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Summary: Objective: To summarize the literature on pharmacotherapy for managing paediatric obesity. Methods: A systematic review and meta‐analysis were conducted of randomized controlled trials (RCTs) with <18‐year‐olds of pharmacotherapeutic agents published up to November 2022. Estimates of effect for outcomes were presented relative to minimal important differences and GRADE certainty of evidence. We examined data on patient/proxy‐reported outcome measures (PROMs), cardiometabolic risk factors, anthropometry and adverse events (AEs). Results: Overall, 35 RCTs were included. Trials examined metformin (n = 26), glucagon‐like peptide‐1 receptor agonists (GLP1RAs) (n = 7) and a lipase inhibitor (orlistat; n = 2). Intervention duration varied (3−24 months). Metformin had little to no benefit on PROMs (e.g., health‐related quality of life [HRQoL]; 6 RCTs), moderate reductions in triglycerides, a moderate decline in insulin resistance, a small to moderate decline in BMI z‐score (BMIz) and a moderate increase in mild to moderate gastrointestinal AEs. Response to GLP1RAs was heterogeneous and results of subgroup analysis demonstrated variability of impact. Liraglutide (2 RCTs) resulted in a small reduction in HOMA‐IR and BMIz, but little to no benefit on other outcomes. Exenatide (4 RCTs) had a moderate reduction on blood pressure and a small decrease in BMIz with little to no benefit on other outcomes. Semaglutide (1 RCT) had a small benefit on HRQoL, a small reduction on SBP, a moderate reduction on total cholesterol and LDL‐cholesterol, a large reduction on triglyceride, and a very large decline in BMIz accompanied by a small increase in mild to moderate gastrointestinal AEs. Orlistat had a moderate reduction in DBP and little to no benefit in other outcomes measured, but had a very large increased risk of mild to moderate gastrointestinal AEs. Serious AEs were rare and for interventions with sufficent AE reporting, were considered not likely attributable to the interventions. Conclusion: Few studies examined the impact of pharmacotherapy on PROMs. There is evidence that metformin and GLP1RAs lead to important improvements in cardiometabolic and anthropometric outcomes while accompanied by mild to moderate AEs. Long‐term effectiveness and safety of GLP1RAs remain to be evaluated. [ABSTRACT FROM AUTHOR]

Background: Androgen deprivation therapy (ADT) in prostate cancer (PCa) has been associated with development of insulin resistance. However, the predominant site of insulin resistance remains unclear. Methods: The ADT & Metabolism Study was a single‐center, 24‐week, prospective observational study that enrolled ADT‐naive men without diabetes who were starting ADT for at least 24 weeks (ADT group, n = 42). The control group comprised men without diabetes with prior history of PCa who were in remission after prostatectomy (non‐ADT group, n = 23). Prevalent diabetes mellitus was excluded in both groups using all three laboratory criteria defined in the American Diabetes Association guidelines. All participants were eugonadal at enrollment. The primary outcome was to elucidate the predominant site of insulin resistance (liver or skeletal muscle). Secondary outcomes included assessments of body composition, and hepatic and intramyocellular fat. Outcomes were assessed at baseline, 12, and 24 weeks. Results: At 24 weeks, there was no change in hepatic (1.2; 95% confidence interval [CI], −2.10 to 4.43; p =.47) or skeletal muscle (−3.2; 95% CI, −7.07 to 0.66; p =.10) insulin resistance in the ADT group. No increase in hepatic or intramyocellular fat deposition or worsening of glucose was seen. These changes were mirrored by those observed in the non‐ADT group. Men undergoing ADT gained 3.7 kg of fat mass. Conclusions: In men with PCa and no diabetes, 24 weeks of ADT did not change insulin resistance despite adverse body composition changes. These findings should be reassuring for treating physicians and for patients who are being considered for short‐term ADT. In this prospective study of hormone‐naive men who were eugonadal and did not have diabetes, 24 weeks of androgen deprivation therapy (ADT) for prostate cancer (PCa) was not associated with worsening of hepatic or skeletal muscle insulin resistance despite a substantial increase in fat mass. These findings have relevance for both physicians and patients when determining treatment for PCa and suggest that a short course of ADT may not worsen metabolic risk in patients without pre‐existing diabetes. [ABSTRACT FROM AUTHOR]

Summary: Interleukin‐18 (IL‐18), a potent and multifunctional pro‐inflammatory cytokine, plays a critical role in regulating β‐cell failure, β‐cell death, insulin resistance, and various complications of diabetes mellitus (DM). It exerts its effects by triggering various signaling pathways, enhancing the production of pro‐inflammatory cytokines and nitric oxide (NO), as well as promoting immune cells infiltration and β‐cells death. Abnormal alterations in IL‐18 levels have been revealed to be strongly associated with the onset and development of DM and its complications. Targeting IL‐18 may present a novel and promising approach for DM therapy. An increasing number of IL‐18 inhibitors, including chemical and natural inhibitors, have been developed and have been shown to protect against DM and diabetic complications. This review provides a comprehensive understanding of the production, biological functions, action mode, and activated signaling pathways of IL‐18. Next, we shed light on how IL‐18 contributes to the pathogenesis of DM and its associated complications with links to its roles in the modulation of β‐cell failure and death, insulin resistance in various tissues, and pancreatitis. Furthermore, the therapeutic potential of targeting IL‐18 for the diagnosis and treatment of DM is also highlighted. We hope that this review will help us better understand the functions of IL‐18 in the pathogenesis of DM and its complications, providing novel strategies for DM diagnosis and treatment. DM is one of the most common chronic metabolic diseases caused by β‐cells β‐cell dysfunction and insulin resistance. IL‐18 contributes to the progression of DM and its complications by inducing β‐cells failure and death, insulin resistance, and pancreatitis. IL‐18 orchestrates β‐cell failure and death, insulin resistance, and pancreatitis through modulation of IL‐18‐related signaling pathway, inflammatory responses, NO production, and immune cells infiltration. [ABSTRACT FROM AUTHOR]

Summary: Adipose tissue is a large endocrine organ that serves numerous physiological functions. As we age, adipose tissue remodels and can develop functional changes that alters its phenotype, potentially contributing to metabolic and cardiovascular disorders. Aging adipose tissue is characterized by regional redistribution of fat, accumulation of senescent cells, fibrosis, and decline in adipocyte differentiation capacities, which collectively impact adipose tissue function and whole body health. A notable transformation involves increased accumulation of intra‐abdominal visceral adipose tissue and ectopic fat around internal organs such as the heart, blood vessels, liver, and kidneys that alter their functions. Other changes associated with aging include alterations in adipokine secretion and changes in adipocyte size and numbers. Aging adipocytes play a role in mediating chronic inflammation, metabolic dysfunction, and insulin resistance. Visceral adipose tissue, which increases in volume with aging, is in particular associated with inflammation, angiogenic dysfunction, and microvascular abnormalities, and mediators released by visceral fat may have adverse consequences systemically in multiple target organs, including the cardiovascular system. Understanding mechanisms underlying adipose tissue aging and its impact on cardiovascular health are important for developing interventions and treatments to promote healthy aging and reduce cardiometabolic disease risk. [ABSTRACT FROM AUTHOR]

Aim: To thoroughly investigate the impact of sustained neuropeptide Y4 receptor (NPY4R) activation in obesity‐associated diabetes. Methods: Initially, the prolonged pharmacodynamic profile of the enzymatically stable pancreatic polypeptide (PP) analogue, [P3]PP, was confirmed in normal mice up to 24 h after injection. Subsequent to this, [P3]PP was administered twice daily (25 nmol/kg) for 28 days to high‐fat‐fed mice with streptozotocin‐induced insulin deficiency, known as HFF/STZ mice. Results: Treatment with [P3]PP for 28 days reduced energy intake and was associated with notable weight loss. In addition, circulating glucose was returned to values of approximately 8 mmol/L in [P3]PP‐treated mice, with significantly increased plasma insulin and decreased glucagon concentrations. Glucose tolerance and glucose‐stimulated insulin secretion were improved in [P3]PP‐treated HFF/STZ mice, with no obvious effect on peripheral insulin sensitivity. Benefits on insulin secretion were associated with elevated pancreatic insulin content as well as islet and beta‐cell areas. Positive effects on islet architecture were linked to increased beta‐cell proliferation and decreased apoptosis. Treatment intervention also decreased islet alpha‐cell area, but pancreatic glucagon content remained unaffected. In addition, [P3]PP‐treated HFF/STZ mice presented with reduced plasma alanine transaminase and aspartate transaminase levels, with no change in circulating amylase concentrations. In terms of plasma lipid profile, triglyceride and cholesterol levels were significantly decreased by [P3]PP treatment, when compared to saline controls. Conclusion: Collectively, these data highlight for the first time the potential of enzymatically stable PP analogues for the treatment of obesity and related diabetes. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the efficacy and safety of dapagliflozin versus placebo as an add‐on in patients with type 2 diabetes who did not achieve adequate glycaemic control with evogliptin and metformin combination. Patients and Methods: In this multicentre, randomized, double‐blind, placebo‐controlled Phase 3 trial, patients with glycated haemoglobin (HbA1c) levels ≥7.0% (≥53 mmol/mol) and ≤10.5% (≤91 mmol/mol) who had received stable‐dose metformin (≥1000 mg) and evogliptin (5 mg) for at least 8 weeks were randomized to receive dapagliflozin 10 mg or placebo once daily for 24 weeks. Participants continued treatment with metformin and evogliptin. The primary endpoint was change in HbA1c level after 24 weeks of treatment from baseline level. Results: In total, 198 patients were randomized, and 195 patients were included in the efficacy analyses (dapagliflozin: 96, placebo: 99). At Week 24, dapagliflozin significantly reduced HbA1c levels. The least squares mean difference in HbA1c level change from baseline after 24 weeks of treatment was −0.70% (−7.7 mmol/mol) (p < 0.0001). The proportion of participants achieving HbA1c <7.0% (≥53 mmol/mol) was higher in the dapagliflozin group than in the placebo group. Compared to placebo, dapagliflozin significantly reduced fasting plasma glucose, mean daily glucose, 2‐h postprandial plasma glucose, fasting insulin, uric acid and gamma‐glutamyl transferase levels, homeostatic model assessment for insulin resistance index, body weight, hepatic steatosis index, and albuminuria. Adiponectin level significantly increased from baseline level after 24 weeks of dapagliflozin treatment. Adverse event rates were similar in the two groups. Conclusion: Dapagliflozin add‐on to evogliptin plus metformin improved glycaemic control and was well tolerated by the target patients. [ABSTRACT FROM AUTHOR]

Objectives: Insulin resistance is associated with increased levels of IGF‐1. IGF‐1 has been shown to increase the risk of laryngeal squamous cell carcinoma. The Triglyceride‐glucose index (TyG index) is a marker of insulin resistance. Our study aimed to investigate the relationship between the TyG index and laryngeal squamous cell carcinoma. Design: Retrospective cohort study. Setting: Two tertiary care academic hospitals. Methods: The study included 53 patients with laryngeal squamous cell carcinoma (Group 1) and 48 healthy volunteers (Group 2). Laryngeal cancer patients were divided into two groups according to their stage. Stages I and II were named Group 1A, and Stages III and IV were called Group 1B. The TyG index was calculated as ln [fasting Triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2]. The effect of the TyG index on laryngeal cancer was investigated on the parameters of sex, age, body mass index, and stage of the disease. Results: There were no significant differences in age, sex, and BMI between the groups. The TyG index of group 1 (4.75 ± 0.33) was significantly higher than that of group 2 (4.59 ± 0.15). The TyG index value of group 1B (4.84 ± 0.31) was significantly higher than both group 1A (4.61 ± 0.32) and group 2 (4.59 ± 0.15). There was no significant difference between the TyG index values of group 1A (4.61 ± 0.32) and group 2 (4.59 ± 0.15). Conclusion: The TyG index may be a promising laryngeal squamous cell carcinoma biomarker. People with a higher TyG index may have a higher incidence of laryngeal squamous cell carcinoma and a higher risk of progression. [ABSTRACT FROM AUTHOR]

Evidence from observational and Mendelian randomization (MR) studies suggested that insulin resistance (IR) was associated with Alzheimer's disease (AD). However, the causal effects of different indicators of IR on AD remain inconsistent. Here, we aim to assess the causal association between the insulin sensitivity index (ISI), a measure of post‐prandial IR, and the risk of AD. We first conducted primary and secondary univariable MR analyses. We selected 8 independent genome‐wide significant (p < 5E‐08, primary analyses) and 61 suggestive (p < 1E‐05, secondary analyses) ISI genetic variants from large‐scale genome‐wide association studies (GWAS; N = 53 657), respectively, and extracted their corresponding GWAS summary statistics from AD GWAS, including IGAP2019 (N = 63 926) and FinnGen_G6_AD_WIDE (N = 412 181). We selected five univariable MR methods and used heterogeneity, horizontal pleiotropy test, and leave‐one‐out sensitivity analysis to confirm the stability of MR estimates. Finally, we conducted a meta‐analysis to combine MR estimates from two non‐overlapping AD GWAS datasets. We further performed multivariable MR (MVMR) to assess the potential mediating role of type 2 diabetes (T2D) on the association between ISI and AD using two MVMR methods. In univariable MR, utilizing 8 genetic variants in primary analyses, we found a significant causal association of genetically increased ISI with decreased risk of AD (OR = 0.79, 95% CI: 0.68–0.92, p = 0.003). Utilizing 61 genetic variants in secondary analyses, we found consistent findings of a causal effect of genetically increased ISI on the decreased risk of AD (OR = 0.89, 95% CI: 0.82–0.96, p = 0.003). Heterogeneity, horizontal pleiotropy test, and leave‐one‐out sensitivity analysis ensured the reliability of the MR estimates. In MVMR, we found no causal relationship between ISI and AD after adjusting for T2D (p > 0.05). We provide genetic evidence that increased ISI is significantly and causally associated with reduced risk of AD, which is mediated by T2D. These findings may inform prevention strategies directed toward IR‐associated T2D and AD. [ABSTRACT FROM AUTHOR]

Summary C‐reactive protein (CRP) appears to improve the ability to detect cardiometabolic risk in young and middle‐aged adults with mild‐to‐moderate obstructive sleep apnea (mmOSA). The aim of this study is to assess utility of CRP in identifying the risk of hypertension and insulin resistance across a wide age range including older patients with mmOSA. Adults (n = 216) of a wide age range (28–90 years old, mean age 52.64 ± 12.74) with mmOSA (5 ≤ AHI < 30) completed in‐lab polysomnography or home sleep apnea testing, physical examination including blood pressure (BP) measures, structured medical history questionnaire, and blood draw for CRP and fasting glucose and insulin levels. In adults < 60 years, lnCRP but not the apnea–hypopnea index (AHI) was associated with greater odds for hypertension (odds ratio [OR] = 2.40, 95% CI = 1.20–4.84, p = 0.01; OR = 1.00, 95% CI = 0.92–1.08, p = 0.92, respectively) and with higher average systolic and diastolic BP. Also, in adults < 60 years lnCRP but not AHI, was associated with higher lnHOMA values. In contrast, in adults > 60 years neither lnCRP nor AHI were associated with greater odds for hypertension, average systolic and diastolic BP, and lnHOMA. Receiver‐operating characteristics curves revealed that adding CRP to standard clinical factors (age, sex, and BMI) yielded moderately good risk models for hypertension in patients < 60 years (AUC = 0.721). In conclusion, CRP improves the ability to detect cardiometabolic risk in young and middle‐aged, but not older adults with mmOSA, suggesting that inflammation may be a primary pathogenetic mechanism in younger patients with OSA. [ABSTRACT FROM AUTHOR]

Non‐alcoholic fatty liver disease (NAFLD) is a liver pathology concomitant with metabolic disarrangement. This study assessed the therapeutic impacts of delphinidin, an anthocyanin, or α‐amyrin, a pentacyclic triterpenoid, on NAFLD in rats and the underlying mechanisms involved. NAFLD was established by feeding a high‐fat diet (HFD) for 10 weeks, either alone or in combination with delphinidin (40 mg/kg, oral) or α‐amyrin (20 mg/kg, oral). Delphinidin or α‐amyrin ameliorated the metabolic and histopathological perturbations induced by HFD. These compounds markedly attenuated NAFLD‐induced hepatic steatosis, as evidenced by a substantial decrease in body weight, insulin resistance, and liver and adipose tissue indices. Alongside normalization of the atherogenic index, both improved HFD‐mediated abnormalities in serum lipids, liver enzymes, leptin, and ghrelin levels. Moreover, their intervention activated the NFE2 like bZIP transcription factor 2 and heme oxygenase 1 pathways and abrogated HFD‐triggered activation of mitogen‐activated protein kinase 1 signaling. These remedies inhibited hepatic apoptosis and modulated the gene expression of lipogenic enzymes. Furthermore, histological analysis corroborated the suppression of lipid accumulation and amelioration of hepatic architecture in the treated rats. Our findings highlight the hepatoprotective value of delphinidin or α‐amyrin against NAFLD and related metabolic diseases through their insulin‐sensitizing, anti‐inflammatory, antioxidant, and antiapoptotic effects. [ABSTRACT FROM AUTHOR]

Summary To evaluate the relationship between serum gamma‐glutamyl transferase (GGT) levels and fatty pancreas in subjects with concurrent obesity, insulin resistance and metabolic dysfunction‐associated steatotic liver disease (MASLD) without a history of pancreatitis. From March 2019 to September 2021, 31 adult subjects with concurrent obesity and MASLD were recruited as part of the study investigating the biological impact of bariatric surgery and lifestyle modification on obesity. Chemical shift encoded MRI of the abdomen, LiverMultiScan, anthropometric, clinical and blood biochemistry analyses were performed prior to any intervention at baseline. GGT (p <.001) was significantly different between those ‘with fatty pancreas’ and ‘without fatty pancreas’ groups. GGT (p <.001) was significantly different between those ‘with both metabolic syndrome and fatty pancreas’ and those ‘with metabolic syndrome but without fatty pancreas.’ GGT (p <.001) was also significantly different between those ‘with both diabetes and fatty pancreas’ and those ‘with diabetes but without fatty pancreas’. Logistic regression analysis showed that abnormal GGT levels (p = .010) and Hypertension (p = .045) were significant independent predictors of fatty pancreas. GGT was associated with fatty pancreas by an odds ratio 7.333 (95% [CI]: 1.467–36.664), while the AUROC of GGT in determining fatty pancreas was 0.849. Elevation in serum GGT might be a potential marker to identify fatty pancreas. [ABSTRACT FROM AUTHOR]

Key points Time‐restricted feeding is known to ameliorate obesity in young mice. However, evaluation of its effect in old age is still lacking. The current work aims to investigate the effects of time‐restricted feeding on treating pre‐existing obesity in old animals. The study utilized middle‐aged and old high fat diet‐induced obese mice and subjected them to 8 h daily time‐restricted feeding. Aged obese mice did not lose fat mass but lost lean mass after 8 weeks of treatment. In addition, time‐restricted feeding reduced adiposity in brown adipose tissue, reversed excessive hepatic lipid accumulation, and improved glucose homeostasis in middle‐aged and old obese mice. Mechanistic studies show that these metabolic benefits were mediated by transcriptional downregulation of essential genes responsible for hepatic adipogenesis and adipose tissue chronic inflammation. These results demonstrate that time‐restricted feeding improves metabolic health and has beneficial effects in combating diet‐induced obesity in aged obese mice. Contrary to in young obese mice, in old obese mice time‐restricted feeding did not significantly reduce body fat but decreased lean mass. Time‐restricted feeding reduced adipose tissue inflammation, reversed fatty liver, and improved glucose homeostasis in aged mice with diet‐induced obesity. Time‐restricted feeding is effective in improving metabolic homeostasis in aged mice, but less effective in terms of reducing obesity. Future studies should investigate the underlying mechanism of how ageing impaired intermittent fasting induced fat loss. [ABSTRACT FROM AUTHOR]

Insulin resistance (IR) is a pathogenic factor in numerous metabolic diseases. The gut microbiota plays a crucial role in maintaining the function of the intestinal barrier and overall human health, thereby influencing IR. Dysbiosis of the gut microbiota can contribute to the development of IR. Therefore, it is essential to maintain a balanced and diverse gut microbiota for optimal health. Akkermansia muciniphila, a widely present microorganism in the human intestine, has been shown to regulate gastrointestinal mucosal barrier integrity, reduce endotoxin penetration, decrease systemic inflammation levels, and improve insulin sensitivity. Reduced abundance of A. muciniphila is associated with an increased risk of IR and other metabolic diseases, highlighting its correlation with IR. Understanding the role and regulatory mechanism of A. muciniphila is crucial for comprehending IR pathogenesis and developing novel strategies for preventing and treating related metabolic disorders. Individual variations may exist in both the gut microbiota composition and its impact on IR among different individuals. Further investigation into individual differences between A. muciniphila and IR will facilitate advancements in personalized medicine by promoting tailored interventions based on the gut microbiota composition, which is a potential future direction that would optimize insulin sensitivity while preventing metabolic disease occurrence. In this review, we describe the physiological characteristics of A. muciniphila, emphasize its roles in underlying mechanisms contributing to IR pathology, and summarize how alterations in its abundance affect IR development, thereby providing valuable insights for further research on A. muciniphila, as well as new drug development targeting diabetes. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Methods Results Conclusion To study the association between dietary patterns and subgingival microbiota.Participants (n = 651) who were enrolled in the Oral Infections, Glucose Intolerance, and Insulin Resistance Study (ORIGINS) with subgingival plaque sampling (n = 890 plaques) and a dietary assessment were included. 16S rRNA gene amplicon sequences of subgingival plaque from sites with either probing depth <4 or ≥4 mm were processed separately and used to obtain α‐diversity metrics (Faith, Shannon, Simpson, Observed) and taxa ratios (Red Complex to Corynebacterium [RCLR], Treponema to Corynebacterium [TCLR], and Treponema to Neisseria [TNLR]). Food frequency questionnaires (FFQs) were processed to calculate Alternate Healthy Eating Index (AHEI) and A Priori Diet Quality Score (APDQS) scores. Mixed regression models examined the mean levels of microbial metrics across quartiles of diet quality. Means ± standard errors are reported along with p‐values.In multivariable models assessing the association between diet scores and α‐diversity metrics, higher AHEI values were significantly associated with lower Faith (p‐value = 0.01) and Observed (p‐value = 0.04) diversity values; similar findings were observed for APDQS (p‐value = 0.01, p‐value = 0.04). In multivariable models assessing the association between diet scores (AHEI and APDQS) and taxa ratios (RCLR, TCLR and TNLR), as the AHEI quartile increased, all taxa ratios decreased significantly as follows: −1.06 ± 0.093 in Q1 to −1.34 ± 0.099 in Q4 (RCLR), −0.43 ± 0.077 in Q1 to −0.64 ± 0.083 in Q4 (TCLR) and −0.09 ± 0.083 in Q1 to −0.38 ± 0.089 in Q4 (TNLR), respectively. In contrast, as the APDQS quartiles increased, only TNLR decreased significantly from −0.08 ± 0.085 in Q1 to −0.34 ± 0.091 in Q4.Diets rich in fruits, vegetables, whole grains and other nutritionally rich plant foods are associated with lower oral microbial diversity and favourable ratios of pathogenic to commensal microbiota. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusions To investigate the associations of high‐density lipoprotein (HDL) subfractions and apolipoprotein A‐I (apo A‐I) with fat in the pancreas.A total of 170 individuals were studied. All participants underwent magnetic resonance imaging on a single 3.0‐Tesla scanner to determine the presence/absence of fatty pancreas. HDL subfractions were measured using a commercially available lipoprotein subfractions testing system and classed as large, intermediate and small HDL. Both unadjusted and adjusted (accounting for demographics, anthropometrics, insulin resistance and other covariates) logistic regression models were built.Individuals with fatty pancreas had significantly lower circulating levels of the large HDL class and apo A‐I. Every unit decrease in the large HDL class was associated with a 93% increase in the likelihood of fatty pancreas in the most adjusted model (P < .001). Every unit decrease in apo A‐I was associated with a 45% increase in the likelihood of fatty pancreas in the most adjusted model (P = .012). The intermediate and small HDL classes were not significantly associated with fatty pancreas.Fat in the pancreas is inversely associated with the circulating levels of large HDL particles and apo A‐I. Purposely designed studies are warranted to investigate the potential of fatty pancreas as an indicator of the risk of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a chronic metabolic disorder affecting millions of people worldwide and causes serious complications such as diabetic nephropathy. Curcumin, a natural polyphenol derived from turmeric, has demonstrated antidiabetic, anti‐inflammatory, and antioxidant properties. However, the molecular mechanisms underlying curcumin's anti‐diabetic effects remain incompletely understood. This study employed network pharmacology, molecular docking, and simulation techniques to explore the potential targets, and key pathways of curcumin in the treatment of diabetes. Using SwissTarget prediction and Superpred databases, we predicted the molecular targets for curcumin, while diabetes‐associated genes were obtained from DisGeNet. We identified 60 common targets for curcumin in diabetes. Protein‐protein interaction (PPI) analysis revealed three sub‐networks and ten hub genes with AKT1, TNF‐α, EGFR, and STAT3 identified as key hub genes that could serve as potential biomarkers. Gene enrichment analysis indicated that these genes primarily regulate insulin resistance and other metabolic pathways. Quantum‐polarized ligand docking (QPLD) showed that curcumin establishes multiple hydrogen and hydrophobic interactions with the essential amino acids of these hub targets. Molecular simulation results demonstrated stable dynamic behavior, a compact structure, and variations in residue flexibility. Binding free energy calculations using MM/GBSA and MM/PBSA methods validate curcumin's strong binding to the potential targets. Total binding free energy using MM/GBSA ranged from −21.35 to −30.94 kcal/mol while MM/PBSA calculations showed total binding free energy values between −19.80 and −26.66 kcal/mol. Altogether, this study provides valuable insights into the molecular targets of curcumin in diabetes and lays the foundation for future advancements in diabetes treatment. [ABSTRACT FROM AUTHOR]

Background: Despite numerous studies confirming the association between insulin resistance (IR) and macrophage polarization, there is a lack of bibliometric analysis in this area. Therefore, our objective is to conduct a comprehensive analysis of published literature and identify potential future research trends using bibliometrics. Method: Publications on the topic of macrophage polarization in IR were gathered from the Web of Science Core Collection database (WoSCC) spanning the years 1999–2023. Bibliometric analysis and visualization were conducted using VOSviewers, CiteSpace, the R package "bibliometrix" and Tableau Public. Result: A total of 3435 articles published between 1999 and 2023 were included in the analysis. These articles originated from 75 countries, with the United States and China leading in contributions. The top five research institutions are the University of California, San Diego, Harvard University, the University of Michigan, Shanghai Jiao Tong University, and Huazhong University of Science and Technology. In this research domain, Diabetes is the most frequently published journal, and the Journal of Clinical Investigation is the most co‐cited. Among the 19,398 authors contributing to these publications, Lumeng CN. not only authored the most papers but also received the highest number of co‐citations. "Insulin resistance" emerges as a primary keyword in the analysis of emerging research hotspots. Conclusion: For the first time, bibliometric methods have been employed to conduct a comprehensive summary of papers relevant to macrophage polarization in IR. This study aims to identify the current research direction and future research hotspots, offering valuable guidance and insights for scholars in the field. [ABSTRACT FROM AUTHOR]

Insulin resistance (IR) is the pivotal pathological hit in non‐alcoholic fatty liver disease (NAFLD). There is specific attention to combination/conjugated therapies for NAFLD management. As myo‐inositol (MI) has been shown to improve IR in animal and human trials, this study aimed to investigate the influence of MI supplementation on glycemic response and IR through AMPK/PI3K/AKT signaling pathway in obese patients with NAFLD. This double‐blinded placebo‐controlled randomized clinical trial was conducted on 48 obese (BMI = 30–40 kg/m2) patients with NAFLD who were randomly assigned to receiving either MI (4 g/day) or placebo (maltodextrin 4 g/day) group for 8 weeks. Before and after the trial, weight, height, serum glycemic parameters (inc. fasting glucose and insulin) as well as IR indices were assessed. Moreover, the mRNA expression levels of AMPK, AKT, and PDK‐1 in peripheral blood mononuclear cells (PBMCs) were determined. MI supplementation resulted in significant increases in the fold changes of AMPK, AKT, and PDK‐1 genes (p =.019, p =.049, and p =.029, respectively). Indeed, IR improved in terms of all IR indices in MI group (p <.05) after adjusting for the confounders, apart from quantitative insulin sensitivity check index (QUICKI). The results showed that MI supplementation not only upregulated AMPK, AKT, and PDK‐1 mRNA in PBMCs but also improved IR in obese patients with NAFLD. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this study is to examine the alterations in subcortical brain volume and cortical thickness among individuals diagnosed with Type 2 diabetes mellitus (T2DM) through the application of morphometry techniques and, additionally, to investigate the potential association between these modifications and insulin resistance (IR). Materials and methods: The present cross‐sectional study comprised a total of 121 participants (n = 48 with healthy controls [HCs] and n = 73 with T2DM) who were recruited and underwent a battery of cognitive testing and structural magnetic resonance imaging (MRI). FreeSurfer was used to process the MRI data. Analysis of covariance compared discrepancies in cortical thickness and subcortical brain volume between T2DM and HCs, adjusting for the potential confounding effects of gender, age, education, and body mass index (BMI). Exploratory partial correlations investigated links between IR and brain structure in T2DM participants. Results: Compared with HCs, individuals with T2DM demonstrated a cortical thickness decrease in the right caudal middle frontal gyrus, right pars opercularis, left precentral gyrus, and bilateral superior frontal gyrus. Furthermore, this study for T2DM found that the severity of IR was inversely related to the volume of the left putamen and left hippocampus, as well as the thickness of the left pars orbitalis, left pericalcarine, right entorhinal area, and right rostral anterior cingulate gyrus. Conclusion: The evidence for structural brain changes in T2DM was observed, and alterations in cortical thickness were concentrated in the frontal lobes. Correlations between IR and frontal cortical thinning may serve as a potential neuroimaging marker of T2DM and lead to various diabetes‐related brain complications. [ABSTRACT FROM AUTHOR]

Elevated circulating branched‐chain amino acids (BCAA) have been linked with the severity of insulin resistance across numerous populations, implicating heightened BCAA metabolism as a potential therapy for insulin resistance. Recently, the angiotensin II type 1 receptor (AT1R) inhibitor Valsartan (VAL) was identified as a potent inhibitor of branched‐chain alpha‐keto acid dehydrogenase kinase (BCKDK), a negative regulator of BCAA metabolism. This work investigated the effect of VAL on myotube metabolism and insulin sensitivity under both insulin sensitive and insulin resistant conditions. C2C12 myotubes were treated with or without VAL at 8 µM for 24 h, both with and without hyperinsulinemic‐induced insulin resistance. Oxygen consumption and extracellular acidification were used to measure mitochondrial and glycolytic metabolism, respectively. Gene expression was assessed via qRT‐PCR, and insulin sensitivity was assessed via Western blot. Insulin resistance significantly reduced both basal and peak mitochondrial function which were rescued to control levels by concurrent VAL. Changes in mitochondrial function occurred without substantial changes in mitochondrial content or related gene expression. Insulin sensitivity and glycolytic metabolism were unaffected by VAL, as was lipogenic signaling and lipid content. Additionally, both VAL and insulin resistance depressed Bckdha expression. Interestingly, an interaction effect was observed for extracellular isoleucine, valine, and total BCAA (but not leucine), suggesting VAL may alter BCAA utilization in an insulin sensitivity‐dependent manner. Insulin resistance appears to suppress mitochondrial function in a myotube model which can be rescued by VAL. Further research will be required to explore the implications of these findings in more complex models. Significance Statement: The angiotensin II type 1 receptor (AT1R) inhibitor Valsartan rescued reduced mitochondrial function during insulin resistance in a myotube model of skeletal muscle. These findings provide proof‐of‐concept data suggesting Valsartan may provide metabolic benefits beyond blood pressure lowering effects. [ABSTRACT FROM AUTHOR]

The article focuses on the use of SGLT2 inhibitors in patients with HNF1A-MODY, a type of monogenic diabetes. Topics include the typical treatment regimen for HNF1A-MODY, the observed clinical outcomes from adding SGLT2 inhibitors to existing therapies, and the specific HNF1A genetic variants found in the study participants.

Background: Premature cardiovascular disease is the leading cause of death in people living with type 1 diabetes. Therapies are urgently needed to address cardiovascular risk in this group. Semaglutide, a long‐acting glucagon‐like peptide‐1 receptor agonist, has been shown to reduce cardiovascular events and improve weight and glycaemia in type 2 diabetes. Semaglutide may offer cardioprotective and metabolic benefits in type 1 diabetes. Methods: We will study 60 adults aged 25–70 years with type 1 diabetes of duration at least 2 years, body mass index ≥25 kg/m2, HbA1c ≥7% and at least one cardiovascular risk factor (microalbuminuria, hypertension or anti‐hypertensive treatment, hyperlipidemia or lipid lowering therapy, current smoking). Participants will receive semaglutide up to 1.0 mg weekly or matched placebo for 26 weeks. The primary outcome is carotid femoral pulse wave velocity, a measure of arterial stiffness, as a surrogate marker of cardiovascular risk. Potential mechanisms for metabolic changes will be explored including change in insulin sensitivity determined by hyperinsulinaemic‐euglycaemic clamp; and incretin and pancreatic hormone action measured during mixed meal tolerance test. Conclusion: The REducing cardiometabolic risk with SEmaglutide in Type 1 diabetes study will investigate whether semaglutide, a long acting glucagon‐like peptide receptor agonist, can improve markers of cardiometabolic health in T1D. Underlying mechanisms predicting response, including insulin resistance and incretin hormone status, will also be explored. [ABSTRACT FROM AUTHOR]

Impulsivity has been proposed to have an impact on glycemic dysregulation. However, it remains uncertain whether an unfavorable glycemic status could also contribute to an increase in impulsivity levels. This study aims to analyze associations of baseline and time‐varying glycemic status with 3‐year time‐varying impulsivity in older adults at high risk of cardiovascular disease. A 3‐year prospective cohort design was conducted within the PREDIMED‐Plus‐Cognition substudy. The total population includes 487 participants (mean age = 65.2 years; female = 50.5%) with overweight or obesity and metabolic syndrome. Insulin resistance (HOMA‐IR), glycated hemoglobin (HbA1c), presence of type 2 diabetes mellitus, and type 2 diabetes control were evaluated. Impulsivity was measured using the Impulsive Behavior Scale questionnaire and various cognitive measurements. Impulsivity z‐scores were generated to obtain Global, Trait, and Behavioral Impulsivity domains. Linear mixed models were used to study the longitudinal associations across baseline, 1‐year, and 3‐year follow‐up visits. HOMA‐IR was not significantly related to impulsivity. Participants with higher HbA1c levels, type 2 diabetes, and poor control of diabetes showed positive associations with the Global Impulsivity domain over time, and those with higher HbA1c levels were further related to increases in the Trait and Behavioral Impulsivity domains over the follow‐up visits. These results suggest a potential positive feedback loop between impulsivity and glycemic‐related dysregulation. [ABSTRACT FROM AUTHOR]

Nesfatin‐1 and ghrelin, initially recognised as hormones involved in regulating energy, have emerged as crucial players with vital functions in various human body systems. In this study, we conducted a comparative assessment of nesfatin‐1 and ghrelin responses in individuals experiencing metabolic stress due to diabetes, those with depressive diabetes characterised by both metabolic and mental stress, and healthy controls. We collected blood samples from a total of 90 participants, consisting of 30 people with type II diabetes mellitus (DM), 30 people with type II DM and major depressive disorders, and 30 healthy individuals. Diabetes was diagnosed based on glycated haemoglobin (HbA1c) levels, while depression was assessed using DSM‐V criteria. Insulin resistance (HOMA‐IR) was calculated, and serum ghrelin and nesfatin‐1 levels were measured using ELISA kits. We observed statistically significant decreases in nesfatin‐1 and ghrelin levels in the diabetic group (p < 0.0001). However, in the depressive diabetic group, nesfatin‐1 levels increased significantly, while ghrelin levels decreased further. The nesfatin‐1 to ghrelin ratio decreased in the diabetic group but increased significantly in the depressive diabetic group (p < 0.0001). Nesfatin‐1 and ghrelin hormones exhibit parallel impacts in response to metabolic stress, but nesfatin‐1 demonstrates contrasting actions compared to ghrelin when mental stress is added to metabolic stress. The findings of this study suggest that nesfatin‐1 and ghrelin hormones may play active roles as protective, prognostic, and even etiological factors in various stress situations, particularly those involving mental stress, in addition to their known functions in regulating energy. [ABSTRACT FROM AUTHOR]

Background & Aims: Metabolic dysfunction‐associated steatohepatitis (MASH) is a growing cause of chronic liver disease, characterized by fat accumulation, inflammation and fibrosis, which development depends on mitochondrial dysfunction and oxidative stress. Highly expressed in the liver during fasting, peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α) regulates mitochondrial and oxidative metabolism. Given the relevant role of mitochondrial function in MASH, we investigated the relationship between PGC‐1α and steatohepatitis. Methods: We measured the hepatic expression of Pgc‐1α in both MASH patients and wild‐type mice fed a western diet (WD) inducing steatosis and fibrosis. We then generated a pure C57BL6/J strain loss of function mouse model in which Pgc‐1α is selectively deleted in the liver and we fed these mice with a WD supplemented with sugar water that accurately mimics human MASH. Results: We observed that the hepatic expression of Pgc‐1α is strongly reduced in MASH, in both humans and mice. Moreover, the hepatic ablation of Pgc‐1α promotes a considerable reduction of the hepatic mitochondrial respiratory capacity, setting up a bioenergetic harmful environment for liver diseases. Indeed, the lack of Pgc‐1α decreases mitochondrial function and increases inflammation, fibrosis and oxidative stress in the scenario of MASH. Intriguingly, this profibrotic phenotype is not linked with obesity, insulin resistance and lipid disbalance. Conclusions: In a MASH model the hepatic ablation of Pgc‐1α drives fibrosis independently from lipid and glucose metabolism. These results add a novel mechanistic piece to the puzzle of the specific and crucial role of mitochondrial function in MASH development. [ABSTRACT FROM AUTHOR]

Metformin treatment decreases elevated concentrations of anterior pituitary hormones. The aim of this prospective, cohort study was to investigate whether hyperthyroidism modulates the impact of metformin on gonadotroph secretory function. The study population included 48 postmenopausal women with untreated type 2 diabetes or prediabetes, 24 of whom had coexisting grade 1 subclinical hyperthyroidism. Both groups were matched for age, insulin sensitivity, and gonadotropin levels. Over the entire study period, all participants were treated with metformin (2.55–3 g daily). Plasma glucose, insulin, thyroid‐stimulating hormone (TSH), total and free thyroid hormones, follicle‐stimulating hormone (FSH), luteinizing hormone (LH), estradiol, prolactin, adrenocorticotropic hormone (ACTH), and insulin‐like growth factor‐1 (IGF‐1) were assayed at entry and 6 months later. At baseline, the study groups differed in levels of TSH and thyroid hormones but not in body mass index, blood pressure, glucose homeostasis markers (fasting glucose, homeostatic model assessment 1 of insulin resistance ratio [HOMA1‐IR], and glycated hemoglobin [HbA1c]), and the remaining hormones. There were no differences between both groups in the degree of reduction in plasma glucose and HbA1c in response to metformin treatment. Although metformin decreased HOMA1‐IR in both groups, this effect was stronger in women with hyperthyroidism than with normal thyroid function (−50 ± 20% vs −30 ± 15%). Similar relationships were observed for FSH (−43 ± 21% vs −21 ± 12%). Only in hyperthyroid women did the drug reduce LH concentration (by 35 ± 17%). Metformin did not affect circulating levels of TSH, total and free thyroxine, total and free triiodothyronine, estradiol, prolactin, ACTH, and IGF‐1. The obtained results indicate that hyperthyroidism enhances the gonadotropin‐lowering effects of metformin, as well as the fact that this agent has a neutral effect on the hypothalamic–pituitary–thyroid axis in case of its overactivity. [ABSTRACT FROM AUTHOR]

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

Objective: To investigate the independent effects of irisin on insulin resistance (IR) in ovary of polycystic ovary syndrome (PCOS) and explore possible pathways. Methods: We established PCOS medel using Poretsky L's method, then PCOS rats were randomly divided into model group (M) and irisin group (I), and normal rats (N) were used as the control. Then rats in the group I were injected with recombinant irisin. Then the levels of circulating fasting blood glucose (FBG), fasting insulin (FINS), homeostasis model assessment of IR (HOMA‐IR) and PI3K/AKT and MAPK/ERK pathways in each group were observed, as well as the effects of irisin on the levels of circulating HOMA‐IR and PI3K/AKT and MAPK/ERK pathways in ovary of PCOS rats were evaluated. Results: Compared with normal group, levels of FBG, FINS, and HOMA‐IR of model group were significantly increased (p < 0.001, p < 0.001, and p < 0.001, respectively), levels of average optical density by IHC of p‐PI3K, PI3K, p‐AKT, and AKT (p = 0.015, p = 0.010, p = 0.005, and p = 0.009, respectively) and levels of mRNA concentration of PI3K and AKT (p = 0.001, and p = 0.005, respectively) were decreased, while the levels of average optical density of p‐ERK, ERK (p = 0.011, and p = 0.013, respectively) and level of mRNA concentration of ERK (p < 0.001) were increased in ovary. After irisin intervention, compared with model group, levels of FBG, FINS, and HOMA‐IR of rats in irisin group were significantly decreased (p = 0.001, p < 0.001, and p < 0.001, respectively), levels of average optical density by IHC of p‐PI3K, PI3K, p‐AKT, and AKT (p = 0.030, p = 0.024, p = 0.012, and p = 0.025, respectively) and levels of mRNA concentration of PI3K and AKT (p = 0.002, and p = 0.003, respectively) were significantly increased, while the levels of average optical density of p‐ERK, ERK (p = 0.004, and p = 0.026, respectively) and level of mRNA concentration of ERK (p = 0.001) were significantly decreased. Conclusion: Our study demonstrated that irisin could not only improve circulating insulin resistance, but may also improve ovarian IR through an increase in the activity of PI3K/AKT signaling and a decrease of MAPK/ERK signaling. [ABSTRACT FROM AUTHOR]

Background: Insulin resistance (IR), hyperuricemia (HUA), and recurrent pregnancy loss (RPL) elevate the risk of cardiovascular disease and metabolic disorders, while also impacting reproductive health. The relationship between IR, HUA, and RPL has not been thoroughly investigated. This study investigates the relationship between four IR surrogates and the risk of HUA in RPL patients. Methods: Data from a real‐world study on RPL in China were analyzed using multivariable regression to determine the relationship between HUA and triglyceride and glucose (TyG) index, triglyceride glucose‐body mass index (TyG‐BMI), triglyceride to high‐density lipoprotein cholesterol (TG/HDL‐c) ratio, and metabolic score for insulin resistance (METS‐IR). The predictive ability of these surrogates for detecting HUA in RPL patients was evaluated using the area under the curve and receiver operating characteristic analysis. Sensitivity analysis was performed using bootstrapping resampling. Results: The study included 769 patients with a mean age of 30 ± 4 years old, 8.32% of whom had HUA. Four IR surrogates were closely related to HUA in patients of RPL after adjusting for age, menstrual cycle, creatinine, alanine transaminase, aspartate transaminase, total cholesterol, homocysteine, and low‐density lipoprotein, with area under the curve values of TyG index (OR = 0.693, 95% confidence interval [CI]: 0.626, 0.759), TyG‐BMI (OR = 0.731 95% CI: 0.657, 0.805), TG/HDL‐C (OR = 0.703, 95% CI: 0.641, 0.764), and METS‐IR (OR = 0.728, 95% CI: 0.655, 0.799). Bootstrap resampling yielded similar results. Conclusions: The TyG index, TyG‐BMI, TG/HDL‐c, and METS‐IR significantly correlated with HUA in patients with RPL. The TyG‐BMI had the highest predictive value of the four IR surrogates. [ABSTRACT FROM AUTHOR]

Aims: Endothelin‐1 (ET‐1) is elevated in patients with obesity and adipose tissue of obese mice fed high‐fat diet (HFD); however, its contribution to the pathophysiology of obesity is not fully understood. Genetic loss of endothelin type B receptors (ETB) improves insulin sensitivity in rats and leads to increased circulating adiponectin, suggesting that ETB activation on adipocytes may contribute to obesity pathophysiology. We hypothesized that elevated ET‐1 in obesity promotes insulin resistance by reducing the secretion of insulin sensitizing adipokines, via ETB receptor. Methods: Male adipocyte‐specific ETB receptor knockout (adETBKO), overexpression (adETBOX), or control littermates were fed either normal diet (NMD) or high‐fat diet (HFD) for 8 weeks. Results: RNA‐sequencing of epididymal adipose (eWAT) indicated differential expression of over 5500 genes (p < 0.05) in HFD compared to NMD controls, and changes in 1077 of these genes were attenuated in HFD adETBKO mice. KEGG analysis indicated significant increase in metabolic signaling pathway. HFD adETBKO mice had significantly improved glucose and insulin tolerance compared to HFD control. In addition, adETBKO attenuated changes in plasma adiponectin, insulin, and leptin that is observed in HFD versus NMD control mice. Treatment of primary adipocytes with ET‐1 caused a reduction in adiponectin production that was attenuated in cells pretreated with an ETB antagonist. Conclusion: These data indicate elevated ET‐1 in adipose tissue of mice fed HFD inhibits adiponectin production and causes insulin resistance through activation of the ETB receptor on adipocytes. [ABSTRACT FROM AUTHOR]

Aim: The relative contributions of insulin secretory defects and possible additional contribution of insulin resistance for the development of cystic fibrosis (CF)‐related diabetes (CFRD) are poorly understood. We aimed to (a) determine which indices of insulin resistance predict progression to CFRD, and (b) to model the relative contributions of insulin secretory function and insulin resistance to predict the risk of CFRD. Materials and Methods: Three hundred and three individuals living with CF underwent a 2‐h oral glucose tolerance test with blood sampling every 30 min at 12–24‐month intervals until they developed CFRD or until the end of follow‐up (up to 15 years). Indices of insulin resistance (e.g. Stumvoll) and insulin secretion were calculated from oral glucose tolerance test glucose and insulin measurements. CFRD‐free survival was assessed by survival analysis. Results: Estimated insulin resistance showed associations with glucose homeostasis and risk of progression to CFRD. The CFRD‐free survival was significantly different between quartiles of insulin resistance (p < 0.0001). When patients were subdivided according to both insulin resistance and insulin secretion (insulinogenic index), CFRD‐free survival was significantly lower in those with combined lowest insulin secretion and highest insulin resistance (Stumvoll) indices (hazard ratio: 11.2; p < 0.0001). There was no significant difference when the same analysis was performed for the nine other indices. Conclusions: Insulin resistance is correlated with glucose homeostasis and the risk of progression to CFRD. Patients combining low insulin secretion and high insulin resistance had the greatest odds of developing CFRD over a 15‐year period. [ABSTRACT FROM AUTHOR]

Aim: Tirzepatide (Tzp), a novel dual agonist glucose‐dependent insulinotropic polypeptide/glucagon‐like peptide‐1, is approved for treating insulin resistance and obesity, and menopausal women consuming a high‐calorie diet are a target to study the Tzp effect. Therefore, we aimed to allometrically scale body weight (BW) in Tzp‐treated obese diabetic menopausal mice. Materials and Methods: Three‐month‐old C57BL/6 female mice had bilateral ovariectomy (Ovx) or a sham procedure and for 12 weeks were fed a control diet or a high‐fat and high sucrose diet (n = 120/each group [control (C), obese diabetic (Od), Ovx (O), sham (S), Tzp (T)]). Tzp was subcutaneously administered (10 nmol/kg) or vehicle once a day for an additional 4 weeks. The analysis considered log‐transformed data and the allometric equation log y = log a + b log x. Results: Od and OdO showed more upward slopes than C and CO. In C, BW was non‐allometric by T administration. Od and OdO showed slightly positive slopes (more prominent in OdO than Od). OdT and OdOT showed negative slopes, significant intercepts, and more robust Pearson coefficients than untreated ones. A potent drug effect was seen with BW allometric decline. Interactions between diet versus Ovx and diet versus Tzp affected weight gain. Diet versus Ovx versus Tzp affected food intake. Conclusions: A model was developed to show three usual factors observed in mature women. Notably, Tzp improved the metabolism and weight loss of OdO mice. Tzp‐treated mice showed negative allometric BW across treatment time, which is a quantitative assessment that allows better comparison between results. [ABSTRACT FROM AUTHOR]

Aim: To assess oxytocin's acute glucoregulatory impact in men with type 2 diabetes in the context of our previous findings that oxytocin improves β‐cell responsivity in healthy men. Methods: In a double‐blind, crossover comparison, intranasal oxytocin (24 IU) and placebo, respectively, were administered to 25 fasted men with non‐insulin–treated type 2 diabetes (age ± standard error of the mean, 63.40 ± 1.36 years; body mass index, 27.77 ± 0.66 kg/m2; HbA1c, 6.86% ± 0.08%; Homeostatic Model Assessment of Insulin Resistance (HOMA‐IR, 3.44 ± 0.39) 60 minutes before an oral glucose tolerance test (oGTT). Key outcomes were compared with previous results in men with normal weight or obesity. Results: Oxytocin compared with placebo increased plasma oxytocin concentrations and reduced the heart rate, but did not alter glucose metabolism in the 3 hours after oGTT onset (area under the curve, glucose, 2240 ± 80.5 vs. 2190 ± 69.5 mmol/L × min; insulin, 45 663 ± 4538 vs. 44 343 ± 4269 pmol/L × min; C‐peptide, 235 ± 5.1 vs. 231 ± 15.9 nmol/L × min). Conclusions: This outcome contrasts with the oxytocin‐induced attenuation of early postprandial glucose excursions in normal‐weight individuals, but is in line with the absence of respective effects in men with obesity. We conclude that insulin resistance in type 2 diabetes is associated with decreased sensitivity to the acute glucoregulatory effect of oxytocin in male individuals. [ABSTRACT FROM AUTHOR]

Aim: To assess the expression and function of miR‐483‐5p in diabetic β cells. Methods: The expression of miR‐483‐5p was evaluated in the pancreatic islets of obesity mouse models by quantitative reverse transcription polymerase chain reaction. Dual‐luciferase activity, and western blotting assays, were utilized for miR‐483‐5p target gene verification. Mice with β cell‐specific miR‐483‐5p downregulation were studied under metabolic stress (i.e. a high‐fat diet) condition. Lineage tracing was used to determine β‐cell fate. Results: miR‐483‐5p increased in the islets of obese mouse models. Expression levels of miR‐483‐5p were significantly upregulated with the treatment of high glucose and palmitate, in both MIN6 cells and mouse islets. Overexpression of miR‐483‐5p in β cells results in impaired insulin secretion and β‐cell identity. Cell lineage‐specific analyses revealed that miR‐483‐5p overexpression deactivated β‐cell identity genes (insulin, Pdx1 and MafA) and derepressed β‐cell dedifferentiation (Ngn3) genes. miR‐483‐5p downregulation in β cells of high‐fat diet‐fed mice alleviated diabetes and improved glucose intolerance by enhancing insulin secretory capacity. These detrimental effects of miR‐483‐5p relied on its seed sequence recognition and repressed expression of its target genes Pdx1 and MafA, two crucial markers of β‐cell maturation. Conclusions: These findings indicate that the miR‐483‐5p–mediated reduction of mRNAs specifies β‐cell identity as a contributor to β‐cell dysfunction via the loss of cellular differentiation. [ABSTRACT FROM AUTHOR]

Summary: Psychological distress has a demonstrable impact on cardiovascular diseases (CVD) and risk factors. Transcendental Meditation (TM) has been shown to reduce stress and improve health and well‐being. The current review aimed to synthesize the evidence on the effects of TM on cardiometabolic outcomes and identify gaps for future research. We searched PubMed/MEDLINE, EMBASE, SCOPUS, and Web of Science databases for relevant literature. Forty‐five papers that reported studies of TM on cardiometabolic risk factors and diseases were included. Evidence shows that TM is effective in reducing blood pressure (BP). We found some evidence that TM can improve insulin resistance and may play a role in improving dyslipidemia, exercise tolerance, and myocardial blood flow, and in reducing carotid intima‐media thickness and left ventricular mass. Studies show that long‐term TM practice can reduce the risk of myocardial infarction, stroke, and CVD mortality. This review identified that certain studies have high participant drop‐out rates, and fewer studies targeted comprehensive cardiometabolic outcomes beyond BP with longer follow‐up periods. We found that most studies were conducted in specific populations, which may limit generalizability. In conclusion, TM has the potential to improve cardiometabolic health; however, research gaps highlight the need for larger phase III multicenter clinical trials with long‐term follow‐ups. [ABSTRACT FROM AUTHOR]

The coexistence of diabetes mellitus (DM) and tuberculosis (TB) presents a significant global burden, with DM being recognized as a major risk factor for TB. This review comprehensively analyzes the immunological aspects of DM‐TB comorbidity, shedding light on the impact of DM on TB pathogenesis and immune responses. It reveals that high blood glucose levels in TB patients contribute to reduced innate immune cell count, compromised phagocytic function, and delayed antigen presentation. These factors ultimately impair the clearance of Mycobacterium tuberculosis (MTB) and delay adaptive immune responses. With the interaction between TB and DM, there is an increase in inflammation and elevated secretion of pro‐inflammatory cytokines by immune cells. This exacerbates the inflammatory response and contributes to poor treatment outcomes in TB. Moreover, the review explores the effects of DM on TB prevention, diagnosis, and treatment. It highlights how poor glycemic control, insulin resistance (IR), DM complications, and genetic factors increase the risk of MTB infection in individuals with DM. Additionally, DM‐related immune suppression adversely affects the sensitivity of traditional diagnostic tests for TB, potentially resulting in underdiagnosis and delayed intervention. To mitigate the burden of TB in DM patients, the review emphasizes the need for further research on the mechanisms underlying DM reactivation in latent TB infection (LTBI). It shows how important it is to find and treat LTBI in DM patients as soon as possible and suggests looking into biomarkers that are specific to DM to make diagnosis more accurate. [ABSTRACT FROM AUTHOR]

Reactive oxygen species, when produced in a controlled manner, are physiological modulators of healthy white adipose tissue (WAT) expansion and metabolic function. By contrast, unbridled production of oxidants is associated with pathological WAT expansion and the establishment of metabolic dysfunctions, most notably insulin resistance and type 2 diabetes mellitus. NADPH oxidases (NOXs) produce oxidants in an orderly fashion and are present in adipocytes and in other diverse WAT‐constituent cell types. Recent studies have established several links between aberrant NOX‐derived oxidant production, adiposity, and metabolic homeostasis. The objective of this review is to highlight the physiological roles attributed to diverse NOX isoforms in healthy WAT and summarize current knowledge of the metabolic consequences related to perturbations in their adequate oxidant production. We detail WAT‐related alterations in preclinical investigations conducted in NOX‐deficient murine models. In addition, we review clinical studies that have employed NOX inhibitors and currently available data related to human NOX mutations in metabolic disturbances. Future investigations aimed at understanding the integration of NOX‐derived oxidants in the regulation of the WAT cellular redox network are essential for designing successful redox‐related precision therapies to curb obesity and attenuate obesity‐associated metabolic pathologies. [ABSTRACT FROM AUTHOR]

Objective: Obesity is a chronic disease that affects more than 400 million adults with severe comorbidities. The search for new treatments to reduce its negative consequences is necessary. Orexins are hypothalamic neuropeptides involved in various physiological processes related to obesity. The aim of this study was to investigate the consequences of chronic orexin‐A treatment in mouse models. Methods: Female wild‐type C57BL/6 mice that were obesity‐prone or obesity‐resistant and mice that were deficient for orexin receptors were fed with a high‐fat diet. Glucose tolerance, indirect calorimetry, expression of brain neuropeptides and receptors, microglial activation, and microbiota were determined to evaluate the role of orexins on metabolic flexibility. Results: Orexin‐A reduces weight gain in obesity‐prone mice. This reduction is associated with a decrease in body fat, food intake, steatosis, and insulin resistance, as well as alterations of intestinal microbiota composition. A decreased expression of orexin receptors and neuropeptides involved in food intake was also observed in the hypothalamus. Conclusions: Our data support the notion that orexin receptor signaling is involved in different aspects of energy metabolism and can mitigate several dysfunctions associated with obesity, suggesting that orexin receptors can represent new targets for obesity treatment. [ABSTRACT FROM AUTHOR]

Summary Background Objectives Methods Results Conclusions Uric acid (UA) and homeostatic model assessment of insulin resistance (HOMA‐IR) are endogenous biomarkers implicated in metabolic disorders and dysfunction.To investigate the structural associations between sugar‐sweetened beverage intake (SSB), UA, HOMA‐IR and adolescent latent MetS construct (MetsC) representing paediatric metabolic syndrome (MetS).A population‐based representative adolescent cohort (n = 1454) was evaluated for risk profiles of MetS. Structural equation modelling was performed to identify multifactor structural associations between study parameters and evaluate mediating effects.Adolescents had a single‐factor latent construct representing MetS. Increased SSB intake was associated with higher UA and HOMA‐IR levels, and the two biomarkers were positively associated with the MetsC score. UA and HOMA‐IR exerted three mediating effects on the association between fructose‐rich tea beverage (FTB) intake of >500 mL/day and MetsC: adjusted standardized coefficient and mediating effect (%), FTB → UA → MetsC: 0.071, 23.1%; FTB → HOMA‐IR → MetsC: 0.034, 11.0%; FTB → UA → HOMA‐IR → MetsC: 0.010, 3.1%. The UA‐associated pathways accounted for 31.1% of the overall mediation on the association between bottled sugar‐containing beverage intake and MetsC. After accounting for the UA‐ and HOMA‐IR‐derived detrimental effects, the fructose‐rich tea beverage intake of >500 mL/day had a tea‐related beneficial effect on MetsC, with an adjusted standardized coefficient of −0.103.UA and HOMA‐IR individually and jointly mediate the adverse effects of high fructose‐rich SSB intake on the mechanisms underlying paediatric MetS. Fructose‐free tea‐based beverages may have a beneficial effect on latent MetS structure in adolescents. [ABSTRACT FROM AUTHOR]

Purpose Experimental design Results Conclusions Prior studies testing the association between insulin resistance (IR) and prostate cancer (PC) risk are inconsistent. We examined the association between Homeostatic Assessment of Insulin Resistance (HOMA‐IR; calculated from fasting baseline insulin and glucose) and PC in REDUCE, a 4‐year randomized trial of dutasteride vs. placebo for PC prevention.All patients had prestudy negative biopsies and underwent study mandated biopsies at 2 and 4 years regardless of prostate‐specific antigen. Multivariable logistic regression models were used to investigate the associations between log‐transformed or categorized HOMA‐IR scores and PC risk. Multinominal regression was used to assess associations between HOMA‐IR scores and tumor grade (low grade [grade group 1]; high‐grade [grade groups 2–5]).Among 5430 REDUCE participants (1212 with PC; 856 low‐ and 356 high‐grade), higher HOMA‐IR was associated with lower PC risk (log‐HOMA‐IR: OR, 0.89; 95% CI, 0.80–0.99; p = .03; categorized HOMA‐IR: p‐trend = .04). When stratified by grade, HOMA‐IR was significantly associated with reduced low‐grade PC risk (log‐HOMA‐IR: OR, 0.84; 95% CI , 0.74–0.94; p = .003; categorized HOMA‐IR: p‐trend = .002) but was unrelated to high‐grade PC (log‐HOMA‐IR: OR, 1.02; 95% CI, 0.86–1.21; p = .81; categorized HOMA‐IR: p‐trend = .26). Results were similar in placebo and treatment arms.In summary, higher HOMA‐IR was associated with a reduced risk of low‐grade PC but was not associated with high‐grade disease. The mechanisms to explain these findings are unclear. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications Physical activity is an effective therapeutic protocol for treating chronic obstructive pulmonary disease (COPD). However, the mechanisms underlying the benefits of physical activity in COPD are not fully elucidated.In a mouse model of COPD, analysis of biological markers and lung proteomics identified the molecular pathways through which exercise ameliorates COPD.Exercise improved pulmonary function, emphysema, small airway disease, pulmonary inflammation, glucose metabolic dysregulation, and insulin resistance in COPD mice. Proteomic analysis revealed 430 differentially expressed proteins (DEPs) between the COPD and COPD + Exercise (COPD + Ex) groups. GO analysis indicated that the enriched pathways were predominantly related to the immune response, inflammatory processes, insulin secretion, and glucose metabolic processes. GO analysis revealed IL‐33 as a crucial target for the exercise‐related amelioration of COPD. KEGG analysis showed that DEPs were significantly enriched in primary immunodeficiency, the intestinal immune network for IgA production, and the NF‐κB signalling pathway. Exercise inhibited NF‐κB activation by suppressing the CD14/TLR4/MyD88 and TNF‐α/TNF‐R1/TRAF2/5 pathways in COPD mice. Exercise inhibited expression of BCR, IgM, IgD, IgG, IgE, and IgA by suppressing B‐cell receptor signalling. Exercise attenuated glucose metabolic dysregulation and insulin resistance through the suppression of proinflammatory mediators, including MHC I, MHC II, TNF‐α, IFN‐γ, and IL‐1β, while concurrently increasing insulin expression. The qRT‐PCR results were consistent with the proteomic results.In a mouse model, exercise improved COPD and its metabolic comorbidities through immune system regulation and inflammation suppression, offering insights into potential therapeutic targets. [ABSTRACT FROM AUTHOR]

ABSTRACT The association of serum N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) with insulin resistance (IR), as measured by homeostasis model assessment of insulin resistance (HOMA‐IR), in the general population is unclear. Our study aimed to characterize its relationship in a large community‐based population. Subjects were recruited from the Danyang city between 2017 and 2019. Serum NT‐proBNP was measured using an enhanced chemiluminescence immunoassay. IR was defined by a HOMA‐IR in the highest sex‐specific quartile. Categorical and continuous analyses were performed with sex‐specific NT‐proBNP tertiles and naturally logarithmically transformed NT‐proBNP (lnNTproBNP), respectively. The 2945 participants (mean age 52.8 years) included 1728 (58.7%) women, 1167 (39.6%) hypertensive patients, 269 (9.1%) diabetic patients, and 736 (25.0%) patients with IR. In simple and multivariate‐adjusted regression analyses, serum lnNTproBNP were both negatively associated with HOMA‐IR (β = −0.19 to −0.25; p < 0.0001). Similar results were also obtained in multiple subgroup analyses. In multiple logistic regression analyses, elevated serum NT‐proBNP was associated with lower risks of IR (odds ratios: 0.68 and 0.39; 95% confidence intervals: 0.61–0.74 and 0.30–0.50 for lnNTproBNP and top vs. bottom tertiles, respectively; p < 0.0001). In conclusion, increased serum NT‐proBNP level was strongly associated with a lower risk of IR in Chinese. [ABSTRACT FROM AUTHOR]

Aims Materials and Methods Results Conclusions To determine if estimated glucose disposal rate (eGDR) can predict cardiovascular disease mortality risk at different levels of glycaemic tolerance.The eGDR levels of 11 656 individuals aged 45–79 years from the National Health and Nutrition Examination Survey cycles 1999 to 2010 were analysed. Associations between eGDR levels and all‐cause and cardiovascular mortality were examined using Cox proportional hazards and Fine and Gray models, respectively.After a median follow‐up of 12.8 years, a total of 2852 participants died, with 777 of those deaths attributed to cardiovascular causes. When comparing participants with eGDR values of ≤4 mg/kg/min to those with eGDR values falling within the ranges of 4–6, 6–8 and >8 mg/kg/min, it was found that the latter groups exhibited lower hazard ratios for both all‐cause mortality (0.61 [0.52–0.72], 0.61 [0.52–0.72] and 0.46 [0.39–0.55]) and cardiovascular mortality (0.44 [0.33–0.57], 0.45 [0.34–0.59] and 0.30 [0.23–0.40]). A U‐shaped relationship between eGDR and all‐cause mortality was observed, with an inflection point at an eGDR of 9.54 mg/kg/min.In the general population, the association between reduced eGDR and all‐cause and cardiovascular mortality was independently significant, contributing to the identification of individuals at high risk for different levels of glucose tolerances. [ABSTRACT FROM AUTHOR]

Background Hypothesis/Objectives Animals Methods Results Conclusions and Clinical Importance Characterizing the lipid response to an oral glucose test (OGT) might improve our understanding of Equine Metabolic Syndrome.To describe the effects of an OGT on lipid metabolism and determine the value of measuring triglyceride and nonesterified fatty acid (NEFA) concentrations in hyperinsulinemic (HI) and insulin‐resistant (IR) horses.Twenty horses including 7 HI‐IR horses, 4 HI‐non‐IR horses, and 9 non‐HI‐non‐IR horses (control).Cross‐sectional design. Horses underwent an OGT, with blood samples collected at 0, 60, 90, and 120 minutes. Insulin, glucose, triglyceride, and NEFA concentrations were measured and compared over time and between groups, with P < .05 considered significant.In all horses, the OGT had a significant effect on triglyceride concentrations (median [interquartile range]: .35 [.30‐.50] mmol/L at 0 minute vs .25 [.21‐.37] mmol/L at 120 minutes, P = .005) and on NEFA concentrations (.1 [.1‐.2] mEq/L at 0 minute vs .05 [.05‐.1] mEq/L at 120 minutes, P = .0009). However, horses with HI and IR had higher triglyceride areas under the curve (AUC, 79.46 ± 46.59 vs 33.32 ± 6.75 mmol/L*min, P = .01) as well as NEFA AUC (9.1 ± 2.9 vs 6.0 ± 6.8 mEq/L*min, P = .03) than control horses. No significant difference was detected between control and HI non‐IR horses.Determining triglyceride and NEFA concentrations might help assess tissue insulin resistance during an OGT. [ABSTRACT FROM AUTHOR]

Obesity and obesity‐related insulin resistance have been a research hotspot. Pituitary adenylate cyclase activating polypeptide (PACAP) has emerged as playing a significant role in energy metabolism, holding promising potential for attenuating insulin resistance. However, the precise mechanism is not fully understood. Palmitic acid and a high‐fat diet (HFD) were used to establish insulin resistance model in Alpha mouse liver 12 cell line and C57BL/6 mice, respectively. Subsequently, we assessed the effects of PACAP both in vivo and in vitro. Lentivirus vectors were used to explore the signaling pathway through which PACAP may ameliorate insulin resistance. PACAP was found to selectively bind to the PACAP type I receptor receptor and ameliorate insulin resistance, which was characterized by increased glycogen synthesis and the suppression of gluconeogenesis in the insulin‐resistant cell model and HFD‐fed mice. These effects were linked to the activation of the Fas apoptotic inhibitory molecule/rapamycin‐insensitive companion of mammalian target of rapamycin/RAC‐alpha serine/threonine‐protein kinase (FAIM/Rictor/AKT) axis. Furthermore, PACAP ameliorated insulin resistance by increasing solute carrier family 2, facilitated glucose transporter members 2/4 and inhibiting gluconeogenesis‐related proteins glucose 6‐phosphatase catalytic subunit 1 and phosphoenolpyruvate carboxykinase 2 expression. Meanwhile, the phosphorylation of hepatic AKT/glycogen synthase kinase 3β was promoted both in vivo and in vitro by PACAP. Additionally, PACAP treatment decreased body weight, food intake and blood glucose levels in obese mice. Our study shows that PACAP ameliorated insulin resistance through the FAIM/Rictor/AKT axis, presenting it as a promising drug candidate for the treatment of obesity‐related insulin resistance. [ABSTRACT FROM AUTHOR]

Iron overload (IO) is known to contribute to metabolic dysfunctions such as type 2 diabetes and insulin resistance. Using L6 skeletal muscle cells overexpressing the CDGSH iron–sulfur domain‐containing protein 1 (CISD1, also known as mitoNEET) (mitoN) protein, we examined the potential role of MitoN in preventing IO‐induced insulin resistance. In L6 control cells, IO resulted in insulin resistance which could be prevented by MitoN as demonstrated by western blot of p‐Akt and Akt biosensor cells. Mechanistically, IO increased; mitochondrial iron accumulation, mitochondrial reactive oxygen species (ROS), Fis1‐dependent mitochondrial fission, mitophagy, FUN14 domain‐containing protein 1 (FUNDC1) expression, and decreased Parkin. MitoN overexpression was able to reduce increases in mitochondrial iron accumulation, mitochondrial ROS, mitochondrial fission, mitophagy and FUNDC1 upregulation due to IO. MitoN did not have any effect on the IO‐induced downregulation of Parkin. MitoN alone also upregulated peroxisome proliferator‐activated receptor gamma coactivator 1 alpha (PGC1α) protein levels, a master regulator of mitochondrial biogenesis. The use of mitochondrial antioxidant, Skq1, or fission inhibitor, Mdivi‐1, prevented IO‐induced insulin resistance implying both mitochondrial ROS and fission play a causal role in the development of insulin resistance. Taken together, MitoN is able to confer protection against IO‐induced insulin resistance in L6 skeletal muscle cells through regulation of mitochondrial iron content, mitochondrial ROS, and mitochondrial fission. [ABSTRACT FROM AUTHOR]

Metabolic associated fatty liver disease (MAFLD) is the most common chronic liver disease worldwide, characterized by excess lipid deposition. Insulin resistance (IR) serves as a fundamental pathogenic factor in MAFLD. However, currently, there are no approved specific agents for its treatment. Farrerol, a novel compound with antioxidant and anti‐inflammatory effects, has garnered significant attention in recent years due to its hepatoprotective properties. Despite this, the precise underlying mechanisms of action remain unclear. In this study, a network pharmacology approach predicted protein tyrosine phosphatase non‐receptor type 1 (PTPN1) as a potential target for farrerol's action in the liver. Subsequently, the administration of farrerol improved insulin sensitivity and glucose tolerance in MAFLD mice. Furthermore, farrerol alleviated lipid accumulation by binding to PTPN1 and reducing the dephosphorylation of the insulin receptor (INSR) in HepG2 cells and MAFLD mice. Thus, the phosphoinositide 3‐kinase/serine/threonine‐protein kinases (PI3K/AKT) signalling pathway was active, leading to downstream protein reduction. Overall, the study demonstrates that farrerol alleviates insulin resistance and hepatic steatosis of MAFLD by targeting PTPN1. [ABSTRACT FROM AUTHOR]

Statins, the first‐line medication for dyslipidemia, are linked to an increased risk of type 2 diabetes. But exactly how statins cause diabetes is yet unknown. In this study, a developed short‐term statin therapy on hyperlipidemia mice show that hepatic insulin resistance is a cause of statin‐induced diabetes. Statin medication raises the expression of progesterone and adiponectin receptor 9 (PAQR9) in liver, which inhibits insulin signaling through degradation of protein phosphatase, Mg2+/Mn2+ dependent 1 (PPM1α) to activate ERK pathway. STIP1 homology and U‐box containing protein 1 (STUB1) is found to mediate ubiquitination of PPM1α promoted by PAQR9. On the other hand, decreased activity of hepatocyte nuclear factor 4 alpha (HNF4α) seems to be the cause of PAQR9 expression under statin therapy. The interventions on PAQR9, including deletion of PAQR9, caloric restriction and HNF4α activation, are all effective treatments for statin‐induced diabetes, while liver specific over‐expression of PPM1α is another possible tactic. The results reveal the importance of HNF4α‐PAQR9‐STUB1‐PPM1α axis in controlling the statin‐induced hepatic insulin resistance, offering a fresh insight into the molecular mechanisms underlying statin therapy. [ABSTRACT FROM AUTHOR]

Central insulin resistance has been linked to the development of neurodegenerative diseases and mood disorders. Various proteins belonging to the enzyme family of protein tyrosine phosphatases (PTPs) act as inhibitors of insulin signaling. Protein tyrosine phosphatase receptor type J (PTPRJ) has been identified as a negative regulator in insulin signaling in the periphery. However, the impact of PTPRJ on insulin signaling and its functional role in neuronal cells is largely unknown. Therefore, we generated a Ptprj knockout (KO) cell model in the murine neuroblast cell line Neuro2a by CRISPR‐Cas9 gene editing. Ptprj KO cells displayed enhanced insulin signaling, as shown by increased phosphorylation of the insulin receptor (INSR), IRS‐1, AKT, and ERK1/2. Further, proximity ligation assays (PLA) revealed both direct interaction of PTPRJ with the INSR and recruitment of this phosphatase to the receptor upon insulin stimulation. By RNA sequencing gene expression analysis, we identified multiple gene clusters responsible for glucose uptake and metabolism, and genes involved in the synthesis of various lipids being mainly upregulated under PTPRJ deficiency. Furthermore, multiple Ca2+ transporters were differentially expressed along with decreased protein biosynthesis. This was accompanied by an increase in endoplasmic reticulum (ER) stress markers. On a functional level, PTPRJ deficiency compromised cell differentiation and neurite outgrowth, suggesting a role in nervous system development. Taken together, PTPRJ emerges as a negative regulator of central insulin signaling, impacting neuronal metabolism and neurite outgrowth. [ABSTRACT FROM AUTHOR]