Glucose Levels Research Articles

Epigenetic modulation of sirt1 and sirt6 in cardiovascular diseases: unraveling autophagy regulation and endothelial function

Abstract Background Heart failure (HF) and cardiovascular diseases (CVD) still represent major causes of death. Dysmetabolic conditions led by epigenetic alterations play a major role as CVD triggers, expecially those related to the modulation and control of autophagy during the remodelling in HF. Accordingly, several studies have strengthened the role of epigenetics in regulating both cardiac/endothelial phenotype and function, demonstrating how sirtuins, a well-acknowledged family of histone deacetylase, can conjunct the control of cardiac fibrosis, angiogenesis and induction of autophagy. However, this link remains to be fully clarified and explored. Thus, novel drugs targeting autophagy trough epigenetic mechanisms are considered appealing as targets from a pharmacological standpoint in CVD. Purpose This project aims to develop and test two epigenetic modulators and allosteric activators targeting SIRT1 and -6 to further elucidate their role in autophagy regulation and in cardiac/endothelial biology. Methods Chemical synthesis of SIRT1 and SIRT6 activator isoform (SRT2104 and MDL800). Evaluation of epigenetic modulation (H3 histone acetylation H3K9) of endothelial cells (HUVEC). HUVEC survival, angiogenic and autophagy activity were assessed undergo hyperglycemic or hypoxic stress, co-treatment with the selected compounds. Results The specific activator of SIRT-1 (SRT2104) and SIRT-6 (MDL800) show epigenetic activity as they induce the deacetylation of histone H3 on lysine 9. Endothelial cell viability is not influenced by the treatment with both modulators in hyperglycemia and upon hypoxic condition. In HUVEC cultures underwent to hyperglycemia-based stress, both molecules can activate autophagy with an increase in LC3 II protein (1,4-fold HG SRT2104 and 2,8-fold HG MDL800), compared to control.The treatment with SRT2104 enhances HUVEC tube formation, suggesting the increased functional angiogenic ability even in presence of high levels of glucose. Interestingly, the treatment with SRT2104 impacts the transcriptional levels of other members of the sirtuins family, by increasing SIRT-2, 3 and 5. In conclusion, the epigenetic activators SRT2104 and MDL800 have a beneficial effect on endothelial cells by enhancing the autophagic process and stimulate neoangiogenesis.The implementation of these results will attempt to understand to what extent epigenetic drugs such as sirtuin activators, could boost the more pleiotropic and less targeted effects of the current cardiovascular drugs, and to evaluate their functional and phenotype-driven drug refinement.

Disparities by region, age, and sex in cardiovascular disease burden attributable to high fasting plasma glucose in China, 2010-2018: a nationwide, population-based study

Abstract Background Elaborating and understanding disparities in the burden of cardiovascular disease (CVD) attributable to high fasting plasma glucose (FPG) is important to improve diabetes prevention and promote cardiovascular health. In this study, we aimed to estimate the burden of CVD and its subtypes attributable to high FPG between 2010 and 2018 in China, by age, sex, region and socio-demographic index (SDI). Methods We pooled data on 791 373 people aged 25 years and older from three population-based surveys, and the temporal-spatial Bayesian hierarchical model was used to estimate age- specific, sex- specific, province- specific, and year-specific average FPG levels from 2010 to 2018. We estimated population attributable fraction for CVD by age and sex for 31 provinces. Data on CVD deaths at the provincial level were obtained from surveillance systems, which were used to compute death numbers and years of life lost (YLLs) due to CVD that could be attributed to high FPG using the counterfactual scenario of theoretical minimum risk level. We also decomposed changes in attributable burdens into four explanatory components, including population growth, population aging, risk exposure to FPG, and in risk-deleted mortality rates for CVD. Results In 2018, an estimated total of 512·29 thousand (95% uncertainty interval [UI] 488·60 to 538·65) adults aged 25 or older were attributable to high FPG in China, with 281·54 thousand (95%UI 267·89 to 295·05) of these deaths occurring in men and 229·75 thousand (95%UI 210·98 to 251·89) in women. The age composition of CVD mortality caused by high FPG suggested a trend toward older ages from 2010 to 2018 (Figure 1). High FPG accounted for 1 093·45 crude YLLs per 100 000 people (95%UI 1 059·13 to 1 131·73) due to FPG-related CVD in 2018, with substantial variation across provinces. The age-standardised CVD mortality rate attributable to high FPG increased by 3·99%, from 41·93 per 100 000 people (95%UI 40·07 to 43·88) in 2010 to 43·60 per 100 000 (95%UI 41·77 to 45·62) in 2018. In 2018, the higher age-standardised CVD mortality rate attributable to high FPG was observed in the high-middle SDI region and the middle SDI region. By province, the age-standardised mortality rate due to FPG-related CVD in both sexes combined varied from 21·31 per 100 000 people in Tibet to 77·66 per 100 000 people in Heilongjiang in 2018. Nationally, compared to 2010, exposure to high FPG and population aging in 2018 were the primary drivers of increased FPG-related deaths due to CVD (Figure 2). Conclusions The CVD burden attributable to high FPG was still large in China, and varied markedly across regions and provinces. Exposure to high FPG and population ageing were associated with substantial changes in the number of FPG-related CVD deaths between 2010 and 2018. Findings of this study emphasize the importance of developing population-specific tailored measures in China and other regions with similar condition.Figure 1Figure 2

Long-term effects of arsenic on glucose-insulin homeostasis: A gene-environment interaction study

Abstract Background Arsenic exposure and genetic factors are associated with an increased risk of type 2 diabetes, yet study of environment-gene interaction on glucose-insulin homeostasis remains scarce. We aimed to investigate the associations and interactions of urinary total arsenic (UTAs) and genetic susceptibility with glucose-insulin homeostasis through a longitudinal epidemiological study. Methods A total of 6136 observations (3063 participants) from the baseline, 3-year follow-up, and 6-year follow-up of the Wuhan-Zhuhai cohort were included in this study. In each study period, we repeatedly measured UTAs, fasting plasma glucose (FPG), fasting plasma insulin (FPI), and homeostasis model-assessed insulin resistance (HOMA-IR) and β-cell function (HOMA-β). Polygenic risk scores (PRSs) specific for all traits were constructed by corresponding genome-wide association summary statistics. Linear mixed models were used to assess associations and interactions of UTAs and PRSs with four indicators of glucose-insulin homeostasis. Results After adjustment for all covariates, the βs (95% CIs) for the annual growth rates of FPG, FPI, and HOMA-IR were 0.020 (0.008, 0.032), 0.007 (0.002, 0.013), and 0.011 (0.004, 0.017), respectively, associated with each ln-unit increase in UTAs. Compared to subjects with the first-quartile PRS and low UTAs, participants with the fourth-quartile PRS and high UTAs had a 0.029 (0.012, 0.047) or 0.032 (0.012, 0.051) ln-unit increase in the annual growth rate of FPI or HOMA-IR, respectively. UTAs and PRS had significant interactions on the longitudinal progressive increases of FPI and HOMA-IR (P interaction < 0.05). Conclusions Arsenic exposure and genetic variants are significantly synergistic risk factors for dysregulation and progressive deterioration of glucose-insulin homeostasis. Our findings emphasize the importance of reducing arsenic exposure to maintain normal glucose-insulin metabolism, especially for those at higher genetic risk. Key messages • Arsenic exposure was associated with annual increased rates of FPG, FPI, and HOMA-IR. • Arsenic exposure and trait-specific PRSs are synergistic risk factors for glucose-insulin homeostasis impairment.

Prognostic impact of composite lipid indices in patients with acute coronary syndrome undergoing percutaneous coronary intervention

Abstract Background Composite lipid indices have been reported to have associations with several cardiovascular diseases and their negative adverse events. Among these, there are four novel indices that can be easily calculated, namely, triglyceride-glucose index (TyG, calculated from fasting plasma glucose [FPG] and triglyceride [TG]), lipid accumulation product (LAP, calculated from waist circumference [WC] and TG), visceral adiposity index (VAI, calculated from WC, TG, body mass index [BMI], and high-density lipoprotein [HDL]), and atherogenic index of plasma (AIP, calculated from TG and HDL). Herein, we aimed to investigate the impact of these indices on the incidence of major adverse cardiovascular and cerebrovascular events (MACCE) in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Methods All the patients with ACS who underwent PCI at our institution during the 2015-2022 period were included in the analyses. Patients were divided based on each of the TyG, VAI, LAP, and AIP indices quartiles (Q). The median follow-up was 378 days and the outcome assessed was MACCE composed of all-cause mortality, myocardial infarction, stroke, target vessel revascularization, target lesion revascularization, and coronary artery bypass grafting surgery. Results There was a total of 13,682 patients with ACS undergoing PCI with a mean age of 62.67 ± 11 years and 72.61% male predominance. Regarding the TyG index, patients in Q4 had a higher incidence of MACCE, compared to those in Q1 (adjusted HR [aHR] 1.271, 95% CI 1.067 – 1.513], p-value < 0.01). While in the crude model, patients in Q2, Q3, and Q4 of LAP had significantly higher rates of MACCE, compared to Q1, this association was not observed in the age- and sex-adjusted model and fully-adjusted model. Similarly, there was no difference among the quartiles of VAI and AIP regarding the incidence of MACCE. Kaplan-Meier curves also show that there were significant differences among TyG and LAP quartiles (p-value = 0.0049 and p-value = 0.035, respectively). Conclusion As our findings suggest, patients with higher TyG levels, as a surrogate marker of insulin resistance, had a higher incidence of MACCE. LAP could also play an important role in the incidence of adverse events after PCI. These novel lipid indices could help clinicians in determining the risks of patients with ACS undergoing PCI in order to provide better care to them.Risk of MACCE in different quartilesKaplan Meier Curves for risk of MACCE

Neonatal hypoglycemia: A review with focus on practical challenges and recent updates on management

At birth, a neonate undergoes a transition from the continuous maternal supply of glucose to a variable and intermittent oral glucose intake, which is regulated by the interplay of hormones and metabolic enzyme induction. Because low plasma glucose concentrations are common in the neonatal period, it may be difficult to identify those who have pathologic hypoglycemia. Hence, it is important to formally evaluate such babies by drawing critical samples. Here, we present two cases of neonatal hypoglycemia where the presentation had some similarities, but the comprehensive evaluation revealed a varied etiological spectrum necessitating lifelong management. Through these case studies, authors discuss practical challenges in the diagnosis, management, and follow-up of neonates with endocrine causes of hypoglycemia.

Association between normal range UACR and insulin resistance and prediabetes among US adults:

Abstract Background Recent studies have shown that urine albumin-to-creatinine ratio (UACR) within the normal range is associated with increased risk of hypertension, diabetes, cardiovascular death and all-cause death. However, the relationship between normal range UACR and the prevalence of insulin resistance (IR) and prediabetes has not been explored. Methods The study included 14,208 US adults with normal range UACR values and without diabetes from the National Health and Nutrition Survey (1999-2018). The outcome variables included IR and prediabetes, as defined by the 2013 American Diabetes Association guidelines. The weighted multivariate linear regression, weighted multivariate logistic regression, restricted cubic spline (RCS) regression, and subgroup analysis were conducted to examine the relationship of UACR with IR and prediabetes. Results The weighted multivariate linear regression analysis showed that a 1-standard deviation (SD) increment in ln (UACR) was positively associated with fasting plasma glucose (FPG) (β = 0.02, 95% CI: 0.01, 0.04), glycosylated hemoglobin (β = 0.01, 95% CI: 0.00, 0.02), fasting serum insulin (FSI) (β = 0.50, 95% CI: 0.31, 0.68), and homeostasis model assessment of insulin resistance (HOMA-IR) (β = 0.14, 95% CI: 0.09, 0.19). The weighted multivariate logistic regression analysis revealed that a 1-SD increment in ln (UACR) was significantly associated with an increased prevalence of prediabetes (OR = 1.10, 95% CI: 1.04-1.15), but not with IR (OR = 1.05, 95% CI: 0.99-1.12). With the lowest quartile of UACR as a reference, ORs (95% CIs) for IR in the second, third, and fourth quartiles were 1.10 (0.86, 1.15), 1.15 (0.98, 1.33), and 1.12 (0.95, 1.32), respectively, and ORs (95% CIs) for prediabetes were 1.35 (1.19, 1.52), 1.32 (1.14, 1.53), and 1.44 (1.24, 1.66), respectively. Subgroup analysis indicated that smoking had a significant impact on the association between UACR and prediabetes. The association between UACR and prediabetes was more significant in smokers than in non-smokers (P for interaction = 0.03). RCS regression analysis revealed a non-linear positive dose-response association between UACR and indicators of diabetes. Conclusion Elevated UACR, even within the normal range, was positively associated with indicators of diabetes and increased prevalence of prediabetes among US adults. Smoking had a significant impact on the association between UACR and prediabetes, with a more pronounced association observed among smokers.uacr with diabetes markersUacr with ir and prediabetes

Effect of COVID-19 pandemic on the management of hypertension and the prevalence of lifestyle disease

Abstract Background/Introduction Behavior restrictions after the advent of COVID-19 dramatically changed our lifestyle, which may have affected self-management of metabolic factors in individuals. Purpose We examined possible changes in the prevalence and management of lifestyle-related diseases in the general population. Methods We enrolled 2582 consecutive participants aged ≥20 years (male=6984, 49.5±11.9 year-old) who visited our hospital for their annual physical check-up at least five times between 2017 and 2022. Participants were divided into 2 groups (with [n=739] or without antihypertensive medication [n=1843]) and changes in parameters that are closely related with lifestyle were examined before (2017-2019) and after (2020-2022) the pandemic of COVID-19. Hypertension was defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or the use of antihypertensive medications. Diabetes mellitus was defined as fasting plasma glucose ≥126 mg/dL, HbA1c ≥ 6.5% or the use of antidiabetic medications. Dyslipidemia was defined as LDL-cholesterol ≥140 mg/dL, HDL-cholesterol <40 mg/dL, triglyceride ≥150 mg/dL, or the use of antidyslipidemic medications. Hyperuricemia was defined as uric acid >7.0 mg/dL for men, >6.0 mg/dL for women or the use of anti-hyperuricemic medications. Metabolic syndrome was defined based on Japanese diagnostic criteria (2005). Results The main results are shown in Table. The levels of all parameters were worse in participants with than without anti-hypertensive medication. The prevalence of hypertension, diabetes, dyslipidemia, hyperuricemia and metabolic syndrome which was higher in subjects with than without anti-hypertensive medication increased after the COVID-19 pandemic. Although the most of parameters were deteriorated after the pandemic, only the management of blood pressure in subjects under antihypertensive medication was improved. Conclusion Behavior restrictions during the pandemic might have unfavorable impact on the prevalence of lifestyle-related diseases. Although the control of blood pressure was not worsened, total management was not excellent during the pandemic in hypertensive individuals under medication.Characteristics of study participants

The triglyceride-glucose index is a marker of thromboembolic events in atrial fibrillation patient under oral anticoagulation therapy

Abstract Background Atrial fibrillation (AF) increases the risk of stroke and thromboembolism; and appropriate risk stratification is central for better targeted patient management. The triglyceride-glucose (TyG) index indirectly assesses insulin resistance, and has been associated with cardiovascular risk. Purpose To investigate whether the TyG index could be a biomarker for assessing the risk of thromboembolic events in patients with AF. Methods We performed an observational prospective cohort study including outpatients diagnosed with AF starting vitamin K antagonist (VKA) or direct-acting oral anticoagulants (DOAC) therapy from January, 2016 to November, 2021. The primary endpoint was a combination of thromboembolic events, considered as the composite of myocardial infarction, and/or venous thromboembolism, and/or ischemic stroke/transient ischemic attack, over 2 years of follow-up. The TyG index was calculated as the natural logarithm (Ln) of the product of baseline plasma glucose and triglyceride using the following formula: Ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)]/2. Patients were stratified into tertiles according to their TyG index (ie. first tertile: TyG index <4.59; second tertile: TyG index 4.59-4.83; third tertile: TyG index >4.83). Results We included 2907 patients (median age 77 [70-83] years; 52.5% female). The median TyG index was 4.71 (4.53-4.91), and 34% (989) where in the third tertile of TyG index. During a follow-up of 2 years, 209 (7.2%) patients suffered a thromboembolic event. Compared to patients in the first or second tertiles of TyG index, patients in the third tertile had an increased annual event rate of thromboembolic events (3.40 per 100 patient-years vs. 4.76 per 100 patient-years, p=0.043; and 3.41 per 100 patient-years vs. 4.76 per 100 patient-years, p=0.044), and higher incidence rate ratio (1.41 [95% CI 1.01-1.98], p=0.044 vs. first tertile; 1.40 [95% CI 1.01-1.97], p=0.044 vs. second tertile). Cox regression analyses adjusted for several risk factors demonstrated that the TyG index was an independent predictor for thromboembolic events (aHR 1.82; 95% CI 1.15-2.89; p=0.011). Patients in the third tertile of TyG index presented a 64% higher risk of thromboembolic events (aHR 1.64; 95% CI 1.17-2.29; p=0.004) (Table), with significantly lower event free survival (log-rank test p-value = 0.016) (Figure). Conclusions In this real-world cohort of AF patients under oral anticoagulation therapy, elevated TyG index was an independent risk factor for thromboembolic events. The TyG index is a simple, low-cost indicator, that could be used as a screening tool in everyday clinical practice.

The projected global burden of modifiable risk factors on cardiovascular disease from 2025 to 2100

Abstract Background Cardiovascular diseases (CVDs) are the primary cause of global mortality and morbidity. Controlling modifiable risk factors driving the CVD epidemic is a vital focus of primary prevention efforts worldwide. Understanding the epidemiological trends in these risk factors is therefore essential in designing effective countermeasures against CVDs for the years to come. Purpose This study aims to forecast the disability-adjusted life years (DALYs) associated with CVDs attributable to high systolic blood pressure (SBP), high body-mass index (BMI), high fasting plasma glucose (FPG), high low-density lipoprotein (LDL) and tobacco use from 2025 to 2100, stratified by GBD super-regions, sex, sociodemographic index (SDI), and age-groups. Methods Historical data on DALYs from 1990 to 2019 from the Global Burden of Disease (GBD) study was used to project DALYs associated with modifiable risk factors of CVDs from 2025 to 2100. Trends across GBD super-regions, sex, SDI, and age-groups were also examined. Results Between 2025 and 2100, age-standardised DALY rates (ASDR) per 100,000 population are forecasted to fall across all modifiable risk factors, with the greatest decline seen in tobacco use (-76.0%) and high LDL (-66.9%). Globally, high SBP and high BMI expect the greatest ASDR in 2100 (both 891 per 100,000 population), while tobacco use expects the least (213 per 100,000 population). High BMI is expected to rise 623.0% in South Asia and 221.5% in South-east Asia, East Asia and Oceania from 2025 to 2100, while high FPG is expected to rise 114.2% in North Africa and the Middle-east and 110.6% in South Asia. Females are expected to have lower overall and greater reductions in ASDR across all modifiable risk factors when compared to males from 2025 to 2100. Notably, males expect a 11.0% rise in high BMI worldwide across this period. The age-prevalence of modifiable risk factors is expected to be bimodal in 2100, highest in those aged 50-59 as well as 75-84 years old, possibly suggesting improvements in global screening efforts or the earlier development of metabolic dysfunction. All modifiable risk factors are predicted to fall in high and high-middle SDI regions from 2025 to 2100. In contrast, low, low-middle, and middle SDI regions expect a rise in high FPG and high BMI across this same time frame. The burden of modifiable CVD risk factors is expected to be highest in low-middle SDI regions in 2100, as compared to high-middle SDI regions in 2025. Conclusion While the global decline in ASDR of modifiable risk factors suggests overall improvements in the primary prevention of CVDs, regional spikes in high BMI and FPG calls for the implementation of timely, targeted interventions accounting for local trends in CVD. Moreover, the disproportionate metabolic burden expected in lower SDI regions in the coming decades requires concerted, international support to alleviate the global burden of CVDs.

COMPLICAÇÕES CRÔNICAS DO DIABETES MELLITUS TIPO 2

Diabetes mellitus is defined as a chronic non-communicable disease (NCD), being a syndrome characterized by persistent hyperglycemia, resulting from metabolic disorders, which may occur due to the destruction of insulin-producing beta cells or resistance to insulin action. The increase in plasma glucose occurs due to defects in the secretion and/or action of insulin produced by the pancreas, and can be subdivided into three main types: Type 1 Diabetes mellitus (autoimmune), Type 2 Diabetes mellitus (insulin resistant) and Diabetes gestational mellitus. Diabetes is characterized by multiple complications, acute and chronic (divided into microvascular and macrovascular), which constitute an important cause of early mortality. Chronic microvascular complications are associated with specific injuries caused by difficulty in passing blood to the endothelium. This obstruction occurs due to chronic hyperglycemia that triggers endothelial inflammation, resulting in the production of advanced glycolysis products, leading to oxidative stress, inflammation and the appearance of microthrombi, making this passage difficult. Macrovascular complications, in addition to hyperglycemia, are also related to problems such as dyslipidemia, systemic arterial hypertension and smoking. Such factors can lead to stroke, acute myocardial infarction and peripheral arterial obstructive disease. This work proposes a critical review of the existing literature on the chronic complications of Type 2 Diabetes mellitus, highlighting screening, prevention and treatment measures. It is concluded that technical and clinical knowledge about the pathophysiology and alternative interventions is essential for the immediate and comprehensive care of patients with Type 2 Diabetes mellitus, as well as the prevention of its chronic complications.

Long-term prognostic impact of fasting plasma glucose and myocardial flow reserve beyond other risk factors and heart disease phenotypes

Abstract Background Cardiometabolic risk factors, including high fasting plasma glucose (hFPG), are emerging determinants of residual mortality risk in patients with coronary artery disease (CAD) or heart failure (HF). Coronary microvascular dysfunction, encompassing a broad spectrum of traditional and emerging risk factors, might be a comprehensive risk predictor in these patients. Purpose To assess whether hFPG and global myocardial blood flow (MBF) reserve measured by positron emission tomography (PET), expressing global coronary function, may predict long-term prognosis beyond other risk factors and the presence of obstructive CAD or left ventricular (LV) dysfunction associated with HF. Methods Among 281 consecutive patients undergoing cardiac PET/CT because of stable chest pain or dyspnea we retrospectively collected long-term follow-up data in 103 patients (mean age 61±10 years, 74 males) in whom MBF measurements, coronary angiography and clinical data were available. Disease phenotypes included obstructive CAD (35%), LV dysfunction without obstructive CAD (43%) or none (22%). Results The mean age was 61±10 years (74 males, 72%). Among CVD risk factors, high LDL-cholesterol (hypercholesterolemia under treatment or LDL-C> 130 mg/dL) was present in 72%, high systemic blood pressure (hypertension under treatment or SBP>130/85 mmHg) in 51%, smoking habits in 49%, obesity (BMI>30 Kg/m2) in 22%, type 2 diabetes under treatment in 17%, low HDL-cholesterol (HDL-C< 40 mg/dL in males and <50 mg/dL in females) in 51%, high triglycerides (TG>150 mg/dL) in 27% and high fasting plasma glucose (FPG>100 mg/dL) in 33%. Global MBF reserve was <2 in 68% of patients. In a median follow-up of 10.9 years (7.8-13.9 IQR), 39 patients (37.8%) died (13.6% cardiac death). At multivariable Cox analyses including all risk factors and MBF reserve, age (HR 1.06, 95% CI 1.02-1.11), high FPG (HR 2.28, 95% CI 1.09-4.79) and depressed MBF reserve (HR 4.79, 95% CI 2.14-10.69) were the only independent predictors of death (Global χ2 36.74, P=0.0001). When disease phenotypes were added to the model, age (HR 1.07, 95% CI 1.02-1.12), high FPG (HR 2.18, 95% CI 1.02-4.63) and depressed MBF reserve (HR 4.47, 95% CI 1.96-10.18) remained independent predictors of death (Global χ2 37.41, P=0.0004) (Figure 1). Figure 2 plots the observed all cause death rate in patients with different disease phenotypes stratified for absence/presence of high FPG or MBF reserve <2. Death rate progressively increases according to disease phenotypes and is significantly associated with high FPG (P=0.049) or impaired MBF reserve (P=0.012) in each patient group. Conclusions These results suggest a strong long-term prognostic role of high FPG and depressed MBF reserve in a selected high-risk population of patients with high prevalence of obstructive CAD or HF.Figure 1 Figure 2

A genome-wide association study identifies genetic determinants of hemoglobin glycation index with implications across sex and ethnicity

IntroductionWe investigated the genetic determinants of variation in the hemoglobin glycation index (HGI), an emerging biomarker for the risk of diabetes complications.MethodsWe conducted a genome-wide association study (GWAS) for HGI in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (N = 7,913) using linear regression and additive genotype encoding on variants with minor allele frequency greater than 3%. We conducted replication analyses of top findings in the Atherosclerosis Risk in Communities (ARIC) study with inverse variance-weighted meta-analysis. We followed up with stratified GWAS analyses by sex and self-reported race.ResultsIn ACCORD, we identified single nucleotide polymorphisms (SNPs) associated with HGI, including a peak with the strongest association at the intergenic SNP rs73407935 (7q11.22) (P = 5.8e−10) with a local replication in ARIC. In black individuals, the variant rs10739419 on chromosome 9 in the Whirlin (WHRN) gene formally replicated (meta-P = 2.2e−9). The SNP-based heritability of HGI was 0.39 (P< 1e−10). HGI had significant sex-specific associations with SNPs in or near GALNT11 in women and HECW2 in men. Finally, in Hispanic participants, we observed genome-wide significant associations with variants near USF1 and NXNL2/SPIN1.DiscussionMany HGI-associated SNPs were distinct from those associated with fasting plasma glucose or HbA1c, lending further support for HGI as a distinct biomarker of diabetes complications. The results of this first evaluation of the genetic etiology of HGI indicate that it is highly heritable and point to heterogeneity by sex and race.

Cardiac corin and atrial natriuretic peptide regulate liver glycogen metabolism and glucose homeostasis

BackgroundCardiovascular function and metabolic homeostasis are closely linked, but the underlying mechanisms are not fully understood. Corin is a protease that activates atrial natriuretic peptide (ANP), an essential hormone for normal blood pressure and cardiac function. The goal of this study is to investigate a potential corin and ANP function in regulating liver glycogen metabolism and glucose homeostasis.MethodsLiver glycogen and blood glucose levels were analyzed in Corin or Nppa (encoding ANP) knockout (KO) mice. ANP signaling was examined in livers from Corin and Nppa KO mice and in cultured human and mouse hepatocytes by western blotting.ResultsWe found that Corin and Nppa KO mice had reduced liver glycogen contents and increased blood glucose levels. By analyzing conditional KO mice lacking either cardiac or renal Corin, we showed that cardiac corin and ANP act in an endocrine manner to enhance cGMP-protein kinase G (PKG)-AKT-GSK3 signaling in hepatocytes. In cultured hepatocytes, ANP treatment stimulated PKG signaling, glucose uptake, and glycogen production, which could be blocked by small molecule PKG and AKT inhibitors.ConclusionsOur results indicate that corin and ANP are important regulators in liver glycogen metabolism and glucose homeostasis, suggesting that defects in the corin and ANP pathway may contribute to both cardiovascular and metabolic diseases.

Activation of fibroblast growth factor 21 by Canagliflozin reduces high-fat diet associated obesity-related cardiac injury: a translational study from bench to bedside

Abstract Aims/hypothesis Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are indicated for the treatment of type 2 diabetes, and evidence shows that they may confer a cardioprotective effect to reduce the incidence of cardiovascular conditions in obese type 2 diabetes patients. The mechanisms underlying this effect remain unclear, but an SGLT2i, canagliflozin (CANA), has been reported to increase levels of fibroblast growth factor-21 (FGF21) and enhance activation of its downstream target proteins. We thus aimed to study whether the effect on FGF21 by CANA can reduce obesity-related cardiac injury. Methods 1) Animal study: Sixteen-week-old normal diet and high-fat diet male mice were treated with or without 30 mg/kg CANA once a day for 24 weeks, and were subsequently examined for body weight, blood glucose levels, adipose tissue changes, lipid accumulation in the liver, and cardiac function. 2) Cell study: An in vitro study that treated H9c2 cardiomyocyte cells cultured in a simulated high-lipid environment containing palmitic acid (PA) with FGF21 recombinant protein was also conducted to examine protein expression profiles. Furthermore, the effect of CANA on FGF21 expression. 3) Human clinical trial: A randomized double-blinded control trial (NCT 05764811) was performed to test effect of CANA on MRI liver fibrosis scores of obese type 2 diabetes patients (n = 40). Results 1) High-fat diet mice treated with CANA for 24 weeks had lower average body weight than untreated controls (34 g vs. 40 g, p < 0.001). In addition, CANA treatment stimulated FGF21 protein production in liver tissue and plasma at higher levels for both normal diet and high-fat diet mice, and reduced expression levels of proteins associated with fibrosis and apoptosis. 2) H9c2 cardiomyocyte culture studies suggested that a simulated high-lipid environment with PA caused higher expression of apoptotic proteins, but the addition of FGF21 recombinant protein significantly reduced apoptosis signalling. 3) MRI before and after 4 weeks of CANA treatment in obese type 2 diabetes patients showed a significant reduction in liver fibrosis scores for those receiving CANA treatment. Conclusion CANA treatment stimulated FGF21 protein expression and reduced fibrosis and apoptosis signalling protein expression. Moreover, reductions in liver fibrosis scores were observed in obese type 2 diabetes patients treated with CANA. Taken together, this suggests that CANA-induced FGF21 expression may exert a cardioprotective effect against fibrosis and apoptosis and can potentially reduce the risk of obesity-related cardiac injury.

Deep quantification of substrate turnover defines protease subsite cooperativity.

Substrate specificity determines protease functions in physiology and in clinical and biotechnological applications, yet quantitative cleavage information is often unavailable, biased, or limited to a small number of events. Here, we develop qPISA (quantitative Protease specificity Inference from Substrate Analysis) to study Dipeptidyl Peptidase Four (DPP4), a key regulator of blood glucose levels. We use mass spectrometry to quantify >40,000 peptides from a complex, commercially available peptide mixture. By analyzing changes in substrate levels quantitatively instead of focusing on qualitative product identification through a binary classifier, we can reveal cooperative interactions within DPP4's active pocket and derive a sequence motif that predicts activity quantitatively. qPISA distinguishes DPP4 from the related C. elegans DPF-3 (a DPP8/9-orthologue), and we relate the differences to the structural features of the two enzymes. We demonstrate that qPISA can direct protein engineering efforts like the stabilization of GLP-1, a key DPP4 substrate used in the treatment of diabetes and obesity. Thus, qPISA offers a versatile approach for profiling protease and especially exopeptidase specificity, facilitating insight into enzyme mechanisms and biotechnological and clinical applications.

Multi-Cavity Nanorefractive Index Sensor Based on MIM Waveguide

Within this manuscript, we provide a novel Fano resonance-driven micro-nanosensor. Its primary structural components are a metal-insulator-metal (MIM) waveguide, a shield with three disks, and a T-shaped cavity (STDTC). The finite element approach was used to study the gadget in theory. It is found that the adjustment of the structure and the change of the dimensions are closely related to the sensitivity (S) and the quality factor (FOM). Different model structural parameters affect the Fano resonance, which in turn changes the transmission characteristics of the resonator. Through in-depth experimental analysis and selection of appropriate parameters, the sensor sensitivity finally reaches 3020 nm/RIU and the quality factor reaches 51.89. Furthermore, the installation of this microrefractive index sensor allows for the quick and sensitive measurement of glucose levels. It is a positive contribution to the field of optical devices and micro-nano sensors and meets the demand for efficient detection when applied in medical and environmental scenarios.

Associations of the TyG index with albuminuria and chronic kidney disease in patients with type 2 diabetes.

Diabetes-related kidney disease reduces patients' quality of life, increases the risk of death, and is associated with insulin resistance (IR). The triglyceride-glucose (TyG) index is a simple and inexpensive alternative to IR measurement. Furthermore, the relationship between albuminuria and chronic kidney disease (CKD) in type 2 diabetes mellitus (T2DM) remains unclear. Therefore, we aimed to investigate the association of TyG index with albuminuria and CKD in patients with T2DM. Data from 01/2013-12/2017 period were obtained from the Population Health Data Archive's Diabetes Complications Data Set. A total of 1048 patients with T2DM were included in this study. CKD is defined as an estimated glomerular filtration rate < 60 ml/min-1.1.73 m-2 or a urinary albumin-to-creatinine ratio (UACR) ≥ 30 mg/g. Albuminuria is defined as a UACR ≥ 30 mg/g. The TyG index is calculated by measuring the triglyceride and fasting blood glucose levels. Logistic regression models were used to analyze the association between albuminuria, CKD with T2DM and TyG index. We identified 1048 subjects, 63.03% of whom were men. The mean age was 46.21 years, and the mean body mass index was 26.742 kg/m2. CKD and albuminuria detection rates showed an increasing trend in the different TyG subgroups. (p = 0.008, p = 0.006). Using the Q1 group as a baseline, the risk of albuminuria and CKD was significantly greater in the group Q3 (OR = 1.514, 95% CI 1.121-2.047 P = 0.05), and the same result was obtained after adjusting for covariates (OR = 2.241, 95% CI 1.245-4.034, P = 0.007). Subgroup analyses revealed a significant increase in the incidence of albuminuria and CKD in the group Q3 compared to that in the Q1 group. The TyG index is positively associated with albuminuria and CKD in patients with T2DM and may be a marker for predicting the occurrence of early kidney injury in patients with T2DM. Clinicians should test this indicator early to detect lesions and improve patient prognosis.

Management of Glucocorticoid-Induced Hyperglycemia in Cancer Patients: A Feasibility Study.

Glucocorticoids are commonly used in the management of patients with hematological and solid malignancies. However, their use may be associated with impaired glycemic metabolism and increased treatment-related morbidity and mortality. This study aimed to examine the feasibility and acceptability of a nurse-led model of care (MOC) for screening and managing glucocorticoid-induced hyperglycemia (GIH) in non-diabetic patients requiring high-dose glucocorticoid (HDG) therapies, as well as patients' and health professionals' experiences with the MOC. This study was a single-site feasibility study. Patients with hematological or oncological malignancies who were >18 years of age, receiving a chemotherapy regimen including HDGs, had no prior diagnosis of diabetes or prediabetes, and were not at the end of life were considered eligible for this study. Participants were recruited from a district hospital's Cancer Centre in Australia. All consenting participants were screened for diabetes and were provided with a blood glucose meter to monitor their blood glucose levels (BGLs) four times a day on the days of glucocorticoid therapy (GT) plus one extra day following GT, for the first four cycles of their treatment, to screen for the presence of GIH. Feasibility and acceptability were assessed using rates of consent, study completion, and staff and patient surveys. Forty-eight percent (35/74) of patients approached consented to participate in the study and had screening tests for preexisting diabetes. None were diagnosed with diabetes. Six out of 35 patients withdrew, and 10/29 patients did not complete the recommended BGL monitoring. Thirteen percent (4/29) of patients developed GIH. The most common reasons for non-participation and study withdrawal were related to the self-monitoring of BGLs. While clinical stakeholders found the MOC feasible and acceptable, the results of this study suggest that alternative methods for encouraging self-monitoring of BGL and monitoring the presence of GIH during high-dose chemotherapy need to be explored to address issues associated with adherence and sustainability.

Molecular Mechanisms of Methylglyoxal in Diabetes-related Macrovascular Complications

Diabetes mellitus (DM) is a chronic endocrine and metabolic disease indicated by the presence of hyperglycemia. It has been known that hyperglycemia and oxidative stress are the main culprit of all DM complications, including macrovascular complications. As a byproduct of lipid, protein, and carbohydrate metabolism, methylglyoxal (MGO) is a highly reactive substance which plays a positive signaling role in helping cells regain redox balance under oxidative stress circumstances. DM-related problems lead to an excess of mitochondrial superoxide in the heart and big and small vascular endothelial cells. Elevated intracellular reactive oxygen species induce impaired angiogenesis in reaction to ischemia, trigger several proinflammatory pathways, and result in enduring epigenetic modifications that propel the continuous expression of proinflammatory genes even after glucose levels return to normal. Over time, the significance of the extremely quick advanced glycation end-products (AGE) production caused by the extremely reactive MGO has been clarified. It is now evident that MGO causes vascular tissue to react maladaptively. Glyoxalase 1 (GLO1) is the primary enzyme in an organism's enzymatic glyoxalase defense mechanism, which converts MGO to D-lactate in order to counteract the harmful effects of MGO. Understanding the role of the MGO–GLO1 pathway in the etiology of vascular disease in diabetes has advanced significantly. Therefore, it can be summarized that vascular damage are linked to diabetes. The AGE precursor MGO are important in determining the connection between diabetes and vascular damage. MGO and AGEs play a role in several phases of the development of diabetes complications. MGO and AGEs may be useful therapeutic targets for diabetes's macrovascular problems.KEYWORDS: hyperglycemia, AGE, methylglyoxal, glyoxalase, D-lactate, gluthatione, oxidative stress.

Association between renal function impairment and body roundness index (BRI) in elderly hypertensive patients

Abstract Objective The purpose of this study was to explore the associations of renal function impairment and body roundness index (BRI) in elderly hypertensive patients. Methods This is a community-based observational and cross-sectional study.A total of 1482 elderly hypertensive patients from our center in 2021 were enrolled. Waist-to-hip ratio(WHR) , Body mass index(BMI) and BRI were calculated with validated formulas. According to tri quantile method of BRI level , the patients were divided into low , medium and high BRI groups. The incidence of renal function impairment in the three groups was compared to explore the associations of renal function impairment and BRI in elderly hypertensive patients. Result According to the estimated glomerular filtration rate (eGFR) level, the patients were divided into two groups: impaired renal function group and non impaired renal function group. 133 cases were included in the group with impaired renal function, and 1349 cases were included in the group without impaired renal function. The proportion of patients with impaired renal function was 8%, 497 were in the low BRI group, 491 in the medium BRI group, and 494 in the high BRI group. Comparing the incidence of renal function impairment in patients with different BRI levels, the results showed that the incidence of renal function impairment in patients with high BRI was higher than that in patients with low BRI (7.0%vs.11.5%,p=0.015). The results of binary logistic regression analysis showed that the risk of renal function impairment increased by 19% for each unit of BRI increase (95%CI 1.037-1.122,P=0.024). After adjusting for age, gender, blood lipid, smoking and drinking history, years of hypertension, diabetes, years of diabetes,and random blood glucose levels, the risk of renal function impairment in high BRI group was still significantly higher than low BRI group (OR=1.697,95%CI 1.031-2.794,P=0.038),shows that BRI is an independent risk factor for renal function impairment in elderly hypertension patients. The receiver operating characteristic curve (ROC) results show that the prediction ability of BRI in the whole population is better than that of BMI and waist circumference (WC), and the prediction ability of BRI in elderly female population is the best (AUC=0.569). Conclusion Increasing of BRI is correlated with the occurrence of renal function impairment in elderly hypertension patients, and has the best predictive value for renal function impairment in elderly women with hypertension.