Possible Modifying Effect of Hemoglobin A1c on Genetic Susceptibility to Severe Diabetic Retinopathy in Patients With Type 2 Diabetes.

Purpose: Glycemic control has been recognized as an important modifiable risk factor for diabetic retinopathy (DR). Whether hemoglobin A1c (HbA1c), as an indicator of glycemic control, could modify the genetic susceptibility to severe DR remains to be investigated. This study aimed to investigate whether HbA1c could modulate the genetic susceptibility to severe DR in Chinese patients with type 2 diabetes. Methods: A total of 3,093 Chinese individuals with type 2 diabetes were included in the cross-sectional case-control study: 1,051 with sight-threatening DR (STDR) and 2,042 without STDR. Sixty-nine top-ranked single nucleotide polymorphisms (SNPs) identified from previous genome-wide association studies were examined for their associations with STDR and proliferative DR as a subgroup analysis. SNPs showing suggestive associations with DR were examined in the stratified analysis by dichotomized HbA1c (<7% vs. ≥7%). An interaction analysis was performed by including an interaction term of SNP × HbA1c in the regression model. Results: Four SNPs showed suggestive associations with STDR. In the stratified analysis, patients with adequate glycemic control (HbA1c <7%) had a 42% lower risk of STDR for carrying each additional protective C allele of COL5A1 rs59126004 (P = 1.76 × 10-4; odds ratio, 0.58; 95% confidence interval, 0.44-0.77). rs59126004 demonstrated a significant interaction with dichotomized HbA1c on the risk of STDR (Pinteraction = 1.733 × 10-3). In the subgroup analysis for proliferative DR, the protective effect of rs59126004 was even more pronouncedly demonstrated (P = 8.35 × 10-5; odds ratio, 0.37; 95% confidence interval, 0.22-0.60) and it showed similar interactions with dichotomized HbA1c (Pinteraction = 1.729 × 10-3). Conclusions: Our data provided evidence for possible interactions between HbA1c and COL5A1 rs59126004 on the risk of severe DR. These findings may provide new insight into the pathophysiologic mechanism of DR.

Impact of Genetic Loci Identified in Genome-Wide Association Studies on Diabetic Retinopathy in Chinese Patients With Type 2 Diabetes.

PURPOSE: Diabetic retinopathy (DR) is a common microvascular complication of type 2 diabetes (T2DM). Genome-wide association studies (GWAS) had identified novel DR-susceptibility genetic variants in various populations. We examined the associations of these DR-associated single nucleotide polymorphisms (SNPs) with severe DR in a Chinese T2DM cohort. METHODS: Cross-sectional case-control studies on sight-threatening DR (STDR) and proliferative DR (PDR) were performed. We genotyped 38 SNPs showing top association signals with DR in previous GWAS in 567 STDR cases, including 309 with PDR and 1490 non-DR controls. Multiple logistic regression models with adjustment for conventional risk factors, including age, sex, duration of diabetes, and presence of hypertension, were employed. RESULTS: The strongest association was found at INSR rs2115386, an intronic SNP of INSR: Padjusted = 9.13 × 10-4 (odds ratio [OR],1.28; 95% confidence interval [95%CI], 1.11-1.48) for STDR, and Padjusted= 1.12 × 10-4 (OR [95%CI],1.44 [1.20-1.74]) for PDR. rs599019 located downstream of COLEC12 (Padjusted = 0.019; OR [95%CI],1.19 [1.03-1.38]) and rs4462262 located at an intergenic region between ZWINT and MRPS35P3 (Padjusted = 0.041; OR [95%CI],1.38[1.01-1.89]) also were significantly associated with STDR, but not with PDR alone. On the other hand, MYT1L-LOC729897 rs10199521 (Padjusted = 0.022; OR [95%CI],1.25 [1.03-1.51]) and API5 rs899036 (Padjusted = 0.049; OR [95%CI],1.36 [1.00-1.85]) showed significant independent associations only with PDR. Similar results were obtained when hemoglobin A1c also was included in the adjustment models. CONCLUSIONS: We demonstrated the significant and independent associations of several GWAS-identified SNPs with DR in Chinese T2DM patients with severe DR. The findings on INSR rs2115386 are supportive of the role of insulin resistance, or the compensatory hyperinsulinemia, in the pathogenesis of DR.

Selective inactivation of c-Jun NH2-terminal kinase in adipose tissue protects against diet-induced obesity and improves insulin sensitivity in both liver and skeletal muscle in mice.

OBJECTIVE: Obesity is associated with increased activation of the c-Jun NH(2)-terminal kinase (JNK) in several metabolic organs, including adipose tissue, liver, and skeletal muscle. In this study, we aimed to define the role of JNK activation in adipose tissue in the development of obesity-related insulin resistance. RESEARCH DESIGN AND METHODS: Transgenic mice with adipose tissue-specific overexpression of dominant-negative JNK (ap2-dn-JNK) under the transcriptional control of the aP2 gene promoter were generated and subjected to metabolic characterization together with the wild-type littermates. RESULTS: On a high-fat diet (HFD), the ap2-dn-JNK mice displayed a marked suppression of both JNK1 and JNK2 activation in their adipose tissue, accompanied by a marked reduction in weight gain, fat mass, and size of the adipocytes. The transgenic mice were resistant to the deleterious impact of an HFD on systemic insulin sensitivity, glucose tolerance, and hepatic steatosis. Reduced hepatic gluconeogenesis was evident in in vivo and ex vivo studies and showed greater insulin-induced glucose uptake in skeletal muscles. These changes were accompanied by reduced macrophage infiltration in adipose tissue, decreased production of proinflammatory adipokines, and increased expression of adiponectin. Indirect calorimetry analysis showed that the transgenic mice had significant increases in oxygen consumption and reductions in respiration exchange rates compared with their wild-type littermates. CONCLUSIONS: Selective suppression of JNK activation in adipose tissue alone is sufficient to counteract HFD-induced obesity and its associated metabolic dysregulations, in part through an increase in energy expenditure and a decrease in systemic inflammation.

Bioavailable testosterone predicts a lower risk of Alzheimer's disease in older men.

There is a paucity of data on the relationship between testosterone and Alzheimer's disease (AD) in older men. The objective of the present study was to investigate the effects of serum total testosterone (TT), bioavailable testosterone (BT), and sex hormone binding globulin (SHBG) levels on the subsequent risk of AD in nondemented Chinese older men. This was a one-year prospective cohort study. 153 ambulatory community-living nondemented Chinese older men, aged 55 years or over, were recruited and followed for one year. Morning serum TT, BT, and SHBG levels were measured at baseline. At one-year of followup, assessment for dementia and AD were performed. AD was diagnosed by the NINCDS-ADRDA criteria for probable AD. Overall, the mean age of the subjects was 72.7 (SD 6.9). 6.5% (n = 10) developed dementia (converters), all having AD. 93.5% (n = 143) did not develop dementia (non-converters). Logistic regression analysis for independent predictors of AD showed that the baseline serum BT level, systolic blood pressure (SBP) and ApoE "4 genotype were significant independent predictors, after adjustment for age, education, BMI, fasting plasma glucose, and serum HDLC levels. The baseline serum BT level predicted a reduced risk of AD (adjusted relative risk (RR) 0.22, 95% CI: 0.07-0.69)). Baseline SBP and ApoE "4 genotype but not SHBG were independent risk factors, with RRs of 1.04 and 5.04 respectively. In conclusion, the serum level of bioavailable testosterone in late life predicts a lower risk of future AD development in older men.

Serum total and bioavailable testosterone levels, central obesity, and muscle strength changes with aging in healthy Chinese men.

OBJECTIVES: To investigate the effects of the changes in serum bioavailable and total testosterone (TT) levels with aging on visceral body fat distribution and muscle strength in Chinese men. DESIGN: Cross-sectional study. SETTING: Ambulatory care. PARTICIPANTS: Four hundred seventy-five healthy ambulatory Chinese men (aged 18-89, body mass index (BMI) 16.4-40.0 kg/m(2)). MEASUREMENTS: Morning serum total and bioavailable testosterone levels, waist circumference (WC), waist-hip ratio (WHR), and right handgrip strength. RESULTS: Mean serum TT levels fell mildly but significantly with aging (P=.02, linear trend; one-way analysis of variance (ANOVA)), whereas mean serum bioavailable testosterone (BT) levels fell greatly with aging (P<.001, linear trend, one-way ANOVA). The rates of decline in serum TT and BT levels were 0.2% and 1.14% per year, respectively. [Correction added after online publication 14-May-2008: BT levels have been corrected from 1.44% to 1.14%.] After adjustment for adiposity according to BMI, multiple linear regression analyses showed that age remained significantly related to serum TT and BT levels. Handgrip strength decreased with age (correlation coefficient (r)=-0.394, P<.001) and was greater with higher serum BT levels (r=0.239, P<.001) but not with higher TT levels. WHR, before and after adjustment for BMI, was inversely related to serum TT (r=-0.34 and -0.197 respectively, P<.001) and BT levels (r=-0.104, P<.05 and -0.161, P<.001, respectively). CONCLUSION: In Chinese men, serum BT levels decreased with aging and may contribute to central obesity and poorer muscle strength in aging men.

A short version of the ADAM Questionnaire for androgen deficiency in Chinese men.

BACKGROUND: A 10-question screening questionnaire for androgen deficiency in aging men (ADAM) was reported in previous white but not Chinese populations. We therefore investigated the validity of a Chinese version of the Saint Louis University ADAM questionnaire to screen for androgen deficiency in Chinese men. METHODS: This was a cross-sectional study. Seven hundred ninety-six ambulatory community-based Chinese men, 18-89 years old, were recruited from October 2003 through June 2006. Self-administered Chinese ADAM questionnaire and morning blood samples for serum total testosterone (TT) and bioavailable testosterone (BT) levels were collected from all participants. Low serum BT levels (androgen deficiency) were defined as <5th percentile of serum BT levels in young healthy Chinese men (18-29 years). RESULTS: The Chinese ADAM questionnaire had good internal consistency (Cronbach alpha = 0.74) and test-retest reliability (Pearson correlation coefficient, r = 0.86; p <.001, two-tailed). As a screening test for low serum BT levels, the Chinese ADAM questionnaire has a high sensitivity of 88% but low specificity of 32%. In 6 of the 10 questions, the mean serum BT levels were significantly lower in those who answered positively than in those who answered negatively. Using a cut-off score of > or =2, a six-question short Chinese ADAM questionnaire demonstrated sensitivity, specificity, and positive and negative predictive values of 86%, 40%, 46%, and 82%, respectively. CONCLUSION: We have validated a full Chinese version and developed a shortened version of the ADAM questionnaire, and demonstrated that they are sensitive but not specific screening tests for androgen deficiency in Chinese men.

Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans.

OBJECTIVE: Fibroblast growth factor 21 (FGF21) is a metabolic regulator with multiple beneficial effects on glucose homeostasis and insulin sensitivity in animal models. This study aimed to investigate the relationship between its serum levels and various cardiometabolic parameters in humans. RESEARCH DESIGN AND METHODS: A newly developed immunoassay was used to measure serum FGF21 levels in 232 Chinese subjects recruited from our previous cross-sectional studies. The mRNA expression levels of FGF21 in the liver and adipose tissues were quantified by real-time PCR. RESULTS: Serum FGF21 levels in overweight/obese subjects were significantly higher than in lean individuals. Serum FGF21 correlated positively with adiposity, fasting insulin, and triglycerides but negatively with HDL cholesterol, after adjusting for age and BMI. Logistic regression analysis demonstrated an independent association between serum FGF21 and the metabolic syndrome. Furthermore, the increased risk of the metabolic syndrome associated with high serum FGF21 was over and above the effects of individual components of the metabolic syndrome. Our in vitro study detected a differentiation-dependent expression of FGF21 in 3T3-L1 adipocytes and human adipocytes. In db/db obese mice, FGF21 mRNA expression was markedly increased in both the liver and adipose tissue compared with that in their lean littermates. Furthermore, FGF21 expression in subcutaneous fat correlated well with its circulating concentrations in humans. CONCLUSIONS: FGF21 is a novel adipokine associated with obesity-related metabolic complications in humans. The paradoxical increase of serum FGF21 in obese individuals, which may be explained by a compensatory response or resistance to FGF21, warrants further investigation.

Bioavailable testosterone is associated with a reduced risk of amnestic mild cognitive impairment in older men.

OBJECTIVE: We investigated the risk of amnestic mild cognitive impairment (aMCI) in relation to serum bioavailable (BT) and total testosterone (TT) levels in older men. DESIGN, SETTING AND SUBJECTS: A cross-sectional study in an ambulatory setting, with older men aged 55-93 years with normal cognition, aMCI and Alzheimer's disease (AD). MEASUREMENTS: Morning serum BT and TT levels were determined. AD was diagnosed by the Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable AD and aMCI by the Petersen criteria. RESULTS: We recruited 203 Chinese older men (48 aMCI, 66 AD and 89 with normal cognition). Mean serum BT, but not TT, levels were significantly lower in the aMCI (mean BT +/- SEM 1.06 +/- 0.10 nmol/l) and AD (0.99 +/- 0.08 nmol/l) groups than in the normal controls (1.82 +/- 0.12 nmol/l) (P < 0.001, one-way anova) with no significant difference between the aMCI and AD groups. After adjustment for education, age and apolipoprotein E (apoE) genotype, logistic regression analyses showed that the serum BT level [adjusted odds ratio (OR) = 0.52, 95% confidence interval (CI) 0.32-0.85] was an independent protective factor for aMCI. For the combined outcome of aMCI and AD, the serum BT level was an independent protective factor but age and apoE epsilon4 were independent risk factors. There was no interaction between BT and age. CONCLUSIONS: In older men, serum BT, but not TT, levels were associated with a lower risk of aMCI and AD.

Interaction between the polyol pathway and non-enzymatic glycation on mesangial cell gene expression.

BACKGROUND/AIMS: Both activation of the polyol pathway and enhanced non-enzymatic glycation have been implicated in the pathogenesis of diabetic glomerulopathy. We investigated the interaction between these two pathways using normal mesangial cells (MCs) and transgenic (TG) MCs with elevated aldose reductase (AR) activity. METHODS: TG mice with expression of the human AR (hAR) gene in kidney MCs were established. Mouse glomeruli and primary cultures of MCs from hAR TG and wild-type (WT) mice were studied regarding the changes in AR activity, transforming growth factor-beta1 (TGF-beta1) and type IV collagen mRNA and protein levels, in response to BSA modified by advanced glycation end-products (AGE-BSA). RESULTS: Ex vivo addition of AGE-BSA increased AR activity, TGF-beta1 and type IV collagen mRNA levels in both WT and TG glomeruli, with greater rise in TG glomeruli. These increments were attenuated by zopolrestat, an AR inhibitor. In cultured MCs, AGE-BSA enhanced AR activity, TGF-beta(1) and type IV collagen mRNA and protein levels both in WT and TG MCs, again with greater increases in TG MCs. The AGE-induced enhancement in TGF-beta1 and type IV collagen expression were suppressed by either zopolrestat or transfection with an AR antisense oligonucleotide. CONCLUSION: These data suggest that the activation of the polyol pathway by AGEs, more marked in genetic conditions with increased AR activity, may contribute to the pathogenesis of diabetic glomerulopathy, through enhancing mesangial cell expression of TGF-beta1 and type IV collagen.