Role of Argininosuccinate Synthase 1 -Dependent L-Arginine Biosynthesis in the Protective Effect of Endothelial Sirtuin 3 Against Atherosclerosis.

Atherosclerosis is initiated with endothelial cell (EC) dysfunction and vascular inflammation under hyperlipidemia. Sirtuin 3 (SIRT3) is a mitochondrial deacetylase. However, the specific role of endothelial SIRT3 during atherosclerosis remains poorly understood. The present study aims to study the role and mechanism of SIRT3 in EC function during atherosclerosis. Wild-type Sirt3f/f mice and endothelium-selective SIRT3 knockout Sirt3f/f; Cdh5Cre/+ (Sirt3EC-KO) mice are injected with adeno-associated virus (AAV) to overexpress PCSK9 and fed with high-cholesterol diet (HCD) for 12 weeks to induce atherosclerosis. Sirt3EC-KO mice exhibit increased atherosclerotic plaque formation, along with elevated macrophage infiltration, vascular inflammation, and reduced circulating L-arginine levels. In human ECs, SIRT3 inhibition resulted in heightened vascular inflammation, reduced nitric oxide (NO) production, increased reactive oxygen species (ROS), and diminished L-arginine levels. Silencing of SIRT3 results in hyperacetylation and deactivation of Argininosuccinate Synthase 1 (ASS1), a rate-limiting enzyme involved in L-arginine biosynthesis, and this effect is abolished in mutant ASS1. Furthermore, L-arginine supplementation attenuates enhanced plaque formation and vascular inflammation in Sirt3EC-KO mice. This study provides compelling evidence supporting the protective role of endothelial SIRT3 in atherosclerosis and also suggests a critical role of SIRT3-induced deacetylation of ASS1 by ECs for arginine synthesis.

Changes in mesenteric fat thickness and its clinical impact in bariatric surgery.

Obesity, especially central obesity is associated with increased risk of metabolic syndrome, non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus. The study aimed to investigate the associations of the changes of abdominal fat thicknesses with changes of anthropometric indexes and improvements of metabolic phenotypes in patients with obesity and T2DM before and after bariatric surgery. Between April 2016 and January 2017, 34 adult patients with concurrent obesity and T2DM scheduled for different bariatric surgeries were prospectively evaluated by ultrasound before and 1-year after bariatric surgery to determine abdominal fat thicknesses (mesenteric fat, preperitoneal fat and subcutaneous fat) and NAFLD. At 1 year, of the 25 patients that finished the study, significant decrease in mesenteric-fat-thickness was associated with significant reduction of obesity, that is, BMI (-24%, p < .001), remission of metabolic syndrome (32%, p = .008), NAFLD (60%, p < .001) and T2DM (44%, p < .001). Lower baseline mesenteric fat thickness was associated with remission of metabolic syndrome. Lower baseline mesenteric-fat-thickness may have the potential to predict metabolic syndrome remission after bariatric surgery.

Duration of type 2 diabetes and liver-related events in nonalcoholic fatty liver disease: A landmark analysis.

BACKGROUND AND AIMS: We aimed to determine the impact of the duration of type 2 diabetes (T2D) on the risk of liver-related events and all-cause mortality in patients with NAFLD. APPROACH AND RESULTS: We conducted a territory-wide cohort study of adult patients with NAFLD diagnosed between January 1, 2000, and July 31, 2021, in Hong Kong. T2D was defined by the use of any antidiabetic agents, laboratory tests, and/or diagnosis codes. The primary endpoint was liver-related events, defined as a composite endpoint of HCC and cirrhotic complications. To conduct a more granular assessment of the duration of T2D, we employed landmark analysis in four different ages of interest (biological age of 40, 50, 60, and 70 years). By multivariable analysis with adjustment of non-liver-related deaths, compared with patients without diabetes at age 60 (incidence rate of liver-related events: 0.70 per 1,000 person-years), the adjusted subdistribution HR (SHR) of liver-related events was 2.51 (95% CI: 1.32-4.77; incidence rate: 2.26 per 1,000 person-years) in patients with T2D duration < 5 years, 3.16 (95% CI: 1.59-6.31; incidence rate: 2.54 per 1,000 person-years) in those with T2D duration of 6-10 years, and 6.20 (95% CI: 2.62-14.65; incidence rate: 4.17 per 1000 person-years) in those with T2D duration more than 10 years. A similar association between the duration of T2D and all-cause mortality was also observed. CONCLUSIONS: Longer duration of T2D is significantly associated with a higher risk of liver-related events and all-cause mortality in patients with NAFLD.

Effects of RAS inhibitors on all-site cancers and mortality in the Hong Kong diabetes surveillance database (2002-2019).

BACKGROUND: Cancer is replacing cardiovascular-disease as a leading cause of death in type 2 diabetes (T2D). The association of RAS-inhibitors (RASi) and cancer, including differences between angiotensin-converting-enzyme-inhibitor (ACEi) and angiotensin-receptor-blocker (ARBs) as well as their associations independent of blood pressure lowering, remains inconclusive in T2D. METHODS: We conducted a cohort study with new-user design in 253,491 patients in the Hong-Kong-Diabetes-Surveillance-Database (HKDSD) in 2002-2019. We evaluated the associations of time-varying RASi use (ACEi and ARBs) with all-site cancer, diabetes-related cancers, and cancer-specific mortality including comparison with new-users of calcium-channel-blockers (CCBs) as an active-comparator group. FINDINGS: Of 253,491, 133,730 (52.8%) were new-RASi and 119,761 (47.2%) were non-RASi users with a median follow-up period of 6.3 (interquartile ragne: 3.4-9.2) years (1,678,719 patient-years). After propensity-score weighting and adjustment for time-varying covariables, RASi use was associated with lower risk of all-site cancer (HR=0.76, 95%CI: 0.74-0.79), diabetes-related cancer (HR=0.79, 95%CI: 0.75-0.84), cancer-specific mortality (HR=0.50, 95%CI: 0.47-0.53), and diabetes-related cancer mortality (HR=0.49, 95%CI: 0.45-0.54) versus non-RASi. Amongst RASi users, ARBs use was associated with lower risk of cancer-specific mortality versus ACEi (HR=0.77, 95%CI: 0.66-0.91). Use of RASi was associated with an estimated-prevention of 2.6 (95%CI: 2.3-3.0) all-site cancer per-1000-person-years and 2.2 (95%CI: 2.0-2.5) cancer-related mortality per-1000-person-years. Lower risk of cancer-specific mortality was similarly observed in new-RASi compared with new-CCBs users. INTERPRETATION: RASi use was independently associated with lower cancer risk in T2D with stronger associations in users of ARBs than ACEi. The benefits of RASi in patients with diabetes might go beyond cardiovascular-renal protection if confirmed by other real-world studies and trials. FUNDING: Dr. Aimin Yang was supported by a CUHK Impact-Research-Fellowship Scheme.

Risk of liver-related events by age and diabetes duration in patients with diabetes and nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Several guidelines recommend screening for NAFLD in patients with type 2 diabetes (T2D). We aimed to determine if there is a threshold of age and duration of T2D for liver-related event development to guide screening strategies. APPROACH AND RESULTS: We conducted a territory-wide retrospective cohort study of adult patients with NAFLD and T2D diagnosed between 2000 and 2014 in Hong Kong to allow for at least 5 years of follow-up. The primary endpoint was liver-related events, defined as a composite of HCC and cirrhotic complications. This study included 7028 patients with NAFLD with T2D (mean age, 56.1 ± 13.3 years; 3363 male [47.9%]). During a follow-up of 77,308 person-years, there was a threshold effect with 1.1%, 4.9%, and 94.0% of patients developing liver-related events at the age of <40, 40-50, and ≥50 years, respectively. Similarly, 3.1%, 5.1%, and 91.8% of patients developed cirrhosis at the age of <40, 40-50, and ≥50 years, respectively. In contrast, liver-related events increased linearly with diabetes duration, with no difference in the annual incidence rate between the first 10 years of T2D diagnosis and subsequent years (0.06% vs. 0.10%; p = 0.136). On multivariable analysis, baseline age ≥50 years (adjusted HR [aHR] 2.01) and cirrhosis (aHR 3.12) were the strongest risk factors associated with liver-related events. Substitution of cirrhosis with the aspartate aminotransferase-to-platelet ratio index or the Fibrosis-4 index yielded similar results. CONCLUSIONS: Age rather than duration of T2D predicts liver-related events in patients with NAFLD and T2D. It is reasonable to screen patients with NAFLD and T2D for advanced liver disease starting at 50 years of age.

Fatty Pancreas Is Independently Associated With Subsequent Diabetes Mellitus Development: A 10-Year Prospective Cohort Study.

BACKGROUND & AIMS: Although the association between fatty pancreas and metabolic syndrome has been suggested in retrospective studies, long-term prospective data on the effect of fatty pancreas on various metabolic outcomes are lacking. We aimed to prospectively investigate the association between fatty pancreas and the development of major metabolic outcomes. METHODS: A total of 631 subjects from a population study using fat-water magnetic resonance imaging to quantify pancreatic and liver fat content during 2008 to 2010 were followed up prospectively until December 2020 (mean follow-up time, 11.1 ± 1.1 y). Subjects with significant alcohol intake and diabetes mellitus (DM) at baseline were excluded. Incidence of newly diagnosed DM, hypertension, dyslipidemia, ischemic heart disease, cardiovascular accidents, pancreatic cancer, and mortality were evaluated. RESULTS: Among the 631 subjects (mean age, 48 ± 11 y), 93 (14.7%) had fatty pancreas. The fatty pancreas group had a higher incidence of DM (33.3% vs 10.4%; P < .001), hypertension (37.7% vs 22.7%; P = .003), and dyslipidemia (37.7% vs 14.6%; P < .001) during long-term follow-up evaluation. Individuals with both fatty liver and pancreas had the highest DM incidence, followed by fatty liver only and fatty pancreas only groups (P < .001). Fatty pancreas was associated independently with DM (adjusted hazard ratio, 1.81; 95% CI, 1.10-3.00; P = .020), but not hypertension or dyslipidemia on multivariate analysis. Each percentage increase of pancreatic fat increased the risk of incident DM by 7% (adjusted hazard ratio, 1.07; 95% CI, 1.01-1.13; P = .016). No participants developed pancreatic cancer during the follow-up period. CONCLUSIONS: Fatty pancreas is associated independently with subsequent DM development, but not hypertension or dyslipidemia.

Detection of increased serum miR-122-5p and miR-455-3p levels before the clinical diagnosis of liver cancer in people with type 2 diabetes.

People with type 2 diabetes (T2D) have increased cancer risk. Liver cancer (LC) has a high prevalence in East Asia and is one of the leading causes of cancer death globally. Diagnosis of LC at early stage carries good prognosis. We used stored serum from patients of Hong Kong Diabetes Register before cancer diagnosis to extract RNA to screen for microRNA markers for early detection of LC in T2D. After screening with Affymetrix GeneChip microarray with serum RNA from 19 incident T2D LC (T2D-LC), 20 T2D cancer free (T2D-CF) and 20 non-T2D non-cancer patients, top signals were validated in a 3-group comparison including 1888 T2D-CF, 127 T2D-LC, and 487 T2D patients with non-liver cancer patients using qPCR. We detected 2.55-fold increase in miR-122-5p and 9.21-fold increase in miR-455-3p in the T2D-LC group. Using ROC analysis, miR-122-5p and miR-455-3p jointly predicted LC with an area under the curve of 0.770. After adjustment for confounders, each unit increase of miR-455-3p increased the odds ratio for liver cancer by 1.022. Increased serum levels of miR-122-5p and miR-455-3p were independently associated with increased risk of incident LC in T2D and may serve as potential biomarkers for early detection of LC in T2D.

Glucose-lowering drugs and outcome from COVID-19 among patients with type 2 diabetes mellitus: a population-wide analysis in Hong Kong.

OBJECTIVES: To investigate the association between baseline use of glucose-lowering drugs and serious clinical outcome among patients with type 2 diabetes. DESIGN: Territory-wide retrospective cohort of confirmed cases of COVID-19 between January 2020 and February 2021. SETTING: All public health facilities in Hong Kong. PARTICIPANTS: 1220 patients with diabetes who were admitted for confirmed COVID-19. PRIMARY AND SECONDARY OUTCOME MEASURES: Composite clinical endpoint of intensive care unit admission, requirement of invasive mechanical ventilation and/or in-hospital death. RESULTS: In this cohort (median age 65.3 years, 54.3% men), 737 (60.4%) patients were treated with metformin, 385 (31.6%) with sulphonylureas, 199 (16.3%) with dipeptidyl peptidase-4 (DPP-4) inhibitors and 273 (22.4%) with insulin prior to admission. In multivariate Cox regression, use of metformin and DPP-4 inhibitors was associated with reduced incidence of the composite endpoint relative to non-use, with respective HRs of 0.51 (95% CI 0.34 to 0.77, p=0.001) and 0.46 (95% CI 0.29 to 0.71, p<0.001), adjusted for age, sex, diabetes duration, glycated haemoglobin (HbA1c), smoking, comorbidities and drugs. Use of sulphonylureas (HR 1.55, 95% CI 1.07 to 2.24, p=0.022) and insulin (HR 6.34, 95% CI 3.72 to 10.78, p<0.001) were both associated with increased hazards of the composite endpoint. CONCLUSIONS: Users of metformin and DPP-4 inhibitors had fewer adverse outcomes from COVID-19 compared with non-users, whereas insulin and sulphonylurea might predict a worse prognosis.

Increased co-expression of PSMA2 and GLP-1 receptor in cervical cancer models in type 2 diabetes attenuated by Exendin-4: A translational case-control study.

BACKGROUND: Type 2 diabetes (T2D) increases the risk of many types of cancer. Dysregulation of proteasome-related protein degradation leads to tumorigenesis, while Exendin-4, a glucagon-like peptide 1 receptor (GLP-1R) agonist, possesses anti-cancer effects. METHODS: We explored the co-expression of proteasome alpha 2 subunit (PSMA2) and GLP-1R in the Cancer Genome Atlas (TCGA) database and human cervical cancer specimens, supplemented by in vivo and in vitro studies using multiple cervical cancer cell lines. FINDINGS: PSMA2 expression was increased in 12 cancer types in TCGA database and cervical cancer specimens from patients with T2D (T2D vs non-T2D: 3.22 (95% confidence interval CI: 1.38, 5.05) vs 1.00 (0.66, 1.34) fold change, P = 0.01). psma2-shRNA decreased cell proliferation in vitro, and tumour volume and Ki67 expression in vivo. Exendin-4 decreased psma2 expression, tumour volume and Ki67 expression in vivo. There was no change in GLP-1R expression in 12 cancer types in TCGA database. However, GLP-1R expression (T2D vs non-T2D: 5.49 (3.0, 8.1) vs 1.00 (0.5, 1.5) fold change, P < 0.001) was increased and positively correlated with PSMA2 expression in T2D-related (r = 0.68)  but not in non-T2D-related cervical cancer specimens. This correlation was corroborated by in vitro experiments where silencing glp-1r decreased psma2 expression. Exendin-4 attenuated phospho-p65 and -IκB expression in the NF-κB pathway. INTERPRETATION: PSMA2 and GLP-1R expression in T2D-related cervical cancer specimens was increased and positively correlated, suggesting hyperglycaemia might promote cancer growth by increasing PSMA2 expression which could be attenuated by Exendin-4. FUNDING: This project was supported by Postdoctoral Fellowship Scheme, Direct Grant, Diabetes Research and Education Fund from the Chinese University of Hong Kong (CUHK).

Deletion of SIRT3 inhibits osteoclastogenesis and alleviates aging or estrogen deficiency-induced bone loss in female mice.

SIRT3 has been speculated to affect osteoclast activity through its important roles in regulating mitochondrial function. It remains unclear whether SIRT3 affects osteoclast activity in female mice which is relevant to postmenopausal osteoporosis. We hypothesized that deletion of SIRT3 could modulate bone remodeling in female mice under physiological aging process or ovariectomy (OVX)-induced bone loss. We found that SIRT3 level was markedly increased in primary bone marrow-derived macrophages (BMMs) from both 26-month-old aged mice and OVX mice. Knockdown of SIRT3 in vitro inhibited osteoclast differentiation and mitochondrial biogenesis, and deletion of SIRT3 increased trabecular bone mass in female mice due to impaired osteoclastogenesis. The effect of SIRT3 on bone remodeling appears to be age-dependent as revealed by comparing the effect of SIRT3 deletion on 5-week-old, 3-month-old and 6-month-old female mice. Interestingly, Sirt3-/- mice were more resistant to bone loss following estrogen deficiency resulting from OVX. Our findings demonstrated that SIRT3 could play critical roles in bone remodeling and estrogen deficiency-induced bone loss in female mice, suggesting that SIRT3 and its downstream effectors might be potential novel therapeutic targets for the management of postmenopausal osteoporosis.

Legacy effect of high glucose on promoting survival of HCT116 colorectal cancer cells by reducing endoplasmic reticulum stress response.

Patients with diabetes have increased risk of cancer and poor response to anti-cancer treatment. Increased protein synthesis is associated with endoplasmic reticulum (ER) stress which can trigger the unfolded protein response (UPR) to restore homeostasis, failure of which can lead to dysregulated cellular growth. We hypothesize that hyperglycemia may have legacy effect in promoting survival of cancer cells through dysregulation of UPR. Using HCT116 colorectal cancer cells as a model, we demonstrated the effects of high glucose (25 mM) on promoting cell growth which persisted despite return to normal glucose medium (5.6 mM). Using the Affymetrix gene expression microarray in HCT116 cells programmed by high glucose, we observed activation of genes related to cell proliferation and cell cycle progression and suppression of genes implicated in UPR including BiP and CHOP. These gene expression changes were validated in HCT116 cancer cells using quantitative real-time PCR and Western blot analysis. We further examined the effects of thapsigargin, an anti-cancer prodrug, which utilized ER stress pathway to induce apoptosis. High glucose attenuated thapsigargin-induced UPR and growth inhibition in HCT116 cells, which persisted despite return to normal glucose medium. Western blot analysis showed activation of caspase-3 in thapsigargin-treated cells in both normal and high glucose medium, albeit with lower levels of cleaved caspase-3 in cells exposed to high glucose, suggesting reduced apoptosis. Flow cytometry analysis confirmed fewer apoptotic cells under thapsigargin treatment in cells exposed to high glucose. Our results suggested that hyperglycemia altered gene expression involved in UPR with increased cell proliferation and facilitated survival of HCT116 cells under thapsigargin-induced ER stress by reducing the apoptotic response.

Hepatic miR-192-3p reactivation alleviates steatosis by targeting glucocorticoid receptor.

BACKGROUND & AIMS: The paradox of hepatic insulin resistance describes the inability for liver to respond to bioenergetics hormones in suppressing gluconeogenesis whilst maintaining lipid synthesis. Here, we report the deficiency of miR-192-3p in the livers of mice with diabetes and its role in alleviating hepatic steatosis. METHODS: As conventional pre-microRNA (miRNA) stem-loop overexpression only boosts guiding strand (i.e. miR-192-5p) expression, we adopted an artificial AAV(DJ)-directed, RNA Pol III promoter-driven miRNA hairpin construct for star-strand-specific overexpression in the liver. Liver steatosis and insulin resistance markers were evaluated in primary hepatocytes, mice with diabetes, and mice with excessive carbohydrate consumption. RESULTS: Functional loss of miR-192-3p in liver exacerbated hepatic micro-vesicular steatosis and insulin resistance in either mice with diabetes or wild-type mice with excessive fructose consumption. Liver-specific overexpression of miR-192-3p effectively halted hepatic steatosis and ameliorated insulin resistance in these mice models. Likewise, hepatocytes overexpressing miR-192-3p exhibited improved lipid accumulation, accompanied with decreases in lipogenesis and lipid-accumulation-related transcripts. Mechanistically, glucocorticoid receptor (GCR, also known as nuclear receptor subfamily 3, group C, member 1 [NR3C1]) was demonstrated to be negatively regulated by miR-192-3p. The effect of miR-192-3p on mitigating micro-vesicular steatosis was ablated by the reactivation of NR3C1. CONCLUSIONS: The star strand miR-192-3p was an undermined glycerolipid regulator involved in controlling fat accumulation and insulin sensitivity in liver through blockade of hepatic GCR signalling; this miRNA may serve as a potential therapeutic option for the common co-mobility of diabetic mellitus and fatty liver disease. LAY SUMMARY: The potential regulatory activity of star strand microRNA (miRNA) species has been substantially underestimated. In this study, we investigate the role and mechanism of an overlooked star strand miRNA (miR-192-3p) in regulating hepatic steatosis and insulin signalling in the livers of mice with diabetes and mice under excessive carbohydrate consumption.

Elevated testosterone increases risk of hepatocellular carcinoma in men with chronic hepatitis B and diabetes mellitus.

BACKGROUND AND AIM: Male sex is a risk factor for hepatocellular carcinoma (HCC). Diabetes mellitus (DM) is associated with a doubled risk of HCC in patients with chronic hepatitis B (CHB). We examined the relationship between serum total testosterone and HCC risk in male CHB patients with DM. METHODS: We performed a retrospective cohort study of male CHB patients with DM between 2000 and 2017 using a territory-wide electronic health-care database in Hong Kong. DM was defined by use of anti-diabetic medications, hemoglobin A1c  ≥ 6.5%, and/or fasting glucose ≥ 7 mmol/L in two measurements or ≥ 11.1 mmol/L in one measurement. RESULTS: Of 928 male CHB patients with DM, 83 (8.9%) developed HCC at a median (interquartile range) of 10.7 (6.1-14.6) years. Higher testosterone was associated with an elevated risk of HCC (adjusted hazard ratio [aHR] per 1 SD increase 1.23, 95% confidence interval [CI] 1.03-1.46, P = 0.024). The upper tertile of testosterone (aHR 1.86, 95% CI 1.02-3.39, P = 0.043), but not middle tertile (aHR 0.84, 95% CI 0.41-1.69 P = 0.620), was associated with a higher risk of HCC than the lower tertile. The cumulative incidence (95% CI) of HCC at 5, 10, and 15 years was 4.4% (2.5-7.2%), 12.4% (8.7-16.7%), and 19.1% (14.2-24.5%), respectively, in patients in the upper tertile of testosterone. By subgroup analysis, the association between testosterone and HCC was stronger in patients aged ≥ 50 years and those not receiving antiviral therapy. CONCLUSION: Higher serum testosterone is associated with a higher incidence of HCC in male CHB patients with DM.

Thiazolidinediones reduce the risk of hepatocellular carcinoma and hepatic events in diabetic patients with chronic hepatitis B.

Thiazolidinediones (TZDs) improve glycaemic control and ameliorate liver steatosis, inflammation and fibrosis in patients with fatty liver disease. We aimed to study the impact of TZD and glycaemic control on the risk of hepatocellular carcinoma (HCC) and hepatic events in diabetic patients with chronic hepatitis B (CHB). We performed a retrospective cohort study on diabetic patients with CHB in 2000-2017 using a territory-wide electronic healthcare database in Hong Kong. Diabetes mellitus was identified by use of any antidiabetic medication, haemoglobin A1c (HbA1c ) ≥6.5%, fasting glucose ≥7 mmol/L in two measurements or ≥11.1 mmol/L in one measurement and/or diagnosis codes. Use of antidiabetic medications was modelled as time-dependent covariates. Of 28 999 diabetic patients with CHB, 3963 (13.7%) developed liver-related events (a composite endpoint of HCC and hepatic events) at a median (interquartile range) follow-up of 7.1 (3.7-11.8) years; 1153 patients received TZD during follow-up. After adjusted for important confounders, TZD use was associated with a reduced risk of liver-related events (adjusted hazard ratio [aHR] 0.46, 95% confidence interval [CI] 0.24-0.88; P = .019). Similar trends were observed in HCC (aHR 0.57) and hepatic events (aHR 0.35) separately. Compared to HbA1c of 6.5% at baseline, patients with HbA1c ≥7% had an increased risk of liver-related events; the risk further increased in 5795 (20.0%) patients with HbA1c ≥9% at baseline (aHR 1.14, 95% CI 1.04-1.26; P = .006). TZD use is associated with a lower risk of liver-related events in diabetic patients with CHB. Liver-related events are more common in patients with high HbA1c levels.

Sleep and Obesity.

Rising global prevalence and incidence of obesity lead to increased cardiovascular-renal complications and cancers. Epidemiological studies reported a worldwide trend towards suboptimal sleep duration and poor sleep quality in parallel with this obesity epidemic. From rodents and human models, it is highly plausible that abnormalities in sleep, both quantity and quality, impact negatively on energy metabolism. While excess dietary intake and physical inactivity are the known drivers of the obesity epidemic, promotion of healthy sleep habits has emerged as a new target to combat obesity. In this light, present review focuses on the existing literature examining the relationship between sleep physiology and energy homeostasis. Notably, sleep dysregulation perturbs the metabolic milieu via alterations in hormones such as leptin and ghrelin, eating behavior, neuroendocrine and autonomic nervous systems. In addition, shift work and trans-meridian air travel may exert a negative influence on the hypothalamic-pituitary-adrenal axis and trigger circadian misalignment, leading to impaired glucose tolerance and increased fat accumulation. Amassing evidence has also suggested that uncoupling of the circadian clock can increase the risk of adverse metabolic health. Given the importance of sleep in maintaining energy homeostasis and that it is potentially modifiable, promoting good sleep hygiene may create new avenues for obesity prevention and treatment.

Low testosterone and clinical outcomes in Chinese men with type 2 diabetes mellitus - Hong Kong Diabetes Registry.

AIMS: To assess the implications of low testosterone on cardiovascular risk factors, metabolic syndrome (MES) and clinical outcomes in Chinese men with Type 2 Diabetes (T2D). METHODS: A prospective cohort study carried out in a university hospital involving a consecutive cohort of 1239 Chinese men with T2D and a median disease duration of 9years followed up for 4.8years. Clinical characteristics, frequency of MES, serum total testosterone and clinical events were analyzed. Multivariate logistic regression was performed to examine the independent association of low testosterone with MES after adjustment for confounding covariates. Cox proportional hazards regression analysis was used to derive hazard ratio for clinical outcomes. RESULTS: More men with low testosterone had cardiovascular-renal disease and MES than those with normal testosterone. The adjusted odds ratio (OR) of low testosterone for MES was 2.63 (95% Confidence Interval [CI] 1.56-4.61). After a median follow-up of 4.8years, the hazard ratio (HR) of low testosterone was 2.22 (95% CI 1.23-4.01) for incident non-prostate cancer. In a multivariate Cox-regression model, the HRs were attenuated but remained significant with adjustment for MES and renal parameters. CONCLUSIONS: Chinese men with low testosterone had high prevalence of cardiovascular disease and MES with high incidence non-prostate cancer.

Aldosterone-producing Adenoma in Primary Aldosteronism: CT-guided Radiofrequency Ablation-Long-term Results and Recurrence Rate.

Purpose To evaluate the long-term biochemical, clinical, and recurrence outcomes of radiofrequency (RF) ablation in treating primary aldosteronism due to aldosterone-producing adenoma (APA). Materials and Methods Institutional review board approval and written informed consent were obtained. The use of computed tomographically (CT) guided percutaneous RF ablation was evaluated in 36 patients (19 men; mean age ± standard deviation, 52.1 years ± 10.4) with APA (17 right and 19 left side; mean size, 15.5 mm ± 5.0). Primary aldosteronism was confirmed by using the oral sodium-loading test. After RF ablation, CT images, aldosterone-to-renin ratio (ARR), serum potassium level, and blood pressure control were assessed at 3 months and at the latest follow-up examination. Long-term treatment success was defined as normalization of ARR at the latest assessment. Comparison of ARR, potassium, and blood pressure levels before and after RF ablation was performed by using the Wilcoxon signed-rank test. Results Primary technical success was achieved in 33 (92%) patients who underwent a single RF ablation session. Secondary technical success was achieved in three (8%) patients who required a second RF ablation. At 3-month follow-up, primary aldosteronism was resolved in 33 (92%) patients, with a starting median ARR of 8583 pmol/L per µg/(L · h) that normalized to 97 pmol/L per µg/(L · h) (P < .01). Mean serum potassium levels increased from 2.6 mmol/L ± 0.4 to 4.0 mmol/L ± 0.3 (P = .01). At long-term follow-up (mean, 6.2 years ± 2.5), treatment success was maintained in 33 patients (92%), all of whom had ARRs in the normal range (P < .01). The long-term recurrence rate was 0%. Hypokalemia was resolved in all patients (2.6 mmol/L ± 0.4 to 4.1 mmol/L ± 0.3, P = .01). Hypertension was resolved in 13 (36%) patients, and its control was improved in seven (19%) patients. One (3%) patient had major complications and six (17%) had minor complications. Conclusion CT-guided RF ablation is an effective treatment for APA, with high sustainable long-term treatment success. It may serve as a justifiable treatment alternative to surgery and medical therapy for APA. © RSNA, 2016.

Emergence of Sex Differences in Insomnia Symptoms in Adolescents: A Large-Scale School-Based Study.

STUDY OBJECTIVES: This study aimed to explore the moderation of pubertal status on the onset of sex differences in the prevalence of insomnia symptoms and their health correlates. METHODS: A total of 7,507 children and adolescents (weighted percentage of female: 48.5%) aged between 6-17 y were recruited from thirty-one primary and secondary schools. Participants with difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), and/or early morning awakening (EMA) ≥ 3 times/week in the past month were considered as having insomnia symptoms. The severity of insomnia was measured by the Insomnia Severity Index (ISI). RESULTS: The prevalence of insomnia symptoms increased from 3.4% to 12.2% in girls (3.6-fold) and from 4.3% to 9.1% in boys (2.1-fold) from Tanner stage 1 to 5. There was a significant interaction between sex and Tanner stage in the prevalence of insomnia (P < 0.001) with an emergence of female preponderance at Tanner stage 4 even after controlling for age, family income, and school start time. Similar sex-Tanner stage interactions were found in DIS, DMS, and ISI total score but not EMA. Insomnia symptoms were strongly associated with behavioral problems, poor mental health, and poor general health in both sexes. Boys with insomnia would report more maladaptive lifestyles (smoking, alcohol, and energy drinks) whereas girls with insomnia were more susceptible to emotional and relationship difficulties. CONCLUSIONS: Pubertal maturation was associated with a progressive increase in the prevalence of insomnia symptoms with the emergence of female preponderance in both the prevalence and severity of insomnia symptoms at late puberty. CLINICAL TRIALS REGISTRATION: Chinese Clinical Trial Register, http://www.chictr.org.cn, ID: ChiCTR-TRC-12002798.

Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study.

OBJECTIVE: Type 2 diabetes is an important risk factor for non-alcoholic fatty liver disease (NAFLD), but current guidelines provide conflicting recommendations on whether diabetic patients should be screened for NAFLD. We therefore studied the strategy of screening diabetic patients by FibroScan. DESIGN: Liver fat and fibrosis were assessed by controlled attenuation parameter (CAP) and liver stiffness measurements (LSM) by FibroScan at a diabetic centre for patients from primary care and hospital clinics. Probe-specific LSM cut-offs were used to detect advanced fibrosis. RESULTS: Of 1918 patients examined, 1799 (93.8%) had valid CAP and 1884 (98.2%) had reliable LSM (1770 with the M probe and 114 with the XL probe). The proportion of patients with increased CAP and LSM was 72.8% (95% CI 70.7% to 74.8%) and 17.7% (95% CI 16.0% to 19.5%), respectively. By multivariable analysis, female gender, higher body mass index, triglycerides, fasting plasma glucose and alanine aminotransferase (ALT) and non-insulin use were associated with increased CAP. Longer duration of diabetes, higher body mass index, increased ALT and spot urine albumin:creatinine ratio and lower high-density lipoprotein-cholesterol were associated with increased LSM. Ninety-four patients (80% had increased LSM) underwent liver biopsy: 56% had steatohepatitis and 50% had F3-4 disease. CONCLUSIONS: Diabetic patients have a high prevalence of NAFLD and advanced fibrosis. Those with obesity and dyslipidaemia are at particularly high risk and may be the target for liver assessment. Our data support screening for NAFLD and/or advanced fibrosis in patients with type 2 diabetes.

Genetic effects of multiple asthma loci identified by genomewide association studies on asthma and spirometric indices.

BACKGROUND: Genomewide association study (GWAS) published by GABRIEL consortium identified 10 asthma-associated loci. However, their relationship with lung functions is unclear. This study investigated the association between asthma traits and single-nucleotide polymorphisms (SNPs) of these GWAS loci. METHODS: Rs3894194 and rs9273349 were not genotyped due to unavailable TaqMan assays. Genetic associations of remaining eight SNPs were investigated in 903 school-age asthmatics and 1205 non-allergic controls. Four significant SNPs were then replicated in 479 adult asthmatics and 746 adult controls, and 1341 Chinese preschool children. Meta-analyses were performed by combining data from school-age children and adults. Generalized multifactor dimensionality reduction (GMDR) was used to analyze their interactions for asthma traits. RESULTS: Childhood asthma was associated with GSDMB_rs2305480 (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.57-0.83). IL13_rs1295686 was associated with all asthma (OR 1.64, 95% CI 1.16-2.32) and early-onset asthma (OR 1.92, 95% CI 1.20-3.06) in adults, whereas GSDMB_rs2305480 was only associated with early-onset asthma (OR 0.69, 95% CI 0.49-0.96). According to meta-analyses, the minor allele of rs2305480 was inversely associated with FEV1 , FVC, and FEV1 /FVC (p < 0.01). GMDR analyses revealed 2-locus models of SLC22A5 with SMAD3 to modulate FEVt /FVC in both preschool children and adults, with IL13 to determine FVC in both school-age children and adults, and with IL2RB to modulate FEV1 /FVC in school-age children. CONCLUSIONS: IL13 and GSDMB are replicated as asthma genes. Rs2305480 of GSDMB is also associated with low FEV1 , FVC, and FEV1 /FVC among asthmatics. Moreover, SLC22A5, IL13, SMAD3, and GSDMB interact to modulate spirometric indices.