Different glycaemia-related risk factors for incident Alzheimer's disease in men and women with type 2 diabetes-A sex-specific analysis of the Hong Kong diabetes database.

AIMS: Sexual dimorphism has been reported in the epidemiology, neurobiologic susceptibility and clinical presentation of Alzheimer's disease (AD). As poor glycaemic control is associated with increased risks of AD, we aimed to investigate whether glycaemia-related risk factors also differ between men and women, using a retrospective, sex-specific analysis of a large Chinese cohort with diabetes. MATERIALS & METHODS: A total of 85,514 Chinese individuals with type 2 diabetes (T2D; 46,783 women and 38,731 men), aged ≥60 years, were identified from electronic health records and observed for incident AD. Multivariable Cox regression analysis was used to evaluate the associations with incident AD of several glycaemia-related risk factors, including severe hypoglycaemia, mean HbA1c and indices of HbA1c variability, in men and women separately. RESULTS: Over a median follow-up of 6 years, women had a higher incidence of AD than men (2.3% vs. 1.2%, p < 0.001). Both men and women shared the same independent non-glycaemic clinical predictors, which included older age, lower body mass index and longer duration of diabetes. However, for glycaemia-related risk factors, we observed that severe hypoglycaemia and indices of HbA1c variability were independent predictors of incident AD in women but not in men, and the associations were irrespective of their baseline glycaemic control and duration of diabetes. CONCLUSIONS: Our findings highlighted that glycaemia-related risk factors for incident AD differ between men and women with T2D. Strategies to maintain glycaemic stability and avoid severe hypoglycaemia might be especially important to preserve healthy cognition in older women with diabetes.

Prospective associations of circulating adipocyte fatty acid-binding protein levels with risks of renal outcomes and mortality in type 2 diabetes.

AIMS/HYPOTHESIS: Elevated circulating adipocyte fatty acid-binding protein (AFABP) levels have been found to correlate with diabetic nephropathy staging in cross-sectional studies. However, it remains unclear whether these higher serum levels reflect a role of AFABP in the development of diabetic kidney disease (DKD), or simply result from its impaired renal clearance in DKD. Here we investigated prospectively the prognostic importance of serum AFABP level in the development of adverse renal outcomes in a large clinic-based cohort of participants with type 2 diabetes. METHODS: Baseline serum AFABP levels were measured in 5454 Chinese participants from the Hong Kong West Diabetes Registry. The association between circulating AFABP levels and incident adverse renal outcomes-defined as a composite endpoint of a sustained 40% decline in eGFR, end-stage renal disease requiring renal replacement therapy or kidney transplantation, or renal deaths-was evaluated using multivariable Cox regression analysis. RESULTS: Over a median follow-up of 5 years, 754 of the 5454 participants developed incident adverse renal outcomes. Elevated circulating AFABP levels were independently associated with incident adverse renal outcomes (HR 1.43, 95% CI 1.31, 1.57, p < 0.001) after adjustments for conventional risk factors for DKD progression. Importantly, the prognostic role of serum AFABP was independent of the baseline albuminuria status or eGFR levels of the study participants. CONCLUSIONS/INTERPRETATION: Circulating AFABP levels were predictive of incident adverse renal outcomes, even in participants with relatively well-preserved kidney function at baseline, suggesting its potential to be a useful marker for early risk stratification in DKD.

Circulating Adipocyte Fatty Acid-Binding Protein Concentrations Predict Multiple Mortality Outcomes among Men and Women with Diabetes.

INTRODUCTION: Raised circulating adipocyte fatty acid-binding protein (AFABP) concentrations are associated with various adverse health conditions. However, their relationship with mortality remains to be defined, especially in view of the sexual dimorphism of circulating AFABP concentrations. Here we investigated prospectively whether serum AFABP concentrations predict multiple mortality outcomes in men and women alike, using a large clinic-based cohort of individuals with type 2 diabetes, a condition with raised AFABP concentrations. METHODS: Baseline serum AFABP concentrations were measured in 5305 research participants with a monoclonal antibody-based sandwich immunoassay. The role of circulating AFABP concentrations in predicting mortality outcomes was evaluated by multivariable Cox regression analysis. RESULTS: Among the 5305 participants (59% men) in this study, over a median follow-up of 5 years, there were 512 deaths (19.3 deaths per 1000 person-years). Circulating AFABP concentrations, with higher levels in women at baseline, predicted all-cause mortality (P < 0.001), cardiovascular mortality (P = 0.037), and infection-related deaths (P < 0.002) among all participants. In sex-specific analyses, circulating AFABP concentration was an independent predictor of all-cause mortality in both men and women and a predictor of cancer-related deaths and infection-related deaths in men only. Furthermore, the addition of serum AFABP concentrations improved the time-dependent c statistics in predicting all-cause mortality in participants with type 2 diabetes (P = 0.008). CONCLUSIONS: Circulating AFABP concentration was an independent predictor of various mortality outcomes in type 2 diabetes over and above known risk factors of reduced survival in men and women. The role of AFABP as a prognostic biomarker and therapeutic target warrants further investigation.

Exome-chip association analysis reveals an Asian-specific missense variant in PAX4 associated with type 2 diabetes in Chinese individuals.

AIMS/HYPOTHESIS: Genome-wide association studies (GWASs) have identified many common type 2 diabetes-associated variants, mostly at the intronic or intergenic regions. Recent advancements of exome-array genotyping platforms have opened up a novel means for detecting the associations of low-frequency or rare coding variants with type 2 diabetes. We conducted an exomechip association analysis to identify additional type 2 diabetes susceptibility variants in the Chinese population. METHODS: An exome-chip association study was conducted by genotyping 5640 Chinese individuals from Hong Kong, using a custom designed exome array, the Asian Exomechip. Single variant association analysis was conducted on 77,468 single nucleotide polymorphisms (SNPs). Fifteen SNPs were subsequently genotyped for replication analysis in an independent Chinese cohort comprising 12,362 individuals from Guangzhou. A combined analysis involving 7189 cases and 10,813 controls was performed. RESULTS: In the discovery stage, an Asian-specific coding variant rs2233580 (p.Arg192His) in PAX4, and two variants at the known loci, CDKN2B-AS1 and KCNQ1, were significantly associated with type 2 diabetes with exome-wide significance (p discovery < 6.45 × 10-7). The risk allele (T) of PAX4 rs2233580 was associated with a younger age at diabetes diagnosis. This variant was replicated in an independent cohort and demonstrated a stronger association that reached genome-wide significance (p meta-analysis [p meta] = 3.74 × 10-15) in the combined analysis. CONCLUSIONS/INTERPRETATION: We identified the association of a PAX4 Asian-specific missense variant rs2233580 with type 2 diabetes in an exome-chip association analysis, supporting the involvement of PAX4 in the pathogenesis of type 2 diabetes. Our findings suggest PAX4 is a possible effector gene of the 7q32 locus, previously identified from GWAS in Asians.

Health Complications of Obesity: 224 Obesity-Associated Comorbidities from a Mechanistic Perspective.

Obesity is associated with a wide range of comorbidities that transverse multiple specialties in clinical medicine. The development of these comorbidities is driven by various mechanistic changes including chronic inflammation and oxidative stress, increased growth-promoting adipokines, insulin resistance, endothelial dysfunction, direct loading and infiltrative effect of adiposity, heightened activities of the renin-angiotensin-aldosterone system and sympathetic nervous system, impaired immunity, altered sex hormones, altered brain structure, elevated cortisol levels, and increased uric acid production, among others. Some of the comorbidities might develop secondary to one or more other comorbidities. Considering the obesity-associated comorbidities in the context of the mechanistic changes is helpful in understanding these conditions and in guiding treatment and future research.

Higher Circulating Adiponectin Concentrations Predict Incident Cancer in Type 2 Diabetes - The Adiponectin Paradox.

INTRODUCTION: Despite the beneficial cardiometabolic effects of adiponectin demonstrated in preclinical studies, paradoxically higher circulating adiponectin concentrations have been found in epidemiological studies to be associated with incident cardiovascular events, renal outcomes, and mortality in patients with diabetes. On the other hand, diabetes is also associated with an increased risk of cancer. Here, we investigated prospectively the association between circulating adiponectin concentrations and incident cancer using a cohort of exclusively individuals with type 2 diabetes. MATERIALS AND METHODS: Baseline serum adiponectin concentrations were measured in 5658 participants recruited from the Hong Kong West Diabetes Registry. The associations of circulating adiponectin concentrations with incident cancer and cancer-related deaths were evaluated using multivariable Cox regression analysis, with hazard ratio (HR) for adiponectin referring to the respective risk per doubling of serum adiponectin concentration. RESULTS: Over a median-follow up of 6.5 years, 7.53% and 3% of participants developed cancer and had cancer-related deaths, respectively. Serum adiponectin concentrations were significantly higher in those who had incident cancer (9.8 µg/mL vs 9.1 µg/mL, P < 0.001) and cancer-related deaths (11.5 µg/mL vs 9.3 µg/mL, P < 0.001) compared with those without. Moreover, in multivariable analyses, serum adiponectin concentration was independently associated with both incident cancer (hazard ratio, 1.19; 95% confidence interval, 1.05-1.35; P = 0.006) and cancer-related deaths (hazard ratio, 1.23; 95% confidence interval, 1.03-1.47; P = 0.024). CONCLUSIONS: Higher serum adiponectin concentration was independently associated with incident cancer and cancer-related deaths in type 2 diabetes, indicating that adiponectin paradox can be observed in another major diabetic complication in addition to cardiovascular and kidney diseases.

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.

Genetic Regulation of Pigment Epithelium-Derived Factor (PEDF): An Exome-Chip Association Analysis in Chinese Subjects With Type 2 Diabetes.

Elevated circulating levels of pigment epithelium-derived factor (PEDF) have been reported in patients with type 2 diabetes (T2D) and its associated microvascular complications. This study aimed to 1) identify the genetic determinants influencing circulating PEDF levels in a clinical setting of T2D, 2) examine the relationship between circulating PEDF and diabetes complications, and 3) explore the causal relationship between PEDF and diabetes complications. An exome-chip association study on circulating PEDF levels was conducted in 5,385 Chinese subjects with T2D. A meta-analysis of the association results of the discovery stage (n = 2,936) and replication stage (n = 2,449) was performed. The strongest association was detected at SERPINF1 (p.Met72Thr; Pcombined = 2.06 × 10-57; ß [SE] -0.33 [0.02]). Two missense variants of SMYD4 (p.Arg131Ile; Pcombined = 7.56 × 10-25; ß [SE] 0.21 [0.02]) and SERPINF2 (p.Arg33Trp; Pcombined = 8.22 × 10-10; ß [SE] -0.15 [0.02]) showed novel associations at genome-wide significance. Elevated circulating PEDF levels were associated with increased risks of diabetic nephropathy and sight-threatening diabetic retinopathy. Mendelian randomization analysis showed suggestive evidence of a protective role of PEDF on sight-threatening diabetic retinopathy (P = 0.085). Our study provided new insights into the genetic regulation of PEDF and further support for its potential application as a biomarker for diabetic nephropathy and sight-threatening diabetic retinopathy. Further studies to explore the causal relationship of PEDF with diabetes complications are warranted.

An Exome-Chip Association Analysis in Chinese Subjects Reveals a Functional Missense Variant of GCKR That Regulates FGF21 Levels.

Fibroblast growth factor 21 (FGF21) is increasingly recognized as an important metabolic regulator of glucose homeostasis. Here, we conducted an exome-chip association analysis by genotyping 5,169 Chinese individuals from a community-based cohort and two clinic-based cohorts. A custom Asian exome-chip was used to detect genetic determinants influencing circulating FGF21 levels. Single-variant association analysis interrogating 70,444 single nucleotide polymorphisms identified a novel locus, GCKR, significantly associated with circulating FGF21 levels at genome-wide significance. In the combined analysis, the common missense variant of GCKR, rs1260326 (p.Pro446Leu), showed an association with FGF21 levels after adjustment for age and sex (P = 1.61 × 10-12; ß [SE] = 0.14 [0.02]), which remained significant on further adjustment for BMI (P = 3.01 × 10-14; ß [SE] = 0.15 [0.02]). GCKR Leu446 may influence FGF21 expression via its ability to increase glucokinase (GCK) activity. This can lead to enhanced FGF21 expression via elevated fatty acid synthesis, consequent to the inhibition of carnitine/palmitoyl-transferase by malonyl-CoA, and via increased glucose-6-phosphate-mediated activation of the carbohydrate response element binding protein, known to regulate FGF21 gene expression. Our findings shed new light on the genetic regulation of FGF21 levels. Further investigations to dissect the relationship between GCKR and FGF21, with respect to the risk of metabolic diseases, are warranted.

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.