J. Paul O'Hare

Omentin-1, a Novel Adipokine, Is Decreased in Overweight Insulin-Resistant Women With Polycystic Ovary Syndrome: Ex Vivo and In Vivo Regulation of Omentin-1 by Insulin and Glucose

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.

Insulin and Metformin Regulate Circulating and Adipose Tissue Chemerin

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.

Higher Prevalence of Retinopathy in Diabetic Patients of South Asian Ethnicity Compared With White Europeans in the Community: A cross-sectional study

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.

Premature cardiovascular events and mortality in south Asians with type 2 diabetes in the United Kingdom Asian Diabetes Study - effect of ethnicity on risk

Abstract 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.

Common variants of the TCF7L2 gene are associated with increased risk of type 2 diabetes mellitus in a UK-resident South Asian population

BackgroundRecent 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.MethodsWe genotyped four single nucleotide polymorphisms (SNPs) of TCF7L2 (rs7901695, rs7903146, rs11196205 and rs12255372) in 831 subjects with diabetes and 437 control subjects.ResultsThe 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).ConclusionOur results support recent findings that TCF7L2 is an important genetic risk factor for the development of type 2 diabetes in multiple ethnic groups.

Effects of 16 Genetic Variants on Fasting Glucose and Type 2 Diabetes in South Asians: ADCY5 and GLIS3 Variants May Predispose to Type 2 Diabetes

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 β value for fasting glucose in our study; this effect size was significantly lower than that seen in Europeans (p = 1.29×10−4). 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 = 9.1×10−4) and 1.16 (95% CI: 1.05, 1.29; p = 3.49×10−3) 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.

Prevalence of microalbuminuria and hypertension in South Asians and white Europeans with type 2 diabetes: a report from the United Kingdom Asian Diabetes Study (UKADS)

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.

Ghrelin and the differential regulation of des‐acyl (DSG) and oct‐anoyl ghrelin (OTG) in human adipose tissue (AT)

Objectives  Ghrelin, an important central acting orexigenic hormone, is predominantly secreted in the gastrointestinal tract. However little is known about the action of ghrelin in human adipose tissue (AT).

The promoter polymorphism -232C/G of the PCK1 gene is associated with type 2 diabetes in a UK-resident South Asian population

BackgroundThe 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.MethodsWe 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.ResultsOf 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).ConclusionThis 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 RegistrationUKADS Trial Registration: ISRCTN38297969

Thiazolidinediones and the renal and hormonal response to water immersion-induced volume expansion in type 2 diabetes mellitus

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.