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Metabolic syndrome (MetS), as a set of medical conditions including hyperglycemia, hypertension, abdominal obesity, and dyslipidemia, represents a highly prevalent disease cluster worldwide. The individual components of MetS together increase the risk of MetS-related disorders. Recent research has demonstrated that bone, as an endocrine organ, releases several systemic cytokines (osteokines), including fibroblast growth factor 23 (FGF23), lipocalin 2 (LCN2), and sclerostin (SCL). This review not only summarizes current knowledge about MetS, osteokines and the most common MetS-related diseases with a detrimental impact on bone quality (type 2 diabetes mellitus: T2DM; cardiovascular diseases: CVDs; osteoporosis: OP), but also provides new interpretations of the relationships between osteokines and individual components of MetS, as well as between osteokines and MetS-related diseases mentioned above. In this context, particular emphasis was given on available clinical studies. According to the latest knowledge, FGF23 may become a useful biomarker for obesity, T2DM, and CVDs, as FGF23 levels were increased in patients suffering from these diseases. LCN2 could serve as an indicator of obesity, dyslipidemia, T2DM, and CVDs. The levels of LCN2 positively correlated with obesity indicators, triglycerides, and negatively correlated with high-density lipoprotein (HDL) cholesterol. Furthermore, subjects with T2DM and CVDs had higher LCN2 levels. SCL may act as a potential biomarker predicting the incidence of MetS including all its components, T2DM, CVDs, and OP. Elevated SCL levels were noted in individuals with T2DM, CVDs and reduced in patients with OP. The aforementioned bone-derived cytokines have the potential to serve as promising predictors and prospective treatment targets for MetS and MetS-related diseases negatively affecting bone quality. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) and obesity are prevalent metabolic disorders in the Indian population, often linked to lifestyle changes leading to metabolic alterations. Elevated levels of circulating saccharides contribute to various metabolic disturbances, including T2DM and associated complications such as renal and retinal dysfunction. This study aimed to identify individuals at risk of T2DM through lipid profiling in Bhiwadi, Rajasthan. A total of 800 participants were enrolled, and parameters including lipid profiling levels (HDL, Cholesterol) were assessed. Among the participants, 400 males and 400 females exhibited lipid profiles indicative of T2DM risk. These findings underscore the significance of lipid profiling in identifying individuals at risk of T2DM and obesity-related complications. Lifestyle modifications and targeted interventions are crucial to mitigate the growing burden of these metabolic disorders, particularly in regions like Bhiwadi, Rajasthan, India. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is associated with obesity and, therefore, it is important to target both overweight and hyperglycaemia. Glucagon plays important roles in glucose, amino acid and fat metabolism and may also regulate appetite and energy expenditure. These physiological properties are currently being exploited therapeutically in several compounds, most often in combination with glucagon‐like peptide‐1 (GLP‐1) agonism in the form of dual agonists. With this combination, increases in hepatic glucose production and hyperglycaemia, which would be counterproductive, are largely avoided. In multiple randomized trials, the co‐agonists have been demonstrated to lead to significant weight loss and, in participants with T2DM, even improved glycated haemoglobin (HbA1c) levels. In addition, significant reductions in hepatic fat content have been observed. Here, we review and discuss the studies so far available. Twenty‐six randomized trials of seven different GLP‐1 receptor (GLP‐1R)/glucagon receptor (GCGR) co‐agonists were identified and reviewed. GLP‐1R/GCGR co‐agonists generally provided significant weight loss, reductions in hepatic fat content, improved lipid profiles, insulin secretion and sensitivity, and in some cases, improved HbA1c levels. A higher incidence of adverse effects was present with GLP‐1R/GCGR co‐agonist treatment than with GLP‐1 agonist monotherapy or placebo. Possible additional risks associated with glucagon agonism are also discussed. A delicate balance between GLP‐1 and glucagon agonism seems to be of particular importance. Further studies exploring the optimal ratio of GLP‐1 and glucagon receptor activation and dosage and titration regimens are needed to ensure a sufficient safety profile while providing clinical benefits. [ABSTRACT FROM AUTHOR]

Obesity has become a major global problem that significantly confers an increased risk of developing life‐threatening complications, including type 2 diabetes mellitus, fatty liver disease and cardiovascular diseases. Protein arginine methyltransferases (PRMTs) are enzymes that catalyse the methylation of target proteins. They are ubiquitous in eukaryotes and regulate transcription, splicing, cell metabolism and RNA biology. As a key, epigenetically modified enzyme, protein arginine methyltransferase 1 (PRMT1) is involved in obesity‐related metabolic processes, such as lipid metabolism, the insulin signalling pathway, energy balance and inflammation, and plays an important role in the pathology of obesity‐related metabolic disorders. This review summarizes recent research on the role of PRMT1 in obesity‐related metabolic disorders. The primary objective was to comprehensively elucidate the functional role and regulatory mechanisms of PRMT1. Moreover, this study attempts to review the pathogenesis of PRMT1‐mediated obesity‐related metabolic disorders, thereby offering pivotal information for further studies and clinical treatment. [ABSTRACT FROM AUTHOR]

Background: Glucosamine is a dietary supplement commonly used to support joint health. However, there has been interest in exploring other effects of glucosamine on health outcomes due to its ant‐inflammation effect. Objective: This study compared the risks of major adverse liver outcomes (MALOs) between regular users and non‐users of glucosamine among patients with type 2 diabetes and metabolic dysfunction associated steatotic liver disease (MASLD) using the data from a large prospective cohort study. Methods: Demographic, anthropometric, laboratory and medication prescription information among 18 753 patients with type 2 diabetes and MASLD was obtained from the UK Biobank. MASLD was identified based on hepatic steatosis defined by fatty liver index ≥60 plus the presence of any clues of metabolic dysregulation and cardio‐metabolic risk factors, excluding patients with moderate to severe alcohol consumption. Results: During a mean follow‐up of 11.4 years, 826 incident MALOs events were recorded. Patients not regularly using glucosamine compared with patients using glucosamine showed a significantly higher risk of the composite MALOs (HR 1.36, 95% confidence interval [CI] 1.09–1.69) as well as most individual MALOs except for ascites. The multivariable‐adjusted HRs of MALOs within 3, 5 and 10 years among non‐users of glucosamine compared with regular users were 1.79 (95% CI.69–2.03), 1.88 (95% CI 1.21–2.54) and 1.32 (95% CI 1.05–1.72), respectively. Further subgroup analyses in participants with different baseline characteristics and sensitivity analyses excluding participants who regularly took any other supplements and participants who used self‐reports to diagnose diabetes confirmed the findings. Conclusions: The present study indicated that habitual use of glucosamine was associated with a low risk of individual and composite MALOs among patients with type 2 diabetes and MASLD. [ABSTRACT FROM AUTHOR]

Obesity compromises metabolic flexibility and increases specific immune responses. Fasting forces metabolic flexibility and alters glucose, fatty acids, glycerol, and amino acids to maintain blood glucose and energy balance. Intermittent fasting (IF) lowers inflammation and opposes metabolic dysfunction during obesity. IF can improve glucose metabolism independent of changes in obesity. Gut microbiota composition altered by IF triggers changes in immunity and metabolism. Intermittent fasting (IF) modifies cell- and tissue-specific immunometabolic responses that dictate metabolic flexibility and inflammation during obesity and type 2 diabetes (T2D). Fasting forces periods of metabolic flexibility and necessitates increased use of different substrates. IF can lower metabolic inflammation and improve glucose metabolism without lowering obesity and can influence time-dependent, compartmentalized changes in immunity. Liver, adipose tissue, skeletal muscle, and immune cells communicate to relay metabolic and immune signals during fasting. Here we review the connections between metabolic and immune cells to explain the divergent effects of IF compared with classic caloric restriction (CR) strategies. We also explore how the immunometabolism of metabolic diseases dictates certain IF outcomes, where the gut microbiota triggers changes in immunity and metabolism during fasting. [ABSTRACT FROM AUTHOR]

Context Surrogate measures of childhood and adolescent obesity have impaired the understanding of the relationship of body composition with insulin resistance in the young population. Objective We aim to examine the longitudinal associations of directly measured total fat mass, trunk fat mass, and lean mass with the risk of hyperglycemia, hyperinsulinemia, and insulin resistance from ages 15 to 24 years, the mediation path through which lipids and inflammation influence insulin resistance, and whether increased fat mass temporally precede insulin resistance. Methods We studied 3160 adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC), UK birth cohort, who had complete dual-energy x-ray absorptiometry measure and fasting blood samples at age 15 years and repeated measures at ages 17- and 24-years clinic visit. Fasting glucose greater than 6.1 mmol/L, insulin greater than 11.78 mU/L, and homeostatic model assessment for insulin resistance (HOMA-IR) greater than or equal to the 75th percentile were categorized as hyperglycemia, hyperinsulinemia, and high insulin resistance, respectively. Longitudinal associations were examined with generalized logit-mixed-effect models, while mediation and temporal path analyses were examined using structural equation models, adjusting for cardiometabolic and lifestyle factors. Results Among 3160 participants (51% female), fat mass and lean mass increased linearly both in males and females, while glucose, insulin, and HOMA-IR had a U-shaped course from age 15 through 24 years. After full adjustment, each 1-kg cumulative increase in total fat mass (odds ratio 1.12 [95% CI, 1.11-1.13]) and trunk fat mass (1.21 [1.19-1.23]) from ages 15 through 24 years were associated with a progressively worsening risk of high insulin resistance as well as hyperglycemia and hyperinsulinemia. The association of increased total fat mass with increased insulin resistance was partly mediated by triglycerides (9% mediation). In the temporal path analysis, higher total fat mass at age 15 years was associated with higher insulin resistance at age 17 years, but not vice versa. Higher total fat mass at age 17 years was bidirectionally associated with higher insulin resistance at 24 years. Conclusion Mid-adolescence may be an optimal time for interrupting the worsening fat mass–insulin resistance pathologic cycle and attenuating the risk of progressively worsening metabolic dysfunction before young adulthood. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is a heavy metal that acts as endocrine disrupting chemical (EDC). Few studies have investigated the effects of Cd exposure on metabolic dysfunctions, such as type 1 and 2 diabetes mellitus (T1DM and T2DM). Thus, we assessed whether subacute Cd exposure at occupational levels causes abnormalities in white adipose tissue (WAT), liver, pancreas, and skeletal muscle. We administered cadmium chloride (CdCl2) (100 ppm in drinking water for 30 days) to female rats and evaluated Cd levels in serum and metabolic organs, morphophysiology, inflammation, oxidative stress, fibrosis, and gene expression. High Cd levels were found in serum, WAT, liver, pancreas, and skeletal muscle. Cd‐exposed rats showed low adiposity, dyslipidemia, insulin resistance, systemic inflammation, and oxidative stress compared to controls. Cd exposure reduced adipocyte size, hyperleptinemia, increased cholesterol levels, inflammation, apoptosis and fibrosis in WAT. Cd‐exposed rats had increased liver cholesterol levels, insulin receptor beta (IRβ) and peroxisome proliferator‐activated receptor‐gamma coactivator‐1alpha (PGC1α) expression, karyomegaly, inflammation, and fibrosis. Cd exposure reduced insulin levels and pancreatic islet size and increased inflammation and fibrosis. Cd exposure reduced skeletal muscle fiber diameter and increased IR expression and inflammation. Finally, strong positive correlations were observed between serum, tissue Cd levels, abnormal morphology, tissue inflammation and fibrosis. Thus, these data suggest that subacute Cd exposure impairs WAT, liver, pancreas and skeletal muscle function, leading to T1DM and T2DM features and other complications in female rats. [ABSTRACT FROM AUTHOR]

Introduction and purpose : Type 2 diabetes is currently a serious problem worldwide. Each year, the number of individuals with carbohydrate metabolism disorders is increasing. This is due to an unhealthy lifestyle, lack of physical activity, and a diet rich in highly processed foods. Currently, the treatment of type 2 diabetes is based on the use of oral antidiabetic medications, with the first choice often being a derivative of biguanides, such as metformin. Berberine has been used in China for many years as a hypoglycemic agent, and its efficacy is compared to metformin preparations. This paper focuses on the benefits of using berberine in patients with prediabetes or type 2 diabetes and compares the effects of berberine preparations to classical medications used in diabetes treatment. Material and methods : The literaue was reviewed in PubMed and Google Scholar scientific database in 2013-2023 using the following keywords : berberine, diabetes mellitus type 2, hyperlipidemia, hyperglicemia. Conclusions : The studies included in this manuscript have shown that berberine is a promising agent for adjunctive treatment in type 2 diabetes. It exhibits a range of positive effects such as lowering blood glucose levels, improving lipid profile, with no serious adverse effects reported. However, further research is needed to confirm these findings and develop an effective treatment plan. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) represents a heterogeneous and multifactorial metabolic disorder, leading to diverse economic challenges and health complications, significantly affecting individuals’ lives. Type 2 diabetes (T2DM) stands as the predominant form of diabetes, with its onset influenced by a range of genetic and environmental factors. Currently, conventional diabetic medications are employed in clinical practice, but they may entail certain side effects. Fortunately, diverse natural polysaccharides extracted from plants exhibit antidiabetic properties, which have been demonstrated to effectively mitigate hyperglycemia, reverse insulin resistance, and forestall complications associated with diabetes. Consequently, exploring the utilization of these polysaccharides as adjuncts to conventional therapies has emerged as a novel research direction in recent years. Thus, this review centers on the extraction, purification, and characterization of plant polysaccharides, providing an overview of the advancements in the antidiabetic effects and mechanisms of natural polysaccharides. This perspective offers fresh insights to explore potential research domains and enhances understanding for the development of diabetic drugs derived from polysaccharides. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) and metabolic-associated fatty liver disease (MAFLD) are both metabolic disorders that negatively impact the cardiovascular system. This study comprehensively analyzed the additive effect of MAFLD on left ventricular function and global strain in T2DM patients by cardiac magnetic resonance (CMR). Methods: Data of 261 T2DM patients, including 109 with and 152 without MAFLD, as well as 73 matched normal controls from our medical center between June 2015 and March 2022 were retrospectively analyzed. CMR-derived parameters, including LV function and global strain parameters, were compared among different groups. Univariate and multivariate linear regression analyses were conducted to investigate the impact of various factors on LV function and global strain. Results: Our investigation revealed a progressive deterioration in LV functional parameters across three groups: control subjects, T2DM patients without MAFLD, and T2DM patients with MAFLD. Statistically significant increases in left ventricular end-diastolic volume index (LVEDVI), left ventricular end-systolic volume index (LVESVI), left ventricular mass index (LVMI) were observed, along with decreases in left ventricular ejection fraction (LVEF) and left ventricular global function index (LVGFI). Among these three groups, significant reductions were also noted in the absolute values of LV global radial, circumferential, and longitudinal peak strains (GRPS, GCPS, and GLPS), as well as in peak systolic (PSSR) and peak diastolic strain rates (PDSR). MAFLD was identified as an independent predictor of LVEF, LVMI, LVGFI, GRPS, GCPS, and GLPS in multivariate linear analysis. Besides, the incidence of late gadolinium enhancement was higher in MAFLD patients than in non-MAFLD patients (50/109 [45.9%] vs. 42/152 [27.6%], p = 0.003). Furthermore, escalating MAFLD severity was associated with a numerical deterioration in both LV function parameters and global strain values. Conclusions: This study thoroughly compared CMR parameters in T2DM patients with and without MAFLD, uncovering MAFLD's adverse impact on LV function and deformation in T2DM patients. These findings highlight the critical need for early detection and comprehensive management of cardiac function in T2DM patients with MAFLD. [ABSTRACT FROM AUTHOR]

While it is generally known that metabolic disorders and circadian dysfunction are intertwined, how the two systems affect each other is not well understood, nor are the genetic factors that might exacerbate this pathological interaction. Blood chemistry is profoundly changed in metabolic disorders, and we have previously shown that serum factors change cellular clock properties. To investigate if circulating factors altered in metabolic disorders have circadian modifying effects, and whether these effects are of genetic origin, we measured circadian rhythms in U2OS cell in the presence of serum collected from diabetic, obese or control subjects. We observed that circadian period lengthening in U2OS cells was associated with serum chemistry that is characteristic of insulin resistance. Characterizing the genetic variants that altered circadian period length by genome‐wide association analysis, we found that one of the top variants mapped to the E3 ubiquitin ligase MARCH1 involved in insulin sensitivity. Confirming our data, the serum circadian modifying variants were also enriched in type 2 diabetes and chronotype variants identified in the UK Biobank cohort. Finally, to identify serum factors that might be involved in period lengthening, we performed detailed metabolomics and found that the circadian modifying variants are particularly associated with branched chain amino acids, whose levels are known to correlate with diabetes and insulin resistance. Overall, our multi‐omics data showed comprehensively that systemic factors serve as a path through which metabolic disorders influence circadian system, and these can be examined in human populations directly by simple cellular assays in common cultured cells. [ABSTRACT FROM AUTHOR]

SH2B1 mutations are associated with obesity, type 2 diabetes, and metabolic dysfunction‐associated steatotic liver disease (MASLD) in humans. Global deletion of Sh2b1 results in severe obesity, type 2 diabetes, and MASLD in mice. Neuron‐specific restoration of SH2B1 rescues the obesity phenotype of Sh2b1‐null mice, indicating that the brain is a main SH2B1 target. However, SH2B1 neurocircuits remain elusive. SH2B1‐expressing neurons in the paraventricular hypothalamus (PVHSH2B1) and a PVHSH2B1→dorsal raphe nucleus (DRN) neurocircuit are identified here. PVHSH2B1 axons monosynaptically innervate DRN neurons. Optogenetic stimulation of PVHSH2B1 axonal fibers in the DRN suppresses food intake. Chronic inhibition of PVHSH2B1 neurons causes obesity. In male and female mice, either embryonic‐onset or adult‐onset deletion of Sh2b1 in PVH neurons causes energy imbalance, obesity, insulin resistance, glucose intolerance, and MASLD. Ablation of Sh2b1 in the DRN‐projecting PVHSH2B1 subpopulation also causes energy imbalance, obesity, and metabolic disorders. Conversely, SH2B1 overexpression in either total or DRN‐projecting PVHSH2B1 neurons protects against diet‐induced obesity. SH2B1 binds to TrkB and enhances brain‐derived neurotrophic factor (BDNF) signaling. Ablation of Sh2b1 in PVHSH2B1 neurons induces BDNF resistance in the PVH, contributing to obesity. In conclusion, these results unveil a previously unrecognized PVHSH2B1→DRN neurocircuit through which SH2B1 defends against obesity by enhancing BDNF/TrkB signaling. [ABSTRACT FROM AUTHOR]

Introduction: Maintaining metabolic balance relies on accumulating nutrients during feeding periods and their subsequent release during fasting. In obesity and metabolic disorders, strategies aimed at reducing food intake while simulating fasting have garnered significant attention for weight loss. Caloric restriction (CR) diets and intermittent fasting (IF) interventions have emerged as effective approaches to improving cardiometabolic health. Although the comparative metabolic benefits of CR versus IF remain inconclusive, this review focuses on various forms of IF, particularly time-restricted eating (TRE). Methods: This study employs a narrative review methodology, systematically collecting, synthesizing, and interpreting the existing literature on TRE and its metabolic effects. A comprehensive and unbiased search of relevant databases was conducted to identify pertinent studies, including pre-clinical animal studies and clinical trials in humans. Keywords such as "Obesity," "Intermittent Fasting," "Time-restricted eating," "Chronotype," and "Circadian rhythms" guided the search. The selected studies were critically appraised based on predefined inclusion and exclusion criteria, allowing for a thorough exploration and synthesis of current knowledge. Results: This article synthesizes pre-clinical and clinical studies on TRE and its metabolic effects, providing a comprehensive overview of the current knowledge and identifying gaps for future research. It explores the metabolic outcomes of recent clinical trials employing different TRE protocols in individuals with overweight, obesity, or type II diabetes, emphasizing the significance of individual chronotype, which is often overlooked in practice. In contrast to human studies, animal models underscore the role of the circadian clock in mitigating metabolic disturbances induced by obesity through time-restricted feeding (TRF) interventions. Consequently, we examine pre-clinical evidence supporting the interplay between the circadian clock and TRF interventions. Additionally, we provide insights into the role of the microbiota, which TRE can modulate and its influence on circadian rhythms. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM), often featuring hyperglycemia or insulin resistance, is a global health concern that is increasing in prevalence in the United States and worldwide. A common complication is metabolic dysfunction-associated steatotic liver disease (MASLD), the hepatic manifestation of metabolic syndrome that is also rapidly increasing in prevalence. The majority of patients with T2DM will experience MASLD, and likewise, individuals with MASLD are at an increased risk for developing T2DM. These two disorders may act synergistically, in part due to increased lipotoxicity and inflammation within the liver, among other causes. However, the pathophysiological mechanisms by which this occurs are unclear, as is how the improvement of one disorder can ameliorate the other. This review aims to discuss the pathogenic interactions between T2D and MASLD, and will highlight novel therapeutic targets and ongoing clinical trials for the treatment of these diseases. [ABSTRACT FROM AUTHOR]

Advanced glycation end-products (AGEs) formation increases with metabolic disorders, leading to higher serum AGE levels in patients with progressive vascular complications. Measuring AGE levels in biological samples requires multiple pre-analytical processing steps, rendering analysis of multiple samples challenging. This study evaluated the progression of diabetic complications by analyzing AGE levels using a pre-analytical processing strategy based on a fully automated solid phase-extraction system. Serum samples from patients with diabetes, with or without macrovascular complications (Mac or non-Mac) or microvascular complications (Mic or non-Mic), were processed with the established methods. Free and total AGE levels in sera were measured using liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS). In patients with diabetes, both free and total AGE levels were elevated in those with complications compared to those without complications. In Mac and Mic groups, free and total AGE levels and z-scores (the sum of normalized AGE levels) also increased. AGE z-scores were markedly higher than those of single AGE levels in distinguishing each complication. Our study demonstrated that the free AGE z-score, measured using a new analytical method without hydrolysis, correlated with the presence of vascular complications and may serve as a marker of disease complications. [ABSTRACT FROM AUTHOR]

Introduction: Vitamin D deficiency, insulin resistance, dyslipidemia, and APOE genotyping are implicated in the pathogenesis of obesity and type 2 diabetes mellitus (T2DM). We wanted to find out if there was a link between a lack of 25(OH) vitamin D, HOMA-IR, and lipids and APOE genotyping in obese people with and without T2DM. Methods: We divided 300 Egyptians of both sexes into three groups in a case-control study: 100 obese cases with a body mass index of more than 30, 100 obese cases diagnosed with T2DM, and 100 controls with a body mass index of less than 30. Levels of 25 (OH) vitamin D, fasting blood sugar (FBS), HbA1C, fasting insulin, HOMA-IR, and lipid profile parameters were measured, and APOE genotypes were assessed using Applied BiosystemsTM TaqMan® SNP Genotyping Assays. Results: Higher levels of FBS, fasting insulin, HOMA-IR, and dyslipidemia were found in obese people with and without T2DM compared to the control group (p < 0.05). Lower levels of 25(OH) vitamin D were also found. Insulin resistance and lipid profile parameters, particularly in obese cases with T2DM, inversely correlate with vitamin D deficiency. The APOE genotyping analysis revealed strong links between vitamin D levels and certain APOE genotypes. Independent of metabolic parameters, higher vitamin D levels were associated with lower odds of E3/E4 and E4/E4 genotypes among obese cases with T2DM. Conclusion: This study highlights the independent role of vitamin D deficiency in modulating APOE genotypes in obese T2DM individuals. The findings suggest potential implications for personalized interventions targeting vitamin D status to mitigate genetic predispositions to metabolic disorders such as obesity and T2DM. [ABSTRACT FROM AUTHOR]

A dangerous side effect of diabetes that can significantly lower quality of life and raise the death rate of diabetic individuals is diabetic autonomic neuropathy. It is essential to identify and anticipate this disease early on for prompt intervention and care. This study aims to predict this diabetic complication using Sudoscan and artificial intelligence. In this study, 172 individuals with type 1 or type 2 diabetes mellitus provided clinical and demographic information. Sudoscan was used to evaluate the subjects' sudomotor dysfunction. Statistical methods were used to link various electrochemical skin conductance values with risk factors for neuropathy such as age, BMI, age of diabetes, or biochemical values such as cholesterol and triglycerides. Different machine-learning algorithms were used to predict the risk of diabetic autonomic neuropathy based on the collected data. The accuracy achieved with Logistic Regression is 92.6%, and with the Random Forest model is 96.3%. Lazzy Classifiers also show that six classifiers have a high performance of 97%. Thus, the use of machine learning algorithms in this field of metabolic diseases offers new perceptions for diagnosis, treatment, and prevention, and improves the quality of life of diabetic patients by reducing the incidence of complications related to this disease. [ABSTRACT FROM AUTHOR]

Objective: The causal relationship between type 2 diabetes mellitus (T2DM) and osteoporosis (OS) remains unclear. This study aims to investigate the causal relationship and explore the potential metabolic mechanism and its mediating role. Methods: We conducted a comprehensive study, gathering data on 490,089 T2DM patients from the genome-wide association study (GWAS) database and selecting OS data from FinnGen and MRC-IEU sources, including 212,778 and 463,010 patients, respectively, for causal analysis. Simultaneously, we explored the potential roles of three obesity traits and 30 metabolic and inflammationrelated mediating variables in the causal relationship. Results: There is a strong causal relationship between T2DM and OS. The data from our two different database sources appeared in the same direction, but after correcting for body mass index (BMI), waist circumference (WC), and waist-tohip ratio (WHR), the direction became the same. T2DM may increase the risk of OS [odds ratio (OR) > 1.5, p < 0.001]. Steiger's test results show that there is no reverse causality. No risk factors related to glycolipid metabolism, amino acid metabolism, and inflammation were found to mediate the causal relationship. Conclusion: This study's findings indicate a robust causal relationship between T2DM and OS, influenced by relevant factors such as BMI. Our results shed light on the pathogenesis of OS and underscore the importance for clinicians to treat metabolic disorders to prevent osteoporosis. [ABSTRACT FROM AUTHOR]

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are two incretins that bind to their respective receptors and activate the downstream signaling in various tissues and organs. Both GIP and GLP-1 play roles in regulating food intake by stimulating neurons in the brain’s satiety center. They also stimulate insulin secretion in pancreatic b-cells, but their effects on glucagon production in pancreatic a-cells differ, with GIP having a glucagonotropic effect during hypoglycemia and GLP-1 exhibiting glucagonostatic effect during hyperglycemia. Additionally, GIP directly stimulates lipogenesis, while GLP-1 indirectly promotes lipolysis, collectively maintaining healthy adipocytes, reducing ectopic fat distribution, and increasing the production and secretion of adiponectin from adipocytes. Together, these two incretins contribute to metabolic homeostasis, preventing both hyperglycemia and hypoglycemia, mitigating dyslipidemia, and reducing the risk of cardiovascular diseases in individuals with type 2 diabetes and obesity. Several GLP-1 and dual GIP/GLP-1 receptor agonists have been developed to harness these pharmacological effects in the treatment of type 2 diabetes, with some demonstrating robust effectiveness in weight management and prevention of cardiovascular diseases. Elucidating the underlying cellular and molecular mechanisms could potentially usher in the development of new generations of incretin mimetics with enhanced efficacy and fewer adverse effects. The treatment guidelines are evolving based on clinical trial outcomes, shaping the management of metabolic and cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Functional genetics has identified drug targets for metabolic disorders. Opioid use impacts metabolic homeostasis, although mechanisms remain elusive. Here, we explore the OPRD1 gene (encoding delta opioid receptor, DOP) to understand its impact on type 2 diabetes. Large-scale sequencing of OPRD1 and in vitro analysis reveal that loss-of-function variants are associated with higher adiposity and lower hyperglycemia risk, whereas gain-of-function variants are associated with lower adiposity and higher type 2 diabetes risk. These findings align with studies of opium addicts. OPRD1 is expressed in human islets and beta cells, with decreased expression under type 2 diabetes conditions. DOP inhibition by an antagonist enhances insulin secretion from human beta cells and islets. RNA-sequencing identifies pathways regulated by DOP antagonism, including nerve growth factor, circadian clock, and nuclear receptor pathways. Our study highlights DOP as a key player between opioids and metabolic homeostasis, suggesting its potential as a therapeutic target for type 2 diabetes. Opioid use impacts metabolic homeostasis, although the mechanisms remain elusive. Here, the authors explore the OPRD1 gene (encoding the delta opioid receptor, DOP) to understand its impact on type 2 diabetes and highlight DOP as a key player between opioids and metabolic homeostasis. [ABSTRACT FROM AUTHOR]

This study investigates the intricate relationship between excessive adipocyte production, leading to Type 2 Diabetes (T2D) and chronic inflammation characterized by elevated reactive oxygen species (ROS) and nitric oxide (NO) levels. Leveraging in silico studies, computational analyses unravel the interaction between major compounds of Kakadu Plum (KKD-NT) including ellagic acid (EA), gallic acid (GA), daidzin (DD), and ascorbic acid (AA) with pivotal obesity-related biomolecules (PPARγ, C/EBPα, β-catenin). Notably, EA and DD display a superior binding affinity with active residues compared to GA, AA, and the control drug Resveratrol (RSV). Experimental validation showcases the capacity of KKD-NT to diminish intracellular ROS in hypertrophied adipocytes by amplifying antioxidant defense enzymes (SOD, Catalase, GPx). KKD-NT further mitigates obesity-induced inflammation by reducing lipid accumulation, NO production, influencing adipogenesis factors (PPARγ, CEBPɑ, and FAS), Wnt signaling (β-catenin), and pro-inflammatory mediators (TNF-ɑ, IL-6, leptin) in 3T3-L1 cells. In vitro evaluations attest to anti-diabetic properties of KKD-NT as evidenced by enhancing glucose uptake and inhibiting α-glucosidase activity. The up-regulation of GLUT4 and adiponectin mRNA expression suggests potential benefits for obesity and diabetes. While acknowledging the need for further research to assess safety and in vivo effectiveness, this study suggests that KKD-NT and its bioactive components hold promise as innovative therapeutic interventions for obesity and related metabolic diseases, opening avenues for future exploration in clinical applications. Inhibitory activity of KKD-NT against Obesity and Obesity-induced diabetes and inflammation. [Display omitted] • Obesity is associated to other metabolic diseases including diabetes and inflammation etc. • Terminalia ferdinandiana (Kakadu Plum) is best known for the high concentration of Vitamin-C along with ellagic acid, gallic acid and daidzin. • Kakadu plum and its phytochemicals inhibit Obesity, Obesity-induced diabetes and inflammation in 3T3-L1 cells. • In-silico studies were evaluate the drug likeliness of Kakadu plum derivatives. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Type 2 diabetes mellitus is a major metabolic disease that seriously endangers life and health, but women with gestational diabetes mellitus are at increased risk for developing type 2 diabetes mellitus. This study aimed to evaluate the effectiveness of postpartum lifestyle intervention on the prevention of type 2 diabetes mellitus, and the effect of lifestyle intervention on glycemic outcomes and anthropometric measures. Materials and Methods: We searched PubMed and other databases to retrieve articles published before May 21, 2023, on randomized controlled trials of postnatal lifestyle interventions (diet and/or physical activity) in women with gestational diabetes mellitus. We estimated the pooled odds ratios using fixed or random effects models and conducted a subgroup analysis of the different intervention methods to explore differences in the different lifestyle interventions. Results: The review included 17 randomized controlled trials. Overall, lifestyle changes started after a pregnancy complicated by gestational diabetes mellitus an 11% (RR = 0.89; 95% CI: 0.74–1.07) reduction in diabetes risk; significant differences were found for weight (MD = −1.33; 95% CI: [−1.76; −0.89], P < 0.00001) body mass index (MD = −0.53; 95% CI: [−0.74, −0.32], P < 0.00001), and waist circumference change (MD = −1.38; 95% CI: [−2.12; −0.64], P = 0.0002) but not for fasting glucose (MD = −0.06; 95% CI: [−0.19; 0.06], P = 0.32), 2 h glucose (MD = −0.12; 95% CI: [−0.30; 0.06], P = 0.19), and hemoglobin A1c (MD = −0.11; 95% CI: [−0.23; 0.02], P = 0.09). Subgroup analyses showed no significant differences in the effects of different lifestyle interventions on the incidence of type 2 diabetes, blood glucose levels, and anthropometric parameters. Conclusion: Our comprehensive meta‐analysis of lifestyle interventions can improve modifiable anthropometric measures in women with gestational diabetes. We need further research to provide more intensive lifestyle intervention, more scientific intervention methods, and to reduce the incidence of type 2 diabetes in patients with gestational diabetes. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Conclusions Fibroblast growth factor 19 (FGF19) is an intestinal‐derived factor that plays a role in metabolic diseases. We performed a differential study of circulating FGF19 levels and investigated the causal effects of FGF19 on metabolic diseases using Mendelian randomization (MR).Firstly, 958 subjects were included in the physical examination center of affiliated hospital from January 2019 to January 2021. Dividing the subjects into different subgroups to compare FGF19 levels. We conducted a two‐sample MR analysis of genetically predicted circulating FGF19 in relation to alcohol, cardiovascular and metabolic biomarkers and diseases, and liver function biomarkers using publicly available genome‐wide association study summary statistics data.The circulating FGF19 levels in nonalcoholic fatty liver disease (NAFLD) patients were lower than those without NAFLD (P < 0.001). The FGF19 levels in participants with obese were lower than those without obese (P < 0.001). In two‐sample MR analyses, genetically predicted higher circulating FGF19 levels was significantly associated with lower aspartate aminotransferase, γ‐glutamyltransferase, triglycerides, total cholesterol, low‐density lipoprotein, and C‐reactive protein concentrations (P < 0.05) and a negative correlation with cardiovascular disease and cirrhosis whereas a positive association with type 2 diabetes mellitus (P < 0.05).Our study found that circulating FGF19 levels were lower in NAFLD and obese populations. Additionally, our MR research results support the causal effects of FGF19 on improved liver function, lipids, and reduced the occurrence of inflammation, cardiovascular disease, and cirrhosis. We found a positive correlation with diabetes, which may indicate a compensatory increase in regulating above FGF19 resistance states in humans. [ABSTRACT FROM AUTHOR]

AbstractType 2 diabetes mellitus (T2DM) is one of the metabolic diseases with the highest morbidity rates in the world. Probiotics have positive health impacts on human health and a considerable amount of research has demonstrated their beneficial effects in treating T2DM. However, probiotic intervention in T2DM has complex mechanisms because the pathogenesis of T2DM is complex. This review summarized the mechanisms of probiotic intervention in diabetes from the perspective of diabetes pathogenesis. First, the objectives of probiotic intervention in diabetes aimed at the intestinal tract reparative effects, pancreatic function, host metabolism and self-recovery were comprehensively reviewed. Next, we concluded the clinical application status of ingested probiotics in patients with T2DM, and an obvious imbalance exists between theoretical probiotic research and clinical applications. Finally, we summarized the emerging research on probiotic interventions in T2DM and analyzed the literature in this regard, including next-generation probiotics; suggestions for probiotics consumption with the aim of diabetic complications; as well as the association between novel mechanisms of diabetes remission with the potential for probiotic intervention. In conclusion, this review sheds light on the potential role of probiotics, from proposed mechanisms to prospects in relieving T2DM. [ABSTRACT FROM AUTHOR]

Glucagon‐like peptide‐1 receptor (GLP‐1R) agonists induce weight loss in patients with type 2 diabetes mellitus (T2DM), but the underlying mechanism is unclear. Recently, the mechanism by which metformin induces weight loss could be explained by an increase in growth differentiation factor 15 (GDF15), which suppresses appetite. Therefore, we aimed to investigate whether the GLP‐1R agonist liraglutide modifies plasma GDF15 levels in patients with T2DM. GDF15 levels were measured in plasma samples obtained from Dutch Europids and Dutch South Asians with T2DM before and after 26 weeks of treatment with daily liraglutide (n = 44) or placebo (n = 50) added to standard care. At baseline, circulating GDF15 levels did not differ between South Asians and Europids with T2DM. Treatment with liraglutide, compared to placebo, decreased body weight, but did not modify plasma GDF15 levels in all patients, or when data were split by ethnicity. Also, the change in plasma GDF15 levels after treatment with liraglutide did not correlate with changes in body weight or HbA1c levels. In addition, the dose of metformin used did not correlate with baseline plasma GDF15 levels. Compared to placebo, liraglutide treatment for 26 weeks does not modify plasma GDF15 levels in Dutch Europid or South Asian patients with T2DM. Thus, the weight loss induced by liraglutide is likely explained by other mechanisms beyond the GDF15 pathway. Highlights: What is the central question of this study?Growth differentiation factor 15 (GDF15) suppresses appetite and is increased by metformin: does the GLP‐1R agonist liraglutide modify plasma GDF15 levels in patients with type 2 diabetes mellitus (T2DM)?What is the main finding and its importance?Plasma GDF15 levels did not differ between South Asians and Europids with T2DM and were not modified by 26 weeks of liraglutide in either ethnicity. Moreover, there was no correlation between the changes in plasma GDF15 levels and dosage of metformin administered, changes in body weight or HbA1c levels. The appetite‐suppressing effect of liraglutide is likely exerted via pathways other than GDF15. [ABSTRACT FROM AUTHOR]

The burden of growing concern about the dysregulation of metabolic processes arises due to complex interplay between environment and nutrition that has great impact on genetics and epigenetics of an individual. Thereby, any abnormality at the level of food intake regulating hormones may contribute to the development of metabolic diseases in any age group due to malnutrition, overweight, changing lifestyle, and exposure to extreme environments such as heat stress (HS), cold stress, or high altitude (HA). Hormones such as leptin, adiponectin, ghrelin, and cholecystokinin regulate appetite and satiety to maintain energy homeostasis. Leptin, an adipokine and a pleiotropic hormone, play major role in regulating the food intake, energy gain and energy expenditure. Using in silico approach, we have identified the major genes (LEP, LEPR, JAK2, STAT3, NPY, POMC, IRS1, SOCS3) that play crucial role in leptin signaling pathway. Further, eight miRNAs (hsa‐miR‐204‐5p, hsa‐miR‐211‐5p, hsa‐miR‐30, hsa‐miR‐3163, hsa‐miR‐33a‐3p, hsa‐miR‐548, hsa‐miR‐561‐3p, hsa‐miR‐7856‐5p) from TargetScan 8.0 database were screened out that commonly target these genes. The role of these miRNAs should be explored as they might play vital role in regulating the appetite, energy metabolism, metabolic diseases (obesity, type 2 diabetes, cardiovascular diseases, inflammation), and to combat extreme environments. The miRNAs regulating leptin signaling and appetite may be useful for developing novel therapeutics for metabolic diseases. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a serious endocrine and metabolic disease that is highly prevalent and causes high mortality and morbidity rates worldwide. This review aims to focus on the potential of probiotics in the management of T2DM and its complications and to summarise the various mechanisms of action of probiotics with respect to T2DM. In this review, experimental studies conducted between 2016 and 2022 were explored. The possible mechanisms of action are based on their ability to modulate the gut microbiota, boost the production of short-chain fatty acids (SCFAs) and glucagon-like peptides, inhibit α-glucosidase, elevate sirtuin 1 (SIRT1) levels while reducing fetuin-A levels, and regulate the level of inflammatory cytokines. This review recommends carrying out further studies, especially human trials, to provide robust evidence-based knowledge on the use of probiotics for the treatment of T2DM. T2DM is prevalent worldwide causing high rates of morbidity and mortality. Gut microbiota play a significant role in the pathogenesis of T2DM. Probiotics can be used as possible therapeutic tools for the management of T2DM. The possible mechanisms of action of probiotics include modulation of the gut microbiota, production of SCFAs and glucagon-like peptides, inhibition of α-glucosidase, raising SIRT1, reducing fetuin-A levels, and regulating the level of inflammatory cytokines. [ABSTRACT FROM AUTHOR]

The lack of an appropriate preclinical model of metabolic dysfunction-associated steatotic liver disease (MASLD) that recapitulates the whole disease spectrum impedes exploration of disease pathophysiology and the development of effective treatment strategies. Here, we develop a mouse model (Streptozotocin with high-fat diet, STZ + HFD) that gradually develops fatty liver, metabolic dysfunction-associated steatohepatitis (MASH), hepatic fibrosis, and hepatocellular carcinoma (HCC) in the context of metabolic dysfunction. The hepatic transcriptomic features of STZ + HFD mice closely reflect those of patients with obesity accompanying type 2 diabetes mellitus, MASH, and MASLD-related HCC. Dietary changes and tirzepatide administration alleviate MASH, hepatic fibrosis, and hepatic tumorigenesis in STZ + HFD mice. In conclusion, a murine model recapitulating the main histopathologic, transcriptomic, and metabolic alterations observed in MASLD patients is successfully established. Metabolic dysfunction-associated steatotic liver disease (MASLD) characterizes a spectrum of liver disorders initiated by hepatic lipid accumulation associated with metabolic syndrome. Here, the authors generate a mouse model that recapitulates the main histopathologic, transcriptomics, and metabolic alterations observed in MASLD patients. [ABSTRACT FROM AUTHOR]

Obesity is a major public health issue that is associated with metabolic diseases including diabetes mellitus type 2 and metabolic syndrome. This pathology leads to detrimental cardiovascular health and secondary effects, such as lipotoxicity, inflammation, and oxidative stress. Recently, extracellular vesicles (EVs) have been highlighted as novel players participating in human physiology and pathophysiology. In obesity, adipose tissue is related to the active shedding of adipocyte-derived extracellular vesicles (AdEVs). The current review explores and highlights the role of AdEVs and their cargo in obesity and metabolic syndrome. AdEVs are proposed to play an important role in obesity and its comorbidities. AdEVs are biological nanoparticles mainly shed by visceral and subcutaneous adipose tissue, acting in physiological and pathophysiological conditions, and also carrying different cargo biomolecules, such as RNA, microRNA (miRNA), proteins, and lipids, among others. RNA and miRNA have local and systemic effects affecting gene expression in target cell types via paracrine and endocrine actions. State of the art analyses identified some miRNAs, such as miR-222, miR-23b, miR-4429, miR-148b, and miR-4269, that could potentially affect cell pathways involved in obesity-related comorbidities, such as chronic inflammation and fibrosis. Similarly, AdEVs-proteins (RBP4, perilipin-A, FABP, mimecan, TGFBI) and AdEVs-lipids (sphingolipids) have been linked to the obesity pathophysiology. The current knowledge about AdEVs along with further research would support and reveal novel pathways, potential biomarkers, and therapeutic options in obesity. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction associated-steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH) is the liver manifestation of metabolic syndrome, which is characterized by insulin resistance, hyperglycemia, hypertension, dyslipidemia, and/or obesity. Environmental pollutant exposure has been recently identified as a risk factor for developing MASH. Heterocyclic amines (HCAs) are mutagens generated when cooking meat at high temperatures or until well-done. Recent epidemiological studies reported that dietary HCA exposure may be linked to insulin resistance and type II diabetes, and we recently reported that HCAs induce insulin resistance and glucose production in human hepatocytes. However, no previous studies have examined the effects of HCAs on hepatic lipid homeostasis. In the present study, we assessed the effects of two common HCAs, MeIQx (2-amino-3, 8-dimethylimidazo [4, 5-f] quinoxaline) and PhIP (2-amino-1-methyl-6-phenylimidazo[4, 5-b] pyridine), on lipid homeostasis in cryopreserved human hepatocytes. Exposure to a single concentration of 25 μM MeIQx or PhIP in human hepatocytes led to dysregulation of lipid homeostasis, typified by significant increases in lipid droplets and triglycerides. PhIP significantly increased expression of lipid droplet-associated genes, PNPLA3 and HSD17B13, and both HCAs significantly increased PLIN2. Exposure to MeIQx or PhIP also significantly increased expression of several key genes involved in lipid synthesis, transport and metabolism, including FASN, DGAT2, CPT1A, SCD, and CD36. Furthermore, both MeIQx and PhIP significantly increased intracellular cholesterol and decreased expression of PON1 which is involved in cholesterol efflux. Taken together, these results suggest that HCAs dysregulate lipid production, metabolism, and storage. The current study demonstrates, for the first time, that HCA exposure may lead to fat accumulation in hepatocytes, which may contribute to hepatic insulin resistance and MASH. [ABSTRACT FROM AUTHOR]

The gut microbiota represents a complex ecosystem of trillions of microorganisms residing in the human gastrointestinal tract, which is known to interact with the host physiology and regulate multiple functions. Alterations in gut microbial composition, diversity, and function are referred to as dysbiosis. Dysbiosis has been associated with a variety of chronic diseases, including Clostridioides difficile infections, but also cardiometabolic diseases, including obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM). The implication of gut microbiota dysbiosis in the pathogenesis of both obesity and T2DM has paved the way to implementing novel therapeutic approaches for metabolic diseases through gut microbial reconfiguration. These interventions include probiotics, prebiotics, and synbiotics, while a more innovative approach has been fecal microbiota transplantation (FMT). FMT is a procedure that delivers healthy human donor stool to another individual through the gastrointestinal tract, aiming to restore gut microbiota balance. Several studies have investigated this approach as a potential tool to mitigate the adverse metabolic effects of gut microbiota aberrations associated with obesity and T2DM. The aim of the present review was to critically summarize the existing evidence regarding the clinical applications of FMT in the management of obesity and T2DM and provide an update on the potential of this method to remodel the entire host microbiota, leading thus to weight loss and sustained metabolic benefits. Safety issues, long-term efficacy, limitations, and pitfalls associated with FMT studies are further discussed, emphasizing the need for further research and standardization in certain methodological aspects in order to optimize metabolic outcomes. [ABSTRACT FROM AUTHOR]

The prevalence of non-obese individuals with insulin resistance (IR) and type 2 diabetes (T2D) is increasing worldwide. This study investigates the metabolic signature of phospholipid-associated metabolites in non-obese individuals with IR and T2D, aiming to identify potential biomarkers for these metabolic disorders. The study cohort included non-obese individuals from the Qatar Biobank categorized into three groups: insulin sensitive, insulin resistant, and patients with T2D. Each group comprised 236 participants, totaling 708 individuals. Metabolomic profiling was conducted using high-resolution mass spectrometry, and statistical analyses were performed to identify metabolites associated with the progression from IS to IR and T2D. The study observed significant alterations in specific phospholipid metabolites across the IS, IR, and T2D groups. Choline phosphate, glycerophosphoethanolamine, choline, glycerophosphorylcholine (GPC), and trimethylamine N-oxide showed significant changes correlated with disease progression. A distinct metabolic signature in non-obese individuals with IR and T2D was characterized by shifts in choline metabolism, including decreased levels of choline and trimethylamine N-oxide and increased levels of phosphatidylcholines, phosphatidylethanolamines, and their degradation products. These findings suggest that alterations in choline metabolism may play a critical role in the development of glucose intolerance and insulin resistance. Targeting choline metabolism could offer potential therapeutic strategies for treating T2D. Further research is needed to validate these biomarkers and understand their functional significance in the pathogenesis of IR and T2D in non-obese populations. [ABSTRACT FROM AUTHOR]

Background and Objectives: The trends in metabolic dysfunction-associated steatotic liver disease (MASLD) and related metabolic dysfunctions in Japan are unknown. Thus, we aimed to clarify these trends before the novel coronavirus disease 2019 pandemic in Japan. Materials and Methods: We included Japanese individuals aged 25–79 years who underwent health examinations at our center. We analyzed anthropometry, lifestyle-related disease, and nutritional intake in relation to MASLD trends from 2010–2019. Results: The prevalence of MASLD increased in all ages and body mass index (BMI) classes, reaching 30.3% in males and 16.1% in females, with MASLD accounting for 75% of steatotic liver cases and more than half of all type 2 diabetes mellitus (T2DM) and high waist circumference (HWC) cases. The increase in the prevalence of MASLD was thought to be largely attributable to an increase in that of the incidence of steatotic liver itself, and there was no increase in the prevalence of other factors, such as overweight, T2DM, hypertension, and dyslipidemia. The prevalence of glucose metabolic disorders (GMDs) and hypertension decreased. National nutritional data showed an increase in energy intake, total fat, saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids, which correlated with a decrease in GMDs. Salt intake also decreased, which correlated with hypertension. The MASLD group had a higher prevalence of all related metabolic factors than the non-MASLD group, especially HWC, T2DM, and hyperlipidemia. Conclusions: The prevalence of MASLD increased with that of steatotic liver, regardless of age or BMI. A relationship between increased dietary fat, increased steatotic liver, and decreased GMDs was suggested. [ABSTRACT FROM AUTHOR]

Background: Exposure to famine in the prenatal period is associated with an increased risk of metabolic disease, including obesity and type 2 diabetes. We employed nuclear magnetic resonance (NMR) metabolomic profiling to identify the metabolic changes that are associated with survival of prenatal famine exposure during the Dutch Famine at the end of World War II and subsequently assess their link to disease. Methods: NMR metabolomics data were generated from serum in 480 individuals prenatally exposed to famine (mean 58.8 years, 0.5 SD) and 464 controls (mean 57.9 years, 5.4 SD). We tested associations of prenatal famine exposure with levels of 168 individual metabolic biomarkers and compared the metabolic biomarker signature of famine exposure with those of 154 common diseases. Results: Prenatal famine exposure was associated with higher concentrations of branched-chain amino acids ((iso)-leucine), aromatic amino acid (tyrosine), and glucose in later life (0.2–0.3 SD, p < 3 × 10−3). The metabolic biomarker signature of prenatal famine exposure was positively correlated to that of incident type 2 diabetes from the UK Biobank (r = 0.77, p = 3 × 10−27), also when re-estimating the signature of prenatal famine exposure among individuals without diabetes (r = 0.67, p = 1 × 10−18). Remarkably, this association extended to 115 common diseases for which signatures were available (0.3 ≤ r ≤ 0.9, p < 3.2 × 10−4). Correlations among metabolic signatures of famine exposure and disease outcomes were attenuated when the famine signature was adjusted for body mass index. Conclusions: Prenatal famine exposure is associated with a metabolic biomarker signature that strongly resembles signatures of a diverse set of diseases, an observation that can in part be attributed to a shared involvement of obesity. [ABSTRACT FROM AUTHOR]

Background: The gut microbiota (GM) and their metabolites have garnered significant attention for their roles in metabolic syndrome (MetS) and associated conditions. MetS, characterized by a cluster of metabolic abnormalities, significantly increases the risk of cardiovascular disease (CVD), obesity, insulin resistance, and type 2 diabetes mellitus (T2DM). The dysbiosis of gut microbiota, marked by changes in microbial composition and function, has been implicated in the pathogenesis of MetS. Main body: This review synthesizes recent findings elucidating the influence of GM composition and microbiota-derived metabolites on MetS pathogenesis and progression. Notably, alterations in GM composition and dysregulation of metabolites such as short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), polyamines, amino acids, and indole derivatives have been implicated in MetS development. These metabolites play crucial roles in metabolic processes, and their imbalance can trigger or exacerbate metabolic disturbances associated with MetS. Various therapeutic approaches, including dietary interventions, probiotics, prebiotics, and precision medicine targeting specific metabolites, offer promising strategies for managing MetS. These interventions aim to restore a healthy GM balance and regulate the production of beneficial metabolites. Conclusion: The complexity of GM interactions and their systemic effects necessitate more standardized research methodologies. Future investigations focusing on personalized therapeutic interventions and non-invasive diagnostic tools are warranted to address the complexities of MetS management. Advancing our understanding of the GM-metabolite-MetS axis will be crucial for developing effective, targeted treatments and improving patient outcomes in MetS. [ABSTRACT FROM AUTHOR]

Background: Hypertension (HTN) and type 2 diabetes mellitus (T2DM) are interconnected metabolic disorders with escalating global incidence and prevalence. However, no longitudinal studies have specifically examined the incidence of HTN and T2DM in the same study population. This study aimed to elucidate the association between HTN and T2DM and ascertain their respective roles in the development of each other. Methods: This retrospective cohort study encompassed 809 Saudi patients from primary healthcare centers in Al Madinah Al Munawarah, Saudi Arabia. The sample was stratified into three cohorts: 226 patients with HTN but without T2DM, 274 patients with T2DM but without HTN, and 309 patients devoid of both T2DM and HTN. Over a retrospective follow-up period of approximately 5 years, incidence density rates (IDR) were computed for HTN in the T2DM cohort, T2DM in the HTN cohort, and both HTN and T2DM in the control cohort. Multiple logistic regression analysis was employed to identify predictors of HTN and T2DM. Results: The IDR of T2DM among patients with HTN stood at 73.9 (95% confidence interval [CI] 56, 92) per 1000 person-years, in contrast to 33.9 (95% CI 24, 44) per 1000 person-years in the control cohort (adjusted odds ratio [OR] = 7.1, 95%CI 3.55, 14.13). Conversely, the IDR of HTN among patients with type-2 T2DM was 55.9 (95% CI 42, 70) per 1000 person-years, while in the control cohort, it was 20.8 (95% CI 13, 28) per 1000 person-years (adjusted OR = 5.8, 95% CI 3.11, 11.09). Significant predictors of HTN in the logistic regression model encompassed age, smoking status, family history of HTN, T2DM status, and body mass index (BMI). Similarly, significant predictors of T2DM in the logistic regression model included age, sex, family history of T2DM, HTN, and BMI. Conclusion: This study unveils HTN and T2DM as mutually significant risk factors. The IDR of each condition in the presence of the other significantly exceeded that among individuals devoid of HTN or T2DM. [ABSTRACT FROM AUTHOR]

Aims: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are employed extensively in the management of type 2 diabetes and obesity. However, there is a paucity of real-world data on their safety and tolerability for metabolic and nutritional adverse events in large sample populations. This study aimed to analyse the metabolic and nutritional safety signatures of different GLP-1 RAs by exploring the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Methods: AEs data were extracted from the FDA Adverse Event Reporting System database for each GLP-1 RA from the time of its launch until the second quarter of 2023. The reported odds ratio (ROR), proportional reporting ratio (PRR), Empirical Bayesian Geometric Mean and Bayesian Confidence Propagation Neural Network were employed to identify AE signals. Results: A system organ class of metabolism and nutrition disorders was employed to filter AE reports, resulting in the identification of 10,450 reports for exenatide, 2,860 reports for liraglutide, 240 reports for albiglutide, 4,847 reports for dulaglutide, 2,905 reports for semaglutide, 1,089 reports for tirzepatide, and 13 reports for lixisenatide. Semaglutide (ROR, 3.34; 95%CI, 3.22), liraglutide (ROR, 2.78; 95%CI, 2.69), and exenatide (ROR, 2.15; 95%CI, 2.11) were associated with metabolism and nutrition disorders. The number of AE signals detected were as follows: albiglutide (n = 1), lixisenatide (n = 2), tirzepatide (n = 11), exenatide (n = 12), liraglutide (n = 16), semaglutide (n = 20), dulaglutide (n = 22). Dehydration was the most frequent AE contributing to serious outcomes for liraglutide (n = 318, 23.93%), dulaglutide (n = 434, 20.90%), semaglutide (n = 370, 25.10%) and tirzepatide (n = 70, 32.86%). The time to onset (TTO) of AE was statistically different between exenatide and the other GLP-1 RAs (p < 0.001), and the Weibull parameters for dehydration for liraglutide, dulaglutide, and semaglutide analyses all showed an early failure-type profile. Conclusion: Our study suggests that exenatide, liraglutide, and semaglutide are more susceptible to metabolic and nutritional AEs than other GLP-1 RAs. Liraglutide, dulaglutide, semaglutide, and tirzepaptide's potential to induce dehydration, necessitates special attention. Despite certain deficiencies, GLP-1 RAs have considerable potential for the treatment of eating disorders. [ABSTRACT FROM AUTHOR]

AbstractThis work investigated the biochemical disturbances and histological alteration in Psammomys obesus animal model fed different high calorie diets (HCDs) during three months. Four diets were used: a low-calorie natural diet, Chenopodiaceae halophyte plant used as control (LCD), a high standard carbohydrate diet rich in protein, HCD 0, a high carbohydrate diet rich in two concentrations of fat, HCD 1 and HCD 2. All animals having received HCDs developed dyslipidemia after one month of experiment with distinction of different sub-groups developing or not obesity and diabetes. HCDs induced a remarkable increasing in blood cholesterol, LDL-cholesterol and triglyceride levels indicating a fast induction of dyslipidemia and a significant increase of aminotransaminases activities revealing a pronounced hepatotoxicity. Animal developing diabetes showed a severe hepatic injury, a degeneration of the adipose tissue and a significant reduction of retinal thickness. P. obesus seems to be an excellent animal model to investigate nutritional metabolic diseases. [ABSTRACT FROM AUTHOR]

Background: Lipodystrophy is characterized by progressive loss of adipose tissue and consequential metabolic abnormalities. With new treatments emerging for lipodystrophy, there is a growing need to understand the prevalence of specific comorbidities that may be commonly associated with lipodystrophy to contextualize the natural history of lipodystrophy without any disease modifying therapy. Objective: To examine the risk of specific clinical characteristics in people living with lipodystrophy (LD) in 2018–2019 compared with the general US population, among the commercially insured US population. Methods: A retrospective cohort study was conducted using the 2018–2019 Clinformatics® Data Mart database. An adult LD cohort (age ≥ 18 years) with at least ≥ 1 inpatient or ≥ 2 outpatient LD diagnoses was created. The LD cohort included non-HIV-associated LD (non-HIV-LD) and HIV-associated LD (HIV-LD) subgroups and compared against age- and sex-matched control groups with a 1:4 ratio from the general population with neither an LD or an HIV diagnosis using odds ratios (ORs) with 95% confidence intervals. Results: We identified 546 individuals with non-HIV-LD (mean age, 60.3 ± 14.9 years; female, 67.6%) and 334 individuals with HIV-LD (mean age, 59.2 ± 8.3 years; female, 15.0%) in 2018–2019. Compared with the general population, individuals with non-HIV-LD had higher risks (odds ratio [95% confidence interval]) for hyperlipidemia (3.32 [2.71–4.09]), hypertension (3.58 [2.89–4.44]), diabetes mellitus (4.72 [3.85–5.79]), kidney disease (2.78 [2.19–3.53]), liver fibrosis or cirrhosis (4.06 [1.66–9.95]), cancer (2.20 [1.59–3.01]), and serious infections resulting in hospitalization (3.00 [2.19–4.10]). Compared with individuals with HIV, those with HIV-LD have higher odds of hypertension (1.47 [1.13–1.92]), hyperlipidemia (2.46 [1.86–3.28]), and diabetes (1.37 [1.04–1.79]). Conclusions: LD imposes a substantial burden on affected individuals due to a high prevalence of metabolic comorbidities and other complications as compared with the general non-LD population. Future longitudinal follow-up studies investigating the causality between LD and observed comorbidities are warranted. [ABSTRACT FROM AUTHOR]

Summary: Micro‐RNAs have emerged as important actors in the onset of metabolic disorders including obesity or type 2 diabetes. Particularly, several micro‐RNAs are known to be key modulators of lipid metabolism, glucose homeostasis, or feeding behavior. Interestingly, the role of extracellular vesicles containing micro‐RNAs, especially adipose‐derived extracellular vesicles, are well‐documented endocrine signals and disease biomarkers. However, the role of adipose‐derived extracellular vesicles on the different tissues is different and highly related to the micro‐RNA content. This review provides recent data about the potential involvement of adipose‐derived extracellular vesicle‐containing micro‐RNAs in metabolic diseases. [ABSTRACT FROM AUTHOR]

Obesity is a major public health issue due to its association with type 2 diabetes, hypertension, and other cardiovascular risks. The BBSome, a complex of eight conserved Bardet–Biedl syndrome (BBS) proteins, has emerged as a key regulator of energy and glucose homeostasis as well as cardiovascular function. However, the importance of adipocyte BBSome in controlling these physiological processes is not clear. Here, we show that adipocyte-specific constitutive disruption of the BBSome through selective deletion of the Bbs1 gene adiponectin (AdipoCre/Bbs1fl/fl mice) does not affect body weight under normal chow or high-fat and high-sucrose diet (HFHSD). However, constitutive BBSome deficiency caused impairment in glucose tolerance and insulin sensitivity. Similar phenotypes were observed after inducible adipocyte-specific disruption of the BBSome (AdipoCreERT2/Bbs1fl/fl mice). Interestingly, a significant increase in renal sympathetic nerve activity, measured using multifiber recording in the conscious state, was observed in AdipoCre/Bbs1fl/fl mice on both chow and HFHSD. A significant increase in tail-cuff arterial pressure was also observed in chow-fed AdipoCre/Bbs1fl/fl mice, but this was not reproduced when arterial pressure was measured by radiotelemetry. Moreover, AdipoCre/Bbs1fl/fl mice had no significant alterations in vascular reactivity. On the other hand, AdipoCre/Bbs1fl/fl mice displayed impaired baroreceptor reflex sensitivity when fed HFHSD, but not on normal chow. Taken together, these data highlight the relevance of the adipocyte BBSome for the regulation of glucose homeostasis and sympathetic traffic. The BBSome also contributes to baroreflex sensitivity under HFHSD, but not normal chow. NEW & NOTEWORTHY: The current study show how genetic manipulation of fat cells impacts various functions of the body including sensitivity to the hormone insulin. [ABSTRACT FROM AUTHOR]

Resistant starch has gained substantial attention in recent years due to its potential health benefits. Among the various sources of RS, legumes have appeared as a prominent and promising contributor. Legumes like beans, lentils, and chickpeas, comprise a unique composition that promotes the resistant starch formation during cooking and processing. The review begins by presenting an overview of resistant starch and its classification based on its structure and digestibility. The mechanisms by which legume‐based resistant starch impacts human health are discussed, including its potential role in controlling postprandial glucose and insulin responses, improve satiety, boost colonic health, and influence lipid metabolism. The promising role of resistant starch from legumes in controlling chronic diseases like obesity, cardiovascular disorders, and type 2 diabetes is also explored. This review briefly covers the recent advancements in regulating the starch biosynthesis pathway through the utilization of RNA interference (RNAi) and CRISPR/Cas9 techniques. In summary, the association between resistant starch and legumes offers a compelling pathway to enhance human health and mitigate the risk of chronic diseases. Legumes as a regular part of the diet can be a viable and effective approach to augment resistant starch intake and harness its potential health‐promoting effects. [ABSTRACT FROM AUTHOR]

The article explores the growing prevalence of metabolic liver disease, specifically focusing on Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), Metabolic Associated Steatotic Hepatitis (MASH), and Metabolic Alcohol-Related Liver Disease (MetALD). It highlights that metabolic risks such as central obesity, high blood pressure, and hyperglycemia significantly contribute to liver disease, which has become the third leading cause of death in the UK.

Objective: In this study, multimodal magnetic resonance imaging (MRI) imaging was used to deeply analyze the changes of hippocampal subfields perfusion and function in patients with type 2 diabetes mellitus (T2DM), aiming to provide image basis for the diagnosis of hippocampal‐related nerve injury in patients with T2DM. Methods: We recruited 35 patients with T2DM and 40 healthy control subjects (HCs). They underwent resting‐state functional MRI (rs‐fMRI), arterial spin labeling (ASL) scans, and a series of cognitive tests. Then, we compared the differences of two groups in the cerebral blood flow (CBF) value, amplitude of low‐frequency fluctuation (ALFF) value, and regional homogeneity (ReHo) value of the bilateral hippocampus subfields. Results: The CBF values of cornu ammonis area 1 (CA1), dentate gyrus (DG), and subiculum in the right hippocampus of T2DM group were significantly lower than those of HCs. The ALFF values of left hippocampal CA3, subiculum, and bilateral hippocampus amygdala transition area (HATA) were higher than those of HCs in T2DM group. The ReHo values of CA3, DG, subiculum, and HATA in the left hippocampus of T2DM group were higher than those of HCs. In the T2DM group, HbAc1 and FINS were negatively correlated with imaging characteristics in some hippocampal subregions. Conclusion: This study indicates that T2DM patients had decreased perfusion in the CA1, DG, and subiculum of the right hippocampus, and the right hippocampus subiculum was associated with chronic hyperglycemia. Additionally, we observed an increase in spontaneous neural activity within the left hippocampal CA3, subiculum, and bilateral HATA regions, as well as an enhanced local neural coordination in the left hippocampal CA3, DG, HATA, and subiculum among patients with type 2 diabetes, which may reflect an adaptive compensation for cognitive decline. However, this compensation may decline with the exacerbation of metabolic disorders. [ABSTRACT FROM AUTHOR]

Introduction and Objectives: Type 2 Diabetes Mellitus (T2DM), a prevalent metabolic disorder, often coexists with a range of complications, with retinopathy being particularly common. Recent studies have shed light on a potential connection between diabetic retinopathy (DR) and hepatic fibrosis, indicating a possible shared pathophysiological foundation in T2DM. This study investigates the correlation between retinopathy and hepatic fibrosis among individuals with T2DM, as well as evaluates the diagnostic value of DR for significant hepatic fibrosis. Materials and Methods: Our cross-sectional analysis incorporated 5413 participants from the National Health and Nutrition Examination Survey (NHANES) 2005-2008. The Fibrosis-4 score (FIB-4) classified hepatic fibrosis into different grades (F0-F4), with significant hepatic fibrosis marked as F2 or higher. Retinopathy severity was determined using retinal imaging and categorized into four levels. The analysis of variance or Chi-square tests facilitated group comparisons. Additionally, the receiver operating characteristic (ROC) analysis appraised the predictive accuracy of retinopathy for significant hepatic fibrosis in the T2DM population. Results: Among 5413 participants, the mean age was 59.56 § 12.41, with 50.2% male. And 20.6% were diagnosed with T2DM. Hepatic fibrosis grading was positively associated with retinopathy severity (OR [odds ratio]: 1.521, 95%CI [confidence interval]: 1.152-2.008, P = 0.003) across the entire population. The association was amplified in the T2DM population according to Pearson’s analysis results. The ROC curve demonstrated retinopathy’s diagnostic capacity for significant hepatic fibrosis in the T2DM population (AUC [area under curve] = 0.72, 95%CI: 0.651-0.793, P < 0.001). Conclusions: Retinopathy could serve as an independent predictor of significant hepatic fibrosis in T2DM population. Ophthalmologists are advised to closely monitor T2DM patients with retinopathy. [ABSTRACT FROM AUTHOR]

Metabolic dysfunctions are among the best documented hallmarks of ageing. Cardiovascular disease, Alzheimer's disease, cancer, type 2 diabetes mellitus, metabolic-dysfunction-associated steatosis liver disease, and fragility fractures are diseases of hyperinsulinaemia that reduce life and healthspan. We studied the effect of suppressing ketosis in 10 lean (BMI 20.5 kg/m2 ± 1.4), metabolically healthy, pre-menopausal women (age 32.3 ± 8.9 years) maintaining nutritional ketosis (NK) for an average of 3.9 years (± 2.3) who underwent three 21-day phases: nutritional ketosis (NK; P1), suppressed ketosis (SuK; P2), and returned to NK (P3). Ketosis suppression significantly increased insulin, 1.83-fold (p = 0.0006); glucose, 1.17-fold (p = 0.0088); homeostasis model assessment for insulin resistance (HOMA-IR), 2.13-fold (p = 0.0008); leptin, 3.35-fold (p = 0.0010); total osteocalcin, 1.63-fold (p = 0.0138); and uncarboxylated osteocalcin, 1.98-fold (p = 0.0417) and significantly decreased beta-hydroxybutyrate, 13.50-fold (p = 0.0012) and glucagon-like peptide-1 (GLP-1), 2.40-fold (p = 0.0209). Sustained NK showed no adverse health effects and may mitigate hyperinsulinemia. All biomarkers returned to basal P1 levels after removing the intervention for SuK, indicating that metabolic flexibility was maintained with long-term euketonaemia. [ABSTRACT FROM AUTHOR]

Introduction and purpose Diabetes is a set of metabolic disorders whose common, characteristic feature is the occurrence of hyperglycemia. Elevated glycemia levels result from impaired insulin secretion and/or defects in its action. In type 2 diabetes, we have modified risk factors such as improper diet, reduced physical activity, and obesity. In the context of these reversible factors, intervention in patients' lifestyle, with particular emphasis on physical activity, seems advisable. To investigate the implementation of recommendations for the treatment of type 2 diabetes, relating to physical activity as a component of behavioral treatment of diabetes. Materials and methods. Author's survey covering patients' knowledge about their disease, needs and expectations regarding education. The questionnaire examines the physical activity of patients newly diagnosed and already treated for type 2 diabetes. Results. The most frequently undertaken exercise was of medium intensity in the form of walking or "Nordic walking". This was also more likely to be intensified. Patients choosing this type of activity practiced it much more often and more regularly than other types of activity. Running and cycling were other activities undertaken by the patients, although in the younger group of patients. Patients who enjoyed physical exercise were more likely and willing to do it and it was more regular. Conclusions. Patients were reluctant to undertake physical exercise and usually did not treat it as an integral part of treatment. Usually, it was not a very intense effort. They also rarely intensified it when the diagnosis was made. Most of the respondents did not understand the role of exercise in the treatment process and its impact on sugar levels. [ABSTRACT FROM AUTHOR]

Introduction and purpose Diabetes comprises a group of metabolic disorders characterized by persistent hyperglycemia. This elevated blood glucose level arises from impaired insulin secretion and/or action. In type 2 diabetes, modifiable risk factors include an unhealthy diet, sedentary lifestyle, and obesity. Given the reversibility of these factors, lifestyle interventions, particularly those promoting physical activity, are deemed beneficial. To evaluate the adherence to type 2 diabetes management guidelines, focusing on the incorporation of physical activity as a critical aspect of behavioral treatment for diabetes. . Materials and methods. Author's survey covering patients' knowledge about their disease, needs and expectations regarding education. The questionnaire examines the physical activity of patients newly diagnosed and already treated for type 2 diabetes. Results The most performed exercise among patients was moderate-intensity activities such as walking or Nordic walking. These activities were more frequently intensified compared to others. Patients engaging in these forms of exercise did so more frequently and consistently than those participating in other types of physical activity. Additional activities included running and cycling, predominantly among the younger patient cohort. Patients who derived enjoyment from physical exercise demonstrated a higher likelihood of regular and willing participation. Conclusions. Patients exhibited reluctance to engage in physical exercise and typically did not regard it as a crucial component of their treatment regimen. The exercise they performed was generally of low intensity, and few patients increased their physical activity following their diagnosis. A significant number of respondents lacked understanding of the role of exercise in the management of their condition and its effect on blood glucose levels. [ABSTRACT FROM AUTHOR]