Role In Insulin Resistance Research Articles

Investigations of associations between TNF-α promoter polymorphisms and genetic susceptibility to type 2 diabetes mellitus: A cross-sectional study in Chinese Han population.

Type 2 diabetes (T2DM) is characterised by insulin resistance and a relative shortage of insulin secretion. Tumour necrosis factor-α (TNF-α) plays an important role in insulin resistance by impairing insulin signal transduction. The variants of the TNF-α promoter region are considered to influence its transcription and are associated with the TNF-α level. Therefore, it is worth detecting the association of the variants in the TNF-α gene with the development of T2DM. The aim of this study was to investigate the association of five variants (rs1799964, rs1800630, rs1799724, rs1800629 and rs361525) in the TNF-α gene promoter region with T2DM in a Chinese Han population. A total of 713 subjects with T2DM and 751 nondiabetic subjects were genotyped using the TaqMan method. The associations of the five variants with the development of T2DM were evaluated. The associations of the five variant genotypes with metabolic traits in nondiabetic subjects were analysed. Our data showed that the A allele of rs1800629 could increase the risk of developing T2DM (p=.002, OR=1.563; 95% CI: 1.18-2.08). According to inheritance mode analysis, compared with the G/G genotype, the G/A+2A/A genotype of rs1800629 showed a risk effect on T2DM in the log-additive mode (p=.002, OR=1.56; 95% CI: 1.17-2.07). The haplotypes analysis identified that the rs1799724-rs1800629CA was associated with high risk of the development of T2DM (p=.002, OR=1.559, 95% CI: 1.173-2.072). Conversely, the rs1799724-rs1800629CG was a protective haplotype of T2DM (p=.001, OR=0.732, 95% CI: 0.607-0.884). Moreover, compared with the rs1799964 (T/T+C/T) genotype, the rs1799964 C/C genotype was associated with higher glycosylated haemoglobin (HbA1c) levels in nondiabetic subjects (p=.017). Our results revealed that the rs1800629 in the TNF-α gene promoter region was associated with T2DM in a Chinese Han population.

Supplementation with cysteine improved metabolic syndrome in rats by increasing antioxidant potential in the liver and adipose tissue, as well as decreasing hepatic NF-κB expression

Insulin resistance is a key characteristic of metabolic syndrome (MetS). The hepatic nuclear factor- κB (NF-κB) signaling pathway plays a crucial role in insulin resistance and the development of type 2 diabetes. Our study aimed to examine the impact of cysteine (Cys) on various biochemical and histopathological parameters in the liver and kidney, hepatic NF-kβ expression, oxidative stress, inflammation, glycation, carbonyl stress markers, and insulin resistance. The study involved four groups of rats, each consisting of seven rats: a control group, a MetS group, and two similar groups receiving Cys treatment. Metabolic syndrome was induced in rats by administering a 40% sucrose solution, while, the treated groups received 50 mg/L Cys in their drinking water. Various factors, including body weight, hepatic NF-kβ expression, levels of antioxidants, anti-glycation, oxidative stress, carbonyl stress, inflammatory, anti-glycation, and glycation markers were assessed in blood and tissues. Liver and kidney function parameters and metabolic profiles were measured. Finally, liver tissue was also evaluated by a pathologist. The results showed that Cys reduced hepatic NF-kβ expression, oxidative stress, inflammation, glycation and carbonyl stress markers, as well as liver fatty content, blood sugar levels, insulin resistance, cardiovascular risk index, and body weight. The treatment also mitigated histopathological liver changes and acute hepatitis (p < 0.001). Cysteine exhibited anti-obesity and anti-atherosclerotic effects, improved β-cell function, insulin sensitivity, and lipid metabolism, and enhanced liver and kidney function, as well as prevented acute hepatitis by restoring the GSH/GSSG ratio, hepatic NF-kβ signaling, and carbonyl stress.

AKT1 and MAPK8: New Targets for Gestational Diabetes Mellitus?

Objective: Gestational diabetes mellitus (GDM) disrupts placental function and increases risks for pregnancy. This study investigates the potential involvement of AKT1 and MAPK8 genes, known for their roles in insulin resistance and cell signaling, in GDM pathophysiology. Methods: Placental tissues from GDM patients and healthy controls were analyzed using real-time PCR to quantify gene expression levels. In silico analysis further explored the functional implications of expression changes. Results: AKT1 and MAPK8 displayed significantly altered expression in GDM placentas compared to controls (p = 0.047 and p = 0.007, respectively). In silico analysis suggests potential functional consequences related to diabetes-associated pathways. Conclusion: This study identifies differential expression of AKT1 and MAPK8 in GDM placentas, suggesting their potential roles in the disease process. Further investigation into their functional contributions could provide valuable insights into GDM pathophysiology and potential therapeutic targets.

Association between iron metabolism markers and triglyceride-glucose index: A cross-sectional study in China Health and Nutrition Survey.

Iron metabolism plays an important role in insulin resistance, and the triglyceride-glucose (TyG) index has been proposed in recent years as a more accessible and cost-effective marker for insulin resistance. This study aims to evaluate the association between iron metabolism markers, including ferritin (FER), transferrin (TRF), and transferrin receptor (TFR), and the TyG index. A total of 6524 Chinese individuals aged between 18 and 75 years were included in this study. Multivariable linear models were used to investigate the association between FER, TRF, and TFR levels, and the TyG index. Further subgroup analyses stratified by age and sex were also performed. There was a positive association between FER and TRF levels and the TyG index in all 3 multivariable linear regression models, regardless of stratification by sex and age. Additionally, TFR was positively associated with the TyG index among females and those aged ≥45 years, but not among males and those aged <45 years. Our findings reveal a positive association between FER and TRF levels and the TyG index in a Chinese population, while the association between TFR levels and the TyG index showed different patterns depending on age and gender.

Type 2 Diabetes Mellitus and Cardiometabolic Prospects: A Rapid Narrative Review.

Cardiometabolic syndrome (CMS), type 2 diabetes mellitus (T2DM), and cardiovascular diseases are among the major altruists to the international liability of disease. The lifestyle and dietary changes attributable to economic growth have resulted in an epidemiological transition towards non-communicable diseases (NCDs) as the leading causes of death. Low- and middle-income countries (LMICs) bear a more substantial disease burden due to limited healthcare sector capacities to address the rapidly growing number of chronic disease patients. The purpose of this narrative review paper was to explore the interrelationships between CMS, T2DM, and cardiovascular impairments in the context of NCDs, as well as major preventative and control interventions. The role of insulin resistance, hyperglycemia, and dyslipidemia in the pathogenesis of T2DM and the development of severe cardiovascular impairments was highlighted. This paper elaborated on the pivotal role of lifestyle modifications, such as healthy diets and physical activity, as cornerstones of addressing the epidemics of metabolic diseases. Foods high in calories, refined sugar, red meat, and processed and ready-to-eat meals were associated with an amplified risk of CMS and T2DM. In contrast, diets based on fruits, legumes, vegetables, and whole grain, home-cooked foods demonstrated protective effects against metabolic diseases. Additionally, the role of a psychological and behavioral approach in addressing metabolic diseases was highlighted, especially regarding its impact on patient empowerment and the patient-centered approach to preventative and therapeutic interventions.

The relationship between dietary intake of live microbes and insulin resistance among healthy adults in the US: a cross-sectional study from NHANES 2003–2020

Dietary intake of live microbes may benefit human health, but less is known about the role in insulin resistance. This study was developed with the goal of evaluating potential relationships between IR and dietary live microbes. The National Health and Nutrition Examination Survey (NHANES) dataset was leveraged to collect data from 6,333 subjects 18 + years of age. The Sanders system for the classification of dietary live microbe intake (containing Low (< 104 CFU/g), Medium (104–107 CFU/g), or High (> 107 CFU/g) levels of live microbes) was then used to separate these patients into three groups (low, medium, or high). Fasting blood glucose and insulin levels were used to approximate IR based on the homeostasis model of insulin resistance (HOMA-IR). Weighted linear regressions were used to assess the relationship between IR and live microbe intake. After fully adjusting for confounding factors, subjects in the groups exhibiting medium and high levels of live microbe intake exhibited HOMA-IR scores that were below those of subjects in the low group. The relationship between live microbe intake and HOMA-IR scores was also potentially impacted by ethnicity. In summary, a negative correlation was detected between dietary live microbe intake and HOMA-IR values.

Insulin resistance as the molecular link between diabetes and Alzheimer's disease.

Diabetes mellitus (DM) and Alzheimer's disease (AD) are two major health concerns that have seen a rising prevalence worldwide. Recent studies have indicated a possible link between DM and an increased risk of developing AD. Insulin, while primarily known for its role in regulating blood sugar, also plays a vital role in protecting brain functions. Insulin resistance (IR), especially prevalent in type 2 diabetes, is believed to play a significant role in AD's development. When insulin signalling becomes dysfunctional, it can negatively affect various brain functions, making individuals more susceptible to AD's defining features, such as the buildup of beta-amyloid plaques and tau protein tangles. Emerging research suggests that addressing insulin-related issues might help reduce or even reverse the brain changes linked to AD. This review aims to explore the rela-tionship between DM and AD, with a focus on the role of IR. It also explores the molecular mechanisms by which IR might lead to brain changes and assesses current treatments that target IR. Understanding IR's role in the connection between DM and AD offers new possibilities for treatments and highlights the importance of continued research in this interdisciplinary field.

Haplotype testing of MTTP alleles on insulin resistance in patients with chronic hepatitis C

BackgroundInsulin resistance is a common manifestation among patients with chronic hepatitis C. The aim of this study was to investigate the effect of haplotypes in the microsomal triglyceride transfer protein (MTTP) gene on insulin resistance in Brazilian patients with chronic hepatitis C. MethodsGenetic variants in the MTTP gene were genotyped by PCR-RFLP.Results: Of the 232 patients with chronic hepatitis C, 34.5 % had insulin resistance (HOMA-IR ≥3) and the majority were ≥50 years old. The minor allele frequencies for the -400A/T (rs1800803), -164T/C (rs1800804), H297Q (rs2306985), I128T (rs3816873), Q95H (rs61733139), Q244E (rs17599091) and -493G/T (rs1800591) variants in the MTTP gene were 0.41, 0.30, 0.49, 0.30, 0.08, 0.06 and 0.32. In multivariate analysis, elevated levels of gamma-glutamyl transpeptidase (GGT) was associated with insulin resistance (p = 0.006). Haplotype-based association testing presented that the haplotype ATCTGGG of the -400A/T, -164T/C, H297Q, I128T, Q95H, Q244E and -493G/T variants was associated with the presence of insulin resistance (p = 0.028) and the haplotype TTGTGCG may be a protective factor (p = 0.012). ConclusionThe combination of alleles in the -400A/T, -164T/C, H297Q, I128T, Q95H, Q244E and -493G/T genetic variants in the MTTP gene may play a relevant role in insulin resistance among patients with chronic hepatitis C.

The relationship between hypomagnesemia and albuminuria in patients with type 2 diabetes mellitus.

Diabetic nephropathy is a prevalent cause of chronic kidney disease worldwide. Magnesium plays a critical role in insulin resistance, and insulin, in turn, regulates magnesium levels. We aimed to investigate the association between hypomagnesemia and albuminuria in patients with type 2 diabetes mellitus (T2DM). This retrospective single-centre study encompassed 1178 patients aged 18 and above with T2DM, who attended our outpatient clinic between January 2019 and August 2020. Albuminuria levels were categorised according to Kidney Disease Outcomes Quality Initiative guidelines. In the literature, when examining cut-off values for hypomagnesemia, it is observed that studies typically use hospital normal level as a reference point. Hypomagnesemia, defined as magnesium levels below 1.6 mg/dL, was compared to normomagnesemia (magnesium between 1.6 and 2.4 mg/dL). The primary objective was to explore the impact of magnesium levels on albuminuria, while the secondary objective was to determine the prevalence of hypomagnesemia. The multivariate logistic regression analyses were performed according to age, gender (male), HbA1c, and presence of hypomagnesemia. The mean age of the participants was 58.7 ± 12.2 years, with 44% being male. Hypomagnesemia was identified in 5.3% of the patients. Advanced age and female gender were more common among patients with hypomagnesemia (p = .001). Magnesium levels exhibited a negative correlation with HbA1c and fasting blood glucose, and a positive correlation with creatinine levels (r = -.117, r = -.131, r = .117, p < .001 for all three variables). Hypomagnesemia was significantly more prevalent in patients with albuminuria (15.9% vs. 4.7%, p < .001). Moreover, participants with the presence of hypomagnesemia were independently associated with a higher risk of albuminuria (odds ratio 3,64 1.76-7.52, p = .001). Albuminuria is more frequently observed in patients with hypomagnesemia.

Histological improvements following energy restriction and exercise: The role of insulin resistance in resolution of MASH

Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most common liver diseases worldwide and is characterized by multi-tissue insulin resistance. The effects of a 10-month energy restriction and exercise intervention on liver histology, anthropometrics, plasma biochemistries, and insulin sensitivity were compared to standard of care (control) to understand mechanisms that support liver health improvements. Following medical diagnosis of MASH, individuals were randomized to treatment (n= 16) or control (n= 8). Liver fat (magnetic resonance spectroscopy), 18-hour plasma biochemical measurements, and isotopically labeled hyperinsulinemic-euglycemic clamps were completed pre- and post-intervention. Body composition and cardiorespiratory fitness (VO2peak) were also measured mid-intervention. Those in the treatment group were counseled to reduce energy intake and completed supervised, high-intensity interval training (3x/week) for 10 months. Controls continued physician-directed care. Treatment induced significant (p <0.05) reductions in body weight, fat mass, and liver injury, while VO2peak (p <0.05) and non-esterified fatty acid suppression (p= 0.06) were improved. Both groups exhibited reductions in total energy intake, hemoglobin A1c, hepatic insulin resistance, and liver fat (p <0.05). Compared to control, treatment induced a two-fold increase in peripheral insulin sensitivity which was significantly related to higher VO2peak and resolution of liver disease. Exercise and energy restriction elicited significant and clinically meaningful treatment effects on liver health, potentially driven by a redistribution of excess nutrients to skeletal muscle, thereby reducing hepatic nutrient toxicity. Clinical guidelines should emphasize the addition of aerobic exercise in lifestyle treatments for the greatest histologic benefit in individuals with advanced MASH. The mechanisms that underpin histologic improvement in individuals with metabolic dysfunction-associated steatohepatitis (MASH) are not well understood. This study evaluated the relationship between liver and metabolic health, testing how changes in one may affect the other. We investigated the effects of energy restriction and exercise on the association between multi-tissue insulin sensitivity and histologic improvements in participants with biopsy-proven MASH. For the first time, these results show that an improvement in peripheral (but not hepatic) insulin sensitivity and systemic markers of muscle function (i.e. cardiorespiratory fitness) were strongly related to resolution of liver disease. Extrahepatic disposal of substrates and improved fitness levels supported histologic improvement, confirming the addition of exercise as crucial to lifestyle interventions in MASH. NCT03151798.

Role of polymeric immunoglobulin receptor in glucose metabolism

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Fundación La Caixa 2022 HR22-0253. Comunidad de Madrid P2022/BMD-7333 INMUNOVAR-CM Background Type 2 diabetes and obesity are leading causes of death and disability worldwide, being both risk factors for cardiovascular disease. Intestinal immune system is being shown to have a key role in insulin resistance (IR). Polymeric immunoglobulin receptor (PIGR) is a transmembrane protein which facilitates the transcytosis of the soluble polymeric isoforms of immunoglobulin A (IgA) and is widely expressed in mucosal epithelial cells. IgA levels are reduced in obesity and the loss of IgA in mice worsens insulin resistance and increases inflammation in adipose tissue. However, the specific role of PIGR in IR has not been fully elucidated. Aim To analyze the role of PIGR in systemic glucose metabolism. Methods To determine the impact of global silencing of Pigr on whole-body glucose metabolism, we metabolically characterized the Pigr-/- female mouse 60% fat diet (HFD). We performed glucose and insulin tolerance tests. In vivo and ex vivo adiposity was measured by dual x-ray absorptiometry (DXA) and adipose tissue depots weight, fasting glucose and insulin plasma levels were determined at endpoint. Circulating IgA levels were measured by ELISA and IgA deposition in liver and adipose tissue of control and Pigr-/- mice was determined by western blot and immunohistochemistry. Results As previously described, we show that IgA serum levels were highly increased in Pigr -/- mice. Besides, we demonstrate that IgA deposition in liver and adipose tissue was increased in these mice. We demonstrate that global deletion of Pigr results in whole-body glucose intolerance and IR mice fed HFD. Fasting glucose levels (169.24±24.49 mg/dl in Pigr -/- mice vs 142±27mg/dl in control mice) and fasting insulin levels (1.27±0.42 ng/ml in Pigr -/- mice vs 0.92±0.37 ng/ml in control mice) were significantly increased in Pigr -/- mice fed HFD for 17 weeks. No differences were found in lipid profile levels (triglycerides, HDL-c, VLDL+LDL-c and NEFA). Interestingly, Pigr-/- mice show significant increased adiposity (46±4.11 % adiposity vs 50.6±4.9 in control) measured by DXA, which results in a significant increase in body weight (BW), compared to control (BW gain over 20 weeks on HFD: 21.85± 3.06 gr in Pigr -/- mice vs 17.93±2.1 gr). mRNA expression of the β isoform of carbohydrate responsive-element binding protein (ChREBPβ) is significantly reduced (0.5 folds vs control group) in Pigr -/- adipose tissue, which might link the whole-body metabolic phenotype to ChREBP-dependent glucose sensing by adipose tissue. Conclusion Global Pigr deletion results in whole-body glucose intolerance and IR in female mice fed HFD. Our results suggest cell-intrinsic mechanisms of Pigr deletion as well as extracellular components (increased IgA serum levels and deposition in tissues) as potential triggers of systemic glucose metabolism disruption. Management of PIGR levels might be key for glucose-metabolism-related pathologies.

Longitudinal characterization of serum metabolome and lipidome reveals that the ceramide profile is associated with metabolic health in early postpartum cows experiencing different lipolysis

Reduced feed intake in early lactation prompts increased fat mobilization to meet dairy cow energy needs for milk production. The increased lipolysis in cows presents significant health risks with unclear mechanisms. The objectives of our study were to compare the longitudinal profiles of metabolites and lipids of serum from high- and low-lipolysis cows. Forty multiparous Holstein dairy cows were enrolled in the retrospective study. Serum samples were collected on d 7 before expected calving, as well as on d 5, 7, 14, and 21 postpartum. Dairy cows were grouped according to mean serum nonesterified fatty acids on d 5 and 7 after parturition as low (<0.600 mmol/L; n = 8; LFM) and high (>0.750 mmol/L; n = 8; HFM), indicating fat mobilization during early lactation. Lactational performance and serum metabolic parameters related to glucose and lipid metabolism, liver functions, oxidative status, and inflammatory responses were determined. Serum samples were subjected to liquid chromatography-MS-based metabolomics and lipidomics. Despite differences in postpartum BW change, there were no observed variations in milk yield and composition between the 2 groups. Serum β-hydroxybutyric acid, glucose, leptin, aspartate aminotransferase, IL-6, and tumor necrosis factor alpha were greater in cows with HFM than in cows with LFM. Serum adiponectin, revised quantitative insulin sensitivity check index, and albumin were lower in cows with HFM than in cows with LFM. Intensified fat mobilization in the HFM cows came along with reduced estimated insulin sensitivity, impaired liver functions, and increased oxidative stress and inflammatory responses. Differences in metabolic patterns were observed across the transition period when comparing serum blood matrixes (e.g., in different amino acids, acylcarnitines, and sphingolipids). The serum metabolome of the HFM cows was characterized by higher concentrations of glycine, acylcarnitines, carnosine, Cer(d20:0/18:0), Cer(d18:1/16:0), and Cer(t18:0/24:0) compared with LFM cows. The differential serum metabolites and lipids at different sampling times during the peripartum period were enriched in the sphingolipid metabolism. Differences in serum metabolic status parameters suggest that cows adopt varied metabolic adaptation strategies to cope with energy deficits postpartum. Our investigation found a comprehensive remodeling of the serum metabolic profiles in transition dairy cattle, highlighting the significance of alterations in sphingolipid species, as they play a crucial role in insulin resistance and metabolic disorders.

Down-regulation of O-GlcNAcylation alleviates insulin signaling pathway impairment following arsenic exposure via suppressing the AMPK/mTOR-autophagy pathway

Impairment of the insulin signaling pathway is a key contributor to insulin resistance under arsenic exposure. Specifically, O-GlcNAcylation, an important post-translational modification, plays a crucial role in insulin resistance. Nevertheless, the concrete effect and mechanism of O-GlcNAcylation in arsenic-induced impairment of the insulin signaling pathway remain elusive. Herein, C57BL/6 mice were continuously fed arsenic-containing food, with a total arsenic concentration of 30 mg/kg. We observed that the IRS/Akt/GSK-3β insulin signaling pathway was impaired, and autophagy was activated in mouse livers and HepG2 cells exposed to arsenic. Additionally, O-GlcNAcylation expression in mouse livers and HepG2 cells was elevated, and the key O-GlcNAcylation homeostasis enzyme, O-GlcNAc transferase (OGT), was upregulated. In vitro, non-targeted metabolomic analysis showed that metabolic disorder was induced, and inhibition of O-GlcNAcylation restored the metabolic profile of HepG2 cells exposed to arsenic. In addition, we found that the compromised insulin signaling pathway was dependent on AMPK activation. Inhibition of AMPK mitigated autophagy activation and impairment of insulin signaling pathway under arsenic exposure. Furthermore, down-regulation of O-GlcNAcylation inhibited AMPK activation, thereby suppressing autophagy activation, and improving the impaired insulin signaling pathway. Collectively, our findings indicate that arsenic can impair the insulin signaling pathway by regulating O-GlcNAcylation homeostasis. Importantly, O-GlcNAcylation inhibition alleviated the impaired insulin signaling pathway by suppressing the AMPK/mTOR-autophagy pathway. This indicates that regulating O-GlcNAcylation may be a potential intervention for the impaired insulin signaling pathway induced by arsenic.

FK506-Binding Protein 51 (FKBP51) Suppresses PPARα Activity and Shifts the Insulin Receptor Alternative Splicing Driving Hepatic Insulin Resistance

FK506-binding protein-51 (FKBP51) is a molecular chaperone protein that has great potential to serve as a treatment target for non-alcoholic fatty liver disease (NAFLD) and type II diabetes (T2DM). FKBP51 has been known to regulate nuclear receptors such as glucocorticoid receptor (GR) and peroxisome proliferator-activated receptor γ (PPARγ). However, the connections between FKBP51 and other PPAR family members, such as peroxisome proliferator-activated receptor α (PPARα), are yet to be identified. FKBP51 can also inhibit protein kinase B (AKT) activation, which may impact the insulin receptor signaling pathway. It has been reported that FKBP51 knockout mice presented less adiposity, reduced liver steatosis, and increased insulin sensitivity and insulin clearance, indicating that FKBP51 plays a role in insulin resistance and fatty liver development. However, how FKBP51 regulates insulin resistance, especially in the liver, still needs to be unveiled. It has been shown that insulin receptor (IR) alternative splicing is associated with insulin sensitivity and that PPARα activation is critical in reducing insulin resistance. Thus, we hypothesize that FKBP51 can regulate hepatic insulin resistance through insulin receptor alternative splicing and PPARα suppression. To test this hypothesis, we developed an FKBP51 knockout mouse hepatocyte cell line, 51KO AML12, and treated the cells with insulin for 1hr. We measured RNA and protein expressions in the cells through RT-PCR and western blotting and found that 51KO AML12 had increased phospho-AKT Ser473 (pAKT S473) and IR isoform B (IR-B), indicating increased insulin signaling activity. We also found increased IR isoform A (IR-A) and IR-B expression in 51KO AML12. In addition, we found an increased ratio of IR-B: IR-A in 51KO AML12 treated with insulin. These data indicate a great potential for FKBP51 to be a novel treatment target for hepatic insulin resistance and T2DM. This research is supported by the National Institute of Health R01DK121797 (T.D.H.), R01DA058933 (T.D.H.), and Start-Up funds from the University of Kentucky (T.D.H.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Intestinal flora: New perspective of type 2 diabetes.

Diabetes comprises a group of metabolic diseases characterized by hyperglycemia stemming from various factors. Current diabetes management primarily focuses on blood glucose control, yet it is inherently progressive, necessitating increased reliance on exogenous blood glucose control methods over time. Therefore, there is an urgent need to explore novel intervention strategies addressing both diabetes and its complications. The human intestinal microbiota, often referred to as the "second genome", exhibits significant diversity and plays a pivotal role in insulin resistance, glucose and lipid metabolism, and inflammatory response. Notably, Li and Guo have elucidated the involvement of intestinal flora in the pathogenesis of type 2 diabetes mellitus (T2DM) and proposed a novel therapeutic approach targeting intestinal microbes. This advancement enhances our comprehension of the multifaceted and multi-target regulation of T2DM by intestinal microflora, thereby offering fresh avenues for understanding its pathogenesis and clinical management. This letter briefly summarizes the role of intestinal flora in T2DM based on findings from animal experiments and clinical studies. Additionally, it discusses the potential clinical applications and challenges associated with targeting intestinal flora as therapeutic interventions.

Correlation of Leptin in Patients With Type 2 Diabetes Mellitus.

The exponential increase in diabetes mellitus (DM) poses serious public health concerns. In this review, we focus on the role of leptin in type 2 DM. The peripheral actions of leptin consist of upregulating proinflammatory cytokines which play an important role in the pathogenesis of type 2 DM and insulin resistance. Moreover, leptin is known to inhibit insulin secretion and plays a significant role in insulin resistance in obesity and type 2 DM. A literature search was conducted on Medline, Cochrane, Embase, and Google Scholar for relevant articles published until December 2023. The following search strings and Medical Subject Headings (MeSH terms) were used: "Diabetes Mellitus," "Leptin," "NPY," and "Biomarker." This article aims to discuss the physiology of leptin in type 2 DM, its glucoregulatory actions, its relationship with appetite, the impact that various lifestyle modifications can have on leptin levels, and, finally, explore leptin as a potential target for various treatment strategies.

Insulin resistance and stroke: mechanisms and therapeutic approaches

The review analyzed literature data on the epidemio­logy, risk factors, and mechanisms of acute cerebrovascular accident (ACVA) in patients with diabetes mellitus. The role of insulin resistance and the effectiveness of therapeutic approaches to its correction in cerebral stroke are considered. Diabetes mellitus is recognized as an independent modifiable risk factor for ACVA. In people with diabetes of different age, the risk of stroke is increased by 2–6 times, and the indicators are especially high in patients of young working age. The presence of diabetes mellitus is associated with more severe symptoms, increased risk of complications, longer hospitalization, and higher mortality. Research results show that insulin resistance is one of the main triggers for the development of ischemic stroke due to embolism caused by oxidative stress, endothelial dysfunction and platelet hyperactivation, as well as due to atherosclerotic changes caused by inflammation, proliferation of smooth muscle cells of the vascular wall, dyslipidemia and hypertension on the background of hyperglycemia and hyperinsulinemia. It has been proven that insulin resistance not only provokes ACVA, but also negatively affects their prognosis. Metformin is a key drug for improving insulin sensitivity and is recognized as one of the most important first-line therapeutic agents to achieve and maintain treatment goals in patients with type 2 diabetes. The results of expe­rimental and clinical studies proved that this agent has a whole range of neuroprotective properties, which generally prevent the development of cerebral ischemia and reduce the negative consequences in case of its occurrence. Animals with experimental acute cerebral ischemia who have been treated with metformin had a better overall neurological score, significantly smaller infarct size, better coordination scores, and higher numbers of neurons and microglia. The neuroprotective effect of metformin in stroke is realized through the AMPK (5’AMP-activated protein kinase) signaling pathway with reduction of oxidative stress, neuroinflammation, stimulation of angiogenesis and neurogenesis, autophagy, and inhibition of apoptosis. According to data from cohort and randomized clinical trials, the use of metformin is associated with a significantly lower risk of developing ACVA. Long-term use of this drug in type 2 diabetes contributes to a milder course of stroke, is associated with better functional recovery, and a decrease in disability and mortality rates.

DID METABOLIC SYNDROME BECOME ACTUAL PROBLEM TODAY?

Article is devoted to the problem of metabolic syndrome, covering its history, main causes, and pathogenetic mechanisms of development, as well as current classifications and their practical significance. The role of insulin resistance in the development of metabolic syndrome is highlighted, and modern methods of its investigation are explained. The article also describes the role of metabolic syndrome in the development of cardiovascular events and other diseases.

Abstract P273: Sex-Stratified Machine Learning Analysis of Proteomics, Phenotypic, and Genomic Influences on Visceral Adipose Tissue Volume in the UK Biobank

Introduction: Adiposity distribution plays an important role in insulin resistance (IR); sex differences in body composition can influence the risk of cardiometabolic disease (CMD). We aimed to assess sex differences in the intersection of proteomic, genomic and phenotypic factors related to visceral adipose tissue (VAT) and IR. Methods: We examined UK biobank participants with proteomic data generated using the Olink proximity extension antibody assay (PEA). Association between proteomics, genomics and phenotypes with VAT volume was evaluated. To assess the complex relationships between features, a multistep approach was employed. Following evaluation of each feature types, the combined effects of proteomics, genomics and phenotypes were assessed. Then, top 30 features from the final model were examined (Figure). R2 was tested as an indicator of the variance of VAT explained by the features in each model and SHAP values were reported. Results: We analyzed a total of 5342 participants (52.2% female, mean age 54.8±7.9 years). Our analysis revealed significant variation in plasma proteins when added to phenotypes and genomic data in both sexes. Polygenic scores, phenotypic factors, proteomics, and the combined model explained 4%, 55%, 57%, and 60% of the variation in VAT in women, respectively. In men, these values were lower at 2%, 49%, 51%, and 56%, respectively. While there were common proteins between men and women, several sex-specific proteins were noted in women (e.g., FGF21, LDLR, INHBC, CES1, WFIKKN2, CLEC4A, CDHR2, PRSS8, TNXB, ERBB2, F9, THBS2, CCL16) and men (e.g., CA14, ADM, PON3, STC1, MEGF10, ASGR1, REN, FURIN, OXT, PSPN, HSP90B1, CTSD, SERPINB5, CNTN3, CTSB, WFDC12, and ADGRG1). Conclusion: Our study demonstrated the presence of significant sex differences in the plasma proteomics associated with VAT. These findings may provide insights into sex differences in protein expression related to CMD and enable an individualized measurement of adiposity as one means of better understanding the biology of IR.

Pathogenesis of MASLD and MASH - role of insulin resistance and lipotoxicity.

Insulin resistance and lipotoxicity are extremely interconnected but fundamental in setting the stage for the development of MASLD/MASH. A comprehensive literature search was performed and key themes were synthesised to provide insight into the underlying molecular mechanisms of insulin resistance and lipotoxicity in the liver, muscle, pancreas and adipose tissue and how organ cross-talk is fundamental to driving disease pathogenesis. Classical thinking postulates that excess FFA load exceeds the storage capacity of adipose tissue, which is predicated upon both genetic and environmental factors. This results in insulin resistance and compensatory hyperinsulinaemia by pancreatic beta cells to overcome target organ insulin resistance. As adipocyte dysfunction worsens, not only are excess FFA delivered to other organs, including skeletal muscle, pancreas and liver but a pro-inflammatory milieu is established with increases in IL-6, TNF-α and changes in adipokine levels (increased leptin and decreased adiponectin). With increased intramuscular lipid accumulation, lipotoxic species decrease insulin signalling, reduce glucose uptake by downregulation of GLUT4 and decrease glycogen synthesis. With this additional reduced capacity, hyperglycaemia is further exacerbated and increased FFA are delivered to the liver. The liver has the largest capacity to oxidise fat and to adapt to these stressors and, therefore, has become the last line of defence for excess lipid storage and utilisation, the capacity of which may be impacted by genetic and environmental factors. However, when the liver can no longer keep up with increasing FFA delivery and DNL, lipotoxic species accumulate with ensuing mitochondrial dysfunction, increased ER stress, oxidant stress and inflammasome activation, all of which drive hepatocyte injury and apoptosis. The resulting wound healing response, marked by stellate cell activation, drives collagen accumulation, progressive fibrosis, and, ultimately, end organ failure and death. This vicious cycle and complex interplay between insulin resistance, hyperinsulinaemia, lipotoxicity and multi-directional cross-talk among different target organs are critical drivers of MASLD/MASH. Targeting tissue-specific insulin resistance and hyperinsulinaemia while decreasing FFA load (lipotoxicity) through dietary and lifestyle changes remain the best upstream interventions.