Metabolic-Dysfunction-Associated Fatty Liver Disease and Hepatic Insulin Resistance: A Type 2 Diabetes Mellitus-like in the liver - A Systematic Review

Metabolic-Dysfunction-Associated Fatty Liver Disease and Hepatic Insulin Resistance: A Type 2 Diabetes Mellitus-like in the liver - A Systematic Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Metabolic-Dysfunction-Associated Fatty Liver Disease and Hepatic Insulin Resistance: A Type 2 Diabetes Mellitus-like in the liver - A Systematic Review Luís Jesuino de Oliveira Andrade, Gabriela Correia Matos de Oliveira, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4739938/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction : Metabolic dysfunction-associated fatty liver disease (MAFLD) comes up as a prominent issue within the realm of chronic liver pathologies on a global scale. Hepatic insulin resistance (HIR) is an important aspect of metabolic dysfunction, serving as a primary driver of dysregulated glucose homeostasis. MAFLD and HIR, Type 2 diabetes mellitus-like in the liver, exhibit a complex interplay in the pathogenesis of metabolic disorders. Objective: To evaluate the relationship between MAFLD and HIR by a systematic review. Methods: To identify relevant studies published between January 1998 and July 2024, a comprehensive search was conducted across electronic databases, including PubMed, Web of Science, Scopus, Embase, and Cochrane Central. To ensure the inclusion of relevant and high-quality studies, inclusion and exclusion criteria were applied. The QUADAS-2, the systematic review ensured that potential biases were systematically identified, evaluated, and accounted for, enhancing the credibility and trustworthiness of the findings. Results: After careful consideration, 8 studies were deemed to meet the stringent inclusion criteria and were subsequently selected for data extraction and analysis. These studies represented the core body of evidence that underpins the findings of this systematic review. Conclusion: Our systematic review demonstrated a consistently demonstrated association between MAFLD and HIR. This association has been supported by findings from various studies, highlighting the significance of MAFLD as a potential risk factor for the development of HIR. Internal Medicine Fatty liver disease associated with metabolic dysfunction Hepatic insulin resistance Systematic review. Figures Figure 1 Figure 2 INTRODUCTION Metabolic dysfunction-associated fatty liver disease (MAFLD) comes up as a prominent issue within the realm of chronic liver pathologies on a global scale, affecting an estimated one-fourth of the world's populace. 1 Diagnosis relies on the detection of hepatic steatosis, characterized by the abnormal buildup of lipids in the liver tissue. The diagnosis of MAFLD necessitates the presence of overweight/obesity, confirmed type 2 diabetes mellitus (T2DM), or observable signs of metabolic dysregulation, alongside the absence of significant alcohol intake. The etiology of MAFLD remains incompletely understood, likely due to a multifaceted interplay of various factors. 2 Current knowledge indicates that insulin resistance (IR), oxidative stress, and inflammatory pathways collectively contribute to the pathological progression of the disease. 3 The clinical presentation of MAFLD encompasses a wide spectrum, ranging from a benign, asymptomatic state to a more severe manifestation termed non-alcoholic steatohepatitis. This latter variant carries a significant risk of progression to cirrhosis, liver failure, and even hepatocellular carcinoma. 4 The IR, a hallmark of metabolic syndrome and a precursor to T2DM, is characterized by the impaired ability of target tissues, primarily skeletal muscle, liver, and adipose tissue, to respond to insulin's signaling. 5 This hormonal discordance disrupts glucose uptake, leading to elevated blood glucose levels. The intricate pathophysiological pathways of IR encompass a myriad of factors, including genetic susceptibility, lifestyle determinants, and inflammatory cascades. 6 The heightened abdominal adiposity, a pivotal contributor to insulin resistance, triggers the secretion of pro-inflammatory cytokines and free fatty acids, eliciting detrimental effects on insulin signaling transduction. Additionally, genetic variations influence insulin receptor sensitivity and intracellular signaling cascades. 7 Hepatic IR (HIR) is an important aspect of metabolic dysfunction, serving as a primary driver of dysregulated glucose homeostasis. Marked by dysfunctional insulin signaling cascades in hepatocytes, this phenomenon plays a crucial role in the pathogenesis of T2DM. 8 This particular type of IR can be seen as a focal representation of diabetes mellitus, termed in situ T2DM, wherein the liver loses its responsiveness to insulin's typical functions. 9 The disruption of hepatic glucose output and lipid processing amplifies systemic IR, underscoring the intricate connections between hepatic performance and overall metabolic well-being in the genesis of T2DM. MAFLD and HIR, T2DM-like in the liver, exhibit a complex interplay in the pathogenesis of metabolic disorders (Fig. 1 ). To evaluate the current understanding of the intricate relationship between MAFLD and HIR, we conducted a systematic review with the aim of evaluating this relationship. METHODS Study Design To uphold the principles of transparency and methodological rigor, our systematic review protocol was prospectively submitted on the International Prospective Register of Systematic Reviews (PROSPERO). This publicly accessible registration serves as a comprehensive documentation of the research planning strategy, inclusion/exclusion criteria, and data extraction methods employed throughout the review process. Furthermore, we adhered to the established guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) throughout the review process. 10 This ensured that the review was conducted in a transparent, replicable, and rigorous manner, encompassing all relevant studies that comprehensively investigated the association between MAFLD and HIR. Literature Search Strategy: A Comprehensive Approach to Identify Relevant Studies To identify relevant studies published between January 1998 and July 2024, a comprehensive search was conducted across electronic databases, including PubMed, Web of Science, Scopus, Embase, and Cochrane Central. The search strategy employed a combination of controlled vocabulary and free-text terms related to MAFLD and HIR. Boolean operators (AND, OR, NOT) were utilized to refine the search strategy and ensure the retrieval of relevant studies. Specific search terms and variations included: Pubmed = (("fatty liver"[MeSH Terms] OR ("fatty"[All Fields] AND "liver"[All Fields]) OR "fatty liver"[All Fields] OR ("hepatic"[All Fields] AND "steatosis"[All Fields]) OR "hepatic steatosis"[All Fields]) OR ("fatty liver"[KYWD] OR ("fatty"[All Fields] AND "liver"[All Fields]) OR "fatty liver"[All Fields] OR ("hepatic"[All Fields] AND "steatosis"[All Fields]) OR "hepatic steatosis"[All Fields])) AND "hepatic insulin resistance"[All Fields]. Web of Science = (TS=(fatty liver) AND TS-(fatty)) OR (TS =(fatty liver) AND (TH=(hepatic) AND (TS = steatosis) AND (TS=(hepatic steatosis) AND (TS=(fatty liver) OR (TSH=(fatty) AND (TS=(liver) OR (TSH=(fatty liver) AND (TS=(hepatic) AND (TS=(steatosis) OR (TS=(hepatic steatosis) AND (TS=(hepatic insulin resistance))). Scopus : (TITLE-ABS-KEY ("fatty liver") AND TITLE-ABS-KEY ("liver")) OR TITLE-ABS-KEY ("fatty liver") AND TITLE-ABS-KEY ("hepatic insulin resistance") OR ("steatosis"))). Embase : ‘fatty liver’/exp AND (‘hepatic insulin resistance’ /exp OR ‘hepatic steatosis’ OR ‘liver’ /exp ‘hepatic insulin resistance’ OR ‘steatosis’ / exp OR ‘hepatic insulin resistance’ /exp). Cochrane Central : (("fatty liver") OR ("fatty") AND "liver") OR "fatty liver" OR ("hepatic" AND "steatosis") OR "hepatic steatosis") OR ("fatty liver" OR ("fatty" AND "liver") OR "fatty liver" OR ("hepatic" AND "steatosis") OR "hepatic steatosis)) AND "hepatic insulin resistance". Refinement Strategy: Boolean operators (AND, OR, NOT) were used to combine and refine the search terms, ensuring a precise and comprehensive retrieval of relevant studies. Inclusion and Exclusion Criteria To ensure the inclusion of relevant and high-quality studies, the following inclusion and exclusion criteria were applied: Inclusion Criteria: Original Research Articles: Studies were included if they were original research articles published in peer-reviewed journals. Human Focus: Studies had to focus on human subjects to be considered eligible. MAFLD-HIR Relationship Investigation: The primary focus of the study had to be the investigation of the association between MAFLD and HIR. Quantitative Data Reporting: Studies were required to report quantitative data on the relationship between MAFLD and HIR, relevant biomarkers, or pathological markers for MAFLD or HIR. Exclusion Criteria: Non-Research Articles: Review articles, editorials, commentaries, case reports, and abstracts without sufficient data were excluded. Limited Scope: Studies that solely examined the peripheral metabolic effects without assessing outcomes related to the MAFLD-HIR association were excluded. Data Extraction and Bias Assessment Upon identification of eligible studies, the next step involved meticulously extracting relevant data from each study. This entailed capturing key information such as study characteristics, participant demographics, HIR parameters, and methodological details. The extracted data served as the foundation for subsequent analyses. To ensure the robustness of the review, a rigorous bias assessment was conducted for each included study. This process involved scrutinizing the study design, sample size, potential sources of confounding, and other factors that could influence the validity of the findings. The assessment aimed to identify and address any potential biases that might have impacted the results. Synthesizing Data and Calculating Effect Sizes The extracted data were meticulously synthesized and analyzed using appropriate statistical methods. This involved combining data from similar studies and employing statistical techniques to calculate effect sizes. Effect sizes represent the magnitude and direction of the association between MAFLD and HIR, providing a quantitative measure of the strength of the relationship. Interpreting Results and Drawing Conclusions Once the data were synthesized and analyzed, the results of the systematic review were carefully interpreted. This involved examining the patterns and trends observed in the data, considering the effect sizes, and evaluating the overall strength of evidence. Based on the comprehensive analysis, well-supported conclusions were drawn regarding the association between MAFLD and hepatic insulin resistance. Bias Assessment Tool To ensure the rigor and transparency of the bias assessment process, the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool was employed. 11 QUADAS-2 is a widely recognized and validated tool specifically designed to assess the risk of bias in studies evaluating diagnostic accuracy. The tool comprises four domains: patient selection, index test, reference test, and flow and timing. Each domain is further divided into signal criteria, which are assessed as present, absent, unclear, or not applicable. The overall risk of bias for each study is categorized as low, moderate, high, or unclear based on the assessment of all four domains. By utilizing QUADAS-2, the systematic review ensured that potential biases were systematically identified, evaluated, and accounted for, enhancing the credibility and trustworthiness of the findings. RESULTS A total of 211 articles were initially identified through the electronic database search. These articles were then subjected to initial screening based on title and abstract to assess their relevance to the research question. Duplicates were removed using specialized software, resulting in a pool of 129 unique articles. The remaining 129 articles were further scrutinized through a thorough review of their full texts. This rigorous assessment involved evaluating the study design, methodology, data collection, and findings to determine their eligibility for inclusion in the systematic review. Articles that met the pre-defined inclusion criteria and provided relevant data on the association between MAFLD and HIR were selected for further analysis. After careful consideration, 8 studies were deemed to meet the stringent inclusion criteria and were subsequently selected for data extraction and analysis. These studies represent the core body of evidence that underpins the findings of this systematic review (Fig. 2 ). The eight studies selected for this systematic review embarked on a diverse journey to investigate the intricate relationship between MAFLD and HIR. These studies, hailing from various corners of the globe, employed a range of methodologies to shed light on this complex association. The sample sizes of the included studies varied considerably, ranging from 57 to 1,120 participants. This spectrum of sample sizes allowed for the examination of the association across a broad range of study settings and populations, enhancing the generalizability of the findings. Characteristics of Studies Study 1 : Gastaldelli A, Cusi K, Pettiti M, Hardies J, Miyazaki Y, Berria R, et al. 12 ; Study Design: Comparative Study; Objective: To examine the relationship between visceral/hepatic fat accumulation and HIR/accelerated gluconeogenesis; Sample Size: 57 subjects; Participant Characteristics: 14 normal glucose tolerant (body mass index [BMI] = 25 +/- 1 kg/m( 2 )) and 43 T2DM (24 nonobese, BMI = 26 +/- 1; 19 obese, BMI = 32 +/- 1 kg/m( 2 )) subjects. Conclusions: "Abdominal adiposity significantly affects both lipid and glucose metabolism. Excess visceral fat primarily increases gluconeogenesis flux. Both visceral and liver fat are associated with HIR"; QUADAS-2 Risk of Bias: The risk of bias for this study using QUADAS-2 is intermediate to high. Study 2 : Sesti G, Fiorentino TV, Hribal ML, Sciacqua A, Perticone F. 13 ; Study Design: cross-sectional study; Objective: To examine the relationship between HIR index, nonalcoholic fatty liver disease and its biomarkers (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, alkaline phosphatase, high-sensitive C reactive protein, insulin-like growth factor-1; Sample Size: 473 subjects; Participant Characteristics: 473 Caucasians subjects (293 men and 180 women); Conclusions: "Were documented significant cross-sectional associations of nonalcoholic fatty liver disease and liver biomarkers with three validated indexes of HIR, with HIR index showing the stronger correlation"; QUADAS-2 Risk of Bias: The risk of bias for this study using QUADAS-2 is intermediate. Study 3 : Smith GI, Shankaran M, Yoshino M, Schweitzer GG, Chondronikola M, Beals JW, et al. 14 ; Study Design: Clinical Trial; Objective: "To (a) determine hepatic De novo lipogenesis (DNL), measured over a prolonged period (3–5 weeks) of daily deuterated water ingestion and corrected for the contribution of fatty acids made de novo in adipose tissue, in 3 distinct cohorts of individuals who were lean with normal oral glucose tolerance and normal intrahepatic triglyceride (IHTG) content (lean), obese with normal oral glucose tolerance and normal IHTG content (obese), or obese with abnormal oral glucose tolerance and NAFLD (obese-NAFLD); (b) determine the relationships among hepatic DNL and IHTG content and key factors that are probably involved in regulating DNL, namely liver and whole-body insulin sensitivity and integrated 24-hour plasma insulin and glucose concentrations; and (c) determine the effect of moderate (10%) weight loss on hepatic DNL, IHTG content, liver and whole-body insulin sensitivity, and integrated 24-hour plasma insulin and glucose concentrations"; Sample Size: 67 subjects; Participant Characteristics: Individuals who were lean (n = 14), obese with normal IHTG content (n = 26), or obese with NAFLD (n = 27); Conclusions: "The data suggest hepatic DNL is an important regulator of IHTG content and that increases in circulating glucose and insulin stimulate hepatic DNL in individuals with NAFLD. Weight loss decreased IHTG content, at least in part, by decreasing hepatic DNL"; QUADAS-2 Risk of Bias: The risk of bias for this study using QUADAS-2 is intermediate. Study 4 : Eshraghian A, Nikeghbalian S, Shamsaeefar A, Kazemi K, Fattahi MR, Malek-Hosseini SA. 15 ; Study Design: Cohort Study; Objective: "To investigate the association between serum adipokines and insulin resistance with hepatic steatosis in liver transplant recipients"; Sample Size: 178 patients; Participant Characteristics: 178 liver transplant recipients were included in the study. There were 99 men (55.6%) and 79 women (44.4%); Conclusions: "Insulin resistance and alterations in adipokines might have central role in pathogenesis of hepatic steatosis after liver transplantation and can be targeted for diagnostic and therapeutic purposes"; QUADAS-2 Risk of Bias: The risk of bias for this study using QUADAS-2 is low. Study 5 : Privitera G, Spadaro L, Alagona C, Calanna S, Piro S, Rabuazzo AM, et al. 16 ; Study Design: Cross-sectional Study; Objective: "To assess hepatic and muscle insulin resistance in NAFLD and its relationship with carotid artery intima-media thickness (IMT) and the apoB/apoAI ratio as markers of atherosclerosis"; Sample Size: 132 patients; Participant Characteristics: The study gathered 132 patients (53 male, 79 female) aged 18–70 years with a non-invasive diagnosis of NAFLD. Mean age was 45 ± 13. Study population was mainly constituted of overweight/obese patients with a mean BMI value of 34 ± 6. According to the severity of steatosis at ultrasound scan, 37% of subjects had mild steatosis, while 62% had moderate/severe steatosis; Conclusions: "The NAFLD was positively associated with carotid IMT, and this association is independent of metabolic syndrome components, but strictly related to HIR that might contribute to the development of atherosclerosis through an impairment of the lipid profile in terms of the apoB/apoAI ratio"; QUADAS-2 Risk of Bias: The risk of bias for this study using QUADAS-2 is low. Study 6 : Lomonaco R, Ortiz-Lopez C, Orsak B, Webb A, Hardies J, Darland C, et al. 17 ; Study Design: Case-control Study; Objective: "To study in depth the metabolic and histological profiles of patients with and without NAFLD"; Sample Size: 229 patients; Participant Characteristics: A total of 229 subjects: ( 1 ) lean subjects without NAFLD (207), as the gold-standard reference group for metabolic variables, and ( 2 ) control group ( 22 ) ‘‘metabolically healthy obese’’ subjects with normal adipose tissue insulin sensitivity and without NAFLD; Conclusions: "Adipose tissue IR plays a key role in the development of metabolic and histological abnormalities of obese patients with NAFLD. Treatment strategies targeting adipose tissue IR (e.g., weight loss and thiazolidinediones) may be of value in this population"; QUADAS-2 Risk of Bias: The risk of bias for this study using QUADAS-2 is low-intermediate. Study 7 : Ter Horst KW, Gilijamse PW, Versteeg RI, Ackermans MT, Nederveen AJ, la Fleur SE, et al. 18 ; Study Design: Clinical Study; Objective: "To ( 1 ) determine the relationship between liver fat content and insulin resistance using gold-standard metabolic flux measurements and ( 2 ) determine whether the subcellular distribution of individual hepatic lipid species and PKCε in liver biopsies is relevant for hepatic insulin resistance in humans"; Sample Size: 133 obese adults; Participant Characteristics: 52 subjects with normal intrahepatic triglyceride (IHTG) by proton magnetic resonance spectroscopy (1H-MRS) (no steatosis, IHTG 15%); Conclusions: "The data offer further support for the diacylglycerol-PKCε hypothesis for lipid-induced HIR in NAFLD and support the development of interventions that target hepatic diacylglycerol-induced PKCε activation for the prevention and/or treatment of T2DM"; QUADAS-2 Risk of Bias: The risk of bias for this study using QUADAS-2 is intermediate. Study 8 : Fiorentino TV, Marini MA, Succurro E, Andreozzi F, Sciacqua A, Hribal ML, et al. 19 ; Study Design: Clinical Study; Objective: "To investigate whether hemoglobin glycation index (HGI) is associated with hepatic steatosis and related biomarkers in subjects without diabetes"; Sample Size: 1,120 individuals; Participant Characteristics: 1,120 White individuals without diabetes stratified in quartiles according to HGI levels. Conclusions: "Higher levels of HGI may identify subjects without diabetes at increased risk of having hepatic steatosis"; QUADAS-2 Risk of Bias: The risk of bias for this study using QUADAS-2 is low. The summary of the included studies and related outcomes is shown in Table 1 . Table 1 Summary of the included studies Author Year Design Sample Size Objective Conclusions Risk of bias as per QUADAS-2 Gastaldelli A, et al. 12 2007 Comparative Study 57 “ To examine the relationship between visceral/hepatic fat accumulation and HIR/accelerated gluconeogenesis” “Abdominal adiposity significantly affects both lipid and glucose metabolism. Excess visceral fat primarily increases gluconeogenesis flux. Both visceral and liver fat are associated with HIR”. Intermediate to High Sesti G, et al. 13 2013 cross-sectional 473 “To examine the relationship between HIR index, nonalcoholic fatty liver disease and its biomarkers” “Were documented significant cross-sectional associations of nonalcoholic fatty liver disease and liver biomarkers with three validated indexes of HIR, with HIR index showing the stronger correlation” Intermediate Smith GI, et al. 14 2020 Clinical Trial 67 “To (a) determine hepatic De novo lipogenesis (DNL), (b) determine the relationships among hepatic DNL and IHTG content and key factors that are probably involved in regulating DNL, and (c) determine the effect of moderate (10%) weight loss on hepatic DNL, IHTG content, liver and whole-body insulin sensitivity” “The data suggest hepatic DNL is an important regulator of IHTG content and that increases in circulating glucose and insulin stimulate hepatic DNL in individuals with NAFLD. Weight loss decreased IHTG content, at least in part, by decreasing hepatic DNL”. Intermediate Eshraghian A, et al. 15 2020 Cohort Study 178 “To investigate the association between serum adipokines and insulin resistance with hepatic steatosis in liver transplant recipients” “Insulin resistance and alterations in adipokines might have central role in pathogenesis of hepatic steatosis after liver transplantation and can be targeted for diagnostic and therapeutic purposes” Low Privitera G, et al. 16 2016 Cross-sectional 132 “To assess hepatic and muscle insulin resistance in NAFLD and its relationship with carotid artery intima-media thickness (IMT) and the apoB/apoAI ratio as markers of atherosclerosis” “The NAFLD was positively associated with carotid IMT, and this association is independent of MS components, but strictly related to HIR that might contribute to the development of atherosclerosis through an impairment of the lipid profile in terms of the apoB/apoAI ratio” Low Lomonaco R, et al. 17 2012 Case-control 229 “To study in depth the metabolic and histological profiles of patients with and without NAFLD” “Adipose tissue IR plays a key role in the development of metabolic and histological abnormalities of obese patients with NAFLD. Treatment strategies targeting adipose tissue IR may be of value in this population” Low-Intermediate Ter Horst KW, et al. 18 2017 Clinical Study 133 “To ( 1 ) determine the relationship between liver fat content and insulin resistance using gold-standard metabolic flux measurements and ( 2 ) determine whether the subcellular distribution of individual hepatic lipid species and PKCε in liver biopsies is relevant for hepatic insulin resistance in humans” “The data offer further support for the diacylglycerol-PKCε hypothesis for lipid-induced HIR in NAFLD and support the development of interventions that target hepatic diacylglycerol-induced PKCε activation for the prevention and/or treatment of T2DM” Intermediate Fiorentino TV, et al. 19 2017 Clinical Study 1,120 “To investigate whether hemoglobin glycation index (HGI) is associated with hepatic steatosis and related biomarkers in subjects without diabetes” “Higher levels of HGI may identify subjects without diabetes at increased risk of having hepatic steatosis” Low DISCUSSION Our systematic review encompassing eight studies demonstrates a compelling link between MAFLD and HIR. While the association between MAFLD and HIR is well established, a definitive causal relationship between hepatic fat accumulation and HIR remains an ongoing endeavor. Nevertheless, a growing body of evidence supports the hypothesis that MAFLD precipitates HIR via the stimulation of gluconeogenesis and the activation of PKC-epsilon and JNK1. These mechanisms can potentially interfere with the tyrosine phosphorylation of IRS-1 and IRS-2, thereby impairing insulin's ability to activate glycogen synthase. 20,21 Emerging as a public health problem, MAFLD has garnered significant attention within the medicine field due to its rising prevalence linked to the escalating rates of obesity observed in recent years. 22 Beyond the well-established association with obesity, MAFLD demonstrates a strong correlation with IR. The updated diagnostic criteria for MAFLD encompass hepatic steatosis along with at least one of the following features: excess body weight/obesity, confirmed T2DM, or demonstrable evidence of metabolic dysregulation. Notably, the exclusion of alternative etiologies for liver disease, such as alcoholic hepatitis, autoimmune hepatitis, or viral hepatitis, is not mandatory for a diagnosis of MAFLD. 23 HIR stands as a hallmark characteristic of MAFLD, evident upon evaluation of insulin action using the euglycemic hyperinsulinemic clamp technique. 24 Despite this established association, the temporal sequence between HIR and hepatic fat accumulation remains a subject of debate. Two primary hypotheses have been proposed: HIR precedes fat accumulation, priming the liver for subsequent steatosis, or HIR arises as a consequence of increased hepatic fat stores. Our systematic review lends support to the latter hypothesis, suggesting that HIR is a downstream consequence of MAFLD. Mounting evidence suggests a close association between intra-abdominal visceral fat accumulation and IR in obese individuals, both non-diabetic and those diagnosed with T2DM. Visceral adiposity in obesity leads to elevated portal vein free fatty acid (FFA) concentrations, which act as a key driver of HIR. 25 Consequently, chronic exposure of the liver to high FFA levels impairs insulin signaling, promoting gluconeogenesis. Furthermore, the concomitant increase in hepatic triglycerides disrupts insulin receptor binding, ultimately culminating in the development of both MAFLD and HIR. In the first reference of our systematic review, Gastaldelli et al. 12 employed on a comparative investigation to elucidate the relationship between visceral/hepatic fat accumulation and HIR alongside accelerated gluconeogenesis. Their findings revealed that abdominal adiposity exerts an import impact on lipid and glucose metabolism, with excessive visceral fat primarily driving the upregulation of gluconeogenic flux. This evidence underscores the link between both visceral adiposity and MAFLD in the pathogenesis of HIR. The identification of disease risk has been significantly enhanced by the burgeoning field of biomarker analysis. 26 These biological biomarker offer an important advantage in the early detection of disease. They facilitate the accurate classification of disease states, enable the staging of disease progression, and potentially provide valuable insights into disease severity. In clinical practice, established markers of hepatic function, such as alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, and alkaline phosphatase, remain instrumental for screening liver diseases and assessing their severity. 27 Within the context of our systematic review, Sesti et al. 13 provided compelling evidence supporting a significant association between MAFLD and hepatic biomarkers, further demonstrating a strong correlation with HIR. The DNL has emerged as a pivotal driver in the pathogenesis of MAFLD. While FFAs liberated from adipose tissue constitute the major source of hepatic triglycerides in individuals with normal hepatic steatosis, the contribution of this pathway remains relatively constant in those with MAFLD. In contrast, hepatic DNL exhibits a marked upregulation in MAFLD patients. 28 DNL is a metabolic process that is intricately regulated by nutritional factors. The carbohydrate-rich diets have been shown to effectively counteract the impairment of hepatic lipogenesis caused by the loss of a single enzyme. This observation highlights the interplay between hepatic DNL, dietary intake, and adipocyte lipolysis in the pathogenesis of MAFLD. 29 A key finding from our systematic review, specifically the work of Smith et al. 14 , identified hepatic DNL as a critical regulator of IHTG content. This study further demonstrated that elevated circulating glucose and insulin levels act to stimulate hepatic DNL in individuals diagnosed with MAFLD. The weight loss interventions were shown to reduce IHTG content, at least partially, through a mechanism involving the downregulation of hepatic DNL, ultimately contributing to improve HIR. The MAFLD has emerged as a growing concern among liver transplant recipients. 30 The pathogenesis of MAFLD in liver transplant recipients is an intricate interplay of factors, encompassing immunosuppressive therapy, altered gut microbiota, and persistent metabolic derangements. 31 This impaired insulin action promotes hepatic lipogenesis, triglyceride accumulation, and ultimately MAFLD. In a cohort study by Eshraghian A et al. 15 , the relationship between serum adipokines and IR in liver transplant recipients with MAFLD was investigated. The study revealed that IR and adipokine alterations might have a pivotal role in the pathogenesis of post-liver transplant MAFLD, potentially serving as diagnostic and therapeutic targets. This finding contrasts with previous studies that have implicated MAFLD as a potential risk factor for the development of IR, prompting the question of whether this discrepancy is attributable to the transplanted liver and the use of immunosuppressive medications. HIR and peripheral IR are intertwined and contribute to the development of MAFLD and increased arterial intima-media thickness (IMT). Several mechanisms underlie this intricate relationship. 32 Excess visceral adipose tissue promotes both HIR and peripheral insulin resistance through the release of pro-inflammatory adipokines and FFAs. 33 These factors impair insulin signaling and glucose uptake in the liver and skeletal muscles, respectively, leading to MAFLD and impaired glucose disposal. 34 Moreover, FFAs influx into the liver triggers lipogenesis and hepatic steatosis, further exacerbating HIR. 35 The interplay between HIR and peripheral IR extends to vascular health. IR promotes endothelial dysfunction, platelet activation, and vascular inflammation, all of which contribute to atherosclerosis. 36 Additionally, MAFLD independently increases IMT through mechanisms involving oxidative stress, inflammation, and impaired endothelial function. 37 In a cross-sectional study by Privitera et al. 16 , evaluated HIR and muscle IR in MAFLD patients, investigating their relationship with carotid artery intima-media thickness (IMT) and the apolipoprotein B to apolipoprotein A-I (apoB/apoAI) ratio, both markers of atherosclerosis. The study concluded that MAFLD was independently associated with increased carotid IMT, even after adjusting for components of the metabolic syndrome. This association was specifically linked to HIR, suggesting that it may contribute to atherogenesis through a detrimental effect on the lipid profile, as evidenced by the altered apoB/apoAI ratio. Several studies have compared the metabolic and histological profiles of patients with and without MAFLD. These studies reveal metabolic abnormalities, suggesting IR as a key feature of MAFLD. Histologically, MAFLD is characterized by the accumulation of fat droplets within hepatocytes. Additionally, inflammation and fibrosis may be present in patients with MAFLD. 38 Lomonaco R, et al. 17 in a case-control study aiming to evaluate the metabolic and histological profiles of patients with and without MAFLD, demonstrated that adipose tissue IR plays a fundamental role in the development of metabolic and histological abnormalities in obese patients with MAFLD. Hepatic fat content exhibits a close correlation with both markers and direct measures of IR. Excessive FFAs influx into the liver can stem from either increased FFAs delivery from peripheral or visceral depots, or FFAs may originate from postprandial chylomicron lipolysis. Within the liver, the accumulation of triglycerides can result from impaired hepatic FFAs oxidation or enhanced FFAs uptake and triglyceride synthesis. The coexistence of MAFLD and IR highlights the latter's role as a precursor to T2DM, while MAFLD itself elevates the risk of cirrhosis. HIR maintains a tight association with hepatic fat content. 39 These findings are consistent with the results of our systematic review. 18 The interplay between hemoglobin glycation index (HGI), HIR, and MAFLD has emerged as a pivotal area of interest in the field of metabolic disease. Elevated HbA1c reflects chronic hyperglycemia and is associated with increased hepatic glucose production and gluconeogenesis, which in turn exacerbate HIR. 40,41 This sequence of events contributes to the accumulation of lipids within the liver, ultimately promoting the development of MAFLD. 42 Moreover, intricate molecular pathways involving pro-inflammatory cytokines and insulin signaling further solidify the relationship between HGI, HIR, and MAFLD. Fiorentino et al. 19 in a large-sample study investigating the association between hemoglobin glycation index (HGI) and MAFLD and related biomarkers in non-diabetic individuals, demonstrated that higher HGI levels can identify non-diabetic individuals at increased risk of MAFLD and consequently HIR. A growing body of evidence from systematic reviews and individual studies has consistently demonstrated an association between MAFLD and HIR. This link highlights MAFLD's significance as a potential risk factor for the development of HIR, underscoring the intricate interplay between metabolic dysregulation and hepatic dysfunction. Several mechanisms contribute to the association between MAFLD and HIR. Excess intrahepatic fat accumulation, disrupts insulin signaling pathways within hepatocytes, leading to impaired insulin sensitivity and the development of HIR. This impaired insulin action subsequently disrupts lipid metabolism, promoting increased hepatic triglyceride synthesis and decreased lipoprotein secretion, further exacerbating MAFLD. Furthermore, the pro-inflammatory milieu associated with MAFLD plays a pivotal role in the development of HIR. CONCLUSION Our systematic review demonstrated a consistently demonstrated association between MAFLD and HIR. This association has been supported by findings from various studies, highlighting the significance of MAFLD as a potential risk factor for the development of HIR. 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Privitera G, Spadaro L, Alagona C, Calanna S, Piro S, Rabuazzo AM, et al. Hepatic insulin resistance in NAFLD: relationship with markers of atherosclerosis and metabolic syndrome components. Acta Diabetol. 2016;53(3):449-59. Lomonaco R, Ortiz-Lopez C, Orsak B, Webb A, Hardies J, Darland C, et al. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology. 2012;55(5):1389-97. Ter Horst KW, Gilijamse PW, Versteeg RI, Ackermans MT, Nederveen AJ, la Fleur SE, et al. Hepatic Diacylglycerol-Associated Protein Kinase Cε Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans. Cell Rep. 2017;19(10):1997-2004. Fiorentino TV, Marini MA, Succurro E, Andreozzi F, Sciacqua A, Hribal ML, et al. Association between hemoglobin glycation index and hepatic steatosis in non-diabetic individuals. Diabetes Res Clin Pract. 2017;134:53-61. Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, et al. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem. 2004;279(31):32345-53. Sakurai Y, Kubota N, Yamauchi T, Kadowaki T. Role of Insulin Resistance in MAFLD. Int J Mol Sci. 2021;22(8):4156. Sangro P, de la Torre Aláez M, Sangro B, D'Avola D. Metabolic dysfunction-associated fatty liver disease (MAFLD): an update of the recent advances in pharmacological treatment. J Physiol Biochem. 2023;79(4):869-879. Alharthi J, Gastaldelli A, Cua IH, Ghazinian H, Eslam M. Metabolic dysfunction-associated fatty liver disease: a year in review. Curr Opin Gastroenterol. 2022;38(3):251-260. Socha P, Wierzbicka A, Neuhoff-Murawska J, Włodarek D, Podleśny J, Socha J. Nonalcoholic fatty liver disease as a feature of the metabolic syndrome. Rocz Panstw Zakl Hig. 2007;58(1):129-37. Miyazaki Y, Glass L, Triplitt C, Wajcberg E, Mandarino LJ, DeFronzo RA. Abdominal fat distribution and peripheral and hepatic insulin resistance in type 2 diabetes mellitus. Am J Physiol Endocrinol Metab. 2002;283(6):E1135-43. Neuman MG, Cohen LB, Nanau RM. Biomarkers in nonalcoholic fatty liver disease. Can J Gastroenterol Hepatol. 2014;28(11):607-18. Vos MB, Abrams SH, Barlow SE, Caprio S, Daniels SR, Kohli R, et al. NASPGHAN Clinical Practice Guideline for the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease in Children: Recommendations from the Expert Committee on NAFLD (ECON) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). J Pediatr Gastroenterol Nutr. 2017;64(2):319-334. Softic S, Cohen DE, Kahn CR. Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease. Dig Dis Sci. 2016;61(5):1282-93. Postic C, Girard J. The role of the lipogenic pathway in the development of hepatic steatosis. Diabetes Metab. 2008;34(6 Pt 2):643-8. Shetty A, Giron F, Divatia MK, Ahmad MI, Kodali S, Victor D. Nonalcoholic Fatty Liver Disease after Liver Transplant. J Clin Transl Hepatol. 2021;9(3):428-435. Watt KD. Metabolic syndrome: is immunosuppression to blame? Liver Transpl. 2011;17 Suppl 3:S38-42. Kim SK, Choi YJ, Huh BW, Park SW, Lee EJ, Cho YW, et al. Nonalcoholic Fatty liver disease is associated with increased carotid intima-media thickness only in type 2 diabetic subjects with insulin resistance. J Clin Endocrinol Metab. 2014;99(5):1879-84. Saponaro C, Sabatini S, Gaggini M, Carli F, Rosso C, Positano V, et al. Adipose tissue dysfunction and visceral fat are associated with hepatic insulin resistance and severity of NASH even in lean individuals. Liver Int. 2022;42(11):2418-2427. Lee WH, Najjar SM, Kahn CR, Hinds TD Jr. Hepatic insulin receptor: new views on the mechanisms of liver disease. Metabolism. 2023;145:155607. Wang JH, Hwang SJ, Lim DW, Son CG. Cynanchum atratum Alleviates Non-Alcoholic Fatty Liver by Balancing Lipogenesis and Fatty Acid Oxidation in a High-Fat, High-Fructose Diet Mice Model. Cells. 2021;11(1):23. Kaur R, Kaur M, Singh J. Endothelial dysfunction and platelet hyperactivity in type 2 diabetes mellitus: molecular insights and therapeutic strategies. Cardiovasc Diabetol. 2018;17(1):121. Cao Y, Li L. Relationship of non-alcoholic steatohepatitis with arterial endothelial function and atherosclerosis]. Zhonghua Gan Zang Bing Za Zhi. 2014;22(3):205-8. Cotrim HP, Parise ER, Oliveira CP, Leite N, Martinelli A, Galizzi J, et al. Nonalcoholic fatty liver disease in Brazil. Clinical and histological profile. Ann Hepatol. 2011;10(1):33-7. Utzschneider KM, Kahn SE, Polidori DC. Hepatic Insulin Extraction in NAFLD Is Related to Insulin Resistance Rather Than Liver Fat Content. J Clin Endocrinol Metab. 2019;104(5):1855-1865. Müller N, Lehmann T, Müller UA, Kloos C. Is there an HbA1c Threshold for Symptoms of Chronic Hyperglycemia? Exp Clin Endocrinol Diabetes. 2022;130(6):386-392. Del Prato S, Matsuda M, Simonson DC, Groop LC, Sheehan P, Leonetti F, et al. Studies on the mass action effect of glucose in NIDDM and IDDM: evidence for glucose resistance. Diabetologia. 1997;40(6):687-97. Kolluru K, Giri A, Kumar S, Acharya S, Agrawal S, Wanjari A, et al. Association of Metabolic-Associated Fatty Liver Disease With Various Anthropometric Parameters in Pre-diabetes in Comparison With Diabetes and Control: A Single Tertiary Care Center Study. Cureus. 2022;14(7):e27130. Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4739938","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":326833340,"identity":"8500e359-7d75-453f-9830-1a51e1b67fda","order_by":0,"name":"Luís Jesuino de Oliveira Andrade","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAElEQVRIiWNgGAWjYBACPgbGBgYGHiCLGYg/MDAkwGQScOhgYEPWwjiDOC1IgJmHKC0Syc0fGGRs7A2O8x58bNtml8fP3sD44WMOQ555Ay4tiW0SDDxpiRsO8yUb57YlF0v2HGCWnLmNoVjmAG4tQL8cTjA4zGMmndvGnLjhRgIbM+82hsQZOB2WCHQYz397sBbLtnqitDQAHXaAcQNIC2PbYSK08DwE+SU5ceZhHmPDnnPHE2f2HGwG+kWiWAKHFn729McfGHvs7PnOnzF88KOsOrGfvfngh4/bbPJwaQEB5r89UBYjOJpAkcuATwMI/IAx/hBQOApGwSgYBSMSAAAthFHtBhERUQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-7714-0330","institution":"Department of Health Sciences, Santa Cruz State University, Ilhéus, Bahia, Brazil","correspondingAuthor":true,"prefix":"","firstName":"Luís","middleName":"Jesuino de Oliveira","lastName":"Andrade","suffix":""},{"id":326833341,"identity":"71d22f64-1420-49da-a0b0-5c78e16ac0f6","order_by":1,"name":"Gabriela Correia Matos de Oliveira","email":"","orcid":"https://orcid.org/0000-0002-8042-0261","institution":"Family Health Progam, Salvador, Bahia, Brazil.","correspondingAuthor":false,"prefix":"","firstName":"Gabriela","middleName":"Correia Matos","lastName":"de Oliveira","suffix":""},{"id":326833342,"identity":"6bc48d51-5f25-4966-a9fb-92ac028cdbb3","order_by":2,"name":"Luis Matos de Oliveira","email":"","orcid":"https://orcid.org/0000-0003-4854-6910","institution":"Bahiana School of Medicine and Public Health - Salvador - Bahia - Brazil.","correspondingAuthor":false,"prefix":"","firstName":"Luis","middleName":"Matos","lastName":"de Oliveira","suffix":""}],"badges":[],"createdAt":"2024-07-14 22:59:33","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-4739938/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4739938/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60430321,"identity":"83c932f1-2f53-425c-b1d8-5f45776e28ea","added_by":"auto","created_at":"2024-07-16 16:18:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":59001,"visible":true,"origin":"","legend":"\u003cp\u003ePotential mechanisms of MAFLD\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4739938/v1/fcddfec2498eedac01cfddec.png"},{"id":60430322,"identity":"86db318c-8781-40a3-9f7f-85511ce52a1e","added_by":"auto","created_at":"2024-07-16 16:18:39","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":109834,"visible":true,"origin":"","legend":"\u003cp\u003eLiterature screening flowchart\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4739938/v1/e18064611db2a7a834eb7430.png"},{"id":60430324,"identity":"d837c1c3-32cb-4d8c-a81e-e70964fddcbe","added_by":"auto","created_at":"2024-07-16 16:18:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":699968,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4739938/v1/aa3c7f90-6d0f-4a52-9e3e-c326f86c22a1.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eMetabolic-Dysfunction-Associated Fatty Liver Disease and Hepatic Insulin Resistance: A Type 2 Diabetes Mellitus-like in the liver -\u003c/strong\u003e \u003cstrong\u003eA Systematic Review\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eMetabolic dysfunction-associated fatty liver disease (MAFLD) comes up as a prominent issue within the realm of chronic liver pathologies on a global scale, affecting an estimated one-fourth of the world's populace.\u003csup\u003e1\u003c/sup\u003e Diagnosis relies on the detection of hepatic steatosis, characterized by the abnormal buildup of lipids in the liver tissue. The diagnosis of MAFLD necessitates the presence of overweight/obesity, confirmed type 2 diabetes mellitus (T2DM), or observable signs of metabolic dysregulation, alongside the absence of significant alcohol intake. The etiology of MAFLD remains incompletely understood, likely due to a multifaceted interplay of various factors.\u003csup\u003e2\u003c/sup\u003e Current knowledge indicates that insulin resistance (IR), oxidative stress, and inflammatory pathways collectively contribute to the pathological progression of the disease.\u003csup\u003e3\u003c/sup\u003e The clinical presentation of MAFLD encompasses a wide spectrum, ranging from a benign, asymptomatic state to a more severe manifestation termed non-alcoholic steatohepatitis. This latter variant carries a significant risk of progression to cirrhosis, liver failure, and even hepatocellular carcinoma.\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe IR, a hallmark of metabolic syndrome and a precursor to T2DM, is characterized by the impaired ability of target tissues, primarily skeletal muscle, liver, and adipose tissue, to respond to insulin's signaling.\u003csup\u003e5\u003c/sup\u003e This hormonal discordance disrupts glucose uptake, leading to elevated blood glucose levels. The intricate pathophysiological pathways of IR encompass a myriad of factors, including genetic susceptibility, lifestyle determinants, and inflammatory cascades.\u003csup\u003e6\u003c/sup\u003e The heightened abdominal adiposity, a pivotal contributor to insulin resistance, triggers the secretion of pro-inflammatory cytokines and free fatty acids, eliciting detrimental effects on insulin signaling transduction. Additionally, genetic variations influence insulin receptor sensitivity and intracellular signaling cascades.\u003csup\u003e7\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHepatic IR (HIR) is an important aspect of metabolic dysfunction, serving as a primary driver of dysregulated glucose homeostasis. Marked by dysfunctional insulin signaling cascades in hepatocytes, this phenomenon plays a crucial role in the pathogenesis of T2DM.\u003csup\u003e8\u003c/sup\u003e This particular type of IR can be seen as a focal representation of diabetes mellitus, termed in situ T2DM, wherein the liver loses its responsiveness to insulin's typical functions.\u003csup\u003e9\u003c/sup\u003e The disruption of hepatic glucose output and lipid processing amplifies systemic IR, underscoring the intricate connections between hepatic performance and overall metabolic well-being in the genesis of T2DM.\u003c/p\u003e \u003cp\u003eMAFLD and HIR, T2DM-like in the liver, exhibit a complex interplay in the pathogenesis of metabolic disorders (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo evaluate the current understanding of the intricate relationship between MAFLD and HIR, we conducted a systematic review with the aim of evaluating this relationship.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eTo uphold the principles of transparency and methodological rigor, our systematic review protocol was prospectively submitted on the International Prospective Register of Systematic Reviews (PROSPERO). This publicly accessible registration serves as a comprehensive documentation of the research planning strategy, inclusion/exclusion criteria, and data extraction methods employed throughout the review process. Furthermore, we adhered to the established guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) throughout the review process.\u003csup\u003e10\u003c/sup\u003e This ensured that the review was conducted in a transparent, replicable, and rigorous manner, encompassing all relevant studies that comprehensively investigated the association between MAFLD and HIR.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eLiterature Search Strategy: A Comprehensive Approach to Identify Relevant Studies\u003c/h2\u003e \u003cp\u003eTo identify relevant studies published between January 1998 and July 2024, a comprehensive search was conducted across electronic databases, including PubMed, Web of Science, Scopus, Embase, and Cochrane Central. The search strategy employed a combination of controlled vocabulary and free-text terms related to MAFLD and HIR. Boolean operators (AND, OR, NOT) were utilized to refine the search strategy and ensure the retrieval of relevant studies. Specific search terms and variations included: \u003cb\u003ePubmed\u003c/b\u003e = ((\"fatty liver\"[MeSH Terms] OR (\"fatty\"[All Fields] AND \"liver\"[All Fields]) OR \"fatty liver\"[All Fields] OR (\"hepatic\"[All Fields] AND \"steatosis\"[All Fields]) OR \"hepatic steatosis\"[All Fields]) OR (\"fatty liver\"[KYWD] OR (\"fatty\"[All Fields] AND \"liver\"[All Fields]) OR \"fatty liver\"[All Fields] OR (\"hepatic\"[All Fields] AND \"steatosis\"[All Fields]) OR \"hepatic steatosis\"[All Fields])) AND \"hepatic insulin resistance\"[All Fields]. \u003cb\u003eWeb of Science\u003c/b\u003e = (TS=(fatty liver) AND TS-(fatty)) OR (TS =(fatty liver) AND (TH=(hepatic) AND (TS\u0026thinsp;=\u0026thinsp;steatosis) AND (TS=(hepatic steatosis) AND (TS=(fatty liver) OR (TSH=(fatty) AND (TS=(liver) OR (TSH=(fatty liver) AND (TS=(hepatic) AND (TS=(steatosis) OR (TS=(hepatic steatosis) AND (TS=(hepatic insulin resistance))). \u003cb\u003eScopus\u003c/b\u003e: (TITLE-ABS-KEY (\"fatty liver\") AND TITLE-ABS-KEY (\"liver\")) OR TITLE-ABS-KEY (\"fatty liver\") AND TITLE-ABS-KEY (\"hepatic insulin resistance\") OR (\"steatosis\"))). \u003cb\u003eEmbase\u003c/b\u003e: \u0026lsquo;fatty liver\u0026rsquo;/exp AND (\u0026lsquo;hepatic insulin resistance\u0026rsquo; /exp OR \u0026lsquo;hepatic steatosis\u0026rsquo; OR \u0026lsquo;liver\u0026rsquo; /exp \u0026lsquo;hepatic insulin resistance\u0026rsquo; OR \u0026lsquo;steatosis\u0026rsquo; / exp OR \u0026lsquo;hepatic insulin resistance\u0026rsquo; /exp). \u003cb\u003eCochrane Central\u003c/b\u003e: ((\"fatty liver\") OR (\"fatty\") AND \"liver\") OR \"fatty liver\" OR (\"hepatic\" AND \"steatosis\") OR \"hepatic steatosis\") OR (\"fatty liver\" OR (\"fatty\" AND \"liver\") OR \"fatty liver\" OR (\"hepatic\" AND \"steatosis\") OR \"hepatic steatosis)) AND \"hepatic insulin resistance\".\u003c/p\u003e \u003cp\u003eRefinement Strategy: Boolean operators (AND, OR, NOT) were used to combine and refine the search terms, ensuring a precise and comprehensive retrieval of relevant studies.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eInclusion and Exclusion Criteria\u003c/h2\u003e \u003cp\u003eTo ensure the inclusion of relevant and high-quality studies, the following inclusion and exclusion criteria were applied:\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eInclusion Criteria:\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eOriginal Research Articles: Studies were included if they were original research articles published in peer-reviewed journals.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eHuman Focus: Studies had to focus on human subjects to be considered eligible.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eMAFLD-HIR Relationship Investigation: The primary focus of the study had to be the investigation of the association between MAFLD and HIR.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eQuantitative Data Reporting: Studies were required to report quantitative data on the relationship between MAFLD and HIR, relevant biomarkers, or pathological markers for MAFLD or HIR.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eExclusion Criteria:\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eNon-Research Articles: Review articles, editorials, commentaries, case reports, and abstracts without sufficient data were excluded.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eLimited Scope: Studies that solely examined the peripheral metabolic effects without assessing outcomes related to the MAFLD-HIR association were excluded.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eData Extraction and Bias Assessment\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eUpon identification of eligible studies, the next step involved meticulously extracting relevant data from each study. This entailed capturing key information such as study characteristics, participant demographics, HIR parameters, and methodological details. The extracted data served as the foundation for subsequent analyses.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eTo ensure the robustness of the review, a rigorous bias assessment was conducted for each included study. This process involved scrutinizing the study design, sample size, potential sources of confounding, and other factors that could influence the validity of the findings. The assessment aimed to identify and address any potential biases that might have impacted the results.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003eSynthesizing Data and Calculating Effect Sizes\u003c/h2\u003e \u003cp\u003eThe extracted data were meticulously synthesized and analyzed using appropriate statistical methods. This involved combining data from similar studies and employing statistical techniques to calculate effect sizes. Effect sizes represent the magnitude and direction of the association between MAFLD and HIR, providing a quantitative measure of the strength of the relationship.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003eInterpreting Results and Drawing Conclusions\u003c/h3\u003e\n\u003cp\u003eOnce the data were synthesized and analyzed, the results of the systematic review were carefully interpreted. This involved examining the patterns and trends observed in the data, considering the effect sizes, and evaluating the overall strength of evidence. Based on the comprehensive analysis, well-supported conclusions were drawn regarding the association between MAFLD and hepatic insulin resistance.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eBias Assessment Tool\u003c/h2\u003e \u003cp\u003eTo ensure the rigor and transparency of the bias assessment process, the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool was employed.\u003csup\u003e11\u003c/sup\u003e QUADAS-2 is a widely recognized and validated tool specifically designed to assess the risk of bias in studies evaluating diagnostic accuracy. The tool comprises four domains: patient selection, index test, reference test, and flow and timing. Each domain is further divided into signal criteria, which are assessed as present, absent, unclear, or not applicable. The overall risk of bias for each study is categorized as low, moderate, high, or unclear based on the assessment of all four domains.\u003c/p\u003e \u003cp\u003eBy utilizing QUADAS-2, the systematic review ensured that potential biases were systematically identified, evaluated, and accounted for, enhancing the credibility and trustworthiness of the findings.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 211 articles were initially identified through the electronic database search. These articles were then subjected to initial screening based on title and abstract to assess their relevance to the research question. Duplicates were removed using specialized software, resulting in a pool of 129 unique articles. The remaining 129 articles were further scrutinized through a thorough review of their full texts. This rigorous assessment involved evaluating the study design, methodology, data collection, and findings to determine their eligibility for inclusion in the systematic review. Articles that met the pre-defined inclusion criteria and provided relevant data on the association between MAFLD and HIR were selected for further analysis. After careful consideration, 8 studies were deemed to meet the stringent inclusion criteria and were subsequently selected for data extraction and analysis. These studies represent the core body of evidence that underpins the findings of this systematic review (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe eight studies selected for this systematic review embarked on a diverse journey to investigate the intricate relationship between MAFLD and HIR. These studies, hailing from various corners of the globe, employed a range of methodologies to shed light on this complex association. The sample sizes of the included studies varied considerably, ranging from 57 to 1,120 participants. This spectrum of sample sizes allowed for the examination of the association across a broad range of study settings and populations, enhancing the generalizability of the findings.\u003c/p\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of Studies\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eStudy 1\u003c/b\u003e: Gastaldelli A, Cusi K, Pettiti M, Hardies J, Miyazaki Y, Berria R, et al.\u003csup\u003e12\u003c/sup\u003e; Study Design: Comparative Study; Objective: To examine the relationship between visceral/hepatic fat accumulation and HIR/accelerated gluconeogenesis; Sample Size: 57 subjects; Participant Characteristics: 14 normal glucose tolerant (body mass index [BMI]\u0026thinsp;=\u0026thinsp;25 +/- 1 kg/m(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)) and 43 T2DM (24 nonobese, BMI\u0026thinsp;=\u0026thinsp;26 +/- 1; 19 obese, BMI\u0026thinsp;=\u0026thinsp;32 +/- 1 kg/m(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)) subjects. Conclusions: \"Abdominal adiposity significantly affects both lipid and glucose metabolism. Excess visceral fat primarily increases gluconeogenesis flux. Both visceral and liver fat are associated with HIR\"; QUADAS-2 Risk of Bias: The risk of bias for this study using QUADAS-2 is intermediate to high.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eStudy 2\u003c/b\u003e: Sesti G, Fiorentino TV, Hribal ML, Sciacqua A, Perticone F.\u003csup\u003e13\u003c/sup\u003e; Study Design: cross-sectional study; Objective: To examine the relationship between HIR index, nonalcoholic fatty liver disease and its biomarkers (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, alkaline phosphatase, high-sensitive C reactive protein, insulin-like growth factor-1; Sample Size: 473 subjects; Participant Characteristics: 473 Caucasians subjects (293 men and 180 women); Conclusions: \"Were documented significant cross-sectional associations of nonalcoholic fatty liver disease and liver biomarkers with three validated indexes of HIR, with HIR index showing the stronger correlation\"; QUADAS-2 Risk of Bias: The risk of bias for this study using QUADAS-2 is intermediate.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eStudy 3\u003c/b\u003e: Smith GI, Shankaran M, Yoshino M, Schweitzer GG, Chondronikola M, Beals JW, et al.\u003csup\u003e14\u003c/sup\u003e; Study Design: Clinical Trial; Objective: \"To (a) determine hepatic De novo lipogenesis (DNL), measured over a prolonged period (3\u0026ndash;5 weeks) of daily deuterated water ingestion and corrected for the contribution of fatty acids made de novo in adipose tissue, in 3 distinct cohorts of individuals who were lean with normal oral glucose tolerance and normal intrahepatic triglyceride (IHTG) content (lean), obese with normal oral glucose tolerance and normal IHTG content (obese), or obese with abnormal oral glucose tolerance and NAFLD (obese-NAFLD); (b) determine the relationships among hepatic DNL and IHTG content and key factors that are probably involved in regulating DNL, namely liver and whole-body insulin sensitivity and integrated 24-hour plasma insulin and glucose concentrations; and (c) determine the effect of moderate (10%) weight loss on hepatic DNL, IHTG content, liver and whole-body insulin sensitivity, and integrated 24-hour plasma insulin and glucose concentrations\"; Sample Size: 67 subjects; Participant Characteristics: Individuals who were lean (n\u0026thinsp;=\u0026thinsp;14), obese with normal IHTG content (n\u0026thinsp;=\u0026thinsp;26), or obese with NAFLD (n\u0026thinsp;=\u0026thinsp;27); Conclusions: \"The data suggest hepatic DNL is an important regulator of IHTG content and that increases in circulating glucose and insulin stimulate hepatic DNL in individuals with NAFLD. Weight loss decreased IHTG content, at least in part, by decreasing hepatic DNL\"; QUADAS-2 Risk of Bias: The risk of bias for this study using QUADAS-2 is intermediate.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eStudy 4\u003c/b\u003e: Eshraghian A, Nikeghbalian S, Shamsaeefar A, Kazemi K, Fattahi MR, Malek-Hosseini SA.\u003csup\u003e15\u003c/sup\u003e; Study Design: Cohort Study; Objective: \"To investigate the association between serum adipokines and insulin resistance with hepatic steatosis in liver transplant recipients\"; Sample Size: 178 patients; Participant Characteristics: 178 liver transplant recipients were included in the study. There were 99 men (55.6%) and 79 women (44.4%); Conclusions: \"Insulin resistance and alterations in adipokines might have central role in pathogenesis of hepatic steatosis after liver transplantation and can be targeted for diagnostic and therapeutic purposes\"; QUADAS-2 Risk of Bias: The risk of bias for this study using QUADAS-2 is low.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eStudy 5\u003c/b\u003e: Privitera G, Spadaro L, Alagona C, Calanna S, Piro S, Rabuazzo AM, et al.\u003csup\u003e16\u003c/sup\u003e; Study Design: Cross-sectional Study; Objective: \"To assess hepatic and muscle insulin resistance in NAFLD and its relationship with carotid artery intima-media thickness (IMT) and the apoB/apoAI ratio as markers of atherosclerosis\"; Sample Size: 132 patients; Participant Characteristics: The study gathered 132 patients (53 male, 79 female) aged 18\u0026ndash;70 years with a non-invasive diagnosis of NAFLD. Mean age was 45\u0026thinsp;\u0026plusmn;\u0026thinsp;13. Study population was mainly constituted of overweight/obese patients with a mean BMI value of 34\u0026thinsp;\u0026plusmn;\u0026thinsp;6. According to the severity of steatosis at ultrasound scan, 37% of subjects had mild steatosis, while 62% had moderate/severe steatosis; Conclusions: \"The NAFLD was positively associated with carotid IMT, and this association is independent of metabolic syndrome components, but strictly related to HIR that might contribute to the development of atherosclerosis through an impairment of the lipid profile in terms of the apoB/apoAI ratio\"; QUADAS-2 Risk of Bias: The risk of bias for this study using QUADAS-2 is low.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eStudy 6\u003c/b\u003e: Lomonaco R, Ortiz-Lopez C, Orsak B, Webb A, Hardies J, Darland C, et al.\u003csup\u003e17\u003c/sup\u003e; Study Design: Case-control Study; Objective: \"To study in depth the metabolic and histological profiles of patients with and without NAFLD\"; Sample Size: 229 patients; Participant Characteristics: A total of 229 subjects: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) lean subjects without NAFLD (207), as the gold-standard reference group for metabolic variables, and (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) control group (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) \u0026lsquo;\u0026lsquo;metabolically healthy obese\u0026rsquo;\u0026rsquo; subjects with normal adipose tissue insulin sensitivity and without NAFLD; Conclusions: \"Adipose tissue IR plays a key role in the development of metabolic and histological abnormalities of obese patients with NAFLD.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eTreatment strategies targeting adipose tissue IR (e.g., weight loss and thiazolidinediones) may be of value in this population\"; QUADAS-2 Risk of Bias: The risk of bias for this study using QUADAS-2 is low-intermediate.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eStudy 7\u003c/b\u003e: Ter Horst KW, Gilijamse PW, Versteeg RI, Ackermans MT, Nederveen AJ, la Fleur SE, et al.\u003csup\u003e18\u003c/sup\u003e; Study Design: Clinical Study; Objective: \"To (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) determine the relationship between liver fat content and insulin resistance using gold-standard metabolic flux measurements and (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) determine whether the subcellular distribution of individual hepatic lipid species and PKCε in liver biopsies is relevant for hepatic insulin resistance in humans\"; Sample Size: 133 obese adults; Participant Characteristics: 52 subjects with normal intrahepatic triglyceride (IHTG) by proton magnetic resonance spectroscopy (1H-MRS) (no steatosis, IHTG\u0026thinsp;\u0026lt;\u0026thinsp;5.56%; 81 subjects with 1H-MRS-defined hepatic steatosis, 41 subjects had mild steatosis (IHTG 5.56\u0026ndash;15%), and 40 subjects had severe steatosis (IHTG\u0026thinsp;\u0026gt;\u0026thinsp;15%); Conclusions: \"The data offer further support for the diacylglycerol-PKCε hypothesis for lipid-induced HIR in NAFLD and support the development of interventions that target hepatic diacylglycerol-induced PKCε activation for the prevention and/or treatment of T2DM\"; QUADAS-2 Risk of Bias: The risk of bias for this study using QUADAS-2 is intermediate.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eStudy 8\u003c/b\u003e: Fiorentino TV, Marini MA, Succurro E, Andreozzi F, Sciacqua A, Hribal ML, et al.\u003csup\u003e19\u003c/sup\u003e; Study Design: Clinical Study; Objective: \"To investigate whether hemoglobin glycation index (HGI) is associated with hepatic steatosis and related biomarkers in subjects without diabetes\"; Sample Size: 1,120 individuals; Participant Characteristics: 1,120 White individuals without diabetes stratified in quartiles according to HGI levels. Conclusions: \"Higher levels of HGI may identify subjects without diabetes at increased risk of having hepatic steatosis\"; QUADAS-2 Risk of Bias: The risk of bias for this study using QUADAS-2 is low.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eThe summary of the included studies and related outcomes is shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of the included studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYear\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDesign\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSample Size\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eObjective\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eConclusions\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRisk of bias as per QUADAS-2\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastaldelli A, et al.\u003csup\u003e12\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eComparative Study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ldquo; To examine the relationship between visceral/hepatic fat accumulation and HIR/accelerated gluconeogenesis\u0026rdquo;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ldquo;Abdominal adiposity significantly affects both lipid and glucose metabolism. Excess visceral fat primarily increases gluconeogenesis flux. Both visceral and liver fat are associated with HIR\u0026rdquo;.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIntermediate to High\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSesti G, et al.\u003csup\u003e13\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ecross-sectional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e473\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ldquo;To examine the relationship between HIR index, nonalcoholic fatty liver disease and its biomarkers\u0026rdquo;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ldquo;Were documented significant cross-sectional associations of nonalcoholic fatty liver disease and liver biomarkers with three validated indexes of HIR, with HIR index showing the stronger correlation\u0026rdquo;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIntermediate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmith GI, et al.\u003csup\u003e14\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eClinical Trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ldquo;To (a) determine hepatic De novo lipogenesis (DNL), (b) determine the relationships among hepatic DNL and IHTG content and key factors that are probably involved in regulating DNL, and (c) determine the effect of moderate (10%) weight loss on hepatic DNL, IHTG content, liver and whole-body insulin sensitivity\u0026rdquo;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ldquo;The data suggest hepatic DNL is an important regulator of IHTG content and that increases in circulating glucose and insulin stimulate hepatic DNL in individuals with NAFLD. Weight loss decreased IHTG content, at least in part, by decreasing hepatic DNL\u0026rdquo;.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIntermediate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEshraghian A, et al.\u003csup\u003e15\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort Study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e178\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ldquo;To investigate the association between serum adipokines and insulin resistance with hepatic steatosis in liver transplant recipients\u0026rdquo;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ldquo;Insulin resistance and alterations in adipokines might have central role in pathogenesis of hepatic steatosis after liver transplantation and can be targeted for diagnostic and therapeutic purposes\u0026rdquo;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrivitera G, et al.\u003csup\u003e16\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCross-sectional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e132\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ldquo;To assess hepatic and muscle insulin resistance in NAFLD and its relationship with carotid artery intima-media thickness (IMT) and the apoB/apoAI ratio as markers of atherosclerosis\u0026rdquo;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ldquo;The NAFLD was positively associated with carotid IMT, and this association is independent of MS components, but strictly related to HIR that might contribute to the development of atherosclerosis through an impairment of the lipid profile in terms of the apoB/apoAI ratio\u0026rdquo;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLomonaco R, et al.\u003csup\u003e17\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e229\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ldquo;To study in depth the metabolic and histological profiles of patients with and without NAFLD\u0026rdquo;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ldquo;Adipose tissue IR plays a key role in the development of metabolic and histological abnormalities of obese patients with NAFLD. Treatment strategies targeting adipose tissue IR may be of value in this population\u0026rdquo;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow-Intermediate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTer Horst KW, et al.\u003csup\u003e18\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eClinical Study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e133\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ldquo;To (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) determine the relationship between liver fat content and insulin resistance using gold-standard metabolic flux measurements and (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) determine whether the subcellular distribution of individual hepatic lipid species and PKCε in liver biopsies is relevant for hepatic insulin resistance in humans\u0026rdquo;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ldquo;The data offer further support for the diacylglycerol-PKCε hypothesis for lipid-induced HIR in NAFLD and support the development of interventions that target hepatic diacylglycerol-induced PKCε activation for the prevention and/or treatment of T2DM\u0026rdquo;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIntermediate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFiorentino TV, et al.\u003csup\u003e19\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eClinical Study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1,120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ldquo;To investigate whether hemoglobin glycation index (HGI) is associated with hepatic steatosis and related biomarkers in subjects without diabetes\u0026rdquo;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026ldquo;Higher levels of HGI may identify subjects without diabetes at increased risk of having hepatic steatosis\u0026rdquo;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eOur systematic review encompassing eight studies demonstrates a compelling link between MAFLD and HIR. While the association between MAFLD and HIR is well established, a definitive causal relationship between hepatic fat accumulation and HIR remains an ongoing endeavor. Nevertheless, a growing body of evidence supports the hypothesis that MAFLD precipitates HIR via the stimulation of gluconeogenesis and the activation of PKC-epsilon and JNK1. These mechanisms can potentially interfere with the tyrosine phosphorylation of IRS-1 and IRS-2, thereby impairing insulin's ability to activate glycogen synthase.\u003csup\u003e20,21\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eEmerging as a public health problem, MAFLD has garnered significant attention within the medicine field due to its rising prevalence linked to the escalating rates of obesity observed in recent years.\u003csup\u003e22\u003c/sup\u003e Beyond the well-established association with obesity, MAFLD demonstrates a strong correlation with IR. The updated diagnostic criteria for MAFLD encompass hepatic steatosis along with at least one of the following features: excess body weight/obesity, confirmed T2DM, or demonstrable evidence of metabolic dysregulation. Notably, the exclusion of alternative etiologies for liver disease, such as alcoholic hepatitis, autoimmune hepatitis, or viral hepatitis, is not mandatory for a diagnosis of MAFLD.\u003csup\u003e23\u003c/sup\u003e HIR stands as a hallmark characteristic of MAFLD, evident upon evaluation of insulin action using the euglycemic hyperinsulinemic clamp technique.\u003csup\u003e24\u003c/sup\u003e Despite this established association, the temporal sequence between HIR and hepatic fat accumulation remains a subject of debate. Two primary hypotheses have been proposed: HIR precedes fat accumulation, priming the liver for subsequent steatosis, or HIR arises as a consequence of increased hepatic fat stores. Our systematic review lends support to the latter hypothesis, suggesting that HIR is a downstream consequence of MAFLD.\u003c/p\u003e \u003cp\u003eMounting evidence suggests a close association between intra-abdominal visceral fat accumulation and IR in obese individuals, both non-diabetic and those diagnosed with T2DM. Visceral adiposity in obesity leads to elevated portal vein free fatty acid (FFA) concentrations, which act as a key driver of HIR.\u003csup\u003e25\u003c/sup\u003e Consequently, chronic exposure of the liver to high FFA levels impairs insulin signaling, promoting gluconeogenesis. Furthermore, the concomitant increase in hepatic triglycerides disrupts insulin receptor binding, ultimately culminating in the development of both MAFLD and HIR. In the first reference of our systematic review, Gastaldelli et al.\u003csup\u003e12\u003c/sup\u003e employed on a comparative investigation to elucidate the relationship between visceral/hepatic fat accumulation and HIR alongside accelerated gluconeogenesis. Their findings revealed that abdominal adiposity exerts an import impact on lipid and glucose metabolism, with excessive visceral fat primarily driving the upregulation of gluconeogenic flux. This evidence underscores the link between both visceral adiposity and MAFLD in the pathogenesis of HIR.\u003c/p\u003e \u003cp\u003eThe identification of disease risk has been significantly enhanced by the burgeoning field of biomarker analysis.\u003csup\u003e26\u003c/sup\u003e These biological biomarker offer an important advantage in the early detection of disease. They facilitate the accurate classification of disease states, enable the staging of disease progression, and potentially provide valuable insights into disease severity. In clinical practice, established markers of hepatic function, such as alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, and alkaline phosphatase, remain instrumental for screening liver diseases and assessing their severity.\u003csup\u003e27\u003c/sup\u003e Within the context of our systematic review, Sesti et al.\u003csup\u003e13\u003c/sup\u003e provided compelling evidence supporting a significant association between MAFLD and hepatic biomarkers, further demonstrating a strong correlation with HIR.\u003c/p\u003e \u003cp\u003eThe DNL has emerged as a pivotal driver in the pathogenesis of MAFLD. While FFAs liberated from adipose tissue constitute the major source of hepatic triglycerides in individuals with normal hepatic steatosis, the contribution of this pathway remains relatively constant in those with MAFLD. In contrast, hepatic DNL exhibits a marked upregulation in MAFLD patients.\u003csup\u003e28\u003c/sup\u003e DNL is a metabolic process that is intricately regulated by nutritional factors. The carbohydrate-rich diets have been shown to effectively counteract the impairment of hepatic lipogenesis caused by the loss of a single enzyme. This observation highlights the interplay between hepatic DNL, dietary intake, and adipocyte lipolysis in the pathogenesis of MAFLD.\u003csup\u003e29\u003c/sup\u003e A key finding from our systematic review, specifically the work of Smith et al.\u003csup\u003e14\u003c/sup\u003e, identified hepatic DNL as a critical regulator of IHTG content. This study further demonstrated that elevated circulating glucose and insulin levels act to stimulate hepatic DNL in individuals diagnosed with MAFLD. The weight loss interventions were shown to reduce IHTG content, at least partially, through a mechanism involving the downregulation of hepatic DNL, ultimately contributing to improve HIR.\u003c/p\u003e \u003cp\u003eThe MAFLD has emerged as a growing concern among liver transplant recipients.\u003csup\u003e30\u003c/sup\u003e The pathogenesis of MAFLD in liver transplant recipients is an intricate interplay of factors, encompassing immunosuppressive therapy, altered gut microbiota, and persistent metabolic derangements.\u003csup\u003e31\u003c/sup\u003e This impaired insulin action promotes hepatic lipogenesis, triglyceride accumulation, and ultimately MAFLD. In a cohort study by Eshraghian A et al.\u003csup\u003e15\u003c/sup\u003e, the relationship between serum adipokines and IR in liver transplant recipients with MAFLD was investigated. The study revealed that IR and adipokine alterations might have a pivotal role in the pathogenesis of post-liver transplant MAFLD, potentially serving as diagnostic and therapeutic targets. This finding contrasts with previous studies that have implicated MAFLD as a potential risk factor for the development of IR, prompting the question of whether this discrepancy is attributable to the transplanted liver and the use of immunosuppressive medications.\u003c/p\u003e \u003cp\u003eHIR and peripheral IR are intertwined and contribute to the development of MAFLD and increased arterial intima-media thickness (IMT). Several mechanisms underlie this intricate relationship.\u003csup\u003e32\u003c/sup\u003e Excess visceral adipose tissue promotes both HIR and peripheral insulin resistance through the release of pro-inflammatory adipokines and FFAs.\u003csup\u003e33\u003c/sup\u003e These factors impair insulin signaling and glucose uptake in the liver and skeletal muscles, respectively, leading to MAFLD and impaired glucose disposal.\u003csup\u003e34\u003c/sup\u003e Moreover, FFAs influx into the liver triggers lipogenesis and hepatic steatosis, further exacerbating HIR.\u003csup\u003e35\u003c/sup\u003e The interplay between HIR and peripheral IR extends to vascular health. IR promotes endothelial dysfunction, platelet activation, and vascular inflammation, all of which contribute to atherosclerosis.\u003csup\u003e36\u003c/sup\u003e Additionally, MAFLD independently increases IMT through mechanisms involving oxidative stress, inflammation, and impaired endothelial function.\u003csup\u003e37\u003c/sup\u003e In a cross-sectional study by Privitera et al.\u003csup\u003e16\u003c/sup\u003e, evaluated HIR and muscle IR in MAFLD patients, investigating their relationship with carotid artery intima-media thickness (IMT) and the apolipoprotein B to apolipoprotein A-I (apoB/apoAI) ratio, both markers of atherosclerosis. The study concluded that MAFLD was independently associated with increased carotid IMT, even after adjusting for components of the metabolic syndrome. This association was specifically linked to HIR, suggesting that it may contribute to atherogenesis through a detrimental effect on the lipid profile, as evidenced by the altered apoB/apoAI ratio.\u003c/p\u003e \u003cp\u003eSeveral studies have compared the metabolic and histological profiles of patients with and without MAFLD. These studies reveal metabolic abnormalities, suggesting IR as a key feature of MAFLD. Histologically, MAFLD is characterized by the accumulation of fat droplets within hepatocytes. Additionally, inflammation and fibrosis may be present in patients with MAFLD.\u003csup\u003e38\u003c/sup\u003e Lomonaco R, et al.\u003csup\u003e17\u003c/sup\u003e in a case-control study aiming to evaluate the metabolic and histological profiles of patients with and without MAFLD, demonstrated that adipose tissue IR plays a fundamental role in the development of metabolic and histological abnormalities in obese patients with MAFLD.\u003c/p\u003e \u003cp\u003eHepatic fat content exhibits a close correlation with both markers and direct measures of IR. Excessive FFAs influx into the liver can stem from either increased FFAs delivery from peripheral or visceral depots, or FFAs may originate from postprandial chylomicron lipolysis. Within the liver, the accumulation of triglycerides can result from impaired hepatic FFAs oxidation or enhanced FFAs uptake and triglyceride synthesis. The coexistence of MAFLD and IR highlights the latter's role as a precursor to T2DM, while MAFLD itself elevates the risk of cirrhosis. HIR maintains a tight association with hepatic fat content.\u003csup\u003e39\u003c/sup\u003e These findings are consistent with the results of our systematic review.\u003csup\u003e18\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe interplay between hemoglobin glycation index (HGI), HIR, and MAFLD has emerged as a pivotal area of interest in the field of metabolic disease. Elevated HbA1c reflects chronic hyperglycemia and is associated with increased hepatic glucose production and gluconeogenesis, which in turn exacerbate HIR.\u003csup\u003e40,41\u003c/sup\u003e This sequence of events contributes to the accumulation of lipids within the liver, ultimately promoting the development of MAFLD.\u003csup\u003e42\u003c/sup\u003e Moreover, intricate molecular pathways involving pro-inflammatory cytokines and insulin signaling further solidify the relationship between HGI, HIR, and MAFLD. Fiorentino et al.\u003csup\u003e19\u003c/sup\u003e in a large-sample study investigating the association between hemoglobin glycation index (HGI) and MAFLD and related biomarkers in non-diabetic individuals, demonstrated that higher HGI levels can identify non-diabetic individuals at increased risk of MAFLD and consequently HIR.\u003c/p\u003e \u003cp\u003eA growing body of evidence from systematic reviews and individual studies has consistently demonstrated an association between MAFLD and HIR. This link highlights MAFLD's significance as a potential risk factor for the development of HIR, underscoring the intricate interplay between metabolic dysregulation and hepatic dysfunction. Several mechanisms contribute to the association between MAFLD and HIR. Excess intrahepatic fat accumulation, disrupts insulin signaling pathways within hepatocytes, leading to impaired insulin sensitivity and the development of HIR. This impaired insulin action subsequently disrupts lipid metabolism, promoting increased hepatic triglyceride synthesis and decreased lipoprotein secretion, further exacerbating MAFLD. Furthermore, the pro-inflammatory milieu associated with MAFLD plays a pivotal role in the development of HIR.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eOur systematic review demonstrated a consistently demonstrated association between MAFLD and HIR. This association has been supported by findings from various studies, highlighting the significance of MAFLD as a potential risk factor for the development of HIR.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eYounossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. 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Can J Gastroenterol Hepatol. 2014;28(11):607-18.\u003c/li\u003e\n \u003cli\u003eVos MB, Abrams SH, Barlow SE, Caprio S, Daniels SR, Kohli R, et al.\u0026nbsp;NASPGHAN Clinical Practice Guideline for the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease in Children: Recommendations from the Expert Committee on NAFLD (ECON) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). J Pediatr Gastroenterol Nutr. 2017;64(2):319-334.\u003c/li\u003e\n \u003cli\u003eSoftic S, Cohen DE, Kahn CR. Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease. Dig Dis Sci. 2016;61(5):1282-93.\u003c/li\u003e\n \u003cli\u003ePostic C, Girard J. The role of the lipogenic pathway in the development of hepatic steatosis. Diabetes Metab. 2008;34(6 Pt 2):643-8.\u003c/li\u003e\n \u003cli\u003eShetty A, Giron F, Divatia MK, Ahmad MI, Kodali S, Victor D. Nonalcoholic Fatty Liver Disease after Liver Transplant. J Clin Transl Hepatol. 2021;9(3):428-435.\u003c/li\u003e\n \u003cli\u003eWatt KD. Metabolic syndrome: is immunosuppression to blame? Liver Transpl. 2011;17 Suppl 3:S38-42.\u003c/li\u003e\n \u003cli\u003eKim SK, Choi YJ, Huh BW, Park SW, Lee EJ, Cho YW, et al. Nonalcoholic Fatty liver disease is associated with increased carotid intima-media thickness only in type 2 diabetic subjects with insulin resistance. J Clin Endocrinol Metab. 2014;99(5):1879-84.\u003c/li\u003e\n \u003cli\u003eSaponaro C, Sabatini S, Gaggini M, Carli F, Rosso C, Positano V, et al.\u0026nbsp;Adipose tissue dysfunction and visceral fat are associated with hepatic insulin resistance and severity of NASH even in lean individuals. Liver Int. 2022;42(11):2418-2427.\u003c/li\u003e\n \u003cli\u003eLee WH, Najjar SM, Kahn CR, Hinds TD Jr. Hepatic insulin receptor: new views on the mechanisms of liver disease. Metabolism. 2023;145:155607.\u003c/li\u003e\n \u003cli\u003eWang JH, Hwang SJ, Lim DW, Son CG. Cynanchum atratum Alleviates Non-Alcoholic Fatty Liver by Balancing Lipogenesis and Fatty Acid Oxidation in a High-Fat, High-Fructose Diet Mice Model. Cells. 2021;11(1):23.\u003c/li\u003e\n \u003cli\u003eKaur R, Kaur M, Singh J. Endothelial dysfunction and platelet hyperactivity in type 2 diabetes mellitus: molecular insights and therapeutic strategies. Cardiovasc Diabetol. 2018;17(1):121.\u003c/li\u003e\n \u003cli\u003eCao Y, Li L. Relationship of non-alcoholic steatohepatitis with arterial endothelial function and atherosclerosis]. Zhonghua Gan Zang Bing Za Zhi. 2014;22(3):205-8.\u003c/li\u003e\n \u003cli\u003eCotrim HP, Parise ER, Oliveira CP, Leite N, Martinelli A, Galizzi J, et al.\u0026nbsp;Nonalcoholic fatty liver disease in Brazil. Clinical and histological profile. Ann Hepatol. 2011;10(1):33-7.\u003c/li\u003e\n \u003cli\u003eUtzschneider KM, Kahn SE, Polidori DC. Hepatic Insulin Extraction in NAFLD Is Related to Insulin Resistance Rather Than Liver Fat Content. J Clin Endocrinol Metab. 2019;104(5):1855-1865.\u003c/li\u003e\n \u003cli\u003eM\u0026uuml;ller N, Lehmann T, M\u0026uuml;ller UA, Kloos C. Is there an HbA1c Threshold for Symptoms of Chronic Hyperglycemia? Exp Clin Endocrinol Diabetes.\u0026nbsp;2022;130(6):386-392.\u003c/li\u003e\n \u003cli\u003eDel Prato S, Matsuda M, Simonson DC, Groop LC, Sheehan P, Leonetti F, et al. Studies on the mass action effect of glucose in NIDDM and IDDM: evidence for glucose resistance. Diabetologia. 1997;40(6):687-97.\u003c/li\u003e\n \u003cli\u003eKolluru K, Giri A, Kumar S, Acharya S, Agrawal S, Wanjari A, et al. Association of Metabolic-Associated Fatty Liver Disease With Various Anthropometric Parameters in Pre-diabetes in Comparison With Diabetes and Control: A Single Tertiary Care Center Study. Cureus. 2022;14(7):e27130.\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Fatty liver disease associated with metabolic dysfunction, Hepatic insulin resistance, Systematic review.","lastPublishedDoi":"10.21203/rs.3.rs-4739938/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4739938/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e: Metabolic dysfunction-associated fatty liver disease (MAFLD) comes up as a prominent issue within the realm of chronic liver pathologies on a global scale. Hepatic insulin resistance (HIR) is an important aspect of metabolic dysfunction, serving as a primary driver of dysregulated glucose homeostasis. MAFLD and HIR, Type 2 diabetes mellitus-like in the liver, exhibit a complex interplay in the pathogenesis of metabolic disorders.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e To evaluate the relationship between MAFLD and HIR by a systematic review.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e To identify relevant studies published between January 1998 and July 2024, a comprehensive search was conducted across electronic databases, including PubMed, Web of Science, Scopus, Embase, and Cochrane Central. To ensure the inclusion of relevant and high-quality studies, inclusion and exclusion criteria were applied. The QUADAS-2, the systematic review ensured that potential biases were systematically identified, evaluated, and accounted for, enhancing the credibility and trustworthiness of the findings.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e After careful consideration, 8 studies were deemed to meet the stringent inclusion criteria and were subsequently selected for data extraction and analysis. These studies represented the core body of evidence that underpins the findings of this systematic review.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e Our systematic review demonstrated a consistently demonstrated association between MAFLD and HIR. This association has been supported by findings from various studies, highlighting the significance of MAFLD as a potential risk factor for the development of HIR.\u003c/p\u003e","manuscriptTitle":"Metabolic-Dysfunction-Associated Fatty Liver Disease and Hepatic Insulin Resistance: A Type 2 Diabetes Mellitus-like in the liver - A Systematic Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-16 16:18:34","doi":"10.21203/rs.3.rs-4739938/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ab6e42e9-7d0a-4b1a-b6b5-00f76d505028","owner":[],"postedDate":"July 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":34580761,"name":"Internal Medicine"}],"tags":[],"updatedAt":"2024-07-16T16:18:34+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-16 16:18:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4739938","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4739938","identity":"rs-4739938","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}