Exacerbated Insulin Resistance Research Articles

BMI and Polycystic Ovary Syndrome: Demographic Trends in Weight and Health.

Introduction Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women in adolescence and reproductive age. The distribution of PCOS across different body mass index (BMI) categories can vary, and research has shown associations between PCOS and weight status. This study tries to evaluate the distribution of PCOS in relation to BMI in women attending the PCOS clinic in a tertiary hospital in eastern India. Methodology This hospital-based cross-sectional study was carried out in the gynecology outpatient departmentof a tertiary care center. The study population included all the women in the age group between 15 and 45 years diagnosed as having PCOSusing the Rotterdam definition. The various physical, clinical, and biochemical parameters were measured in the study population and compared among the obese and lean PCOS patients. Results and discussion A total of 143 women were included in the study. The mean age of the study population was 26.8 years. Among these, the underweight and normal weight patients were categorized as lean PCOS patients, 35 in number (24.5%), and overweight and obese patients were categorized as obese PCOS patients, 108 in number (75.5%). All the physical parametermeasures like age (mean = 28.05, SD = 5.722), height (mean = 153.384, SD = 6.679), weight (mean = 68.182, SD = 11.501), waist circumference (mean = 95.135, SD = 10.291), hip circumference (mean = 101.47, SD = 9.320), waist-to-hip ratio (mean = 0.940, SD = 0.0831), and neck circumference (mean = 34.85, SD = 2.445) were significantly higher in the obese group as compared to the lean group. Menstrual irregularity was significantly more common in the obese PCOS patients as compared to the lean PCOS group (p = 0.02). There was a significant difference (p < 0.05) between the obese and lean PCOS patients when the biochemical parameters like fasting insulin, fasting glucose, and homeostatic model assessment of insulin resistance (HOMA-IR) were compared. There is a strong link between obesity, insulin resistance, and PCOS. Obesity can exacerbate insulin resistance, a common feature of PCOS, leading to increased levels of insulin and androgens. Conclusion The demographic distribution of PCOS in relation to BMI is essential for tailoring interventions and treatments.

Arsenic and adipose tissue: an unexplored pathway for toxicity and metabolic dysfunction.

Arsenic-contaminated drinking water can induce various disorders by disrupting lipid and glucose metabolism in adipose tissue, leading to insulin resistance. It inhibits adipocyte development and exacerbates insulin resistance, though the precise impact on lipid synthesis and lipolysis remains unclear. This review aims to explore the processes and pathways involved in adipogenesis and lipolysis within adipose tissue concerning arsenic-induced diabetes. Although arsenic exposure is linked to type 2 diabetes, the specific role of adipose tissue in its pathogenesis remains uncertain. The review delves into arsenic's effects on adipose tissue and related signaling pathways, such as SIRT3-FOXO3a, Ras-MAP-AP-1, PI(3)-K-Akt, endoplasmic reticulum stress proteins, CHOP10, and GPCR pathways, emphasizing the role of adipokines. This analysis relies on existing literature, striving to offer a comprehensive understanding of different adipokine categories contributing to arsenic-induced diabetes. The findings reveal that arsenic detrimentally impacts white adipose tissue (WAT) by reducing adipogenesis and promoting lipolysis. Epidemiological studies have hinted at a potential link between arsenic exposure and obesity development, with limited research suggesting a connection to lipodystrophy. Further investigations are needed to elucidate the mechanistic association between arsenic exposure and impaired adipose tissue function, ultimately leading to insulin resistance.

Krill Oil Ameliorates Liver Injury in Diabetic Mice by Activating Antioxidant Capacity and Inhibiting Ferroptosis.

Diabetic liver injury (DLI) has raised attention in recent years. Liver injury results from type 2 diabetes mellitus (T2DM), and in turn accelerates T2DM development by exacerbating insulin resistance. However, effective approaches for mitigating DLI are surprisingly rare. Krill oil (KO) is an alternative source of omega-3 polyunsaturated fatty acids, possessing antioxidant and anti-inflammatory capacities. Here we investigated the effect of KO supplementation on DLI in a mouse model of T2DM induced by streptozotocin and high-fat diet. The diabetic mice developed glucose intolerance, elevated serum alanine aminotransferase and aspartate aminotransferase, and hepatic pathological injuries such as vacuolation, lipid accumulation and fibrosis deposition, the effects of which were mitigated by KO. Further investigation showed that KO ameliorated the DM-induced expression of fibrotic and inflammatory genes. Notably, KO dramatically reduced hepatic oxidative gene expression, lipid peroxidation and ROS production, all of which are hallmarks of ferroptosis. The inhibitory effect of KO on ferroptosis was confirmed by the KO-decreased hepatic expression of GPX4, COX2 and ACSL4, as well as the KO-reduced hepatic iron deposition. Further, KO restored hepatic NRF2 antioxidant signaling which combats ferroptosis. The present study may provide KO supplementation as a viable approach for the intervention of DLI.

Unraveling the cGAS/STING signaling mechanism: impact on glycerolipid metabolism and diseases.

The cyclic GMP-AMP synthase (cGAS) and its downstream effector, the stimulator of interferon genes (STING), are crucial components of the innate immune response, traditionally recognized for their role in detecting cytosolic DNA from pathogens and damaged host cells. However, recent research indicates that the cGAS-STING pathway also significantly impacts metabolic processes, particularly glycerolipid metabolism. Glycerolipids are essential for energy storage and cellular membrane integrity, and their dysregulation is linked to metabolic disorders such as obesity, insulin resistance, and non-alcoholic fatty liver disease (NAFLD). Both cGAS and STING are expressed in various metabolic tissues, suggesting a potential role in lipid homeostasis. Chronic activation of the cGAS-STING pathway may promote inflammatory states that exacerbate insulin resistance and lipid accumulation, forming a feedback loop of metabolic dysfunction. This review explores the emerging relationship between cGAS/STING signaling and glycerolipid metabolism, discussing the mechanisms through which this pathway influences lipid regulation and the potential for therapeutic interventions. By integrating insights from immunology and metabolism, we aim to provide a comprehensive understanding of how the cGAS-STING axis may serve as a novel target for addressing metabolic disorders and enhancing metabolic health outcomes.

BAFF neutralization impairs the autoantibody-mediated clearance of dead adipocytes and aggravates obesity-induced insulin resistance.

B cell-activating factor (BAFF) is a critical TNF-family cytokine that regulates homeostasis and peripheral tolerance of B2 cells. BAFF overproduction promotes autoantibody generation and autoimmune diseases. During obesity, BAFF is predominantly produced by white adipose tissue (WAT), and IgG autoantibodies against adipocytes are identified in the WAT of obese humans. However, it remains to be determined if the autoantibodies formed during obesity affect WAT remodeling and systemic insulin resistance. Here, we show that IgG autoantibodies are generated in high-fat diet (HFD)-induced obese mice that bind to apoptotic adipocytes and promote their phagocytosis by macrophages. Next, using murine models of obesity in which the gonadal WAT undergoes remodeling, we found that BAFF neutralization depleted IgG autoantibodies, increased the number of dead adipocytes, and exacerbated WAT inflammation and insulin resistance. RNA sequencing of the stromal vascular fraction from the WAT revealed decreased expression of immunoglobulin light-chain and heavy-chain variable genes suggesting a decreased repertoire of B cells after BAFF neutralization. Further, the B cell activation and the phagocytosis pathways were impaired in the WAT of BAFF-neutralized mice. In vitro, plasma IgG fractions from BAFF-neutralized mice reduced the phagocytic clearance of apoptotic adipocytes. Altogether, our study suggests that IgG autoantibodies developed during obesity, at least in part, dampens exacerbated WAT inflammation and systemic insulin resistance.

Effects of the ApoE genotype on cognitive function in aging mice fed with a high-fat diet and the protective potential of n-3 polyunsaturated fatty acids.

The ApoE4 allele is the strongest genetic determinant for Alzheimer's disease (AD), while obesity is a strong environmental risk for AD. The modulatory effect of the ApoE genotype on aging-related cognitive function in tandem with a high-fat diet (HFD) remains uncertain. This study aimed to elucidate the effects of ApoE3/ApoE4 genotypes in aged mice exposed to a HFD, and the benefits of n-3 polyunsaturated fatty acids (PUFAs) from fish oil. Remarkably, the HFD led to weight gain and lipid accumulation, more pronounced in ApoE3 mice, while ApoE4 mice experienced exacerbated cerebral insulin resistance, neuroinflammation, and oxidative stress. Critically, n-3 PUFAs modulated the cerebral insulin signaling via the IRS-1/AKT/GLUT4 pathway, mitigated microglial hyperactivity, and reduced IL-6 and MDA levels, thereby counteracting cognitive deficits. These findings highlight the contrasting impacts of ApoE genotypes on aging mice exposed to a HFD, supporting n-3 PUFAs as a strategic nutritional intervention for brain health, especially for ApoE4 carriers.

Obesity: A Major Factor in Diabetes

Obesity is currently recognized as a significant risk factor contributing to the onset of diabetes, presenting a substantial challenge to public health worldwide. This abstract provides a concise overview of the intricate relationship between obesity and diabetes, with a specific focus on the impact of excess body weight on insulin resistance and beta-cell dysfunction. These two mechanisms serve as the primary contributors to the development of diabetes. The abstract delves into the complex interplay between adipose tissue, insulin signaling, and inflammation, elucidating the underlying mechanisms by which obesity exacerbates insulin resistance. Additionally, the role of visceral adiposity, genetic factors, and lifestyle modifications are explored within the context of obesity-related diabetes. The abstract also highlights the adverse health consequences associated with obesity-related diabetes, particularly the heightened risk of cardiovascular disease and other comorbidities. Acknowledging these detrimental effects strengthens the urgency in addressing this widespread issue. Consequently, the abstract briefly outlines the various effective management strategies available to combat obesity-related diabetes, including weight loss interventions, pharmacotherapy, and bariatric surgery. In conclusion, the abstract underscores the necessity of adopting a comprehensive and multidisciplinary approach in tackling both obesity and diabetes. Prevention measures are emphasized as a crucial component in alleviating the burden posed by these two interrelated health conditions. By implementing proactive strategies, it is possible to mitigate the escalating prevalence of obesity-related diabetes and enhance public health outcomes.

Lead exposure aggravates glucose metabolism disorders through gut microbiota dysbiosis and intestinal barrier damage in high-fat diet-fed mice.

Lead (Pb) is an ancient toxic metal and is still a major public health issue. Our previous study found that Pb exposure promotes metabolic disorders in obese mice, but the molecular mechanisms remain unclear. The present study explored the effects of Pb exposure on glucose homeostasis in mice fed a normal diet (ND) and high-fat diet (HFD) from the perspective of gut microbiota. Pb exposure had little effect on glucose metabolism in ND mice, but exacerbated hyperglycemia and insulin resistance, and impaired glucose tolerance in HFD mice. Pb exposure impaired intestinal tight junctions and mucin expression in HFD mice, increasing intestinal permeability and inflammation. Moreover, Pb exposure altered the composition and structure of the gut microbiota and decreased short-chain fatty acids (SCFAs) levels in HFD mice. Correlation analysis revealed that the gut microbiota and SCFAs were significantly correlated with the gut barrier and glucose homeostasis. Furthermore, the fecal microbiota transplantation from Pb-exposed HFD mice resulted in glucose homeostasis imbalance, intestinal mucosal structural damage and inflammation in recipient mice. However, Pb did not exacerbate the metabolic toxicity in HFD mice under depleted gut microbiota. The findings of the present study suggest that Pb induces impairment of glucose metabolism in HFD mice by perturbing the gut microbiota. Our study offers new perspectives on the mechanisms of metabolic toxicity of heavy metals and demonstrates that the gut microbiota may be a target of action for heavy metal exposure. © 2023 Society of Chemical Industry.

Metabolic syndrome in systemic lupus erythematosus patients under Mediterranean diet

Background and aimsMetabolic syndrome (MetS) is a chronic proinflammatory and prothrombotic condition that exacerbates insulin resistance, oxidative damage, and cardiovascular risk, being more prevalent in patients with systemic lupus erythematosus (SLE), a chronic multisystemic autoimmune disorder. This study aim was to determine the prevalence of MetS and associations with SLE clinical characteristics, cardiovascular risk and dietary pattern in a population of Spanish SLE patients. Design and methodsCross-sectional study of 293 patients was conducted (90.4% females; mean age 46.8 (12.94)). The diagnosis of MetS was established based on the criteria of the National Cholesterol Education Program Adult Treatment Panel III. SLE Disease Activity Index (SLEDAI-2K) and SDI Damage Index were used to assess disease activity and disease-related damage, respectively. Med Diet adherence was assessed through a 14 items questionnaire on food consumption frequency and habits. ResultsMetS was present in 15% SLE patients. Triglycerides, high-density lipoprotein cholesterol, systolic blood pressure and waist circumference were significantly increased (p<0.001) in the group of MetS patients. Patients with MetS showed significantly increased SDI damage index (1.70 (1.69) vs 0.88 (1.12), p<0.001) and complement C3 level (118.70 (32.67) vs 107.55 (26.82), p=0.011). No significant differences were observed according to Med Diet adherence level. ConclusionWe observed a lower prevalence of MetS in SLE than that reported in previous studies, which may be a result of the good level of adherence to the MedDiet in our study sample. Additionally, MetS was associated with higher SDI and complement C3 levels but no with medication use.

The Effect of Glycemic Control on Morbidity and Mortality in Critically Ill COVID-19 Patients.

Background COVID-19 infection has caused a global pandemic affecting a group of patients with chronic conditions including diabetes with exacerbating insulin resistance and hyperglycemia. Investigators noted that pre-existing diabetes and newly diagnosed diabetes are associated with an increased risk of all-cause mortality in hospitalized patients with COVID-19 infection. Aim To evaluate the relationship between ICU patients infected with COVID-19 and mortality among those with high versus low glucose levels. Methods This is a retrospective study of critically ill adult patients infected with COVID-19 who were admitted to the ICU from April 5, 2020, to October 14, 2020. The participants were from San Bernardino County which is a diverse and underserved community. Overall, 84 patients were included in the final analysis. The average age was 59.67 (standard deviation=15.55) with 59.5% being males. Overall mortality was 44.1%. Results Around one-fifth of patients had glucose under control as measured by peak glucose level of <180 mg/dL during hospital stay. A statistically significant association was seen between tighter serum glucose control and mortality (p=0.0354). Patients with serum glucose maintained <180 mg/dL were associated with significantly lower mortality than their counterparts (22.2% vs. 50%). Conclusions This study suggests that maintaining a tighter control of the glycemic index in critically ill COVID-19 patients will improve morbidity and mortality.

RING finger protein 13 protects against nonalcoholic steatohepatitis by targeting STING-relayed signaling pathways

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide. Recent studies show that innate immunity-related signaling pathways fuel NAFLD progression. This study aims to identify potent regulators of innate immunity during NAFLD progression. To this end, a phenotype-based high-content screening is performed, and RING finger protein 13 (RNF13) is identified as an effective inhibitor of lipid accumulation in vitro. In vivo gain- and loss-of-function assays are conducted to investigate the role of RNF13 in NAFLD. Transcriptome sequencing and immunoprecipitation-mass spectrometry are performed to explore the underlying mechanisms. We reveal that RNF13 protein is upregulated in the liver of individuals with NASH. Rnf13 knockout in hepatocytes exacerbate insulin resistance, steatosis, inflammation, cell injury and fibrosis in the liver of diet-induced mice, which can be alleviated by Rnf13 overexpression. Mechanically, RNF13 facilitates the proteasomal degradation of stimulator of interferon genes protein (STING) in a ubiquitination-dependent way. This study provides a promising innate immunity-related target for NAFLD treatment.

Inositol polyphosphate multikinase modulates free fatty acids-induced insulin resistance in primary mouse hepatocytes.

Insulin resistance is a critical mediator of the development of nonalcoholic fatty liver disease (NAFLD). An excess influx of fatty acids to the liver is thought to be a pathogenic cause of insulin resistance and the development of NAFLD. Although elevated levels of free fatty acids (FFA) in plasma contribute to inducing insulin resistance and NAFLD, the molecular mechanism is not completely understood. This study aimed to determine whether inositol polyphosphate multikinase (IPMK), a regulator of insulin signaling, plays any role in FFA-induced insulin resistance in primary hepatocytes. Here, we show that excess FFA decreased IPMK expression, and blockade of IPMK decrease attenuated the FFA-induced suppression of protein kinase B (Akt) phosphorylation in primary mouse hepatocytes (PMH). Moreover, overexpression of IPMK prevented the FFA-induced suppression of Akt phosphorylation by insulin, while knockout of IPMK exacerbated insulin resistance in PMH. In addition, treatment with MG132, a proteasomal inhibitor, inhibits FFA-induced decrease in IPMK expression and Akt phosphorylation in PMH. Furthermore, treatment with the antioxidant N-acetyl cysteine (NAC) significantly attenuated the FFA-induced reduction of IPMK and restored FFA-induced insulin resistance in PMH. In conclusion, our findings suggest that excess FFA reduces IPMK expression and contributes to the FFA-induced decrease in Akt phosphorylation in PMH, leading to insulin resistance. Our study highlights IPMK as a potential therapeutic target for preventing insulin resistance and NAFLD.

4EBP2-regulated protein translation has a critical role in high-fat diet–induced insulin resistance in hepatocytes

A high-fat diet (HFD) plays a critical role in hepatocyte insulin resistance. Numerous models and factors have been proposed to elucidate the mechanism of palmitic acid (PA)-induced insulin resistance. However, proteomic studies of insulin resistance by HFD stimulation are usually performed under insulin conditions, leading to an unclear understanding of how a HFD alone affects hepatocytes. Here, we mapped the phosphorylation rewiring events in PA-stimulated HepG2 cells and found PA decreased the phosphorylation level of the eukaryotic translation initiation factor 4E-binding protein 2 (4EBP2) at S65/T70. Further experiments identified 4EBP2 as a key node of insulin resistance in either HFD mice or PA-treated cells. Reduced 4EBP2 levels increased glucose uptake and insulin sensitivity, whereas the 4EBP2_S65A/T70A mutation exacerbated PA-induced insulin resistance. Additionally, the nascent proteome revealed many glycolysis-related proteins translationally regulated by 4EBP2 such as hexokinase-2, pyruvate kinase PKM, TBC1 domain family member 4, and glucose-6-phosphate 1-dehydrogenase. In summary, we report the critical role of 4EBP2 in regulating HFD-stimulated insulin resistance in hepatocytes.

Subfertility as Overlapping of Nutritional, Endocrine, Immune, and Cardiometabolic Dysregulations-A Study Focused on Biochemical Endophenotypes of Subfertile Couples.

Subfertility is a global health issue, and as many as 30% of cases are attributed to unexplained reasons. A hypercaloric, high-fat diet stimulates the expansion of pro-inflammatory gut microbiota with a consequent rise in circulating lipopolysaccharides. Adverse gut microbiota remodeling can exacerbate insulin resistance, while sex and thyroid hormones may influence the variability in gut microbiota. This cross-sectional study included 150 participants and was designed to determine a biochemical, nutritional-related pattern that may distinguish subfertile from fertile individuals and couples. A panel of 28 biomarkers was assessed. Four biochemical phenotypes of unexplained subfertility were found, including two metabolic and two immune, when assessed using binary logistic regression models. Two phenotypes were distinguished in women: cardio-metabolic with atherogenic dyslipidemia (LowHDL-cholesterol: OR = 10.9; p < 0.05) and autoimmune thyroid disorder (Highanti-thyroid-peroxidase: OR = 5.5; p < 0.05) and two in men: hepato-metabolic with elevated liver injury enzymes (HighHOMA-IR: OR = 6.1; p < 0.05) and immune type-2 response (HighIgE: OR = 6.4; p < 0.05). The chances of a couple's subfertility rose with the number of laboratory components of metabolic syndrome in the couple (OR = 1.7; p < 0.05) and if at least one partner had an elevated total IgE level (>100 kU/L) (OR = 6.5; p < 0.05). This study found that unexplained subfertility may be accompanied by mutually overlapping immune and metabolic dysregulations in individuals and couples. We propose one-time laboratory diagnostics taking into account the lipid profile, insulin resistance, anti-thyroid-peroxidase, and total IgE in both males and females with unexplained subfertility. This may allow for a one-time assessment of targeted medical and nutritional interventions and help optimize patients' health. The gut-organ axes related to subfertility are discussed in the context of the obtained results.

Dityrosine Aggravates Hepatic Insulin Resistance in Obese Mice by Altering Gut Microbiota and the LPS/TLR4/NF-κB Inflammatory Pathway.

Dityrosine is the main product of protein oxidation, which has been proved to be a threat to human health. This study aims to investigate whether dityrosine exacerbates insulin resistance by inducing gut flora disturbance and associated inflammatory responses. Mice fed with normal diet or high-fat diet (HFD) received daily gavage of dityrosine (320µgkg-1 BW) or saline for consecutive 13 weeks. The effects of dityrosine on gut microbiota are verified by in vitro fermentation using fecal microbiota from db/m mice and db/db mice. As a result, dityrosine causes the insulin resistance in mice fed normal diet, and aggravates the effects of HFD on insulin sensitivity. Dityrosine increases the levels of lipopolysaccharide (LPS), lipopolysaccharide-binding protein (LBP), toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8) but decreases levels of interleukin-10 (IL-10) in the plasma of CON and HFD-fed mice. The changes of gut flora composition caused by dityrosine are significantly correlated with the changes of inflammatory biomarkers. The effects of dityrosine on insulin resistance may be attributed to the reshaping of the gut microbiota composition and promoting the activity of the LPS/TLR4/NF-κB inflammatory pathway in HFD-induced obese individuals.

METTL3 exacerbates insulin resistance in hepatocytes by regulating m6A modification of cytochrome P450 2B6

BackgroundInsulin resistance (IR) in hepatocytes endangers human health, and frequently results in the development of non-alcoholic fatty liver disease (NAFLD). Research on m6A methylation of RNA molecules has gained popularity in recent years; however, the molecular mechanisms regulating the processes of m6A modification and IR are not known. The cytochrome P450 (CYP450) enzyme system, which is mainly found in the liver, is associated with the pathogenesis of NAFLD. However, few studies have been conducted on CYP450 related m6A methylation. Here, we investigated the role of the methyltransferase METTL3 in exacerbating IR in hepatocytes, mainly focusing on the regulation of m6A modifications in CYP2B6.Methods and resultsAnalysis using dot blot and epitranscriptomic chips revealed that the m6A modification pattern of the transcriptome in high-fat diet (HFD)-induced fatty liver and free fatty acid (FFA)-induced fatty hepatocytes showed significant changes. CYP450 family members, especially Cyp2b10, whose homolog in humans is CYP2B6, led to a noticeable increase in m6A levels in HFD-induced mice livers. Application of the METTL3 methyltransferase inhibitor, STM2457, increased the level of insulin sensitivity in hepatocytes. We then analyzed the role of METTL3 in regulating m6A modification of CYP2B6 in hepatocytes. METTL3 regulated the m6A modification of CYP2B6, and a positive correlation was found between the levels of CYP2B6 translation and m6A modifications. Furthermore, interference with METTL3 expression and exposure to STM2457 inhibited METTL3 activity, which in turn interfered with the phosphorylated insulin receptor substrate (pIRS)-glucose transporter 2 (GLUT2) insulin signaling pathway; overexpression of CYP2B6 hindered IRS phosphorylation and translocation of GLUT2 to membranes, which ultimately exacerbated IR.ConclusionThese findings offer unique insights into the role that METTL3-mediated m6A modifications of CYP2B6 play in regulating insulin sensitivity in hepatocytes and provide key information for the development of strategies to induce m6A modifications for the clinical treatment of NAFLD.

Irisin deficiency exacerbates diet-induced insulin resistance and cardiac dysfunction in type II diabetes in mice.

Irisin is involved in the regulation of a variety of physiological conditions, metabolism, and survival. We and others have demonstrated that irisin contributes critically to modulation of insulin resistance and the improvement of cardiac function. However, whether the deletion of irisin will regulate cardiac function and insulin sensitivity in type II diabetes remains unclear. We utilized the CRISPR/Cas-9 genome-editing system to delete irisin globally in mice and high-fat diet (HFD)-induced type II diabetes model. We found that irisin deficiency did not result in developmental abnormality during the adult stage, which illustrates normal cardiac function and insulin sensitivity assessed by glucose tolerance test in the absence of stress. The ultrastructural analysis of the transmission electronic microscope (TEM) indicated that deletion of irisin did not change the morphology of mitochondria in myocardium. Gene expression profiling showed that several key signaling pathways related to integrin signaling, extracellular matrix, and insulin-like growth factors signaling were coordinately downregulated by deletion of irisin. However, when mice were fed a high-fat diet and chow food for 16 wk, ablation of irisin in mice exposed to HFD resulted in much more severe insulin resistance, metabolic derangements, profound cardiac dysfunction, and hypertrophic response and remodeling as compared with wild-type control mice. Taken together, our results indicate that the loss of irisin exacerbates insulin resistance, metabolic disorders, and cardiac dysfunction in response to HFD and promotes myocardial remodeling and hypertrophic response. This evidence reveals the molecular evidence and the critical role of irisin in modulating insulin resistance and cardiac function in type II diabetes.NEW & NOTEWORTHY By utilizing the CRISPR/Cas-9 genome-editing system and high-fat diet (HFD)-induced type II diabetes model, our results provide direct evidence showing that the loss of irisin exacerbates cardiac dysfunction and insulin resistance while promoting myocardial remodeling and a hypertrophic response in HFD-induced diabetes. This study provides new insight into understanding the molecular evidence and the critical role of irisin in modulating insulin resistance and cardiac function in type II diabetes.

Lipotoxicity-polarised macrophage-derived exosomes regulate mitochondrial fitness through Miro1-mediated mitophagy inhibition and contribute to type 2 diabetes development in mice.

Insulin resistance is a major pathophysiological defect in type 2 diabetes and obesity. Numerous experimental and clinical studies have provided evidence that sustained lipotoxicity-induced mitophagy deficiency can exacerbate insulin resistance, leading to a vicious cycle between mitophagy dysfunction and insulin resistance, and thereby the onset of type 2 diabetes. Emerging evidence suggests that exosomes (Exos) from M2 macrophages play an essential role in modulating metabolic homeostasis. However, how macrophages are affected by lipotoxicity and the role of lipotoxicity in promoting macrophage activation to the M1 state have not been determined. The objective of this study was to determine whether M1 macrophage-derived Exos polarised by lipopolysaccharide (LPS) + palmitic acid (PA)-induced lipotoxicity contribute to metabolic homeostasis and impact the development of insulin resistance in type 2 diabetes. Lipotoxicity-polarised macrophage-derived M1 Exos were isolated from bone marrow (C57BL/6J mouse)-derived macrophages treated with LPS+PA. Exos were characterised by transmission electron microscopy, nanoparticle tracking analysis and western blotting. Flow cytometry, H&E staining, quantitative real-time PCR, immunofluorescence, glucose uptake and output assays, confocal microscopy imaging, western blotting, GTTs and ITTs were conducted to investigate tissue inflammation, mitochondrial function and insulin resistance in vitro and in vivo. The roles of miR-27-3p and its target gene Miro1 (also known as Rhot1, encoding mitochondrial rho GTPase 1) and relevant pathways were predicted and assessed in vitro and in vivo using specific miRNA mimic, miRNA inhibitor, miRNA antagomir and siRNA. miR-27-3p was highly expressed in M1 Exos and functioned as a Miro1-inactivating miRNA through the miR-27-3p-Miro1 axis, leading to mitochondria fission rather than fusion as well as mitophagy impairment, resulting in NOD-like receptor 3 inflammatory activation and development of insulin resistance both in vivo and in vitro. Inactivation of miR-27-3p induced by M1 Exos prevented type 2 diabetes development in high-fat-diet-fed mice. These findings suggest that the miR-27-3p-Miro1 axis, as a novel regulatory mechanism for mitophagy, could be considered as a new therapeutic target for lipotoxicity-related type 2 diabetes disease development.

Abdominal Obesity in Women with Polycystic Ovary Syndrome and Its Relationship with Diet, Physical Activity and Insulin Resistance: A Pilot Study.

Abdominal obesity is a common feature of women with polycystic ovary syndrome (PCOS), and it is known to exacerbate insulin resistance (IR). Improper dietary and physical activity patterns are crucial environmental factors involved in the development of obesity, and they can significantly influence the central deposition of adipose tissue. Therefore, in this cross-sectional study, we aimed to evaluate the relationship between abdominal adiposity (measured by VAT (visceral adipose tissue), SAT (subcutaneous adipose tissue), VAT/SAT ratio (visceral to subcutaneous fat ratio), and WHR (waist-to-hip ratio)) and the prevalence and odds ratios of IR (measured by the homeostatic model assessment of insulin resistance (HOMA-IR), the homeostatic model assessment-adiponectin (HOMA-AD) and leptin to adiponectin ratio (L/A ratio)) in 56 PCOS women. Furthermore, we investigated the relationship between these abdominal obesity indices and diet and physical activity. An original food frequency questionnaire and Actigraph GT3X-BT were used to assess adherence to the diet recommended in IR and the level of physical activity, respectively. We observed a higher prevalence of IR among women with higher VAT, VAT/SAT, and WHR values compared to women with normal values of those abdominal obesity indices. Moreover, VAT/SAT seemed to be the best predictor of IR measured by HOMA-IR and HOMA-AD. However, VAT appeared to be the best and strongest predictor of IR measured by the L/A ratio. We also observed that higher adherence to the diet recommended in IR and higher levels of vigorous physical activity were associated with lower values of central fat accumulation indices and a greater chance of their normal values. Our findings indicate that central obesity increases the odds of IR and supports the beneficial role of diet and physical activity in the management of abdominal obesity in PCOS women.

Glycemic Index and Glycemic Load Estimates in the Dietary Approach of Polycystic Ovary Syndrome.

Polycystic ovary syndrome is a common endocrine disorder characterized by hormonal imbalances and various metabolic abnormalities linked to insulin resistance via a vicious cycle. Genetic and environmental factors underlie its pathogenesis and evolution. Nutrition, in terms of nutrient composition, dietary patterns, endocrine-disrupting chemicals, and food processing and preparation, has gained significant attention in the pathogenesis and the therapeutic approach of polycystic ovary syndrome. Carbohydrate intake seems to be a critical point in the diet assignment. Glycemic index and glycemic load constitute indexes of the impacts of dietary carbohydrates on postprandial glucose levels. Numerous studies have indicated that a high glycemic index and glycemic load diet may exacerbate insulin resistance, a key feature of the syndrome, and offer a risk for its development and its complications. Conversely, low-glycemic index and low-glycemic load diets seem to improve insulin sensitivity, regulate menstrual cycles, and mitigate the risk of comorbidities associated with polycystic ovary syndrome, such as obesity, alterations in body composition, type 2 diabetes, cardiovascular disease, and quality of life. This comprehensive review aims to explore the relevance of nutrition and more specifically, the association of glycemic index and glycemic load with the various aspects of polycystic ovary syndrome, as well as to assess the potential benefits of manipulating those indexes in the dietary approach for the syndrome.