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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 immersioninduced 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. rosiglitazone; atrial natriuretic peptide; renin; aldosterone; cyclic guanosine monophosphate

Abstract Background The PCK1 gene, encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), has previously been implicated as a candidate gene for type 2 diabetes (T2D) susceptibility. Rodent models demonstrate that over-expression of Pck1 can result in T2D development and a single nucleotide polymorphism (SNP) in the promoter region of human PCK1 (-232C/G) has exhibited significant association with the disease in several cohorts. Within the UK-resident South Asian population, T2D is 4 to 6 times more common than in indigenous white Caucasians. Despite this, few studies have reported on the genetic susceptibility to T2D in this ethnic group and none of these has investigated the possible effect of PCK1 variants. We therefore aimed to investigate the association between common variants of the PCK1 gene and T2D in a UK-resident South Asian population of Punjabi ancestry, originating predominantly from the Mirpur area of Azad Kashmir, Pakistan. Methods We used TaqMan assays to genotype five tagSNPs covering the PCK1 gene, including the -232C/G variant, in 903 subjects with T2D and 471 normoglycaemic controls. Results Of the variants studied, only the minor allele (G) of the -232C/G SNP demonstrated a significant association with T2D, displaying an OR of 1.21 (95% CI: 1.03 - 1.42, p = 0.019). Conclusion This study is the first to investigate the association between variants of the PCK1 gene and T2D in South Asians. Our results suggest that the -232C/G promoter polymorphism confers susceptibility to T2D in this ethnic group. Trial Registration UKADS Trial Registration: ISRCTN38297969

Abstract 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.

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. [ABSTRACT FROM PUBLISHER]

Background: Disruption of endogenous circadian rhythms has been shown to increase the risk of developing type 2 diabetes, suggesting that circadian genes might play a role in determining disease susceptibility. We present the results of a pilot study investigating the association between type 2 diabetes and selected single nucleotide polymorphisms (SNPs) in/near nine circadian genes. The variants were chosen based on their previously reported association with prostate cancer, a disease that has been suggested to have a genetic link with type 2 diabetes through a number of shared inherited risk determinants. Methodology/Principal Findings: The pilot study was performed using two genetically homogeneous Punjabi cohorts, one resident in the United Kingdom and one indigenous to Pakistan. Subjects with (N = 1732) and without (N = 1780) type 2 diabetes were genotyped for thirteen circadian variants using a competitive allele-specific polymerase chain reaction method. Associations between the SNPs and type 2 diabetes were investigated using logistic regression. The results were also combined with in silico data from other South Asian datasets (SAT2D consortium) and white European cohorts (DIAGRAM+) using meta-analysis. The rs7602358G allele near PER2 was negatively associated with type 2 diabetes in our Punjabi cohorts (combined odds ratio [OR] = 0.75 [0.66-0.86], p = 3.18×10-5), while the BMAL1 rs11022775T allele was associated with an increased risk of the disease (combined OR = 1.22 [1.07-1.39], p = 0.003). Neither of these associations was replicated in the SAT2D or DIAGRAM+ datasets, however. Meta-analysis of all the cohorts identified disease associations with two variants, rs2292912 in CRY2 and rs12315175 near CRY1, although statistical significance was nominal (combined OR = 1.05 [1.01-1.08], p = 0.008 and OR = 0.95 [0.91-0.99], p = 0.015 respectively). Conclusions/significance: None of the selected circadian gene variants was associated with type 2 diabetes with studywide significance after meta-analysis. The nominal association observed with the CRY2 SNP, however, complements previous findings and confirms a role for this locus in disease susceptibility. [ABSTRACT FROM AUTHOR]

Background: The Meta-Analysis of Glucose and Insulin related traits Consortium (MAGIC) recently identified 16 loci robustly associated with fasting glucose, some of which were also associated with type 2 diabetes. The purpose of our study was to explore the role of these variants in South Asian populations of Punjabi ancestry, originating predominantly from the District of Mirpur, Pakistan. Methodology/Principal Findings: Sixteen single nucleotide polymorphisms (SNPs) were genotyped in 1678 subjects with type 2 diabetes and 1584 normoglycaemic controls from two Punjabi populations; one resident in the UK and one indigenous to the District of Mirpur. In the normoglycaemic controls investigated for fasting glucose associations, 12 of 16 SNPs displayed β values with the same direction of effect as that seen in European studies, although only the SLC30A8 rs11558471 SNP was nominally associated with fasting glucose (β = 0.063 [95% CI: 0.013, 0.113] p = 0.015). Of interest, the MTNR1B rs10830963 SNP displayed a negative b value for fasting glucose in our study; this effect size was significantly lower than that seen in Europeans (p = 1.29610-4). In addition to previously reported type 2 diabetes risk variants in TCF7L2 and SLC30A8, SNPs in ADCY5 (rs11708067) and GLIS3 (rs7034200) displayed evidence for association with type 2 diabetes, with 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. Conclusions/Significance: Although only the SLC30A8 rs11558471 SNP was nominally associated with fasting glucose in our study, the finding that 12 out of 16 SNPs displayed a direction of effect consistent with European studies suggests that a number of these variants may contribute to fasting glucose variation in individuals of South Asian ancestry. We also provide evidence for the first time in South Asians that alleles of SNPs in GLIS3 and ADCY5 may confer risk of type 2 diabetes. [ABSTRACT FROM AUTHOR]

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 < 0.0001) but not WE (P = 0.189). Mean age at death was 66.8 (11.8) for SA vs. 74.2 (12.1) for WE, a difference of 7.4 years (95% CI 1.0 to 13.7 years), P = 0.023. The adjusted odds ratio of CVD event or death from CVD was greater but not significantly so in SA than in WE (OR 1.4 [0.9 to 2.2]). Limitations: Fewer events in both groups and short period of follow-up are key limitations. Longer follow-up is required to see if the observed differences between the ethnic groups persist. Conclusion: South Asian patients with type 2 diabetes in the UK have a higher cardiovascular risk and present with cardiovascular events at a significantly younger age than white Europeans. Enhanced and ethnicity specific targets and effective treatments are needed if these inequalities are to be reduced. [ABSTRACT FROM AUTHOR]

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. Diabetes 58:1971-1977, 2009 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 x 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 x 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

Abstract: Objective: To study the diurnal variation and the effect of insulin on adiponectin multimers and nuclear factor-kappaB (NF-κB) activity in human endothelial cells. Methods and results: 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 (P <0.05, P <0.01). There were no significant changes to MMW and LMW adiponectin levels (P >0.05). Conclusion: 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. [ABSTRACT FROM AUTHOR]

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)., 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., 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., 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, Merck & Co., Darmstadt, Germany), 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, Boehringer Ingelheim, Bracknell, UK)., Funding: The National Institute for Health Research Health Technology Assessment programme.

Background: The PCK1 gene, encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), has previously been implicated as a candidate gene for type 2 diabetes (T2D) susceptibility. Rodent models demonstrate that over-expression of Pck1 can result in T2D development and a single nucleotide polymorphism (SNP) in the promoter region of human PCK1 (-232C/G) has exhibited significant association with the disease in several cohorts. Within the UK-resident South Asian population, T2D is 4 to 6 times more common than in indigenous white Caucasians. Despite this, few studies have reported on the genetic susceptibility to T2D in this ethnic group and none of these has investigated the possible effect of PCK1 variants. We therefore aimed to investigate the association between common variants of the PCK1 gene and T2D in a UK-resident South Asian population of Punjabi ancestry, originating predominantly from the Mirpur area of Azad Kashmir, Pakistan., Methods: We used TaqMan assays to genotype five tagSNPs covering the PCK1 gene, including the -232C/G variant, in 903 subjects with T2D and 471 normoglycaemic controls., Results: Of the variants studied, only the minor allele (G) of the -232C/G SNP demonstrated a significant association with T2D, displaying an OR of 1.21 (95% CI: 1.03 - 1.42, p = 0.019)., Conclusion: This study is the first to investigate the association between variants of the PCK1 gene and T2D in South Asians. Our results suggest that the -232C/G promoter polymorphism confers susceptibility to T2D in this ethnic group., Trial Registration: UKADS Trial Registration: ISRCTN38297969.