Methods— One thousand and ten patients screened by fundal photography and ophthalmoscopy were studied retrospectively. Fundal photographs were quality graded with poor quality pictures being excluded from the analysis. Each patient was reviewed initially by both retinal photographs and ophthalmoscopy by an ophthalmologist, the “gold standard”. Six months later the fundal photographs were reviewed and reported in a blinded manner by the ophthalmologist. Results— Two thousand and fourteen photographs were obtained, of which 162 (8%) had to be excluded because of poor quality. On review of the remaining 18S2 photographs in isolation, of 77 cases of severe retinopathy as determined by the “gold standard”, 67 had severe changes on photography—detection rate 87%. Of the 1775 cases without sight threatening retinopathy only five were judged to have sight threatening changes on photography—false positive rate 0.3%. Considering sight threatening and background retinopathy together, the detection rate was 69% (2S7 of 375) and the false positive rate 1.6% (23 of 1477). Conclusion— Good quality fundal photographs alone seem specific enough to screen for sight threatening diabetic retinopathy, but will underdetect background retinopathy.

Atrial fibrillation (AF) is an important risk factor for stroke and anticoagulation is now indicated in many patients at increased risk. Studies however have shown that many patients at risk are not anticoagulated for reasons that are not well explored. We identified prospectively the reasons for non-anticoagulation in patients with AF in 94 consecutive hospital patients with cardiac or cerebrovascular disease who had AF. Patients with intermittent or lone AF and60 years were excluded n = 16. The remaining group had a mean age of 76 +/- 7 years with a mental test score of 7.4 +/- 2 (normal 10), 31 lived alone and they lived an average of 14 +/- 11 miles from the hospital laboratory. The reasons for non-anticoagulation overlapped and were: medical in 29: cognitive impairment/compliance in 32: and monitoring problems in 50. Anticoagulation for AF in the elderly is a complex enterprise which must take into account social and cognitive as well as medical issues.

Objective To examine the experiences of patients, health professionals and screeners; their interactions with and understandings of diabetic retinopathy screening (DRS); and how these influence uptake.\ud \ud Design Purposive, qualitative design using multiperspectival, semistructured interviews and thematic analysis.\ud \ud Setting Three UK Screening Programme regions with different service-delivery modes, minority ethnic and deprivation levels across rural, urban and inner-city areas, in general practitioner practices and patients’ homes.\ud \ud Participants 62 including 38 patients (22 regular-screening attenders, 16 non-regular attenders) and 24 professionals (15 primary care professionals and 9 screeners).\ud \ud Results Antecedents to attendance included knowledge about diabetic retinopathy and screening; antecedents to non-attendance included psychological, pragmatic and social factors. Confusion between photographs taken at routine eye tests and DRS photographs was identified. The differing regional invitation methods and screening locations were discussed, with convenience and transport safety being over-riding considerations for patients. Some patients mentioned significant pain and visual disturbance from mydriasis drops as a deterrent to attendance.\ud \ud Conclusions In this, the first study to consider multiperspectival experiential accounts, we identified that proactive coordination of care involving patients, primary care and screening programmes, prior to, during and after screening is required. Multiple factors, prior to, during and after screening, are involved in the attendance and non-attendance for DRS. Further research is needed to establish whether patient self-management educational interventions and the pharmacological reformulation of shorter acting mydriasis drops, may improve uptake of DRS. This might, in turn, reduce preventable vision loss and its associated costs to individuals and their families, and to health and social care providers, reducing current inequalities.

We report experiences in 3 patients with acromegaly while using the somatostatin analogue octreotide. In case 1, a 44 year old male developed pneumococcal meningitis 3 months after having transphenoidal surgery for a pituitary tumour. This occurred with the re-emergence of communication between the surgical tract and the C.S.F. In case 2 a 52 year old male with insulin resistant diabetes mellitus requiring 240 units/day, with greatly elevated growth hormone concentrations was able to stop insulin within 5 days of starting octreotide. In case 3, a 52 year old male with sleep apnoea syndrome, respiratory failure and resistant heart failure made a dramatic improvement which is maintained 2 years later. All cases were associated with substantial falls in growth hormone and insulin like growth factor-1 concentrations.

We examined patient behaviour and the components of delay to hospitalisation in 149 consecutive cases of proven acute myocardial infarction (AMI) prospectively. The median total delay from onset of chest pain to hospitalisation was 210 mns (range 5 mns to 7 days). The median delay before seeking medical help was 105 mns. Seventy-eight patients (52%) contacted a G.P. Median delay to G.P. contact was 15 mns. The median delay in transportation to hospital was 20 mns. There was no evident diurnal variation in the onset of symptoms. There was no significant differences in help seeking delay between the sexes, between young and old or between those with a previous history of ischaemic heart disease similar to studies in the U.S. and U.K. Patient delay to seeking help remains the major and most crucial component of delay in treating AMI.

Context:The novel adipokine, nesfatin-1/NUCB-2, reduces food intake, levels of which are elevated in overweight individuals. Objectives:The aim of the study was to investigate the mechanisms underlying brain nesfatin-1/NUCB-2 uptake and to determine whether reduced uptake may contribute to nesfatin-1/NUCB-2 resistance. Design:Cerebrospinal fluid (CSF) and corresponding plasma nesfatin-1/NUCB-2 were measured by ELISA [18 men and 20 women; age, 19–80 yr; body mass index (BMI), 16.2–38.1 kg/m2] and correlated to body adiposity and metabolic parameters. Results:CSF/plasma nesfatin-1/NUCB-2 ratio was significantly negatively associated with BMI, body weight, fat mass, and CSF glucose. BMI was predictive of CSF/plasma nesfatin-1/NUCB-2 ratio (β = −0.786; P = 0.045). CSF nesfatin-1/NUCB-2 was significantly positively associated with plasma nesfatin-1/NUCB-2 (R = 0.706; P < 0.01). There was a significant linear relation between CSF and plasma nesfatin-1/NUCB-2 in lean (BMI

A case of 5α-reductase deficiency is described who presented clinically as primary amenorrhoea. Plasma levels of the two isomers resulting from the 5α-reduction of testosterone provide a simple method for diagnosing this condition. An intermediate abnormality was found in other family members consistent with the heterozygous state.