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Obesity is a major risk factor for cancers including hepatocellular carcinoma (HCC) that develops from a background of non-alcoholic fatty liver disease (NAFLD). Hypercholesterolemia is a common comorbidity of obesity. Although cholesterol biosynthesis mainly occurs in the liver, its role in HCC development of obese people remains obscure. Using high-fat high-carbohydrate diet-associated orthotopic and spontaneous NAFLD-HCC mouse models, we found that hepatic cholesterol accumulation in obesity selectively suppressed natural killer T (NKT) cell-mediated antitumor immunosurveillance. Transcriptome analysis of human liver revealed aberrant cholesterol metabolism and NKT cell dysfunction in NAFLD patients. Notably, cholesterol-lowering rosuvastatin restored NKT expansion and cytotoxicity to prevent obesogenic diet-promoted HCC development. Moreover, suppression of hepatic cholesterol biosynthesis by a mammalian target of rapamycin (mTOR) inhibitor vistusertib preceded tumor regression, which was abolished by NKT inactivation but not CD8(+) T cell depletion. Mechanistically, sterol regulatory element-binding protein 2 (SREBP2)-driven excessive cholesterol production from hepatocytes induced lipid peroxide accumulation and deficient cytotoxicity in NKT cells, which were supported by findings in people with obesity, NAFLD and NAFLD-HCC. This study highlights mTORC1/SREBP2/cholesterol-mediated NKT dysfunction in the tumor-promoting NAFLD liver microenvironment, providing intervention strategies that invigorating NKT cells to control HCC in the obesity epidemic.

Previous observational studies reported associations between non-steroidal anti-inflammatory drugs (NSAIDs) and major depressive disorder (MDD), however, these associations are often inconsistent and underlying biological mechanisms are still poorly understood. We conducted a two-sample Mendelian randomisation (MR) study to examine relationships between genetic variants and NSAID target gene expression or DNA methylation (DNAm) using publicly available expression, methylation quantitative trait loci (eQTL or mQTL) data and genetic variant-disease associations from genome-wide association studies (GWAS of MDD). We also assessed drug exposure using gene expression and DNAm levels of NSAID targets as proxies. Genetic variants were robustly adjusted for multiple comparisons related to gene expression, DNAm was used as MR instrumental variables and GWAS statistics of MDD as the outcome. A 1-standard deviation (SD) lower expression of NEU1 in blood was related to lower C-reactive protein (CRP) levels of −0.215 mg/L (95% confidence interval (CI): 0.128–0.426) and a decreased risk of MDD (odds ratio [OR] = 0.806; 95% CI: 0.735–0.885; p = 5.36 × 10−6). A concordant direction of association was also observed for NEU1 DNAm levels in blood and a risk of MDD (OR = 0.886; 95% CI: 0.836–0.939; p = 4.71 × 10−5). Further, the genetic variants associated with MDD were mediated by NEU1 expression via DNAm (β = −0.519; 95% CI: −0.717 to −0.320256; p = 3.16 × 10−7). We did not observe causal relationships between inflammatory genetic marker estimations and MDD risk. Yet, we identified a concordant association of NEU1 messenger RNA and an adverse direction of association of higher NEU1 DNAm with MDD risk. These results warrant increased pharmacovigilance and further in vivo or in vitro studies to investigate NEU1 inhibitors or supplements for MDD.

BackgroundAdipose tissue plays a pivotal role in the pathology of metabolic disorders. In the past decade, brown and brown-like adipose tissues were detected in adult humans and show therapeutic potential in ageing-related metabolic diseases.ObjectiveThis study investigated expressions of major brown adipose markers in white adipose tissue (WAT) of different ages. Their associations with metabolic parameters and key adipokines were interrogated.DesignCross-sectional study, 2019-2021.MethodsWe recruited 21 young, 67 middle-aged, and 34 older patients. Omental adipose tissues were collected, and expressions of key brown markers and adipokines and the adipocyte size were evaluated. The fat depot distribution was evaluated by computed tomography.ResultsUCP1 and PRDM16 mRNA expressions declined with ageing in WAT and were more associated with age, than with the body mass index (BMI). The increased visceral adipose tissue (VAT) amount, as well as the VAT to subcutaneous adipose tissue (SAT) ratio, was decreased in the highest tertile of UCP1 expression, while individuals in different PRDM16 mRNA tertiles exhibited similar fat distribution. UCP1 mRNA was positively correlated with ADIPOQ and the strength of the correlation declined with ageing. In contrast, the association between UCP1 and LEP was insignificant in young and middle-aged groups but became significantly correlated in the older-people group. We also found a positive correlation between UCP1 and PRDM16.ConclusionsPRDM16 and UCP1, despite their key functions in adipose browning, exhibit differential clinical correlations with metabolic features in human WAT in an age-dependent manner. These two genes may participate in the pathogenesis of ageing-related metabolic diseases, but with distinct mechanisms.

Objective We aimed to evaluate the impact of early initiation of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiovascular (CV) outcomes in people with type 2 diabetes (T2D) with known or at risk of atherosclerotic cardiovascular disease (ASCVD). Research design and methods T2D with first prescription of SGLT2i (Dx-to-Rx time) ≤12 months were matched with >12 months using propensity score derived from logistic regression. T2D were divided into 3 groups: (i) known ASCVD; (ii) additional CV risk factor(s) and; (iii) without ASCVD or additional CV risk factors. Incidence rates of 3-point major adverse cardiovascular events (MACE, including non-fatal stroke, non-fatal myocardial infarction and CV death) were compared between Dx-to-Rx time ≤12 months and >12 months across 3 subgroups. Results Median follow-up was 2.8 years (IQR 2.2 to 3.4). Among 29,309 T2D (mean age 57.6±11.4 years, 59.0% men), 23.6% had established ASCVD and 66.6% had additional CV risk factors. Overall, 19.0% of patients had Dx-to-Rx time ≤12 month which was associated with lower rates of MACE [hazard ratio (HR) = 0.27, 95%CI: 0.17–0.42]. Benefits of early initiation of SGLT2i was observed in patients with additional CV risk factors or known ASCVD but not in those without CV risk factors or ASCVD (P for interaction = 0.001). Conclusion Early initiation of SGLT2 inhibitor was associated with lower MACE rates in T2D with known or at risk of ASCVD.

Insulin deficiency (ID) and resistance (IR) contribute to progression from normal glucose tolerance to diabetes to insulin requirement although their relative contributions in young-onset diabetes is unknown.We examined the associations of HOMA2 using fasting plasma glucose and C-peptide in Chinese aged 20-50 years with (1) progression to type 2 diabetes (T2D) in participants without diabetes in a community-based cohort (1998-2013) and (2) glycaemic deterioration in patients with T2D in a clinic-based cohort (1995-2014). We defined ID as HOMA2-%B below median and insulin IR as HOMA2-IR above median.During 10-year follow-up, 62 (17.9%) of 347 community-dwelling participants progressed to T2D. After 8.6 years, 291 (48.1%) of 609 patients with T2D had glycaemic deterioration. At baseline, progressors for T2D had higher HOMA2-IR, while in patients with T2D, progressors for glycaemic deterioration had higher HOMA2-IR and lower HOMA2-%B than non-progressors. The non-ID/IR group and the ID/IR group had an adjusted odds ratios of 2.47 (95% CI: 1.28, 4.94) and 5.36 (2.26, 12.79), respectively, for incident T2D versus the ID/non-IR group. In patients with T2D, 50% of the ID/IR group required insulin at 6.7 years versus around 11 years in the non-ID/IR or ID/non-IR, and more than 15 years in the non-ID/non-IR group. Compared with the latter group, the adjusted hazard ratios were 2.74 (1.80, 4.16) in the ID/non-IR, 2.73 (1.78, 4.19) in the non-ID/IR and 4.46 (2.87, 6.91) in the ID/IR group (p-interaction = 0.049).In young Chinese adults, IR and ID contributed to progression to T2D and glycaemic deterioration.

Background The prevalence of type 2 diabetes has increased in both young and old people. We examined age-specific associations and population attributable fractions (PAFs) of risk factors for all-cause and cause-specific mortality in people with type 2 diabetes. Methods and findings We analysed data from 360,202 Chinese with type 2 diabetes who participated in a territory-wide diabetes complication screening programme in Hong Kong between January 2000 and December 2019. We compared the hazard ratios and PAFs of eight risk factors, including three major comorbidities (cardiovascular disease [CVD], chronic kidney disease [CKD], all-site cancer) and five modifiable risk factors (suboptimal HbA1c, suboptimal blood pressure, suboptimal low-density lipoprotein cholesterol, smoking, and suboptimal weight), for mortality across four age groups (18 to 54, 55 to 64, 65 to 74, and ≥75 years). During a median 6.0 years of follow-up, 44,396 people died, with cancer, CVD, and pneumonia being the leading causes of death. Despite a higher absolute mortality risk in older people (crude all-cause mortality rate: 59.7 versus 596.2 per 10,000 person-years in people aged 18 to 54 years versus those aged ≥75 years), the relative risk of all-cause and cause-specific mortality associated with most risk factors was higher in younger than older people, after mutually adjusting for the eight risk factors and other potential confounders including sex, diabetes duration, lipid profile, and medication use. The eight risk factors explained a larger proportion of mortality events in the youngest (PAF: 51.6%, 95% confidence interval [CI] [39.1%, 64.0%], p < 0.001) than the oldest (PAF: 35.3%, 95% CI [27.2%, 43.4%], p < 0.001) age group. Suboptimal blood pressure (PAF: 16.9%, 95% CI [14.7%, 19.1%], p < 0.001) was the leading attributable risk factor for all-cause mortality in the youngest age group, while CKD (PAF: 15.2%, 95% CI [14.0%, 16.4%], p < 0.001) and CVD (PAF: 9.2%, 95% CI [8.3%, 10.1%], p < 0.001) were the leading attributable risk factors in the oldest age group. The analysis was restricted to Chinese, which might affect the generalisability to the global population with differences in risk profiles. Furthermore, PAFs were estimated under the assumption of a causal relationship between risk factors and mortality. However, reliable causality was difficult to establish in the observational study. Conclusions Major comorbidities and modifiable risk factors were associated with a greater relative risk for mortality in younger than older people with type 2 diabetes and their associations with population mortality burden varied substantially by age. These findings highlight the importance of early control of blood pressure, which could reduce premature mortality in young people with type 2 diabetes and prevent the onset of later CKD and related mortality at older ages.

Background Little is known about the lifetime risk of progression to diabetes in the Asian population. We determined remaining lifetime risk of diabetes and life years spent with diabetes in Chinese people with normoglycemia and prediabetes. Methods and findings Using territory-wide diabetes surveillance data curated from electronic medical records of Hong Kong Hospital Authority (HA), we conducted a population-based cohort study in 2,608,973 individuals followed from 2001 to 2019. Prediabetes and diabetes were identified based on laboratory measurements, diagnostic codes, and medication records. Remaining lifetime risk and life years spent with diabetes were estimated using Monte Carlo simulations with state transition probabilities based on a Markov chain model. Validations were performed using several sensitivity analyses and modified survival analysis. External replication was performed using the China Health and Retirement Longitudinal Survey (CHARLS) cohort (2010 to 2015). The expected remaining lifetime risk of developing diabetes was 88.0 (95% confidence intervals: 87.2, 88.7)% for people with prediabetes and 65.9 (65.8, 65.9)% for people with normoglycemia at age 20 years. A 20-year-old person with prediabetes would live with diabetes for 32.5 (32.0, 33.1) years or 51.6 (50.8, 52.3)% of remaining life years, whereas a person with normoglycemia at 20 years would live 12.7 (12.7, 12.7) years with diabetes or 18.4 (18.4, 18.5)% of remaining life years. Women had a higher expected remaining lifetime risk and longer life years with diabetes compared to men. Results are subjected to possible selection bias as only people who undertook routine or opportunistic screening were included. Conclusions These findings suggest that Hong Kong, an economically developed city in Asia, is confronted with huge challenge of high lifetime risk of diabetes and long life years spent with diabetes, especially in people with prediabetes. Effective public health policies and targeted interventions for preventing progression to diabetes are urgently needed.

We aim to assess the long-term impact of acute kidney injury (AKI) on progression of diabetic kidney disease (DKD) and all-cause mortality and investigate determinants of AKI in Chinese patients with type 2 diabetes (T2D). A consecutive cohort of 9,096 Chinese patients with T2D from the Hong Kong Diabetes Register was followed for 12 years (mean ± SD age 57 ± 13.2 years; 46.9% men; median duration of diabetes 5 years). AKI was defined based on the Kidney Disease: Improving Global Outcomes (KDIGO) criteria using serum creatinine. Estimated glomerular filtration rate measurements were used to identify the first episode with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Polygenic risk score (PRS) composed of 27 single nucleotide polymorphisms (SNPs) known to be associated with serum uric acid (SUA) in European populations was used to examine the role of SUA in pathogenesis of AKI, CKD, and ESRD. Validation was sought in an independent cohort including 6,007 patients (age 61.2 ± 10.9 years; 59.5% men; median duration of diabetes 10 years). Patients with AKI had a higher risk for developing incident CKD (hazard ratio 14.3 [95% CI 12.69–16.11]), for developing ESRD (12.1 [10.74–13.62]), and for all-cause death (7.99 [7.31–8.74]) compared with those without AKI. Incidence rate for ESRD among patients with no episodes of AKI and one, two, and three or more episodes of AKI was 7.1, 24.4, 32.4, and 37.3 per 1,000 person-years, respectively. Baseline SUA was a strong independent predictor for AKI. A PRS composed of 27 SUA-related SNPs was associated with AKI and CKD in both discovery and replication cohorts but not ESRD. Elevated SUA may increase the risk of DKD through increasing AKI. The identification of SUA as a modifiable risk factor and PRS as a nonmodifiable risk factor may facilitate the identification of individuals at high risk to prevent AKI and its long-term impact in T2D.

The long-term effects of metformin in individuals with type 2 diabetes who are at increased risk of severe respiratory infections are unknown. This study aimed to evaluate the effects of metformin use on the risk of first pneumonia hospitalisation and pneumonia-related death in a cohort of Chinese individuals with type 2 diabetes.We performed a retrospective analysis of a consecutive cohort of 22,638 individuals with type 2 diabetes in the Hong Kong Diabetes Register enrolled between 2001 and 2018, with follow-up until 31 December 2019. Overlap propensity-score weighting was performed to balance baseline characteristics.Of 22,638 individuals with type 2 diabetes, after excluding those who had not been prescribed any glucose-lowering drugs (GLDs) and/or with eGFR ≤30 ml minLong-term use of metformin was associated with reduced risk of pneumonia and pneumonia-related death among Chinese individuals with diabetes. The relevance of these results to other respiratory infections merits further investigation.

We postulated that the increased lifetime risk of chronic kidney disease (CKD) in young-onset diabetes is attributable to both long disease duration and more aggressive disease. We examined whether age at diabetes diagnosis modifies the effect of diabetes duration on risk of CKD.We included 436,744 people with incident type 2 diabetes in the Hong Kong Diabetes Surveillance Database (HKDSD) and 16,979 people with prevalent type 2 diabetes in the Hong Kong Diabetes Register (HKDR). We used Poisson models to describe joint effects of age at diabetes diagnosis, diabetes duration and attained age on incidence of CKD in HKDSD. We used Cox proportional hazards models to examine interaction effect of age at diabetes diagnosis and diabetes duration on risk of CKD with adjustment for confounders in HKDR.During a median follow-up of 5.3 years, 134,043 cases of CKD were recorded in the HKDSD. The incidence rate ratio for CKD comparing people of the same attained age but diagnosed with diabetes at ages 5 years apart was higher for people with a younger age at diabetes diagnosis, but decreased with increasing age at diabetes diagnosis. During a median follow-up of 6.3 years, 6500 people developed CKD in the HKDR. The increased risk of CKD with longer diabetes duration decreased with older age at diabetes diagnosis. The adjusted HR for CKD associated with 5 year increase in diabetes duration was 1.37 (95% CI 1.13, 1.65) in people with diabetes diagnosed at 20-29 years and 1.01 (95% CI 0.87, 1.18) in those diagnosed at ≥70 years.Young age at diabetes diagnosis amplified the effect of increasing diabetes duration on increased risk of CKD.

Background Type 2 diabetes (T2D) is a progressive disease whereby there is often deterioration in glucose control despite escalation in treatment. There is significant heterogeneity to this progression of glycemia after onset of diabetes, yet the factors that influence glycemic progression are not well understood. Given the tremendous burden of diabetes in the Chinese population, and limited knowledge on factors that influence glycemia, we aim to identify the clinical and genetic predictors for glycemic progression in Chinese patients with T2D. Methods and findings In 1995–2007, 7,091 insulin-naïve Chinese patients (mean age 56.8 ± 13.3 [SD] years; mean age of T2D onset 51.1 ± 12.7 years; 47% men; 28.4% current or ex-smokers; median duration of diabetes 4 [IQR: 1–9] years; mean HbA1c 7.4% ± 1.7%; mean body mass index [BMI] 25.3 ± 4.0 kg/m2) were followed prospectively in the Hong Kong Diabetes Register. We examined associations of BMI and other clinical and genetic factors with glycemic progression defined as requirement of continuous insulin treatment, or 2 consecutive HbA1c ≥8.5% while on ≥2 oral glucose-lowering drugs (OGLDs), with validation in another multicenter cohort of Hong Kong Diabetes Biobank. During a median follow-up period of 8.8 (IQR: 4.8–13.3) years, incidence of glycemic progression was 48.0 (95% confidence interval [CI] 46.3–49.8) per 1,000 person-years with 2,519 patients started on insulin. Among the latter, 33.2% had a lag period of 1.3 years before insulin was initiated. Risk of progression was associated with extremes of BMI and high HbA1c. On multivariate Cox analysis, early age at diagnosis, microvascular complications, high triglyceride levels, and tobacco use were additional independent predictors for glycemic progression. A polygenic risk score (PRS) including 123 known risk variants for T2D also predicted rapid progression to insulin therapy (hazard ratio [HR]: 1.07 [95% CI 1.03–1.12] per SD; P = 0.001), with validation in the replication cohort (HR: 1.24 [95% CI 1.06–1.46] per SD; P = 0.008). A PRS using 63 BMI-related variants predicted BMI (beta [SE] = 0.312 [0.057] per SD; P = 5.84 × 10−8) but not glycemic progression (HR: 1.01 [95% CI 0.96–1.05] per SD; P = 0.747). Limitations of this study include potential misdiagnosis of T2D and lack of detailed data of drug use during follow-up in the replication cohort. Conclusions Our results show that approximately 5% of patients with T2D failed OGLDs annually in this clinic-based cohort. The independent associations of modifiable and genetic risk factors allow more precise identification of high-risk patients for early intensive control of multiple risk factors to prevent glycemic progression., Author summary Why was this study done? There is marked heterogeneity in the rate of progression to insulin requirement in patients with type 2 diabetes (T2D). Whereas some patients can maintain optimal glycemic control with oral glucose-lowering drugs for prolonged periods, others experience rapid deterioration in glycemia, requiring early insulin treatment. It is important to gain insight into what factors are associated with glycemic progression. Previous studies identified baseline HbA1c, young age, and weight gain as independent clinical predictors for glycemic progression in White populations, but there is a paucity of data in Asians. Besides environmental and lifestyle factors including obesity, it is well known that genetic factors play a pivotal role in the onset of diabetes. However, it remains unclear whether genetic variants of body mass index (BMI) and T2D predicts glycemic progression once T2D develops. Moreover, genetic variants associated with response to oral glucose-lowering drugs might also predict glycemic progression. What did the researchers do and find? We investigated glycemic progression among 7,091 Chinese patients with T2D from the Hong Kong Diabetes Register enrolled between 1995 and 2007. We explored the associations of clinical variables and different polygenic risk scores (PRSs) of obesity, T2D, and response to oral glucose-lowering drugs with glycemic progression and validated the associations of PRSs in another multicenter prospective cohort of Hong Kong Diabetes Biobank (HKDB). We found that there was an approximately 1.3-year delay of insulin use after oral glucose-lowering drug failure in real-world practice. We observed a U-shape association between BMI and glycemic progression and found that young age of diagnosis, high HbA1c and triglyceride, use of tobacco, and presence of microvascular complications also predicted rapid glycemic progression. We found that the PRS derived from 123 known risk variants for T2D was associated with early age of diagnosis and rapid glycemic progression, with validation in the replication cohort of HKDB, whereas the PRS derived from 63 BMI-related variants was associated with BMI but not glycemic progression. What do these findings mean? This study highlighted the delay in insulin treatment after oral glucose-lowering drug failure, which represents an important treatment gap in clinical practice. This work emphasized the importance of both genetic and modifiable risk factors, notably lipo-glucotoxicity, obesity, and tobacco use on glycemic progression, which enables identification of high-risk patients for optimal control of risk factors to improve glycemic durability. This study provides novel insights toward the underlying pathophysiology underlining glycemic progression, highlighting some overlap with pathogenesis of T2D. Our work highlights the potential utility of incorporating PRSs for drug response to guide clinical management of T2D.

Diabetic kidney disease (DKD) and its comorbidities can be prevented by treating multiple targets. Technology-assisted team-based care with regular feedback and patient empowerment can improve the attainment of multiple targets and clinical outcomes in patients with type 2 diabetes, but the effects of this intervention on patients with DKD are unclear.To evaluate the effect of the Joint Asia Diabetes Evaluation (JADE) web portal, nurse reminders, and team-based care on multiple risk factors in patients with DKD.This 12-month multinational, open-label randomized clinical trial was conducted between June 27, 2014, and February 19, 2019, at 13 hospital-based diabetes centers in 8 countries or regions in Asia. All patients who participated had DKD. The intention-to-treat data analysis was performed from April 7 to June 30, 2020.Patients were randomized in a 1:1:1 ratio at each site to usual care, empowered care, or team-based empowered care. All patients underwent a JADE web portal-guided structured assessment at baseline and month 12. Patients in the usual care and empowered care groups received a medical follow-up. Patients in the empowered care group also received a personalized JADE report and nurse telephone calls every 3 months. Patients in the team-based empowered care group received additional face-to-face reviews every 3 months from a physician-nurse team.The primary outcome was the proportion of patients who attained multiple treatment targets (defined as ≥3 of 5 targets: HbA1c level7.0% [53 mmol/mol], blood pressure130/80 mm Hg, low-density lipoprotein cholesterol level1.8 mmol/L, triglyceride level1.7 mmol/L, and/or persistent use of renin-angiotensin-aldosterone system inhibitors).A total of 2393 patients (mean [SD] age, 67.7 [9.8] years; 1267 men [52.9%]) were randomized to the usual care group (n = 795), empowered care group (n = 802), and team-based empowered care group (n = 796). At baseline, 34.7% patients (n = 830) were on 3 treatment targets. On intention-to-treat analysis, the team-based empowered care group had the highest proportion of patients who had further increase in attainment of multiple treatment targets (within-group differences: usual care group, 3.9% [95% CI, 0.0%-7.8%]; empowered care group, 1.3% [95% CI, -2.8% to 5.4%]; team-based empowered care group, 9.1% [95% CI, 4.7%-13.5%]). The team-based empowered care group was more likely to attain multiple treatment targets than the usual care group (risk ratio [RR], 1.17; 95% CI, 1.00-1.37) and the empowered care group (RR, 1.25; 95% CI, 1.06-1.48) after adjustment for site. Compared with the group that did not attain multiple treatment targets, the group that attained multiple treatment targets reported a lower incidence of cardiovascular, kidney, and cancer events (8.4% [n = 51] vs 14.5% [n = 134]; P = .004). Analysis of the per-protocol population yielded similar results.This trial found that technology-assisted team-based care for 12 months improved the attainment of multiple treatment targets as well as empowerment in patients with DKD.ClinicalTrials.gov Identifier: NCT02176278.

Recent reviews recommended the use of the aldosterone/renin ratio (ARR) to screen for primary hyperaldosteronism. However, widely different cutoff levels have been proposed, and test characteristics of ARR under different conditions of sampling are not known. We conducted a retrospective review among 45 subjects with carefully validated diagnoses of primary hyperaldosteronism and 17 subjects with essential hypertension to study the utility of ARR. Sixty-two patients with 75 sets of plasma renin activity (PRA), aldosterone, and ARR values from a postural study and 48 sets of values from a saline suppression test were analyzed. Ninety-four percent of these subjects underwent investigations because of hypokalemic hypertension.ARR yielded larger areas under the curve in the receiver-operating-characteristics curve than PRA or aldosterone under all conditions of testing. Our results confirmed the superiority of ARR to either aldosterone or PRA alone as a diagnostic test for primary hyperaldosteronism.ARR cutoff levels were significantly affected by the condition of testing. Depending on posture and time of day, it varied from 13.1-35.0 ng/dl per ng/ml.h in our study population. When using ARR for screening primary hyperaldosteronism, posture and time of sampling should be standardized both within and between centers to minimize variability in cutoff levels.

In type 2 diabetes (T2D), copresence of low-density lipoprotein cholesterol (LDL-C)2.8 mmol/L with triglyceride1.7 mmol/L or with albuminuria synergistically increased cancer risk. We tested whether use of renin angiotensin system inhibitors attenuated the increased cancer risk associated with these two risk subphenotypes.A prospective cohort of 4307 patients with T2D enrolled from December 1996 to January 2005 was analysed using a new user cohort design. Cox model analysis was used to obtain hazard ratios and 95% confidence intervals. The study measured additive interactions between nonuse of renin angiotensin system inhibitors and low LDL-C plus low triglyceride or albuminuria for the risk of cancer. A positive interaction suggests a specific drug effect on the low LDL-C-related cancer risk.During 18 769 person years of follow-up (median follow-up years: 4.44), 4.48% (n = 193) of patients developed cancer. Use of renin angiotensin system inhibitors was associated with reduced cancer risk among patients with copresence of low LDL-C plus low triglyceride or low LDL-C plus albuminuria but not in patients without these subphenotypes. In multivariable analysis, renin angiotensin system inhibitor usage attenuated the hazard ratio of copresence of low LDL-C plus low triglyceride versus lack of this subphenotype for cancer from 2.08 (95% CI: 1.25-3.47) to 1.13 (0.61-2.11) with significant additive interaction (p = 0.0225). Similarly, RAS inhibitor usage attenuated the hazard ratio of copresence of low LDL-C plus albuminuria versus lack of this subphenotype for cancer from 1.99 (95% CI: 1.12-3.56) to 0.82 (0.43-1.54) with significant additive interaction (p = 0.0009).In T2D, renin angiotensin system inhibitor usage may specifically attenuate the low LDL-C-related cancer risk.

Diabetes is a disorder of energy metabolism associated with increased cancer risk, but the underlying mechanism is poorly understood. In a prospective cohort of patients enrolled in the Hong Kong Diabetes Registry, we explored risk factors for cancer including drug usage in type 2 diabetes. In a series of published papers, we reported a linear risk association of cancer with glycated haemoglobin with a threshold at 6.0%-6.5% and non-linear risk associations of body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride and white blood cell (WBC) count in V-shaped or A-shaped manners. Detailed pharmacoepidemiological analysis revealed markedly attenuated cancer risk in patients treated with insulin and oral anti-diabetic drugs compared with non-users of these drugs. We further observed significant drug-subphenotype interactions with attenuated cancer risk in metformin users with low high-density lipoprotein cholesterol, renin-angiotensin system (RAS) inhibitor users with high WBC count and statin users with co-presence of low low-density lipoprotein cholesterol plus albuminuria or low triglyceride. These novel observations corroborate with experimental findings of possible consequences of hyperglycaemia on dysregulation of cholesterol metabolism, renin-angiotensin system and adenosine 5'-monophosphate-activated protein kinase pathways, all of which may be implicated in carcinogenesis. On the basis of these epidemiological and experimental findings, we argue for the strong need to strengthen the health care system to ensure that type 2 diabetes subjects receive appropriate drugs to optimize internal milieu to reduce all events including cancer. Apart from mechanistic studies, large-scale, randomized clinical trials using medications such as statin, renin-angiotensin system inhibitors and metformin in patients with risk-conferring subphenotypes are needed to confirm their anti-cancer effects.

To explore the genetic effect of the GH receptor (GHR) on obesity and related metabolic parameters in Hong Kong Chinese adolescents.Obesity is a growing global epidemic. Increasing evidence suggests that the GH-IGF-I axis plays an important role in regulating adiposity and insulin sensitivity.We examined the associations of genetic variants of GHR with serum IGF-I and IGFBP-3 levels as well as obesity-related metabolic traits in Hong Kong Chinese adolescents.Nine hundred and eighty-one randomly selected Hong Kong Chinese adolescents from 14 schools.We genotyped 17 single nucleotide polymorphisms (SNP) at GHR and measured serum IGF-I and IGFBP-3 levels as well as obesity-related metabolic traits including fasting plasma glucose, insulin and lipid levels.There were significant associations between rs4410646 and the body composition (P = 0.0044) and blood pressure factor scores (P = 0.00017). Carriers of the CC genotype had lower body mass index, percentage body fat, waist and hip circumferences than AC and AA genotype carriers (P = 0.00030-0.0094). There was also association between rs7703713 and the IGF-I activity factor score (P = 0.0033). The GA and AA carriers of rs7703713 had higher serum IGF-I, higher serum IGFBP-3 and higher IGF-I/IGFBP-3 molar ratio (P = 0.00069-0.025). Haplotype analysis did not increase the significance of associations.Our results support the role of GHR gene polymorphisms in modulating adiposity and IGF-I activity in adolescents. Examination of interactions of these SNPs with lifestyle, environmental and perinatal factors may provide further insights into their long-term effects on obesity and metabolic risks.

To review our results of laparoscopic adjustable gastric banding, laparoscopic sleeve gastrectomy, and laparoscopic gastric bypass for the treatment of morbid obesity.Prospective cohort study.Bariatric Surgery Centre, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong.All patients consisted of those referred to our Combined Obesity Clinic (to provide multidisciplinary weight management for severely obese patients) during the period July 2002 to December 2007. For patients who received bariatric surgeries as treatment of morbid obesity, peri-operative data, postoperative weight change, and co-morbidity improvements were collected and prospectively reviewed.During the study period, 531 patients attended our Clinic for treatment of obesity. Their mean (standard deviation) body weight was 96 (22) kg, mean body mass index was 36 (6) kg/m(2), mean age was 40 (10) years, and 64% were female. Of these patients, 94 (18%) underwent bariatric surgery, which included: laparoscopic adjustable gastric banding (n=57), laparoscopic sleeve gastrectomy (n=30), and laparoscopic gastric bypass (n=7). Adverse events occurred in 11 (12%) of these 94 patients, but there was no operative mortality. At 2 years, the mean percentage weight loss for patients having laparoscopic adjustable gastric banding, laparoscopic sleeve gastrectomy, and laparoscopic gastric bypass were 34%, 51% and 61%, respectively. After operative treatment, obesity-related co-morbidities including metabolic syndrome, type 2 diabetes, hypertension, and sleep apnoea had also improved significantly.Through a multidisciplinary weight management programme and various bariatric procedures, favourable results can be achieved in Chinese patients with severe obesity.

OBJECTIVE—Type 2 diabetes is the leading cause of end-stage renal disease worldwide. Aside from hyperglycemia and hypertension, other metabolic factors may determine renal outcome. We examined risk associations of metabolic syndrome with new onset of chronic kidney disease (CKD) in 5,829 Chinese patients with type 2 diabetes enrolled between 1995 and 2005. RESEARCH DESIGN AND METHODS—Metabolic syndrome was defined by National Cholesterol Education Program Adult Treatment Panel III criteria with the Asian definition of obesity. Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease formula modified for the Chinese population. New onset of CKD was defined as eGFR

OBJECTIVE—The study aims to test whether biological interaction between hyperglycemia and albuminuria can explain the inconsistent findings from epidemiological studies and clinical trials about effects of hyperglycemia on stroke in type 2 diabetes. RESEARCH DESIGN AND METHODS—A total of 6,445 Hong Kong Chinese patients with type 2 diabetes and free of stroke at enrollment were followed up for a median of 5.37 years. Spline Cox proportional hazard regression was used to obtain hazard ratio curves, which were used to identify cutoff points of A1C and spot urinary albumin–to–creatinine ratio for increased ischemic stroke risk. The identified cutoff point of A1C was used to check biological interaction between A1C and albuminuria (micro- and macroalbuminuria). The biological interaction was estimated using relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index. RESULTS—During the follow-up period, 4.45% (n = 287) of patients developed ischemic stroke. A1C was associated with increased hazard ratios of ischemic stroke in a near-linear manner except for two points—6.2 and 8.0%—where the slope between these two points accelerated. For A1C values

OBJECTIVE—We report the independent risk association of type 2 diabetic nephropathy with the z−2 allele of the 5′-(CA)n microsatellite and C-106T promoter polymorphisms of the aldose reductase gene (ALR2) using a case-control design. In this expanded cohort, we examined their predictive roles on new onset of cardiorenal complications using a prospective design. RESEARCH DESIGN AND METHODS—In this 8-year prospective cohort of 1,074 type 2 diabetic patients (59% male, median age 61 years; disease duration 7 years) with an observation period of 8,592 person-years, none had clinical evidence of coronary heart disease (CHD) or chronic kidney disease at recruitment. The renal end point was defined as new onset of estimated glomerular filtration rate

Diabetes reduces life expectancy by 10 to 12 years, but whether death can be predicted in type 2 diabetes mellitus remains uncertain.A prospective cohort of 7583 type 2 diabetic patients enrolled since 1995 were censored on July 30, 2005, or after 6 years of follow-up, whichever came first. A restricted cubic spline model was used to check data linearity and to develop linear-transforming formulas. Data were randomly assigned to a training data set and to a test data set. A Cox model was used to develop risk scores in the test data set. Calibration and discrimination were assessed in the test data set.A total of 619 patients died during a median follow-up period of 5.51 years, resulting in a mortality rate of 18.69 per 1000 person-years. Age, sex, peripheral arterial disease, cancer history, insulin use, blood hemoglobin levels, linear-transformed body mass index, random spot urinary albumin-creatinine ratio, and estimated glomerular filtration rate at enrollment were predictors of all-cause death. A risk score for all-cause mortality was developed using these predictors. The predicted and observed death rates in the test data set were similar (P.70). The area under the receiver operating characteristic curve was 0.85 for 5 years of follow-up. Using the risk score in ranking cause-specific deaths, the area under the receiver operating characteristic curve was 0.95 for genitourinary death, 0.85 for circulatory death, 0.85 for respiratory death, and 0.71 for neoplasm death.Death in type 2 diabetes mellitus can be predicted using a risk score consisting of commonly measured clinical and biochemical variables. Further validation is needed before clinical use.