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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: Central obesity and sub-clinical inflammation increase metabolic risk, this study examined the intracellular inflammatory pathways in adipose tissue (AT) that contribute to this risk. DESIGN AND METHODS: This study therefore addressed the influence of NFκB and JNK activation in human abdominal subcutaneous (AbdSc) and omental (Om) AT, the effect of adiposity, T2DM status and the role of TNFα in vitro, using molecular biology techniques. RESULTS: Our data showed NFκB activity is increased in Om AT versus AbdSc AT (P

The rapid increase in the prevalence of diabetes is not abating across the world. The cost burden of managing diabetes and its complications is putting significant strain on healthcare resources worldwide. Increasingly large proportions of patients with diabetes, including those with complications, are managed by primary care. This has resulted in disjointed as well as huge variation in care, even in managed care systems and the National Health Service (NHS) in the UK. Several attempts have been made to manage patients in the community, such as the widely adopted GPwSI (GP with special interest) model in the UK but with no real evidence of its clinical or cost-effectiveness. The data on cardiovascular risk factors has been captured comprehensively since the introduction of quality outcomes framework (QoF) in the UK. However, longitudinal data has not been utilised to proactively identify and improve individualised care due to the lack of joined-up care, particularly the digital integration of data. To address these issues, we designed two separate projects: a cluster randomised trial of intermediate care clinics in diabetes and proactive identification and management of diabetes patients through a novel web-based digital integration of the data from 12 general practices. The cluster-randomised trial was an ambitious attempt and highlighted the difficulties of conducting large scale RCTs with a high number of follow-up rates. It did however show the importance of team-change, need for local champions and proactive case-finding approach to drive improvements in chronic diseases such as diabetes. The innovation project showed that proactive case-finding and individualised care plan development is feasible utilising existing resources if technology is adopted and used. For this to be sustainable, upskilling of the primary care with tailor made educational workshops, acceptance by the commissioners and providers in the healthcare economy are needed.

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.

Background This trial compared outcomes after foam sclerotherapy in patients wearing compression bandaging for 24 h or 5 days after treatment. Methods Consecutive patients with primary uncomplicated varicose veins were randomized after foam sclerotherapy treatment. The primary endpoint was 6-week Aberdeen Varicose Vein Severity Score (AVVSS) and Burford pain score. Results Some 124 legs were randomized, 61 to 24 h and 63 to 5 days of bandaging. Target vein occlusion rates at 6-week duplex imaging were 90 and 89 per cent respectively (P = 0·842). There was no significant difference in phlebitis after 2 weeks (P = 0·445) or skin discoloration after 6 weeks (46 versus 40 per cent; P = 0·546). There was no significant difference in the change in AVVSS from baseline to 2 weeks (−0·29 versus −0·80; P = 0·717) or to 6 weeks (−5·89 versus −5·14; 95 per cent confidence interval (c.i.) for the difference −3·29 to 1·80; P = 0·563), or in change in Burford pain score from baseline to 2 weeks (−9·04 versus −2·80; P = 0·248) or to 6 weeks (−17·32 versus −8·46; 95 per cent c.i. for the difference −19·06 to 1·33; P = 0·088), or in change in Short Form 36 score from baseline to 6 weeks (2·02 versus 1·74; P = 0·903). Conclusion There was no advantage to compression bandaging for more than 24 h when thromboembolus deterrent stockings were worn for the remainder of 14 days. Registration number: NCT00991497 (http://www.clinicaltrials.gov).

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.

Context: Dipeptidyl peptidase IV (DPP-IV) inactivates the incretin hormone glucagon-like peptide. It can also affect the orexigenic hormone neuropeptide Y (NPY1–36) which is truncated by DPP-IV to NPY3–36, as a consequence NPY’s affinity changes from receptor Y1, which mediates the antilipolytic function of NPY, to other NPY receptors. Little is known whether DPP-IV inhibitors for the treatment of type 2 diabetic (T2DM) patients could influence these pathways. Aims: To investigate the in vitro effects of NPY with DPP-IV inhibition in isolated abdominal subcutaneous (AbdSc) adipocytes on fat metabolism, and assessment of NPY receptor and DPP-IV expression in adipose tissue (AT). Methods: Ex vivo human AT was taken from women undergoing elective surgery (body mass index: 27.5 (mean ± s.d.) ± 5 kg/m2, age: 43.7 ± 10 years, n = 36). Isolated AbdSc adipocytes were treated with human recombinant (rh)NPY (1–100 nM) with and without DPP-IV inhibitor (1 M); glycerol release and tissue distribution of DPP-IV, Y1 and Y5 messenger RNA (mRNA) were measured and compared between lean and obese subjects. Results and conclusion: rhNPY reduced glycerol release, an effect that was further enhanced by co-incubation with a DPP-IV inhibitor [control: 224 (mean ± s.e.) ± 37 μmol/l; NPY, 100 nM: 161 ± 27 μmol/l**; NPY 100 nM/DPP-IV inhibitor, 1 M: 127 ± 14 μmol/l**; **p < 0.01, n = 14]. DPP-IV was expressed in AbdSc AT and omental AT with relative DPP-IV mRNA expression lower in AbdSc AT taken from obese [77 ± 6 signal units (SU)] vs. lean subjects (186 ± 29 SU*, n = 10). Y1 was predominantly expressed in fat and present in all fat depots but higher in obese subjects, particularly the AbdSc AT-depot (obese: 1944 ± 111 SU vs. lean: 711 ± 112 SU**, n = 10). NPY appears to be regulated by AT-derived DPP-IV. DPP-IV inhibitors augment the antilipolytic effect of NPY in AT. Further studies are required to show whether this explains the lack of weight loss in T2DM patients treated with DPP-IV inhibitors.

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.

NPY is an important central orexigenic hormone, but little is known about its peripheral actions in human adipose tissue (AT) or its potential paracrine effects. Our objective was to examine NPY's role in AT, specifically addressing NPY protein expression, the effect of NPY on adipokine secretion, and the influence of insulin and rosiglitazone (RSG) on adipocyte-derived NPY in vitro. Ex vivo human AT was obtained from women undergoing elective surgery [age: 42.7 ± 1.5 yr (mean ± SE), BMI: 26.2 ± 0.7 kg/m2; n = 38]. Western blot analysis was used to determine NPY protein expression in AT depots. Abdominal subcutaneous (AbSc) adipocytes were isolated and treated with recombinant (rh) NPY, insulin, and RSG. NPY and adipokine levels were measured by ELISA. Our results were that NPY was localized in human AT and adipocytes and confirmed by immunohistochemistry. Depot-specific NPY expression was noted as highest in AbSc AT (1.87 ± 0.23 ODU) compared with omental (Om; 1.03 ± 0.15 ODU, P = 0.029) or thigh AT (Th; 1.0 ± 0.29 ODU, P = 0.035). Insulin increased NPY secretion (control: 0.22 ± 0.024 ng/ml; 1 nM insulin: 0.26 ± 0.05 ng/ml; 100 nM insulin: 0.29 ± 0.04 ng/ml; 1,000 nM insulin: 0.3 ± 0.04 ng/ml; P < 0.05, n = 13), but cotreatment of RSG (10 nM) with insulin (100 nM) had no effect on NPY secretion. Furthermore, adipocyte treatment with rh-NPY downregulated leptin secretion (control: 6.99 ± 0.89 ng/ml; 1 nmol/l rh-NPY: 4.4 ± 0.64 ng/ml; 10 nmol/l rh-NPY: 4.3 ± 0.61 ng/ml, 100 nmol/l rh-NPY: 4.2 ± 0.67 ng/ml; P < 0.05, n = 10) but had no effect on adiponectin or TNF-α secretion. We conclude that NPY is expressed and secreted by human adipocytes. NPY secretion is stimulated by insulin, but this increment was limited by cotreatment with RSG. NPY's antilipolytic action may promote an increase in adipocyte size in hyperinsulinemic conditions. Adipose-derived NPY mediates reduction of leptin secretion and may have implications for central feedback of adiposity signals.

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.

There has been intense interest in the adipokines of the C1q complement/TNF-related protein (CTRP) superfamily. Adipolin (CTRP12) has been described as a novel adipokine, abundantly expressed in adipose tissue with insulin-sensitising and anti-inflammatory effects. We wanted to investigate the effects of acute and chronic hyperinsulinaemia on circulating adipolin concentrations (ELISA) via a prolonged insulin–glucose infusion in humans. We also examined the effects of insulin and the insulin sensitiser, rosiglitazone, on adipolin concentrations (western blotting) in human adipose tissue explants. We found that hyperinsulinaemic induction in healthy lean human subjects significantly increased circulating levels of adipolin (PPPPPPPP

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.

Background Maternal mortality in much of sub-Saharan Africa is very high whereas there has been a steady decline in over the past 60 years in Europe. Perinatal mortality is 12 times higher than maternal mortality accounting for about 7 million neonatal deaths; many of these in sub-Saharan countries. Many of these deaths are preventable. Countries, like Malawi, do not have the resources nor highly trained medical specialists using complex technologies within their healthcare system. Much of the burden falls on healthcare staff other than doctors including non-physician clinicians (NPCs) such as clinical officers, midwives and community health-workers. The aim of this trial is to evaluate a project which is training NPCs as advanced leaders by providing them with skills and knowledge in advanced neonatal and obstetric care. Training that will hopefully be cascaded to their colleagues (other NPCs, midwives, nurses). Methods/design This is a cluster randomised controlled trial with the unit of randomisation being the 14 districts of central and northern Malawi (one large district was divided into two giving an overall total of 15). Eight districts will be randomly allocated the intervention. Within these eight districts 50 NPCs will be selected and will be enrolled on the training programme (the intervention). Primary outcome will be maternal and perinatal (defined as until discharge from health facility) mortality. Data will be harvested from all facilities in both intervention and control districts for the lifetime of the project (3–4 years) and comparisons made. In addition a process evaluation using both quantitative and qualitative (e.g. interviews) will be undertaken to evaluate the intervention implementation. Discussion Education and training of NPCs is a key to improving healthcare for mothers and babies in countries like Malawi. Some of the challenges faced are discussed as are the potential limitations. It is hoped that the findings from this trial will lead to a sustainable improvement in healthcare and workforce development and training. Trial registration ISRCTN63294155