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Biology Open Jun 2024Metabolic syndrome has become a global epidemic, affecting all developed countries/communities with growing economies. Worldwide, increasing efforts have been directed...
Metabolic syndrome has become a global epidemic, affecting all developed countries/communities with growing economies. Worldwide, increasing efforts have been directed at curbing this growing problem. Mice deleted of the gene encoding Type 1 Transient Receptor Potential Canonical Channel (Trpc1) were found to weigh heavier than controls. They had fasting hyperglycemia and impaired glucose tolerance vs. wild type controls. Beyond 1 year of age, plasma triglyceride level in null mice was elevated. Plasma cholesterol tended to be higher than controls. Livers in null mice were heavier, richer in triglyceride, and more echogenic vs. controls on ultrasound evaluation. Hematocrit was lower in null mice of both genders beginning at 2nd/3rd month of age in the absence of bleeding/ hemolysis. Measured by indirect tail-cuff method or by the direct arterial cannulation, blood pressures in null mice were lower than controls. We conclude that Trpc1 gene regulates body metabolism and that except for hypertension, phenotypes of mice after deletion of the Trpc1 gene resemble the metabolic syndrome, suggesting that this could be a good experimental model for future investigation on the pathogenesis and management of this disorder.
PubMed: 38885005
DOI: 10.1242/bio.060280 -
The Israel Medical Association Journal... Jun 2024Diabetic ketoacidosis (DKA) is an acute metabolic, life-threatening complication of diabetes mellitus with a mortality rate that now stand at less than 1%. Although...
BACKGROUND
Diabetic ketoacidosis (DKA) is an acute metabolic, life-threatening complication of diabetes mellitus with a mortality rate that now stand at less than 1%. Although mortality is coupled with the etiology of DKA, literature on the influence of DKA etiology on patient outcome is scarce.
OBJECTIVES
To study different triggers for DKA and their effect on outcomes.
METHODS
We conducted a retrospective study that include 385 DKA patients from 2004 to 2017. The study compared demographics, clinical presentation, and mortality rates by different precipitating factors.
RESULTS
Patients with DKA due to infections had a higher risk to develop in-hospital mortality after controlling for age and sex (odds ratio 4.40, 95% confidence interval 1.35-14.30), had a higher Charlson Comorbidity Index score, a higher risk of being mechanical ventilated (14% vs. 3%, P < 0.01), and a longer duration of hospitalization (5 days vs. 3 days, P < 0.001).
CONCLUSIONS
It is crucial to find the triggers that precipitate DKA and start the treatment as early as possible in addition to the metabolic aspect of the treatment especially when the trigger is an infectious disease.
Topics: Humans; Diabetic Ketoacidosis; Male; Female; Retrospective Studies; Prognosis; Middle Aged; Hospital Mortality; Adult; Risk Factors; Length of Stay; Precipitating Factors; Respiration, Artificial; Infections; Israel; Aged
PubMed: 38884305
DOI: No ID Found -
Frontiers in Pediatrics 2024Congenital Long QT Syndrome (LQTS) is common in a First Nations community in Northern British Columbia due to the founder variant p.V205M. Although well characterized...
A mild phenotype associated with p.V205M mediated long QT syndrome in First Nations children of Northern British Columbia: effect of additional variants and considerations for management.
INTRODUCTION
Congenital Long QT Syndrome (LQTS) is common in a First Nations community in Northern British Columbia due to the founder variant p.V205M. Although well characterized molecularly and clinically in adults, no data have been previously reported on the pediatric population. The phenotype in adults has been shown to be modified by a splice site variant in (p.L353L). The p.P479L metabolic variant, also common in Northern Indigenous populations, is associated with hypoglycemia and infant death. Since hypoglycemia can affect the corrected QT interval (QTc) and may confer risk for seizures (also associated with LQTS), we sought to determine the effect of all three variants on the LQTS phenotype in children within our First Nations cohort.
METHODS
As part of a larger study assessing those with LQTS and their relatives in a Northern BC First Nation, we assessed those entering the study from birth to age 18 years. We compared the corrected peak QTc and potential cardiac events (syncope/seizures) of 186 children from birth to 18 years, with and without the (p.V205M and p.L353L) and variants, alone and in combination. Linear and logistic regression and student -tests were applied as appropriate.
RESULTS
Only the p.V205M variant conferred a significant increase in peak QTc 23.8 ms ( < 0.001) above baseline, with females increased by 30.1 ms ( < 0.001) and males by 18.9 ms ( < 0.01). There was no evidence of interaction effects with the other two variants studied. Although the p.V205M variant was not significantly associated with syncope/seizures, the odds of having a seizure/syncope were significantly increased for those homozygous for p.P479L compared to homozygous wild type (Odds Ratio [OR]3.0 [95% confidence interval (CI) 1.2-7.7]; = 0.019).
CONCLUSION
While the p.V205M variant prolongs the peak QTc, especially in females, the p.P479L variant is more strongly associated with loss of consciousness events. These findings suggest that effect of the p.V205M variant is mild in this cohort, which may have implications for standard management. Our findings also suggest the p.P479L variant is a risk factor for seizures and possibly syncope, which may mimic a long QT phenotype.
PubMed: 38884101
DOI: 10.3389/fped.2024.1394105 -
Frontiers in Endocrinology 2024Metabolic dysfunction-associated steatotic liver disease (MASLD) presents a growing health concern in pediatric populations due to its association with obesity and...
Bioelectrical impedance parameters add incremental value to waist-to-hip ratio for prediction of metabolic dysfunction associated steatotic liver disease in youth with overweight and obesity.
INTRODUCTION
Metabolic dysfunction-associated steatotic liver disease (MASLD) presents a growing health concern in pediatric populations due to its association with obesity and metabolic syndrome. Bioelectrical impedance analysis (BIA) offers a non-invasive and potentially effective alternative for identifying MASLD risk in youth with overweight or obesity. Therefore, this study aimed to assess the utility of BIA for screening for MASLD in the youth.
METHOD
This retrospective, cross-sectional study included 206 children and adolescents aged <20 years who were overweight and obese. The correlations between anthropometric measurements and BIA parameters and alanine aminotransferase (ALT) levels were assessed using Pearson's correlation analysis. Logistic regression analysis was performed to examine the associations between these parameters and ALT level elevation and MASLD score. Receiver operating characteristic (ROC) curves were generated to assess the predictive ability of the parameters for MASLD.
RESULTS
Pearson's correlation analysis revealed that waist-to-hip ratio (WHR), percentage body fat (PBF), and BIA parameters combined with anthropometric measurements were correlated with ALT level. Logistic regression revealed that WHR, skeletal muscle mass/WHR, PBF-WHR, fat-free mass/WHR, and appendicular skeletal muscle mass/WHR were correlated with ALT level elevation after adjusting for age, sex, and puberty. WHR, PBF-WHR, and visceral fat area (VFA)-WHR were positively correlated with the MASLD score in the total population after adjusting for age, sex, and puberty. PBF-WHR and VFA-WHR were correlated with the MASLD score even in youth with a normal ALT level. The cutoff points and area under the ROC curves were 34.6 and 0.69 for PBF-WHR, respectively, and 86.6 and 0.79 for VFA-WHR, respectively.
DISCUSSION
This study highlights the utility of combining BIA parameters and WHR in identifying the risk of MASLD in overweight and obese youth, even in those with a normal ALT level. BIA-based screening offers a less burdensome and more efficient alternative to conventional MASLD screening methods, facilitating early detection and intervention in youth at risk of MASLD.
Topics: Humans; Male; Female; Electric Impedance; Child; Cross-Sectional Studies; Adolescent; Retrospective Studies; Waist-Hip Ratio; Overweight; Pediatric Obesity; Metabolic Syndrome; Fatty Liver; Body Composition; Body Mass Index; Prognosis
PubMed: 38883602
DOI: 10.3389/fendo.2024.1385002 -
Frontiers in Endocrinology 2024The global prevalence of cardiovascular diseases (CVD) continues to rise steadily, making it a leading cause of mortality worldwide. Atherosclerosis (AS) serves as a... (Review)
Review
The global prevalence of cardiovascular diseases (CVD) continues to rise steadily, making it a leading cause of mortality worldwide. Atherosclerosis (AS) serves as a primary driver of these conditions, commencing silently at an early age and culminating in adverse cardiovascular events that severely impact patients' quality of life or lead to fatality. Dyslipidemia, particularly elevated levels of low-density lipoprotein cholesterol (LDL-C), plays a pivotal role in AS pathogenesis as an independent risk factor. Research indicates that abnormal LDL-C accumulation within arterial walls acts as a crucial trigger for atherosclerotic plaque formation. As the disease progresses, plaque accumulation may rupture or dislodge, resulting in thrombus formation and complete blood supply obstruction, ultimately causing myocardial infarction, cerebral infarction, and other common adverse cardiovascular events. Despite adequate pharmacologic therapy targeting LDL-C reduction, patients with cardiometabolic abnormalities remain at high risk for disease recurrence, highlighting the importance of addressing lipid risk factors beyond LDL-C. Recent attention has focused on the causal relationship between triglycerides, triglyceride-rich lipoproteins (TRLs), and their remnants in AS risk. Genetic, epidemiologic, and clinical studies suggest a causal relationship between TRLs and their remnants and the increased risk of AS, and this dyslipidemia may be an independent risk factor for adverse cardiovascular events. Particularly in patients with obesity, metabolic syndrome, diabetes, and chronic kidney disease, disordered TRLs and its remnants levels significantly increase the risk of atherosclerosis and cardiovascular disease development. Accumulation of over-synthesized TRLs in plasma, impaired function of enzymes involved in TRLs lipolysis, and impaired hepatic clearance of cholesterol-rich TRLs remnants can lead to arterial deposition of TRLs and its remnants, promoting foam cell formation and arterial wall inflammation. Therefore, understanding the pathogenesis of TRLs-induced AS and targeting it therapeutically could slow or impede AS progression, thereby reducing cardiovascular disease morbidity and mortality, particularly coronary atherosclerotic heart disease.
Topics: Humans; Cardiovascular Diseases; Lipoproteins; Triglycerides; Atherosclerosis; Animals; Dyslipidemias; Risk Factors
PubMed: 38883601
DOI: 10.3389/fendo.2024.1409653 -
Diabetes, Metabolic Syndrome and... 2024Metabolic Syndrome (MS) greatly increases the risk of heart disease and Heart Failure(HF). Insulin Resistance (IR) is considered to be the key to the pathophysiology of...
PURPOSE
Metabolic Syndrome (MS) greatly increases the risk of heart disease and Heart Failure(HF). Insulin Resistance (IR) is considered to be the key to the pathophysiology of MS. The purpose of this study was to evaluate the predictive effect of different alternative indicators of IR on adverse cardiovascular events in patients with MS complicated with HF.
METHODS
Patients with HF who were diagnosed with MS in the heart center of the first affiliated Hospital of Xinjiang Medical University were selected continuously. The baseline data of the patients in the group were compared. The diagnostic value of alternative indexes of IR was evaluated by the working characteristic curve of subjects. The relationship between different alternative indicators of IR and survival rate was evaluated by survival curve. COX regression was used to analyze the effects of different alternative indicators of IR on the risk of end-point events.
RESULTS
The levels of TyG, TyG-BMI, TyG-WC, TG/HDL-C and METS-IR were significantly increased in patients with Major Adverse Cardiovascular Events (MACEs). Among the five alternative indexes of IR, METS-IR had the highest AUC (0.691, 95% CI:0.657-0.752, P < 0.001) in predicting MACEs. No matter which alternative index of IR was used, the survival rate of MACEs in High group was significantly decreased. TyG, TyG-BMI, TyG-WC, TG/HDL-C and METS-IR can independently predict the occurrence of MACEs events, even if some confounding factors are adjusted.
CONCLUSION
Our study shows that alternative indicators of IR, especially METS-IR, are independently associated with adverse cardiovascular events in patients with MS and HF.
PubMed: 38881693
DOI: 10.2147/DMSO.S457598 -
SAGE Open Medicine 2024Dolutegravir is an integrase inhibitor and is recommended by the World Health Organization as the preferred first-line and second-line human immunodeficiency virus... (Review)
Review
Dolutegravir is an integrase inhibitor and is recommended by the World Health Organization as the preferred first-line and second-line human immunodeficiency virus treatment in all populations. Excessive weight gain associated with dolutegravir-based regimens is an emerging issue; however, the long-term metabolic consequences of this effect have not been fully understood. Growing evidence shows that this leads to a higher incidence of hyperglycemia, hypertension, and metabolic syndrome, along with elevated cardiovascular risk. Dolutegravir-based regimens, also associated with greater adipocyte differentiation and greater expression of markers associated with lipid storage, continue to be a problem among patients living with human immunodeficiency virus. The mechanisms by which certain antiretroviral therapy agents differentially contribute to weight gain remain unknown. Some clinical investigators speculate that dolutegravir could interfere with central nervous system appetite regulation (melanocortin-4 receptor) and insulin signaling, or may have better penetration of adipose tissue where they could exert a direct impact on adipose tissue adipogenesis, fibrosis, and insulin resistance. This review summarizes our current understanding of weight gain and fat changes associated with dolutegravir and its possible secondary metabolic comorbidities.
PubMed: 38881592
DOI: 10.1177/20503121241260613 -
Disease Models & Mechanisms Jun 2024MECP2 duplication syndrome (MDS) is a neurodevelopmental disorder caused by tandem duplication of the MECP2 locus and its surrounding genes, including IRAK1. Current MDS...
MECP2 duplication syndrome (MDS) is a neurodevelopmental disorder caused by tandem duplication of the MECP2 locus and its surrounding genes, including IRAK1. Current MDS mouse models involve transgenic expression of MECP2 only, limiting their applicability to the study of the disease. Herein, we show that an efficient and precise CRISPR/Cas9 fusion proximity-based approach can be utilized to generate an Irak1-Mecp2 tandem duplication mouse model ("Mecp2 Dup"). The Mecp2 Dup mouse model recapitulates the genomic landscape of human MDS by harbouring a 160 kb tandem duplication encompassing Mecp2 and Irak1, representing the minimal disease-causing duplication, and the neighbouring genes Opnmw1 and Tex28. The Mecp2 Dup model exhibits neuro-behavioral abnormalities, and an abnormal immune response to infection not previously observed in other mouse models, possibly owing to Irak1 overexpression. The Mecp2 Dup model thus provides a tool to investigate MDS disease mechanisms and develop potential therapies applicable to patients.
PubMed: 38881329
DOI: 10.1242/dmm.050528 -
Signal Transduction and Targeted Therapy Jun 2024Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK, an endothelial transmembrane receptor...
Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK, an endothelial transmembrane receptor signaling through PIK3CA. Venous malformations are associated with pain, bleedings, thrombosis, pulmonary embolism, esthetic deformities and, in severe cases, life-threatening situations. No authorized medical treatment exists for patients with venous malformations. Here, we created a genetic mouse model of PIK3CA-related capillary venous malformations that replicates patient phenotypes. We showed that these malformations only partially signal through AKT proteins. We compared the efficacy of different drugs, including rapamycin, a mTORC1 inhibitor, miransertib, an AKT inhibitor and alpelisib, a PI3Kα inhibitor at improving the lesions seen in the mouse model. We demonstrated the effectiveness of alpelisib in preventing vascular malformations' occurrence, improving the already established ones, and prolonging survival. Considering these findings, we were authorized to treat 25 patients with alpelisib, including 7 children displaying PIK3CA (n = 16) or TEK (n = 9)-related capillary venous malformations resistant to usual therapies including sirolimus, debulking surgical procedures or percutaneous sclerotherapies. We assessed the volume of vascular malformations using magnetic resonance imaging (MRI) for each patient. Alpelisib demonstrated improvement in all 25 patients. Vascular malformations previously considered intractable were reduced and clinical symptoms were attenuated. MRI showed a decrease of 33.4% and 27.8% in the median volume of PIK3CA and TEK malformations respectively, over 6 months on alpelisib. In conclusion, this study supports PI3Kα inhibition as a promising therapeutic strategy in patients with PIK3CA or TEK-related capillary venous malformations.
Topics: Class I Phosphatidylinositol 3-Kinases; Animals; Mice; Humans; Vascular Malformations; Capillaries; Female; Male; Sirolimus; Child; Disease Models, Animal; Molecular Targeted Therapy; Thiazoles
PubMed: 38880808
DOI: 10.1038/s41392-024-01862-9 -
Cardiovascular Diabetology Jun 2024Stroke is a common complication of hypertension, but the predictive value of metabolic syndrome parameters' variability on stroke risk in individuals with hypertension...
BACKGROUND
Stroke is a common complication of hypertension, but the predictive value of metabolic syndrome parameters' variability on stroke risk in individuals with hypertension remains unclear. Therefore, our objective was to investigate the relationship between metabolic syndrome parameters' variability and the risk of total stroke and its subtypes in hypertensive patients.
METHODS
This prospective cohort study included 17,789 individuals with hypertension from the Kailuan study since 2006. Metabolic syndrome parameters, including waist circumference (WC), fasting blood glucose (FBG), systolic blood pressure (SBP), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG), were collected at three follow-up visits in the 2006, 2008, and 2010 surveys. We assess the variability utilizing the coefficient of variation (CV), standard deviation (SD), average real variation (ARV), and variability independent of the mean (VIM), with CV initially assessed. Participants were categorized based on the number of high-variability metabolic syndrome parameters (0, 1, 2, ≥ 3). Stroke cases were identified by reviewing medical records. The associations between variability in metabolic syndrome parameters and the risk of total stroke and its subtypes were analyzed using Cox proportional hazard regression models.
RESULTS
During a median follow-up of 9.32 years, 1223 cases of stroke were recorded. Participants with ≥ 3 high-variability metabolic syndrome parameters had an increased risk of total stroke (HR: 1.29, 95%CI 1.09-1.52), as well as an increased risk of ischemic stroke (HR: 1.31, 95%CI 1.05-1.63) compared to those without high-variability parameters. The study also examined variability in each metabolic syndrome parameter, and significant associations with an increased risk of total stroke were observed for variability in SBP (HR: 1.24, 95%CI 1.05-1.46) and HDL-C (HR: 1.34, 95%CI 1.09-1.64).
CONCLUSIONS
Long-term fluctuations in metabolic syndrome parameters significantly increase the risk of total stroke, especially ischemic stroke. Maintaining low variability in metabolic syndrome parameters could benefit health, and hypertensive individuals must be regularly monitored.
Topics: Humans; Metabolic Syndrome; Female; Male; Middle Aged; Hypertension; Prospective Studies; Risk Factors; Incidence; Risk Assessment; Aged; Stroke; Blood Glucose; Time Factors; Blood Pressure; Biomarkers; China; Prognosis; Triglycerides; Waist Circumference; Cholesterol, HDL; Adult
PubMed: 38879482
DOI: 10.1186/s12933-024-02282-3