Biomimetic nanoplatform with microbiome modulation and antioxidant functions ameliorating insulin resistance and pancreatic ß-cell dysfunction for T2DM management.

Insulin resistance and pancreatic ß-cell dysfunction are the main pathogenesis of type 2 diabetes mellitus (T2DM). However, insulin therapy and diabetes medications do not effectively solve the two problems simultaneously. In this study, a biomimetic oral hydrogen nanogenerator that leverages the benefits of edible plant-derived exosomes and hydrogen therapy was constructed to overcome this dilemma by modulating gut microbiota and ameliorating oxidative stress and inflammatory responses. Hollow mesoporous silica (HMS) nanoparticles encapsulating ammonia borane (A) were used to overcome the inefficiency of H2 delivery in traditional hydrogen therapy, and exosomes originating from ginger (GE) were employed to enhance biocompatibility and regulate intestinal flora. Our study showed that HMS/A@GE not only considerably ameliorated insulin resistance and liver steatosis, but inhibited the dedifferentiation of islet ß-cell and enhanced pancreatic ß-cell proportion in T2DM model mice. In addition to its antioxidant and anti-inflammatory effects, HMS/A@GE augmented the abundance of Lactobacilli spp. and tryptophan metabolites, such as indole and indole acetic acid, which further activated the AhR/IL-22 pathway to improve intestinal-barrier function and metabolic impairments. This study offers a potentially viable strategy for addressing the current limitations of diabetes treatment by integrating gut-microbiota remodelling with antioxidant therapies.

Downregulation of CerS4 Instead of CerS2 in Liver Effectively Alleviates Hepatic Insulin Resistance in HFD Male Mice.

OBJECTIVE: Consumption of a high-fat diet (HFD) induces insulin resistance (IRes), significantly affecting the maintenance of normal glucose homeostasis. Nevertheless, despite decades of extensive research, the mechanisms and pathogenesis of IRes remain incomplete. Recent studies have primarily explored lipid intermediates such as diacylglycerol (DAG), given a limited knowledge about the role of ceramide (Cer), which is a potential mediator of the IRes in the liver. METHODS: In order to investigate the role of Cer produced by CerS2 and CerS4 for the purpose of inducing the hepatic IRes, we utilized a unique in vivo model employing shRNA-mediated hydrodynamic gene delivery in the liver of HFD-fed C57BL/6J mice. RESULTS: Downregulation of CerS4 instead of CerS2 reduced specific liver Cers, notably C18:0-Cer and C24:0-Cer, as well as acylcarnitine levels. It concurrently promoted glycogen accumulation, leading to enhanced insulin sensitivity and glucose homeostasis. CONCLUSION: Those findings demonstrate that CerS4 downregulating lowers fasting blood glucose levels and mitigates the HFD-induced hepatic IRes. It suggests that inhibiting the CerS4-mediated C18:0-Cer synthesis holds a promise to effectively address insulin resistance in obesity.

Polysaccharides in Medicinal and Food Homologous Plants regulate intestinal flora to improve type 2 diabetes: Systematic review.

BACKGROUND: Medicinal and food homologous plants (MFHPs) which can improve Type 2 Diabetes Mellitus (T2DM) draw significant attention among the public due to their low toxicity and more safety. Polysaccharides, one of the various active components of MFHPs, are recognized as effective modulators of the intestinal flora. By altering the composition of intestinal flora and affecting their metabolic products, polysaccharides can improve T2DM, making them a central focus of anti-diabetic research. PURPOSE: The purpose of this study is to systematically review the mechanism by which polysaccharides from MFHPs (MFHPPs) regulate the composition of intestinal flora and its metabolic products to improve T2DM. METHODS: This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and conducts a comprehensive search on the PubMed, Web of Science and Embase databases. All experimental articles published up to March 4, 2024, are included in the search. RESULTS: Among the 5733 articles reviewed, 29 were selected, covering 22 different MFHPs. MFHPPs can improve T2DM, particularly in lowering blood glucose levels, with consistent results. MFHPPs can regulate the diversity of intestinal flora in T2DM animal models, primarily affecting four phyla: decreasing Firmicutes and Proteobacteria while increasing Bacteroidetes and Actinobacteriota. At the genus level, the improvement of T2DM by MFHPPs is associated with the modulation of 12 key genera: Allobaculum, Akkermansia, Bifidobacterium, Lactobacillus, Helicobacter, Halomonas, Olsenella, Oscillospira, Shigella, Escherichia-Shigella, Romboutsia and Bacteroides. At the molecular level, MFHPPs primarily act by modulating the intestinal flora to increase short-chain fatty acid levels, promote the secretion of glucagon-like peptide-1, influence the IGF1/PI3K/AKT signaling pathway, or the PI3K/AKT/GSK-3ß pathway, to lower blood glucose levels. They may also improve T2DM by working in glucose metabolism through the "microbiota-gut-organ" axis. MFHPPs can also alleviate T2DM by mitigating inflammation and oxidative stress: MFHPPs regulate intestinal flora to reduce lipopolysaccharide "leakage" and enhance intestinal mucosal permeability to tackle the inflammation associated with T2DM; MFHPPs enhance the expression of oxidative stress-related enzymes to alleviate oxidative stress and improve T2DM. Lastly, from a metabolic pathway perspective, MFHPPs are primarily involved in the metabolism of amino acids and their derivatives, carbohydrate metabolism and glutathione metabolism. CONCLUSION: MFHPPs can improve T2DM by enhancing the composition of intestinal flora, regulating its metabolic products to promote insulin secretion, inhibiting glucagon-like peptide secretion, facilitating glycogen synthesis, reducing inflammation levels and alleviating oxidative stress. Furthermore, MFHPPs demonstrate potential protective effects on critical organs such as the pancreas, liver, kidneys and heart. Therefore, MFHPPs demonstrate significant clinical potential. However, most studies can only indicate the potential of MFHPPs intervention in improving T2DM through the intestinal flora. The causality between MFHPPs regulating the intestinal flora and T2DM requires further investigation.

A review of metabolic and microbial influences on women with polycystic ovarian syndrome.

INTRODUCTION: Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine and metabolic disorder affecting reproductive-aged women worldwide. Characterized by irregular menstruation, signs of hyperandrogenism, polycystic ovaries via ultrasound ovarian dysfunction. AREA COVERED: The review delves into the intricate pathophysiological mechanisms underlying the syndrome. Dysregulation of the hypothalamic-pituitary-ovarian axis, IR, obesity, and hyperandrogenism contribute to anovulation and follicular dysfunction which is associated with gut dysbiosis, bile metabolites, and an unhealthy diet. Metabolomics and genomics analyses offer insights into the metabolism of bile acids (BAs) and gut microbiota dysbiosis in PCOS. BAs, crucial for metabolic regulation, are influenced by microbes, impacting hormonal balance. Disruptions in gut microbiota contribute to hormonal dysregulation. Interconnected pathways involving BAs and gut microbiota are pivotal in PCOS. Therapeutic implications include a healthy diet, exercise, and interventions targeting gut microbiota modulation and BAs metabolite to alleviate PCOS symptoms and improve metabolic health. CONCLUSION: PCOS requires a multifaceted, multidisciplinary approach for effective management, including lifestyle changes, medications, and emerging therapies. Tailored strategies considering individual needs and personalized treatment plans are crucial for successful PCOS management. Despite existing knowledge, comprehensive investigations are needed to bridge research gaps and discern the interconnected pathways linking the development of PCOS and the gut-bile axis which are interconnected with metabolic disorders and the development of PCOS. Gut microbiota and hormonal regulation offer promising avenues for innovative therapeutic strategies aimed at addressing the root causes of PCOS and improving patient outcomes.

Lifestyle Profiling Using Wearables and Prediction of Glucose Metabolism in Individuals with Normoglycemia or Prediabetes.

This study examined the relationship between lifestyles (diet, sleep, and physical activity) and glucose responses at a personal level. 36 healthy adults in the Bay Area were monitored for their lifestyles and glucose levels using wearables and continuous glucose monitoring (NCT03919877). Gold-standard metabolic tests were conducted to phenotype metabolic characteristics. Through the lifestyle data (2,307 meals, 1,809 nights, and 2,447 days) and 231,206 CGM readings from metabolically-phenotyped individuals with normoglycemia or prediabetes, we found: 1) eating timing was associated with hyperglycemia, muscle insulin resistance (IR), and incretin dysfunction, whereas nutrient intakes were not; 2) timing of increased activity in muscle IS and IR participants was associated with differential benefits of glucose control; 3) Integrated ML models using lifestyle factors predicted distinct metabolic characteristics (muscle, adipose IR or incretin dysfunction). Our data indicate the differential impact of lifestyles on glucose regulation among individuals with different metabolic phenotypes, highlighting the value of personalized lifestyle modifications.

Association between triglyceride glucose-body mass index and all-cause mortality in critically ill patients with acute pancreatitis.

This study delves into the correlation between the triglyceride glucose-body mass index (TyG-BMI) index upon hospital admission and clinical outcomes among this patient population. We investigated the association between TyG-BMI at hospital admission and clinical outcomes in this patient group, and analyzed data from the Medical Information Mart for Intensive Care IV database, identifying acute pancreatitis (AP) patients admitted to ICUs and stratifying them by TyG-BMI quartiles. We assessed the relationship between TyG-BMI and mortality (both in-hospital and ICU) using Cox proportional hazards regression and restricted cubic splines. The cohort included 419 patients, average age 56.34 ± 16.62 years, with a majority being male (61.58%). Hospital and ICU mortality rates were 11.93% and 7.16%, respectively. Higher TyG-BMI was positively correlated with increased all-cause mortality. Patients in the highest TyG-BMI quartile had significantly greater risks of in-hospital and ICU mortality. An S-shaped curve in the spline analysis indicated a threshold effect at a TyG-BMI of 243 for increased in-hospital mortality risk. TyG-BMI is a reliable predictor of both in-hospital and ICU mortality in severely ill AP patients, suggesting its utility in enhancing risk assessment and guiding clinical interventions for this vulnerable population.

The improvement of modified Si-Miao granule on hepatic insulin resistance and glycogen synthesis in type 2 diabetes mellitus involves the inhibition of TNF-α/JNK1/IRS-2 pathway: network pharmacology, molecular docking, and experimental validation.

BACKGROUND: Modified Si-Miao granule (mSMG), a traditional Chinese medicine, is beneficial for T2DM and insulin resistance (IR), but the underlying mechanism remains unknown. METHODS: Using network pharmacology, we screened the compounds of mSMG and identified its targets and pathway on hepatic IR in T2DM. Using molecular docking, we identified the affinity between the compounds and hub target TNF-α. Then these were verified in KK-Ay mice and HepG2 cells. RESULTS: 50 compounds and 170 targets of mSMG against IR in T2DM were screened, and 9 hub targets such as TNF and MAPK8 were identified. 170 targets were mainly enriched in insulin resistance and TNF pathway, so we speculated that mSMG might act on TNF-α, JNK1 and then regulate insulin signaling to mitigate IR. Experimental validation proved that mSMG ameliorated hyperglycemia, IR, and TNF-α, enhanced glucose consumption and glycogen synthesis, relieved the phosphorylation of JNK1 and IRS-2 (Ser388), and elevated the phosphorylation of Akt (Ser473) and GSK-3ß (Ser9) and GLUT2 expression in KK-Ay mice. Molecular docking further showed berberine from mSMG had excellent binding capacity with TNF-α. Then, in vitro validation experiments, we found that 20% mSMG-MS or 50 µM berberine had little effect in IR-HepG2 cell viability, but significantly increased glucose consumption and glycogen synthesis and regulated TNF-α/JNK1/IRS-2 pathway. CONCLUSION: Network pharmacology and molecular docking help us predict potential mechanism of mSMG and further guide experimental validation. mSMG and its representative compound berberine improve hepatic IR and glycogen synthesis, and its mechanism may be related to the inhibition of TNF-α/JNK1/IRS-2 pathway.

Astaxanthin attenuates glucose-induced liver injury in largemouth bass: role of p38MAPK and PI3K/Akt signaling pathways.

BACKGROUND: Astaxanthin (ASX) has been documented to exert beneficial influence on various processes in fish. Largemouth bass (Micropterus salmoides) serves as a common model for studying glucose-induced liver disease, making it imperative to investigate the regulatory mechanisms underlying its liver health. METHODS: Largemouth bass were fed with a control diet (CON), a high carbohydrate diet (HC), or a HC diet supplemented astaxanthin (HCA) for 8-weeks, followed by the glucose tolerance test (GTT). Primary hepatocytes were treated with low glucose and high glucose combined with different concentrations of astaxanthin for 48 h. The histopathology, enzymology, transcriptomics, molecular biology and cell biology were combined to investigate the mechanism of liver injury. RESULTS: This study provides evidence for the protective effects of ASX against growth performance reduction and hepatic liver injure in largemouth bass fed HC diet. In GTT, HCA diet exhibited an improvement in glucose tolerance following glucose loading. Although HCA diet did not restore the expression of insulin resistance-related genes in livers at different time during the GTT, the addition of ASX in the long-term HC diet did improve the insulin resistance pathway by regulating the PTP1B/PI3K/Akt signaling pathway. Hepatic transcriptome analyses showed that ASX plays an essential role in the modulation of glucose homeostasis in response to treated with HC diet. In in vitro study, ASX treatment resulted in an exaltation in cell viability and a reduction in the rate of cell apoptosis and reactive oxygen species (ROS). Additionally, astaxanthin was observed to improve apoptosis induced by high-glucose via p38MAPK/bcl-2/caspase-3 signaling pathway. CONCLUSIONS: Astaxanthin exhibited a protective effect against apoptosis by regulating p38MAPK/bcl-2/caspase-3 pathway, and ameliorated insulin resistance by activating the PTP1B/PI3K/Akt pathway. This study elucidated the mechanism of astaxanthin in the liver injury of largemouth bass from a new perspective and provided a new target for the treatment of insulin resistance.

Association between triglyceride-glucose index and all-cause mortality in patients underwent transcatheter aortic valve replacement.

BACKGROUNDS: The prognosis of the triglyceride-glucose (TyG) index, a validated surrogate marker for insulin resistance, in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) remains unknown. METHODS: This study consecutively enrolled patients diagnosed with severe AS who underwent TAVR in a Chinese tertiary hospital from March 2013 to September 2023. Participants were stratified based on the TyG index cut-off value. Cox proportional hazards regression models were utilized to explore the association between the TyG index and all-cause mortality, including an assessment of interactions between the TyG index and various covariates on mortality outcomes. RESULTS: Among 1045 patients (mean age 74.7 years, 58.2% male), there was 134 all-cause mortality, resulting in a crude mortality rate of 64.3 per 1000 person-years. Adjusting for age, sex, body mass index, smoking, hypertension, diabetes mellitus, bicuspid aortic valve, atrial fibrillation, Society of Thoracic Surgeons (STS) score, and left ventricular ejection fraction, a per-unit increase in the TyG index was associated with a 41% higher all-cause mortality risk (HR 1.41, 95% CI 1.03-1.93, p = 0.030). Notably, the relationship between the TyG index and all-cause mortality was significantly modified by age (pinteraction = 0.027), sex (pinteraction = 0.007), hypertension (pinteraction = 0.030), and STS score (pinteraction = 0.002). CONCLUSIONS: A higher TyG index is significantly associated with an increased risk of all-cause mortality in AS patients after TAVR. These results underscore the importance of considering the TyG index in the prognostic evaluation of AS patients following TAVR.

Chronic whole-body heat treatment in obese insulin-resistant C57BL/6J mice.

AIM: This study examined the effects of hyperthermic therapy (HT) on mice fed normal chow or a high-fat diet (HFD) for 18 or 22 weeks, undergoing four or eight weekly HT sessions. METHODS: Mice were housed within their thermoneutral zone (TNZ) to simulate a physiological response. HFD-induced obesity-related changes, including weight gain, visceral fat accumulation, muscle loss (indicative of obesity sarcopenia), glucose intolerance, and hepatic triglyceride buildup. MAIN RESULTS: HT upregulated HSP70 expression in muscles, mitigated weight gain, normalised QUICK index, and reduced plasma HSP70 concentrations. It also lowered the H-index of HSP70 balance, indicating improved immunoinflammatory status, and decreased activated caspase-1 and proliferative senescence in adipose tissue, both linked to insulin resistance. CONCLUSION: The findings suggest that even animals on a "control" diet but with insufficient physical activity and within their TNZ may experience impaired glycaemic homeostasis.

The regulatory mechanism of natural polysaccharides in type 2 diabetes mellitus treatment.

Diabetes is a complex, multifactorial disease that is caused by a pathological combination of insulin resistance and pancreatic islet dysfunction. Polysaccharides are extensively dispersed in nature and have a very complicated structure with various biological properties. Natural polysaccharides have potentially extraordinary beneficial health effects on managing metabolic diseases such as diabetes, obesity and cardiovascular disease. Thus, a systematic review of the latest research into and possible regulatory mechanisms of natural polysaccharides for type 2 diabetes mellitus treatment is of great significance for a better understanding of their pharmaceutical value. We discuss the regulatory mechanisms of natural polysaccharides for the treatment of diabetes, and especially their role in reshaping dysfunctional gut microbiota. Natural polysaccharides could be developed as new and safe antidiabetic drugs, and detailed mechanistic studies could further clarify the molecular targets of polysaccharides in the treatment of diabetes.

Impact of spinach thylakoid extract-induced 12-week high-intensity functional training on specific adipokines in obese males.

BACKGROUND: Obesity presents multifarious etiopathologies with its management being a global challenge. This article presents the first ever report on the impact of spinach thylakoid extract-induced high-intensity functional training (HIFT) on obesity management via regulating the levels of novel adipokine, C1q/TNF-related Protein-12 (CTRP-12), furin, and Krüppel-like factor 15 (KLF-15). METHODS: Sixty-eight obese male subjects were randomly divided into four groups: control group (CG), supplement group (SG), training group (TG), and the combined training and supplement group (TSG). After initial assessments of all groups, the training group commenced a twelve-week HIFT using the CrossFit program (comprising of three training sessions per week, each lasting 30 min). Eligible candidates were randomly assigned to either receive thylakoid-rich spinach extract (5 g per day) or a matching placebo (5 g per day of corn starch, 30 min before lunch) for a total duration of 12 weeks. All required data and investigations were collected at 48 h pre- and post-training. RESULTS: The results indicated a substantial correlation between exercise and the time of KLF-15, furin, and CTRP-12 demonstrating effect sizes of 0.3, 0.7, and 0.6, respectively. Additionally, the training and supplementation group (TSG) exhibited a substantial decrease in low-density lipoprotein (LDL), total cholesterol (TC), and triglyceride (TG) levels (p < 0.0001). Concurrently, there was a significant increase in high-density lipoprotein-cholesterol (HDL-C) levels (p = 0.0001). Furthermore, a notable difference between the groups emerged in HDL, LDL, TC, and TG levels, supported by effect sizes of 0.73, 0.86, 0.96, and 0.89, respectively (p < 0.05). CONCLUSION: The study offered novel insights into the management of obesity using supplements induced by spinach-derived thylakoid extract during a 12-week HIFT program. The proposed combination intervention may reverse obesity-induced insulin resistance and metabolic dysfunctions by positive regulation of CTRP-12/adipolin and KLF15 and simultaneous suppression of furin levels.

Diagnostic Utility of Triglyceride-Glucose Index in Non-Alcoholic Fatty Liver Disease: A Cross-Sectional Study on Lean Population.

Background: Approximately 10-20% of individuals with non-alcoholic fatty liver disease (NAFLD) are lean, and the underlying pathophysiology is not yet understood. This study aims to explore the characteristics and the diagnostic value of triglyceride-glucose index (TyG) in early diagnosis of lean NAFLD. Methods: 99 patients with lean NAFLD and 1891 healthy controls were included in the health examination. The characteristics were compared between groups. Restricted cubic spline was utilized to analyze the relationship between TyG index and the risk of lean NAFLD. Logistic regression and receiver operating curve (ROC) were applied to explore the diagnostic value of TyG index for lean NAFLD. Results: Overall, 99 (4.97%) patients had lean NAFLD. Patients with lean NAFLD have significant abnormal glycolipid metabolism and higher TyG index. Restriction cube spline analysis showed a significant dose-response relationship between the TyG index and risk of lean NAFLD. After adjusting for confounders, the relationship remained and the risk of developing lean NAFLD increased 2.99 times for per unit increase of TyG index (95% CI: 1.94, 4.67, P<0.001). The areas under the ROC of the TyG index for lean NAFLD detection were 0.851 (0.815 to 0.886). Conclusion: The TyG index is positively associated with the risk of developing lean NAFLD and could be a useful marker for early diagnosis of lean NAFLD.

Effect of dietary intake of advanced glycation end products on biomarkers of type 2 diabetes: a systematic review and meta-analysis.

Thermal treatment of food may undergo Maillard reactions and produce harmful substances, e.g., advanced glycation end products (AGEs). Current studies show different results about the effects of dietary AGE intake on the biomarkers of type 2 diabetes mellitus (T2DM). Therefore, this work conducted a systematic review and meta-analysis to explore the effect of dietary AGE intake on the biomarkers of T2DM, the available evidence, and the bias of this evidence. This meta-analysis focused on the association between high AGE intake and fasting plasma glucose, fasting plasma insulin, HbA1c, and HOMA-IR. Thirteen parallel studies and 4 randomized crossover studies were finally included. In the pooled analysis, fasting glucose (SMD: 0.98; 95% CI: 0.23, 1.73; p = .011), fasting insulin (SMD: 1.44; 95% CI: 0.63, 2.25; p < .01), and HOMA-IR (SMD: 1.47; 95% CI: 0.59, 2.34; p < .01) significantly increased after dietary intake with high AGEs. In the subgroup analyses, high-AGE diets and healthy participants were associated with changes in the biomarkers of T2DM. Taken together, the intake of high dietary AGE was related to the development of T2DM.

The characteristic activity of regulatory B cells during the occurrence and development of insulin resistance.

PURPOSE: To investigate the aberrant distribution and clinical relevance of regulatory B cells (Bregs) subsets in the peripheral blood of individuals with different levels of insulin resistance (IR). METHODS: A cohort of 124 subjects were divided into five groups according to their insulin resistance index (HOMA-IR) and diabetes diagnosis. The groups comprised Group 1 (IR- with good glycemic control) and Group 2 (IR- with poor glycemic control) at HOMA-IR < 3, Group 3 (IR+ without T2DM) and Group 4 (IR+ with T2DM), at 3 ≤ HOMA-IR < 6, and Group 5 (IR++ with T2DM) at HOMA-IR ≥ 6. Peripheral blood samples were collected from each group, the percentages of CD19+CD24+CD27+ and CD19+CD24+CD38+ Bregs and the levels of IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α, IFN-γ were detected by flow cytometry and flow microsphere matrix method. Additionally, the cytokines levels were validated through ELISA. The activation of Bregs and the production of IL-10 among different groups were analyzed. Spearman correlation analysis was used to analyze the correlation between Bregs activation rate and IR degree. RESULTS: The results showed that the levels of CD19+CD24+CD27+ and CD19+CD24+CD38+ cells were increased whether in IR+ without or with type 2 diabetes mellitus (T2DM) groups compared to the IR- groups, with the most significant increase observed in Group 5. Moreover, the plasma levels of IL-6, IL-10, IL-17, TNF-α and IFN-γ in the IR+ group were higher than those in the IR- group. The expression and activation level of Bregs were positively correlated with the severity of IR in T2DM. CONCLUSION: These results suggest that the increase level of Bregs is closely related to the severity of IR, highlighting the potential significance of Bregs in the clinical progression of T2DM and its associated insulin resistance.

Brain insulin resistance in Down syndrome: Involvement of PI3K-Akt/mTOR axis in early-onset of Alzheimer's disease and its potential as a therapeutic target.

Down syndrome (DS) is the most common genetic cause of intellectual impairment, characterised by an extra copy of chromosome 21. After the age of 40, DS individuals are highly susceptible to accelerated ageing and the development of early-onset Alzheimer-like neuropathology. In the context of DS, the brain presents a spectrum of neuropathological mechanisms and metabolic anomalies. These include heightened desensitisation of brain insulin and insulin-like growth factor-1 (IGF-1) reactions, compromised mitochondrial functionality, escalated oxidative stress, reduced autophagy, and the accumulation of amyloid beta and tau phosphorylation. These multifaceted factors intertwine to shape the intricate landscape of DS-related brain pathology. Altered brain insulin signalling is linked to Alzheimer's disease (AD). This disruption may stem from anomalies in the extracellular aspect (insulin receptor) or the intracellular facet, involving the inhibition of insulin receptor substrate 1 (IRS1). Both domains contribute to the intricate mechanism underlying this dysregulation. The PI3K-Akt/mammalian target of the rapamycin (mTOR) axis is a crucial intracellular element of the insulin signalling pathway that connects numerous physiological processes in the cell cycle. In age-related neurodegenerative disorders like AD, aberrant modulation of the PI3K-Akt signalling cascade is a key factor contributing to their onset. Aberrant and sustained hyperactivation of the PI3K/Akt-mTOR axis in the DS brain is implicated in early symptoms of AD development. Targeting the PI3K-Akt/mTOR pathway may help delay the onset of early-onset AD in individuals with DS, offering a potential way to slow disease progression and enhance their quality of life.

Unraveling Quercetin's Potential: A Comprehensive Review of Its Properties and Mechanisms of Action, in Diabetes and Obesity Complications.

The prevalence of diabetes is escalating alarmingly, placing a significant economic burden on the global healthcare system. The use of chemical substances extracted from plants has been demonstrated to be an effective method for the treatment and control of insulin resistance and Type 2 diabetes mellitus (T2DM). New research indicates that natural phytochemicals present in fruits and vegetables are expected to become drugs for the treatment of diabetes and the prevention of related complications. Quercetin, a widely distributed flavonoid, is well-known for its antioxidant, anti-inflammatory, anticancer, and antidiabetic properties. This article provides a comprehensive account of the mechanism of action of quercetin on diabetes and obesity complications in vivo and in vitro. It elucidates the impact of quercetin on various cells. These include hepatocytes, renal cells, skeletal muscle cells, and adipocytes. Furthermore, this article discusses the mechanism of quercetin on organ damage in diabetic mice induced by STZ, alloxan, diet, and spontaneous Type 2 diabetic mice caused by genetic defects. Additionally, it addresses the pharmacokinetics of quercetin and its potential for synergistic effects with existing diabetic drugs.

Metabolic Perturbations associated with hIAPP-induced insulin resistance in Skeletal Muscles: Implications to the Development of Type 2 Diabetes.

The human islet amyloid polypeptide (hIAPP) tends to misfold and self-assemble to form amyloid fibrils, which has been associated with the loss of function and viability of pancreatic ß-cells in type 2 diabetes mellitus (T2DM). The role of hIAPP in the development of insulin resistance (a hallmark of T2DM) in skeletal muscles - the major sites for glucose utilization - needs further investigation. Even though, insulin-resistant conditions have been known to stimulate hIAPP aggregation, the events that lead to the development of insulin resistance due to hIAPP aggregation in skeletal muscles remain unidentified. Here, we have attempted to identify metabolic perturbations in L6 myotubes that were exposed to increasing concentrations of recombinant hIAPP for different time durations. It was observed that hIAPP exposure was associated with increased mitochondrial and cellular ROS levels, loss in mitochondrial membrane potential and viability of the myotubes. Metabolomic investigations of hIAPP-treated myotubes revealed significant perturbations in o-phosphocholine, sn-glycero-3-phosphocholine and dimethylamine levels (p < 0.05). Therefore, we anticipate that defects in glycerophospholipid metabolism and the associated oxidative stress and membrane damage may play key roles in the development of insulin resistance due to protein misfolding in skeletal muscles. In summary, the perturbed metabolites and their pathways have not only the potential to be used as early biomarkers to predict the onset of insulin resistance and T2DM but also as therapeutic targets for the effective management of the same.

Association between triglyceride-glucose index and arterial stiffness progression: A retrospective cohort study. / ç”˜æ²¹ä¸‰é ¯-è‘¡è„ç³–ä¹˜ç§¯æŒ‡æ•°ä¸ŽåŠ¨è„‰ç¡¬åŒ–è¿›å±•çš„å›žé¡¾æ€§é˜Ÿåˆ—ç ”ç©¶.

OBJECTIVES: Insulin resistance (IR) is closely associated with atherosclerosis and adverse cardiovascular events. The triglyceride-glucose (TyG) index is an effective indicator for assessing IR. This study aims to explore the relationship between the TyG index and the risk of arterial stiffness progression. METHODS: This retrospective cohort study included adults who had undergone at least 2 health examinations with arteriosclerosis testing at the Health Management Medical Center of the Third Xiangya Hospital, Central South University, between January 2012 and December 2022. Clinical data were collected. The TyG index was calculated using the formula of ln (triglycerides×fasting blood glucose/2). The baseline TyG index was assessed as both a continuous variable and as a quartile-based categorical variable. The progression of arteriosclerosis was evaluated by the annual change rate of brachial-ankle pulse wave velocity (baPWV) and the new onset of increased arterial stiffness. Linear regression model and Cox proportional hazard model were used to explore whether the TyG index is an independent risk factor for arterial stiffness progression. Subgroup analyses were performed based on age, gender, body mass index (BMI), and the presence of type 2 diabetes, hypertension, or hyperlipidemia to determine the characteristics of the association between the TyG index and arterial stiffness progression. RESULTS: A total of 4 971 participants were included, with a follow-up period of (3.01±1.98) years. During follow-up, the annual baPWV change rate was (24.94±81.15) cm/s, and 278 cases of new onset of increased aterial stiffness were recorded. After fully adjusting for confounding factors, the baseline TyG index was independently positively correlated with both the annual baPWV change rate (ß=17.5, 95% CI 9.00 to 25.94, P<0.001) and the risk of new onset of increased aterial stiffness [hazard ratio (HR)=1.43, 95% CI 1.18 to 1.74, P<0.001] when the TyG index was treated as a continuous variable. When treated as a categorical variable, higher TyG index quartiles were associated with progressively higher baPWV change rates and new onset of increased arterial stiffness (all P<0.05). In subgroups of participants aged ≥45 years, males, BMI<28 kg/m2, those with or without hypertension, and those without type 2 diabetes or hyperlipidemia, the baseline TyG index (both continuous and categorical) was significantly associated with new onset of increased arterial stiffness (all P<0.05), with no significant interactions observed across subgroups (all P>0.05). CONCLUSIONS: The TyG index is independently associated with an increased risk of arterial stiffness progression and may serve as a useful indicator for assessing arterial stiffness progression risk in health check-up populations.