Interaction of diet and adipose glucocorticoid action in metabolic syndrome

Metabolic syndrome, a combination of co-associated features including visceral obesity, dyslipidemia, hypertension, insulin resistance and increased risk of cardiovascular disease, has reached epidemic levels. Recent evidence has indicated a pathogenic role for elevated glucocorticoid (GC) levels within adipose tissue specifically, in obesity. Levels of the glucocorticoid regenerating enzyme 11β- hydroxysteroid dehydrogenase type 1 (11β-HSD-1), which converts inactive GC into active forms within cells, are elevated in adipose tissues of obese humans. Transgenic overexpression of 11β-HSD1 in adipose tissue recapitulates metabolic syndrome in mice, including visceral obesity, perhaps because glucocorticoid receptor (GR) levels are higher in visceral than subcutaneous adipose tissue. Therefore, increased adipose GC action, especially in visceral adipose tissue, might explain the striking similarities between idiopathic metabolic syndrome and rare Cushing’s syndrome of plasma GC excess. One of the major contributors to obesity and metabolic syndrome is consumption of excessive amounts of dietary fat. Specifically, saturated fats are associated with obesity and insulin resistance whereas unsaturated fats are reported to ameliorate some aspects of metabolic disease. Interestingly, chronic high fat feeding in mice decreases adipose 11β-HSD1 expression, usually without changing expression in liver. The reduced glucocorticoid regeneration in adipose tissue may ameliorate metabolic disease. This study investigated the effect of diets enriched in saturated or unsaturated fats on adipose tissue glucocorticoid action, focusing on 11β-HSD1 and glucocorticoid receptor expression. Two studies were carried out, one with pair-feeding (to control low-fat diet) and one with ab libitum feeding. In both studies, a diet high in saturated fat (stearate) resulted in significant weight loss whereas a diet consisting of 58% mixed fats resulted in significant weight gain. In the ab libitium study (but not in pair-fed animals) both mono-unsaturated (oleic) and poly-unsaturated (safflower) fat-enriched diets induced weight gain and hyperinsulinaemia and lowered levels of adipose11β-HSD1 when compared to control diet. These data suggest that diets high in saturated fats elevate adipose tissue and liver 11β-HSD1 levels which might contribute detrimentally to, or offset, any improvements in the systemic metabolic profile. Conversely, unsaturated fats cause an adipose-specific down-regulation of 11β-HSD1. In addition, genetic evidence from human and animal studies has shown that regulation of glucocorticoid production and receptor density may be an important factor determining visceral adiposity. The role of adipocyte GR levels in determining visceral adiposity was investigated. Two types of transgenic mice were generated with altered GR levels in adipocytes using the adipocyte-specific aP2 promoter; one with a “sense” rat GR cDNA (2 independent lines; D- and B-FSG) and one with an “anti-sense” rat GR-cDNA (GR-5). Initial characterisation of D- and B-FSG mice showed expression of rat GR mRNA in both female and male transgenic mice with D-FSG showing a higher copy number than B-FSG. In D-FSG transgenic mice, female mice of the F1 generation had greater adipose tissue mass than non-transgenic littermates. A 6-month high fat study was then carried out on line D-FSG. However, no differences in body weight, food intake, adipose tissue weight or blood pressure were found in either males or females. Further investigations of the levels of rat GR mRNA expression within various adipose tissues showed variable transgene expression between different generations of B- and D-FSG lines and even between adipose tissues within the same mouse. In contrast, following 6-months high fat diet, female mice under-expressing GR within adipose tissues (GR-5) showed a significant reduction in body weight and subcutaneous adipose tissue weight compared to their non-transgenic littermates. These data suggest that adipose GR density is an important determinant of visceral adiposity, in a sex-specific manner. Collectively, the data in this thesis support a role for GR density and GC metabolism in adipose tissue as important determinants of adiposity in mice. Drugs that manipulate these targets are of therapeutic interest

Utilising an in silico model to predict outcomes in senescence-driven acute liver injury

Currently liver transplantation is the only treatment option for liver disease, but organ availability cannot meet patient demand. Alternative regenerative therapies, including cell transplantation, aim to modulate the injured microenvironment from inflammation and scarring towards regeneration. The complexity of the liver injury response makes it challenging to identify suitable therapeutic targets when relying on experimental approaches alone. Therefore, we adopted a combined in vivo-in silico approach and developed an ordinary differential equation model of acute liver disease able to predict the host response to injury and potential interventions. The Mdm2fl/fl mouse model of senescence-driven liver injury was used to generate a quantitative dynamic characterisation of the key cellular players (macrophages, endothelial cells, myofibroblasts) and extra cellular matrix involved in liver injury. This was qualitatively captured by the mathematical model. The mathematical model was then used to predict injury outcomes in response to milder and more severe levels of senescence-induced liver injury and validated with experimental in vivo data. In silico experiments using the validated model were then performed to interrogate potential approaches to enhance regeneration. These predicted that increasing the rate of macrophage phenotypic switch or increasing the number of pro-regenerative macrophages in the system will accelerate the rate of senescent cell clearance and resolution. These results showcase the potential benefits of mechanistic mathematical modelling for capturing the dynamics of complex biological systems and identifying therapeutic interventions that may enhance our understanding of injury-repair mechanisms and reduce translational bottlenecks

Incident heart failure and myocardial infarction in sodium-glucose cotransporter-2 vs. dipeptidyl peptidase-4 inhibitor users

Aims This study aimed to compare the rates of major cardiovascular adverse events in sodium-glucose cotransporter-2 inhibitors (SGLT2I) and dipeptidyl peptidase-4 inhibitors (DPP4I) users in a Chinese population. SGLT2I and DPP4I are increasingly prescribed for type 2 diabetes mellitus patients. However, few population-based studies are comparing their effects on incident heart failure or myocardial infarction. Methods and results This was a population-based retrospective cohort study using the electronic health record database in Hong Kong, including type 2 diabetes mellitus patients receiving either SGLT2I or DPP4I from 1 January 2015 to 31 December 2020. Propensity score matching was performed in a 1:1 ratio based on demographics, past comorbidities, and non-SGLT2I/DPP4I medications with nearest neighbour matching (caliper = 0.1). Univariable and multivariable Cox models were used to identify significant predictors for new-onset heart failure, new-onset myocardial infarction, cardiovascular mortality, and all-cause mortality. Sensitivity analyses with competing risk models and multiple propensity score matching approaches were conducted. A total of 41 994 patients (58.89% males, median admission age at 58 years old, interquartile range [IQR]: 51.2–65.3) were included with a median follow-up of 5.6 years (IQR: 5.32–5.82). In the matched cohort, SGLT2I use was significantly associated with lower risks of new-onset heart failure (hazard ratio [HR]: 0.73, 95% confidence interval [CI]: [0.66, 0.81], P < 0.0001), myocardial infarction (HR: 0.81, 95% CI: [0.73, 0.90], P < 0.0001), cardiovascular mortality (HR: 0.67, 95% CI: [0.53, 0.84], P < 0.001), and all-cause mortality (HR: 0.26, 95% CI: [0.24, 0.29], P < 0.0001) after adjusting for significant demographics, past comorbidities, and non-SGLT2I/DPP4I medications. Conclusions SGLT2 inhibitors are protective against adverse cardiovascular events including new-onset heart failure, myocardial infarction, cardiovascular mortality, and all-cause mortality. The prescription of SGLT2I is preferred when taken into consideration individual cardiovascular and metabolic risk profiles in addition to drug–drug interactions

Gender-specific clinical risk scores incorporating blood pressure variability for predicting incident dementia

Introduction: The present study examined the gender-specific prognostic value of blood pressure (BP) and its variability in the prediction of dementia risk and developed a score system for risk stratification. Materials and Methods This was a retrospective, observational population-based cohort study of patients admitted to government-funded family medicine clinics in Hong Kong between January 1, 2000 and March 31, 2002 with at least 3 blood pressure measurements. Gender-specific risk scores for dementia were developed and tested. Results The study consisted of 74 855 patients, of whom 3550 patients (incidence rate: 4.74%) developed dementia over a median follow-up of 112 months (IQR= [59.8–168]). Nonlinear associations between diastolic/systolic BP measurements and the time to dementia presentation were identified. Gender-specific dichotomized clinical scores were developed for males (age, hypertension, diastolic and systolic BP and their measures of variability) and females (age, prior cardiovascular, respiratory, gastrointestinal diseases, diabetes mellitus, hypertension, stroke, mean corpuscular volume, monocyte, neutrophil, urea, creatinine, diastolic and systolic BP and their measures of variability). They showed high predictive strengths for both male (hazard ratio [HR]: 12.83, 95% confidence interval [CI]: 11.15–14.33, P value &amp;lt; .0001) and female patients (HR: 26.56, 95% CI: 14.44–32.86, P value &amp;lt; .0001). The constructed gender-specific scores outperformed the simplified systems without considering BP variability (C-statistic: 0.91 vs 0.82), demonstrating the importance of BP variability in dementia development. Conclusion Gender-specific clinical risk scores incorporating BP variability can accurately predict incident dementia and can be applied clinically for early disease detection and optimized patient management

Dietary manipulation reveals an unexpected inverse relationship between fat mass and adipose 11β-hydroxysteroid dehydrogenase type 1

Increased dietary fat intake is associated with obesity, insulin resistance, and metabolic disease. In transgenic mice, adipose tissue-specific overexpression of the glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) exacerbates high-fat (HF) diet-induced visceral obesity and diabetes, whereas 11β-HSD1 gene knockout ameliorates this, favoring accumulation of fat in nonvisceral depots. Paradoxically, in normal mice HF diet-induced obesity (DIO) is associated with marked downregulation of adipose tissue 11β-HSD1 levels. To identify the specific dietary fats that regulate adipose 11β-HSD1 and thereby impact upon metabolic disease, we either fed mice diets enriched (45% calories as fat) in saturated (stearate), monounsaturated (oleate), or polyunsaturated (safflower oil) fats ad libitum or we pair fed them a low-fat (11%) control diet for 4 wk. Adipose and liver mass and glucocorticoid receptor and 11β-HSD1 mRNA and activity levels were determined. Stearate caused weight loss and hypoinsulinemia, partly due to malabsorption, and this markedly increased plasma corticosterone levels and adipose 11β-HSD1 activity. Oleate induced pronounced weight gain and hyperinsulinemia in association with markedly low plasma corticosterone and adipose 11β-HSD1 activity. Weight gain and hyperinsulinemia was less pronounced with safflower compared with oleate despite comparable suppression of plasma corticosterone and adipose 11β-HSD1. However, with pair feeding, safflower caused a selective reduction in visceral fat mass and relative insulin sensitization without affecting plasma corticosterone or adipose 11β-HSD1. The dynamic depot-selective relationship between adipose 11β-HSD1 and fat mass strongly implicates a dominant physiological role for local tissue glucocorticoid reactivation in fat mobilization

Comparison of sodium-glucose cotransporter-2 inhibitor and dipeptidyl peptidase-4 inhibitor on the risks of new-onset atrial fibrillation, stroke and mortality in diabetic patients: A propensitysScore-matched study in Hong Kong

Objective To compare the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2Is) and dipeptidyl peptidase-4 inhibitors (DPP4Is) on adverse outcomes in diabetic patients in Hong Kong. Methods This was a retrospective population-based cohort study of type 2 diabetes mellitus patients (n = 72,746) treated with SGLT2I or DPP4I between January 1, 2015, and December 31, 2020, in Hong Kong. Patients with exposure to both DPP4I and SGLT2I therapy, without complete demographics or mortality data, or who had prior atrial fibrillation (AF) were excluded. The study outcomes were new-onset AF, stroke/transient ischemic attack, cardiovascular mortality and all-cause mortality. Propensity score matching (1:1 ratio) between SGLT2I and DPP4I users was performed. Results The unmatched study cohort included 21,713 SGLT2I users and 39,510 DPP4I users (total: n = 61,233 patients; 55.37% males, median age: 62.7 years [interquartile range (IQR): 54.6–71.9 years]). Over a median follow-up of 2030 (IQR: 1912–2117) days, 2496 patients (incidence rate [IR]: 4.07%) developed new-onset AF, 2179 patients (IR: 3.55%) developed stroke/transient ischemic attack, 1963 (IR: 3.20%) died from cardiovascular causes and 6607 patients (IR: 10.79%) suffered from all-cause mortality. After propensity score matching (SGLT2I: n = 21,713; DPP4I: n = 21,713), SGLT2I users showed lower incidence of new-onset AF (1.96% vs. 2.78%, standardized mean difference [SMD] = 0.05), stroke (1.80% vs. 3.52%, SMD = 0.11), cardiovascular mortality (0.47% vs. 1.56%, SMD = 0.11) and all-cause mortality (2.59% vs. 7.47%, SMD = 0.22) compared to DPP4I users. Cox regression found that SGLT2I users showed lower risk of new-onset AF (hazard ratio [HR]: 0.68, 95% confidence interval [CI]: [0.56, 0.83], P = 0.0001), stroke (HR: 0.64, 95% CI: [0.53, 0.79], P < 0.0001), cardiovascular mortality (HR: 0.39, 95% CI: [0.27, 0.56], P < 0.0001) and all-cause mortality (HR: 0.44, 95% CI: [0.37, 0.51], P < 0.0001) after adjusting for significant demographics, past comorbidities, medications and laboratory tests. Conclusions Based on real-world data of type 2 diabetic patients in Hong Kong, SGLT2I use was associated with lower risk of incident AF, stroke/transient ischemic attack, and cardiovascular and all-cause mortality outcomes compared to DPP4I use

Comparisons of the risk of myopericarditis between COVID-19 patients and individuals receiving COVID-19 vaccines: a population-based study.

Both COVID-19 infection and COVID-19 vaccines have been associated with the development of myopericarditis. The objective of this study is to (1) analyse the rates of myopericarditis after COVID-19 infection and COVID-19 vaccination in Hong Kong, (2) compared to the background rates, and (3) compare the rates of myopericarditis after COVID-19 vaccination to those reported in other countries. This was a population-based cohort study from Hong Kong, China. Patients with positive RT-PCR test for COVID-19 between 1st January 2020 and 30th June 2021 or individuals who received COVID-19 vaccination until 31st August were included. The main exposures were COVID-19 positivity or COVID-19 vaccination. The primary outcome was myopericarditis. This study included 11,441 COVID-19 patients from Hong Kong, four of whom suffered from myopericarditis (rate per million: 326; 95% confidence interval [CI] 127-838). The rate was higher than the pre-COVID-19 background rate in 2019 (rate per million: 5.5, 95% CI 4.1-7.4) with a rate ratio of 55.0 (95% CI 21.4-141). Compared to the background rate, the rate of myopericarditis among vaccinated subjects in Hong Kong was similar (rate per million: 5.5; 95% CI 4.1-7.4) with a rate ratio of 0.93 (95% CI 0.69-1.26). The rates of myocarditis after vaccination in Hong Kong were comparable to those vaccinated in the United States, Israel, and the United Kingdom. COVID-19 infection was associated with significantly higher rate of myopericarditis compared to the vaccine-associated myopericarditis. [Abstract copyright: © 2022. The Author(s).

Sulfonylurea is associated with higher risks of ventricular arrhythmia or sudden cardiac death compared with metformin: A population-based cohort study

Background Commonly prescribed diabetic medications such as metformin and sulfonylurea may be associated with different arrhythmogenic risks. This study compared the risk of ventricular arrhythmia or sudden cardiac death between metformin and sulfonylurea users in patients with type 2 diabetes. Methods and Results Patients aged ≥40 years who were diagnosed with type 2 diabetes or prescribed antidiabetic agents in Hong Kong between January 1, 2009, and December 31, 2009, were included and followed up until December 31, 2019. Patients prescribed with both metformin and sulfonylurea or had prior myocardial infarction were excluded. The study outcome was a composite of ventricular arrhythmia or sudden cardiac death. Metformin users and sulfonylurea users were matched at a 1:1 ratio by propensity score matching. The matched cohort consisted of 16 596 metformin users (47.70% men; age, 68±11 years; mean follow‐up, 4.92±2.55 years) and 16 596 sulfonylurea users (49.80% men; age, 70±11 years; mean follow‐up, 4.93±2.55 years). Sulfonylurea was associated with higher risk of ventricular arrhythmia or sudden cardiac death than metformin hazard ratio (HR, 1.90 [95% CI, 1.73–2.08]). Such difference was consistently observed in subgroup analyses stratifying for insulin usage or known coronary heart disease. Conclusions Sulfonylurea use is associated with higher risk of ventricular arrhythmia or sudden cardiac death than metformin in patients with type 2 diabetes

Initiation of warfarin is associated with decreased mortality in patients with infective endocarditis: A population-based cohort study.

The use of warfarin to prevent thromboembolism in patients with infective endocarditis (IE) remains controversial due to potentially increased bleeding risks. Population-based retrospective cohort study. Patients aged 18 or older and diagnosed with IE in Hong Kong between January 1st, 1997 and August 31st, 2020 were included. Patients with use of any anticoagulant 30 days before IE diagnosis were excluded. Patients initiated on warfarin within 14 days of IE diagnosis and patients without warfarin use were matched for baseline characteristics using 1:1 propensity score matching. Warfarin use within 14 days of IE diagnosis. Patients were followed up to 90 days for the outcomes of ischemic stroke, all-cause mortality, intracranial hemorrhage, and gastrointestinal bleeding. Cox regression was used to determine hazard ratios (HRs) [95 % confidence intervals (CIs)] between treatment groups. Fine-Gray competing risk regression with all-cause mortality as the competing event was performed as a sensitivity analysis. In addition to 90-day analyses, landmark analyses were performed at 30 days of follow-up. The matched cohort consisted of 675 warfarin users (57.0 % male, age 59 ± 16 years) and 675 warfarin non-users (53.5 % male, age 61 ± 19 years). Warfarin users had a 50 % decreased 90-day risk in all-cause mortality (HR:0.50 [0.39-0.65]), without significantly different 90-day risks of ischemic stroke (HR:1.04 [0.70-1.53]), intracranial hemorrhage (HR:1.25 [0.77-2.04]), and gastrointestinal bleeding (HR:1.04 [0.60-1.78]). Thirty-day landmark analysis showed similar results. Competing risk regression showed significantly higher 30-day cumulative incidence of intracranial hemorrhage in warfarin users (sub-HR:3.34 [1.34-8.31]), but not at 90-day (sub-HR:1.63 [0.95-2.81]). Results from Fine-Gray regression were otherwise congruent with those from Cox regression. Warfarin initiated within 14 days of IE diagnosis was associated with significantly decreased risks of mortality but higher risks of intracranial hemorrhage, with similar risks of ischemic stroke and gastrointestinal bleeding, compared with non-use of warfarin with 14 days of IE diagnosis. Question: Is warfarin, initiated within 14 days of a diagnosis of infective endocarditis (IE), efficacious and safe? In this propensity score-matched, population-based, prospective cohort study from Hong Kong, warfarin use within 14 days of IE diagnosis was associated with a 50 % decrease in the risk of all-cause mortality, albeit with higher risk of intracranial hemorrhage, and without significant differences in the risk of ischaemic stroke and gastrointestinal bleeding. Meaning: In patients with IE, warfarin use within 14 days of diagnosis may have mortality benefits, despite increased risks of intracranial hemorrhage. [Abstract copyright: Copyright © 2023. Published by Elsevier Ltd.