Chia-Po Fu

Genome-wide association study in a Chinese population with diabetic retinopathy

Diabetic retinopathy (DR) is a leading cause of preventable blindness in adults. To identify genetic contributions in DR, we studied 2071 type 2 diabetics. We first conducted a genome-wide association study of 1007 individuals, comparing 570 subjects with ≥8 years duration without DR (controls) with 437 PDR (cases) in the Chinese discovery cohort. Cases and controls were similar for HbA1c, diabetes duration and body mass index. Association analysis with imputed data identified three novel loci: TBC1D4-COMMD6-UCHL3 (rs9565164, P = 1.3 × 10(-7)), LRP2-BBS5 (rs1399634, P = 2.0 × 10(-6)) and ARL4C-SH3BP4 (rs2380261, P = 2.1 × 10(-6)). Analysis of an independent cohort of 585 Hispanics diabetics with or without DR though did not confirm these signals. These genes are still of particular interest because they are involved in insulin regulation, inflammation, lipid signaling and apoptosis pathways, all of which are possibly involved with DR. Our finding nominates possible novel loci as potential DR susceptibility genes in the Chinese that are independent of the level of HbA1c and duration of diabetes and may provide insight into the pathophysiology of DR.

MRI Measured Epicardial Adipose Tissue Thickness at the Right AV Groove Differentiates Inflammatory Status in Obese Men With Metabolic Syndrome

Epicardial adipose tissue (EAT) is a metabolically active visceral fat, which secretes inflammatory cytokines and adipokines. In this study, our aim was to examine which measurements of EAT thickness by magnetic resonance imaging (MRI) could best help differentiate inflammatory status, classified by levels of high‐sensitivity C‐reactive protein (hs‐CRP), in obese men with metabolic syndrome (MetS). We prospectively enrolled 32 men with central obesity (waist circumference ≥90 cm) and at least two other MetS criteria. MRI examinations for measurements of EAT, subcutaneous fat, and abdominal visceral fat as well as recordings of anthropometric parameters and tests for serum inflammatory cytokines and adipokines were conducted. Subjects with MetS (N = 32) were divided into three subgroups: (i) low inflammatory status (hs‐CRP < 0.3 mg/dl, N = 8), (ii) intermediate inflammatory status (hs‐CRP 0.1–0.3 mg/dl, N = 15), and (iii) high inflammatory status (hs‐CRP >0.3 mg/dl, N = 9). EAT thickness at the right atrioventricular (AV) groove showed a significant linear trend among the three subgroups of MetS (P for trend = 0.004). High inflammatory status MetS subgroup had a significantly thicker right AV groove EAT than did the low inflammatory status MetS subgroup (19.3 ± 3.1 vs. 14.4 ± 3.3 mm, P = 0.015). In binary logistic regression analysis, right AV groove EAT thickness was an independent predictor for differentiating inflammatory status in MetS while abdominal visceral fat area and insulin‐resistance index were not. In conclusion, MRI measured EAT thickness at the right AV groove could be a useful marker for differentiating the inflammatory status in obese men with MetS.

Performance of HbA1c and Fasting Plasma Glucose in Screening for Diabetes in Patients Undergoing Coronary Angiography

OBJECTIVE The performance of glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) was compared in screening for diabetes by an oral glucose tolerance test (OGTT) in patients undergoing coronary angiography (CAG). RESEARCH DESIGN AND METHODS Patients without known diabetes admitted for CAG were eligible. OGTT and HbA1c were assessed 2–4 weeks after hospital discharge. The performance of HbA1c and FPG was evaluated by using receiver operating characteristic (ROC) analysis. RESULTS Diabetes was diagnosed in 83 of 400 patients (20.8%). The area under the ROC curve was higher for FPG than for HbA1c (0.81 vs. 0.73, P = 0.032). We proposed a screening algorithm and validated it in another 170 patients. Overall, this algorithm reduced the number of OGTTs by 71.4% (sensitivity 74.4%, specificity 100%). CONCLUSIONS FPG performed better than HbA1c in screening for diabetes in patients undergoing CAG. A screening algorithm might help to reduce the number of OGTTs.

Persistent elevation of paraoxonase-1 specific enzyme activity after weight reduction in obese non-diabetic men with metabolic syndrome

BACKGROUND Paraoxonase-1 (PON1) is an esterase associated with the high-density lipoprotein (HDL) in serum. To date, there have been few reports about circulating PON1 protein concentration and specific activity in subjects with metabolic syndrome (MetS). More importantly, it is unknown whether weight loss could alter PON1 protein expression or specific activity in obese non-diabetic men with MetS. METHODS We prospectively enrolled a total of 40 obese non-diabetic men with MetS. Among them, 22 subjects finished the 3-month course of weight loss program and complied for longer follow-ups post-weight loss at the 3rd, 12th, and 18th month from the beginning of the program. Twenty-six healthy volunteers served as controls. Serum circulating PON1 concentration was measured by an enzyme linked immunosorbent kit (ELISA) and PON1 activity was measured by an automated PON1 activity assay. RESULTS Obese non-diabetic men with MetS (n=40) had a higher PON1 protein concentration (31.0 ± 11.3 vs. 24.8 ± 9.7 μg/ml, p=0.025) but lower specific enzyme activity (7.5 ± 4.0 vs. 11.2 ± 7.2 mU/μg, p=0.023) than those of the controls. Multivariate regression analysis of baseline PON1 specific activity revealed that adiponectin was a significant positive predictor (p=0.044) while monocyte chemotactic protein-1 (MCP-1) was a negative predictor (p=0.031). After a 3-month weight loss program, obese MetS men (n=22) had a significant weight reduction (95.8 ± 9.0 to 86.3 ± 10.4 kg, with a 9.9 ± 5.4% decrease, p<0.001). PON1 protein decreased significantly after weight loss and kept declining through the 3rd month till the 18th month follow-up. PON1 specific enzyme activity (baseline 7.5 ± 2.6 mU/μg) increased significantly after weight loss and kept increasing through the 12th month till the 18th month follow-ups (11.8 ± 6.4 mU/μg, p=0.001 vs. baseline). CONCLUSIONS Weight loss by a 3-month diet and exercise program time-sequentially increased PON1 specific enzyme activity in obese non-diabetic men with MetS.

Effects of weight loss on epicardial adipose tissue thickness and its relationship between serum soluble CD40 ligand levels in obese men

BACKGROUND Epicardial adipose tissue (EAT) induces activated inflammatory cells secreting cytokines, including soluble CD40 ligand (sCD40L). In turn, the serum sCD40L can trigger inflammatory responses. We examined the reduction of EAT in response to weight loss (WL) and its relationship with alterations in sCD40L in obese men. METHODS We prospectively provided dietary education and exercise intervention for 3 months for 32 non-diabetic obese men with metabolic syndrome. Twenty-five age-matched healthy men served as controls. Circulating sCD40L was measured, and EAT thickness (EATt) was determined by magnetic resonance imaging before and after WL. RESULTS EATt was increased in the obese individuals, but there were no significant differences in baseline serum sCD40L levels between the 2 groups. Serum concentrations of sCD40L were higher in individuals with high right atrioventricular groove (RAVG)-EATt. EATt was reduced significantly in individuals who completed the weight-loss program. In addition, a positive correlation was shown between changes in sCD40L and RAVG-EATt. Multiple linear regression analysis showed the change in sCD40L to be independently associated with the change in RAVG-EATt. CONCLUSION WL can significantly reduce epicardial fat thickness, and the reduced EATt after WL may provide a beneficial reduction in circulating levels of sCD40L in obese males.

Brain-derived neurotrophic factor not associated with metabolic syndrome but inversely correlated with vascular cell adhesion molecule-1 in men without diabetes.

BACKGROUND Excessive visceral fat with unbalanced adipokines is a critical pathogenic factor of metabolic syndrome (MetS), which is associated with disorders of the central nervous system and cardiovascular disease. Because brain-derived neurotrophic factor (BDNF) plays an important role in neurons, we examined the relationship of BDNF to MetS, adipose tissue and biomarkers in men. METHODS Thirty-four non-diabetic men with MetS and another 24 age-matched men without MetS were enrolled. In addition to fasting blood samples, the area of adipose tissue at the waist was assessed by magnetic resonance imaging (MRI). RESULTS There was no significant difference in serum BDNF concentrations between men with or without MetS (40.9±8.0 vs. 43.2±6.1 ng/ml, P=0.235). However, the serum concentration of soluble vascular cell adhesion molecule-1 (VCAM-1) was higher in the subjects with a lower BDNF level (737±230 vs. 628±115 ng/ml, P=0.025). An inverse correlation between VCAM-1 and BDNF was observed (r=-0.391, P=0.002). After adjusting for visceral adipose tissue, VCAM-1 was found to be independently associated with BDNF [95% confidence interval (-0.025, -0.005), P=0.004]. CONCLUSION These data show no difference in serum BDNF levels between the men with MetS and controls. However, serum BDNF was inversely correlated with serum VCAM-1 in men without diabetes.

Comparing HbA1c, fasting and 2-h plasma glucose for screening for abnormal glucose regulation in patients undergoing coronary angiography.

Abstract Background: We aimed to investigate the prevalence of undiagnosed abnormal glucose regulation (AGR, including diabetes and prediabetes) in patients undergoing coronary angiography (CAG) by using both glycated hemoglobin (HbA1c) and oral glucose tolerance test (OGTT) to screen, and to compare the performance of fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), and HbA1c for screening for AGR. Methods: Eligible patients were adults without known diabetes who were admitted for CAG. Patients’ glucose regulation status was defined by conducting HbA1c and OGTT 2–4 weeks after hospital discharge. The performance of FPG, 2hPG, and HbA1c for detecting AGR was evaluated using receiver operating characteristic (ROC) analysis. Results: A total of 689 subjects were included. According to OGTT, the prevalence rates of diabetes and prediabetes were 19.9% and 41.7%, respectively. The corresponding values were 28.0% and 60.4%, respectively, when HbA1c was adopted as a diagnostic criterion in addition to OGTT. For detecting diabetes, the area under the ROC curve (AUC) was higher for HbA1c than for FPG (0.87 vs. 0.80, p=0.005), but was not significantly different from that for 2hPG (0.87 vs. 0.88, p=0.58). For detecting AGR, the AUC was higher for HbA1c than for either FPG (0.94 vs. 0.74, p<0.001) or 2hPG (0.94 vs. 0.83, p<0.001). Conclusions: Using HbA1c and OGTT to screen, we reported an extremely high prevalence of previously undiagnosed AGR (28.0% diabetes and 60.4% prediabetes) in patients admitted for CAG. HbA1c may be adopted as an alternative to OGTT for screening for AGR in patients undergoing CAG.

The levels of circulating and urinary monocyte chemoattractant protein-1 are associated with chronic renal injury in obese men.

BACKGROUND Monocyte chemoattractant protein-1 (MCP-1) is a vital inflammatory marker of obesity. Whether obesity by itself increases the risk of chronic kidney injury and accelerates its progression is unknown. More importantly, it is unknown whether obesity could induce kidney injury by MCP-1. METHODS We enrolled 40 obese men and 26 healthy volunteers who served as controls. The degree of insulin resistance was evaluated by the homeostasis model assessment (HOMA-IR) method, and kidney function was determined based on the estimated glomerular filtration rate (eGFR), albuminuria, the concentration of serum cystatin C (S-CysC), and the urinary cystatin C to creatinine ratio (UCCR). RESULTS The obese subjects had significantly higher S-CysC concentration (1114±288 vs.962±169 mg/L, p=0.021) and a higher UCCR (3.5±1.6 vs. 2.5±0.8 μg/g, p=0.002) than those of controls. The concentration of circulating MCP-1 and the urinary MCP-1 to creatinine ratio (UMCR) were higher in the obese group and were correlated with fat mass and HOMA-IR. Using stepwise multiple linear regression analysis, circulating MCP-1 concentration was found to be independently associated with the amount of S-CysC. In addition, the UMCR was independently associated with the UCCR. CONCLUSION The concentrations of circulating and urinary monocyte chemoattractant protein-1 are associated with chronic renal injury in obese men.

Relationship between body weight and the increment in serum brain-derived neurotrophic factor after oral glucose challenge in men with obesity and metabolic syndrome: A prospective study

Abstract Brain-derived neurotrophic factor (BDNF) plays a role in energy homeostasis. However, the postprandial BDNF change has not been well investigated. We hypothesized that the BDNF increment after oral glucose challenge is associated with body weight. To address this possibility, man adults with obesity in conjunction with metabolic syndrome were compared with normal weight controls at baseline in the initial cross-sectional protocol. The obese subjects then underwent a 12-week program for body-weight reduction in the prospective protocol. The area under the curve (AUC) of serum BDNF was recorded during a 75 g oral glucose tolerant test and the BDNF AUC index was defined as [(AUC of BDNF) − (fasting BDNF*2 hours)]/(fasting BDNF*2 hours). A total of 25 controls and 36 obese subjects completed the study assessments. In the cross-sectional protocol, the BDNF AUC index was significantly higher in the obese subjects than in the controls (9.0 ± 16.5% vs. − 8.0 ± 22.5%, P = 0.001). After weight reduction (from 97.0 ± 12.5 kg to 88.6 ± 12.9 kg, P < 0.001), the percentage change of body weight was significantly associated with the BDNF AUC index after the study (95% CI between 0.21 and 1.82, P = 0.015). Using 6% weight reduction as a cut-off value, a larger weight reduction was able to reliably predict a negative BDNF AUC index. In conclusion, a high BDNF AUC index was observed for obese men in this study, whereas the index value significantly decreased after body-weight reduction. These findings suggest that postprandial BDNF increment may be associated with obesity.

The synergistic effect of vascular cell adhesion molecule-1 and coronary artery disease on brain-derived neurotrophic factor.

BACKGROUND Brain-derived neurotrophic factor (BDNF) is important for neural protection and energy homeostasis. In this study, we examined the effects of vascular cell adhesion molecule-1 (VCAM-1) and coronary artery disease (CAD) on BDNF. METHODS Subjects who had undergone diagnostic angiography for angina were recruited, and a total of 240 subjects (144 with CAD and 96 without CAD) were enrolled. Serum BDNF was determined at 0, 30, and 120min during an oral glucose tolerance test (OGTT) to calculate the area under the curve (AUC) for BDNF. Serum VCAM-1 was determined at fasting. RESULTS Significantly lower AUC of BDNF (42.8±10.7 vs. 47.4±11.7ng-h/ml, P=0.002) and higher serum VCAM-1 (583±383 vs. 482±171ng/ml, P=0.017) were noted in subjects with CAD compared to those without CAD. High VCAM-1 level was an independent predictor of low AUC of BDNF in subjects with and without CAD (95%CI between -0.011 and -0.002, P=0.008; -0.033 and -0.002, P=0.029, respectively). Serum BDNF was lowest in the CAD subjects with high VCAM-1 levels at all time points during OGTT. CONCLUSION Our results showed that CAD was associated with low serum BDNF in response to OGTT, and VCAM-1 had a synergistic effect with CAD on the BDNF.