Dissociation between liver fat content and fasting metabolic markers of selective hepatic insulin resistance in humans.

OBJECTIVE: Fasting hyperglycemia and hypertriglyceridemia are characteristic of insulin resistance (IR) and rodent work has suggested this may be due to selective hepatic IR; defined by increased hepatic gluconeogenesis and de novo lipogenesis (DNL), but this has not been shown in humans. DESIGN: Cross-sectional study in men and women across a range of adiposity. METHODS: Medication-free participants (n=177) were classified as normoinsulinemic (NI) or hyperinsulinemic (HI) and as having low (LF) or high (HF) liver fat content measured by magnetic resonance spectroscopy. Fractional gluconeogenesis (frGNG) and hepatic DNL were measured using stable isotope tracer methodology following an overnight fast. RESULTS: Although HI and HF groups had higher fasting plasma glucose and triglyceride concentrations when compared to NI and LF groups respectively, there was no difference in frGNG. However, HF participants tended to have lower frGNG than LF participants. HI participants had higher DNL compared to NI participants but there was no difference observed between liver fat groups. CONCLUSIONS: Taken together, we found no metabolic signature of selective hepatic IR in fasting humans. DNL may contribute to hypertriglyceridemia in individuals with HI but not those with HF. Glycogenolysis and systemic glucose clearance may have a larger contribution to fasting hyperglycemia than gluconeogenesis, especially in those with HF and these pathways should be considered for therapeutic targeting.

Effect of Hyperinsulinemia on Leptin and Ghrelin Levels in Polycystic Ovarian Syndrome: A Meta-Analysis.

Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Leptin and ghrelin are important markers in PCOS due to their correlation with obesity, insulin resistance, and fertility. There is currently a debate in the literature about whether altered leptin and ghrelin levels in women with PCOS are a result of the disease itself or if they are due to factors such as the hyperinsulinemic state characteristic of PCOS. This meta-analysis aims to assess if insulin levels impact leptin and ghrelin levels in PCOS.  Eight case-control studies assessing the relationship between insulin and leptin, as well as five case-control studies assessing the relationship between insulin and ghrelin, were identified in PubMed. Pearson's correlation coefficient (PCC) and the sample size were extracted, and two meta-analyses were conducted using a random-effects model. Total heterogeneity (I2) with a confidence interval of 95% was then determined. "Leave-one out" diagnostics were calculated for each case. If a study was identified as being significantly influential, the study was removed from the data set, and the trim and fill procedure was applied. Publication bias was assessed using Egger's regression test and rank correlation test.  Our results showed a moderate positive relationship (r=0.56, 95% confidence interval (CI) (0.42, 0.71), with substantial heterogeneity I2=81.35%, 95% CI (25.2799, 88.2451)) between insulin and leptin levels, and a moderate negative relationship (r=-0.33, 95% CI (-0.43, -0.24)), with low heterogeneity (I2=0.00%, 95% CI (0.0000, 80.8159)) between insulin and ghrelin levels. Therefore, there is a significant relationship between insulin and higher leptin and lower ghrelin levels in women with PCOS. Better insulin control may have a positive effect on fertility, appetite, weight, body image, and quality of life in these women. This correlation is likely multifactorial, and further studies are needed to isolate factors influencing these hormones.

Insulinemic potential of diet and the risk of type 2 diabetes: a meta-analysis and systematic review.

BACKGROUND: The possible role of the insulinemic potential of diet in the etiology of type 2 diabetes (T2D) has recently received significant attention in observational studies. This meta-analysis aimed to synthesize available evidence and quantify the potential association between the empirical dietary index for hyperinsulinemia (EDIH) score and T2D risk. METHODS: Various electronic databases, including Scopus, PubMed, and Web of Science, were comprehensively searched up to January 2024 using related keywords to identify relevant studies. The hazard ratios (HR) or odds ratios were extracted from eligible cohort studies, and a random-effects model with an inverse variance weighting method was used to calculate the pooled effect size, which was expressed as HR. RESULTS: The analysis included six cohort studies (four publications), with sample sizes ranging from 3,732 to 90,786 individuals aged 20 to 79 years. During follow-up periods of 5 to over 20 years, 31,284 T2D incidents were identified. The pooled results showed that a higher EDIH score was associated with an increased risk of T2D incidence (HR: 1.47; 95%CI 1.21-1.77; I2 = 91.3%). Significant publication bias was observed in the present meta-analysis (P = 0.020). Geographical region and follow-up period can be as sources of heterogeneity (Pheterogeneity <0.001). CONCLUSION: Our meta-analysis of observational studies suggested that a diet with a higher EDIH score may be associated with an increased risk of incidence of T2D.

Dietary flaxseed oil suppresses hyperglycemia and hyperinsulinemia through increasing in α-linolenic acid content in the muscle.

Types of fats and oils affect the onset of lifestyle diseases. In this study, we investigated the relationship between the postprandial hyperglycemia and fatty acids content in the skeletal muscle of C57BL/6 mice given 20% lard, palm oil, corn oil, safflower oil, and flaxseed oil for 16 weeks. Lard increased plasma glucose and insulin levels at the end of feeding period, whereas flaxseed oil did not. It was noteworthy that there is a positive correlation between palmitic acid content in the muscle and postprandial hyperglycemia, and a negative correlation between α-linolenic acid content and hyperglycemia. Alternatively, mice were given 30% lard for 16 weeks. When lard was partially substituted with flaxseed oil (10-50% substitution), flaxseed oil dose-dependently prevented lard-induced hyperglycemia and hyperinsulinemia. In conclusion, flaxseed oil prevents the adverse effects of lard through increasing in α-linolenic acid content in the muscle.

Dietary and lifestyle insulinemic potentials, plasma metabolome, and risk of diverticulitis: a prospective cohort study.

BACKGROUND: Diet and lifestyle factors have been linked to developing diverticulitis. However, it remains largely unknown whether the associations are mediated by metabolic disturbance, such as hyperinsulinemia and corresponding metabolomic perturbations. OBJECTIVES: We investigated associations of the insulinemic potential of diet, lifestyle (diet, physical activity, body weight), and metabolomic patterns with the risk of incident diverticulitis. METHODS: We conducted a prospective cohort study including participants in 3 nationwide cohorts of United States health professionals. The risk of incident diverticulitis was estimated according to quintiles of the empirical dietary index for hyperinsulinemia (EDIH) and empirical lifestyle index for hyperinsulinemia (ELIH). In a subset of participants with metabolomic measurements, we developed metabolomic dietary index for hyperinsulinemia (MDIH) and metabolomic lifestyle index for hyperinsulinemia (MLIH), metabolite profile scores correlating with EDIH and ELIH, respectively, and tested their associations with subsequent risk of diverticulitis. We also examined whether the associations of EDIH and ELIH with diverticulitis were mediated by the metabolite profile scores. RESULTS: Among 184,508 participants [median age, 51 (interquartile range, 46-56) y], we documented 9123 incident diverticulitis cases over 3,419,945 person-years. Compared with those in the lowest quintile, participants with the most hyperinsulinemic diets and lifestyles (highest quintiles of EDIH and ELIH) had a hazard ratio for the risk of diverticulitis of 1.22 [95% confidence interval (CI): 1.13, 1.31] and 1.69 (95% CI: 1.57, 1.81), respectively. Similarly, the metabolite profile scores were significantly associated with the diverticulitis risk with odds ratio of 1.96 for MDIH (95% CI: 1.47, 2.60) and 1.93 for MLIH (95% CI: 1.48, 2.51) when comparing extreme quintiles. The explainable proportions of EDIH- and ELIH-related diverticulitis risk by MDIH and MLIH were 70% (95% CI: 6%, 99%) and 57% (95% CI: 23%, 86%), respectively (P < 0.0001 for both). CONCLUSIONS: Participants with dietary and lifestyle patterns corresponding to higher insulinemic potential had an increased risk of diverticulitis, which might be mediated by metabolomic profiles.

Eosinophils prevent diet-induced airway hyperresponsiveness in mice on a high-fat diet.

Eosinophils contribute to metabolic homeostasis and airway hyperresponsiveness, but their specific role in obesity-related airway hyperresponsiveness remains unclear. To address this, we utilized transgenic mice that overexpress interleukin-5 (IL-5) in peripheral T cells (+IL-5T) and wild type controls. On a normal diet, +IL-5T and wild type mice have similar body weight, body fat, and airway nerve-mediated reflex bronchoconstriction in response to inhaled serotonin. Feeding wild type mice a 61.6% high-fat diet resulted in significantly increased body weight, body fat, fasting glucose, fasting insulin, and reflex bronchoconstriction induced by serotonin, which was blocked by vagotomy. In contrast, +IL-5T mice on a high-fat diet gained less body weight and fat than wild type mice on same diet and did not exhibit potentiation in fasting glucose, fasting insulin, or reflex bronchoconstriction induced by serotonin. Compared to wild type mice, +IL-5T mice on normal diet had significantly more adipose tissue eosinophils, and this was further increased by high-fat diet. High-fat diet did not increase adipose tissue eosinophils in wild type mice. Our findings suggest that adipose tissue eosinophils may play a role in regulating body fat, thereby reducing insulin, which is a mediator of obesity-related airway hyperresponsiveness. Thus, our data indicate adipose tissue eosinophils may be an important avenue for research in obesity-related asthma.

Effects of T2DM on cancer progression: pivotal precipitating factors and underlying mechanisms.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder affecting people worldwide. It is characterized by several key features, including hyperinsulinemia, hyperglycemia, hyperlipidemia, and dysbiosis. Epidemiologic studies have shown that T2DM is closely associated with the development and progression of cancer. T2DM-related hyperinsulinemia, hyperglycemia, and hyperlipidemia contribute to cancer progression through complex signaling pathways. These factors increase drug resistance, apoptosis resistance, and the migration, invasion, and proliferation of cancer cells. Here, we will focus on the role of hyperinsulinemia, hyperglycemia, and hyperlipidemia associated with T2DM in cancer development. Additionally, we will elucidate the potential molecular mechanisms underlying their effects on cancer progression. We aim to identify potential therapeutic targets for T2DM-related malignancies and explore relevant directions for future investigation.

Obesity-Associated Breast Cancer: Analysis of Risk Factors and Current Clinical Evaluation.

Several studies show that a significantly stronger association is obvious between increased body mass index (BMI) and higher breast cancer incidence. Additionally, obese and postmenopausal women are at higher risk of all-cause and breast cancer-specific mortality compared with non-obese women with breast cancer. In this context, increased levels of estrogens, excessive aromatization activity of the adipose tissue, overexpression of pro-inflammatory cytokines, insulin resistance, adipocyte-derived adipokines, hypercholesterolemia, and excessive oxidative stress contribute to the development of breast cancer in obese women. Genetic evaluation is an integral part of diagnosis and treatment for patients with breast cancer. Despite trimodality therapy, the four-year cumulative incidence of regional recurrence is significantly higher. Axillary lymph nodes as well as primary lesions have diagnostic, prognostic, and therapeutic significance for the management of breast cancer. In clinical setting, because of the obese population primary lesions and enlarged lymph nodes could be less palpable, the diagnosis may be challenging due to misinterpretation of physical findings. Thereby, a nomogram has been created as the "Breast Imaging Reporting and Data System" (BI-RADS) to increase agreement and decision-making consistency between mammography and ultrasonography (USG) experts. Additionally, the "breast density classification system," "artificial intelligence risk scores," ligand-targeted receptor probes," "digital breast tomosynthesis," "diffusion-weighted imaging," "18F-fluoro-2-deoxy-D-glucose positron emission tomography," and "dynamic contrast-enhanced magnetic resonance imaging (MRI)" are important techniques for the earlier detection of breast cancers and to reduce false-positive results. A high concordance between estrogen receptor (ER) and progesterone receptor (PR) status evaluated in preoperative percutaneous core needle biopsy and surgical specimens is demonstrated. Breast cancer surgery has become increasingly conservative; however, mastectomy may be combined with any axillary procedures, such as sentinel lymph node biopsy (SLNB) and/or axillary lymph node dissection whenever is required. As a rule, SLNB-guided axillary dissection in breast cancer patients who have clinically axillary lymph node-positive to node-negative conversion following neoadjuvant chemotherapy is recommended, because lymphedema is the most debilitating complication after any axillary surgery. There is no clear consensus on the optimal treatment of occult breast cancer, which is much discussed today. Similarly, the current trend in metastatic breast cancer is that the main palliative treatment option is systemic therapy.

Analysis of beta-cell maturity and mitochondrial morphology in juvenile non-human primates exposed to maternal Western-style diet during development.

Introduction: Using a non-human primate (NHP) model of maternal Western-style diet (mWSD) feeding during pregnancy and lactation, we previously reported altered offspring beta:alpha cell ratio in vivo and insulin hyper-secretion ex vivo. Mitochondria are known to maintain beta-cell function by producing ATP for insulin secretion. In response to nutrient stress, the mitochondrial network within beta cells undergoes morphological changes to maintain respiration and metabolic adaptability. Given that mitochondrial dynamics have also been associated with cellular fate transitions, we assessed whether mWSD exposure was associated with changes in markers of beta-cell maturity and/or mitochondrial morphology that might explain the offspring islet phenotype. Methods: We evaluated the expression of beta-cell identity/maturity markers (NKX6.1, MAFB, UCN3) via florescence microscopy in islets of Japanese macaque pre-adolescent (1 year old) and peri-adolescent (3-year-old) offspring born to dams fed either a control diet or WSD during pregnancy and lactation and weaned onto WSD. Mitochondrial morphology in NHP offspring beta cells was analyzed in 2D by transmission electron microscopy and in 3D using super resolution microscopy to deconvolve the beta-cell mitochondrial network. Results: There was no difference in the percent of beta cells expressing key maturity markers in NHP offspring from WSD-fed dams at 1 or 3 years of age; however, beta cells of WSD-exposed 3 year old offspring showed increased levels of NKX6.1 per beta cell at 3 years of age. Regardless of maternal diet, the beta-cell mitochondrial network was found to be primarily short and fragmented at both ages in NHP; overall mitochondrial volume increased with age. In utero and lactational exposure to maternal WSD consumption may increase mitochondrial fragmentation. Discussion: Despite mWSD consumption having clear developmental effects on offspring beta:alpha cell ratio and insulin secretory response to glucose, this does not appear to be mediated by changes to beta-cell maturity or the beta-cell mitochondrial network. In general, the more fragmented mitochondrial network in NHP beta cells suggests greater ability for metabolic flexibility.

Diabetes and its Silent Partner: A Critical Review of Hyperinsulinemia and its Complications.

In this complex realm of diabetes, hyperinsulinemia is no longer regarded as just a compensatory response to insulin resistance but rather has evolved into an integral feature. This comprehensive review provides a synthesis of the current literature, including various aspects associated with hyperinsulinemia in diabetic complications. Hyperinsulinemia has been shown to be more than just a compensatory mechanism, and the key findings demonstrate how hyperinsulinism affects the development of cardiovascular events as well as microvascular complications. Additionally, recognizing hyperinsulinemia as a modifiable factor, the diabetes management paradigm shifts towards cognitive ones that consider the use of lifestyle modifications in combination with newer pharmacotherapies and precision medicine approaches. These findings have crucial implications for the clinical work, requiring a careful appreciation of hyperinsulinemia's changing aspects as well as incorporation in personalized treatment protocol. In addition, the review focuses on bigger issues related to public health, showing that prevention and early diagnosis will help reduce the burden of complications. Research implications favor longitudinal studies, biomarker discovery, and the study of emerging treatment modalities; clinical practice should adopt global evaluations, patient education, and precision medicine adaptation. Finally, this critical review provides an overview of the underlying processes of hyperinsulinemia in diabetes and its overall health effects.

The Pathophysiological Mechanism and Clinical Treatment of Polycystic Ovary Syndrome: A Molecular and Cellular Review of the Literature.

Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder among women of reproductive age, characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. The pathogenesis of PCOS involves a complex interplay of genetic and environmental factors, including insulin resistance (IR) and resultant hyperinsulinemia. Insulin receptors, primarily in skeletal muscle, liver, and adipose tissue, activate downstream signaling pathways like PI3K-AKT and MAPK-ERK upon binding. These pathways regulate glucose uptake, storage, and lipid metabolism. Genome-wide association studies (GWASs) have identified several candidate genes related to steroidogenesis and insulin signaling. Environmental factors such as endocrine-disrupting chemicals and lifestyle choices also exacerbate PCOS traits. Other than lifestyle modification and surgical intervention, management strategies for PCOS can be achieved by using pharmacological treatments like antiandrogens, metformin, thiazolidinediones, aromatase inhibitor, and ovulation drugs to improve insulin sensitivity and ovulatory function, as well as combined oral contraceptives with or without cyproterone to resume menstrual regularity. Despite the complex pathophysiology and significant economic burden of PCOS, a comprehensive understanding of its molecular and cellular mechanisms is crucial for developing effective public health policies and treatment strategies. Nevertheless, many unknown aspects of PCOS, including detailed mechanisms of actions, along with the safety and effectiveness for the treatment, warrant further investigation.

Unraveling the mechanisms of hepatogenous diabetes and its therapeutic perspectives.

The review focused mainly on the pathogenesis of hepatogenous diabetes (HD) in liver cirrhosis (LC). This review reveals parallels between the mechanisms of metabolic dysfunction observed in LC and type II diabetes (T2DM), suggesting a shared pathway leading to HD. It underscores the role of insulin in HD pathogenesis, highlighting key factors such as insulin signaling, glucose metabolism, insulin resistance (IR), and the influence of adipocytes. Furthermore, the impact of adipose tissue accumulation, fatty acid metabolism, and pro-inflammatory cytokines like Tumor necrosis factor-α (TNF-α) on IR are discussed in the context of HD. Altered signaling pathways, disruptions in the endocrine system, liver inflammation, changes in muscle mass and composition, and modifications to the gut microbiota collectively contribute to the complex interplay linking cirrhosis and HD. This study highlights how important it is to identify and treat this complex condition in cirrhotic patients by thoroughly analyzing the link between cirrhosis, IR, and HD. It also emphasizes the vitality of targeted interventions. Cellular and molecular investigations into IR have revealed potential therapeutic targets for managing and preventing HD.

Insulin Autoimmune Syndrome: A Case Report Highlighting Diagnostic Pitfalls.

Insulin autoimmune syndrome (IAS) is characterized by spontaneous hyperinsulinemic hypoglycemia and the presence of insulin autoantibodies in high titers without exogenous insulin use. The C-peptide level during a hypoglycemia episode is useful for differentiating spontaneous hypoglycemia. Generally, low C-peptides are suspicious for exogenous insulin administration. We report a 47-year-old male nurse who presented with an initial episode of hypoglycemia. Despite the pattern of hyperinsulinemic hypoglycemia and low C-peptide, he was diagnosed with IAS based on the presence of insulin autoantibodies. This case underscores the importance of suspecting IAS in non-diabetic adults with hypoglycemia, even in the setting of low C-peptide levels.

Association between Coffee Consumption and Polycystic Ovary Syndrome: An Exploratory Case-Control Study.

Polycystic ovary syndrome (PCOS) is a leading cause of infertility, with an estimated worldwide prevalence between 5% and 15%. We conducted a case-control study with 121 PCOS patients and 155 controls to assess the association between coffee intake and the presence of having a diagnosis of PCOS in women in Murcia, Spain. The PCOS diagnosis was determined following Rotterdam criteria (the presence of two of the following three conditions: hyperandrogenism, oligo-anovulation, and/or polycystic ovarian morphology). Coffee consumption was assessed using a validated food frequency questionnaire. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multiple logistic regression. Coffee consumption was categorized into never, less than one cup per day, one cup per day, and two or more cups per day. We found a significant inverse linear trend: the higher the coffee consumption, the lower the probability of having PCOS in multivariable analysis (p-trend = 0.034). Women who presented with PCOS were less likely to drink one cup of coffee compared to those who had never drunk coffee (OR = 0.313, 95% CI: 0.141-0.69). The consumption of at least one cup of coffee per day may be associated with a decrease in PCOS symptoms.

Insulin Resistance/Hyperinsulinemia as an Independent Risk Factor That Has Been Overlooked for Too Long.

Unfortunately, cardiovascular diseases and cancers are still the leading causes of death in developed and developing countries despite the considerable progress made in the prevention and treatment of diseases. Maybe we missed something? Insulin resistance (IR) with associated hyperinsulinemia (Hypein) is a silent pandemic whose prevalence is continually growing in developed and developing countries, now exceeding 51% of the general population. IR/Hypein, despite the vast scientific literature supporting its adverse action on the development of type 2 diabetes, cardiovascular alterations, tumors, neurological disorders, and cellular senescence, is not yet considered an independent risk factor and, therefore, is not screened in the general population and adequately treated. There are now numerous substances, drugs, and natural substances that, in association with the correction of a wrong lifestyle, can help to reduce IR/Hypein. We are convinced that the time has come to implement a prevention plan against this critical risk factor. Therefore, this manuscript aims to highlight IR/Hypein as an independent risk factor for type 2 diabetes, cardiovascular diseases, cancers, cellular senescence, and neuropsychiatric disorders, supporting our conviction with the available scientific literature on the topic.

Pancreatic Insulinoma Masquerading as Neurological Disease: Diagnosis and Treatment of a Rare Tumor.

Insulinomas are rare functional pancreatic neuroendocrine tumors that typically manifest with classic hypoglycemic symptoms, such as diaphoresis, palpitations, and tremors. Although infrequent, neuroglycopenic symptoms associated with insulinomas have been reported, often leading to delayed diagnoses. Here, we present the case of a 31-year-old male with pancreatic insulinoma who experienced recurrent episodes of seizures and confusion preceded by diaphoresis, tremors, and palpitations. During these episodes, he was found to be hypoglycemic. Comprehensive evaluations, including brain and abdominal imaging, as well as biochemical and serological testing, were conducted. The findings confirmed a diagnosis of pancreatic insulinoma. The patient underwent surgical resection of the tumor, and a biopsy confirmed the insulinoma diagnosis. He remained asymptomatic during subsequent follow-ups.

Hereditary Severe Insulin-resistance Syndrome and Acanthosis Nigricans Caused by Novel Mutations in the INSR Gene.

Most cases associated with Hereditary Severe Insulin Resistance Syndrome (H-SIRS) are linked to mutations in the insulin receptor (INSR) gene. Patients with H-SIRS typically manifest symptoms of hyperinsulinemia, insulin resistance, and diabetes mellitus. Other symptoms include impaired glucose regulation, hyperandrogenism, and the presence of acanthosis nigricans (AN). In this report, we present two cases of H-SIRS in female children exhibiting various symptoms, such as hyperinsulinemia, fasting hypoglycemia, postprandial hyperglycemia, overweight, fatty liver, hyperandrogenism, and varying degrees of AN. One patient also presented with mental retardation. Gene sequencing identified specific mutations in the INSR gene for both patients: c.2663A > G (p.Tyr888Cys) and c.38_61del (p.Pro13_Ala20del). These mutations have the potential to disrupt the interaction between INSR and insulin, leading to abnormal insulin signaling, insulin resistance, and various clinical manifestations.

Insulin Mimicking Mystery: Decoding Recurrent Hypoglycemia.

Insulin antibody syndrome (IAS), also known as Hirata disease, is a rare condition characterized by spontaneous hypoglycemic episodes unrelated to exogenous insulin exposure. It is caused by elevated serum levels of insulin autoantibodies (IAA). IAS typically occurs when a triggering factor, such as medication or viral infection, interacts with a predisposing genetic background. Diagnosing IAS is challenging due to its rarity and the presence of multiple potential causes for hyperinsulinemic hypoglycemia. The presence of Whipple triad-symptoms of hypoglycemia, low plasma glucose concentration, and relief of symptoms after raising plasma glucose-strongly supports the diagnosis of IAS. However, the detection of IAA is considered the most reliable test. Timely diagnosis can facilitate appropriate treatment and prevent unnecessary imaging studies and invasive procedures, thereby reducing costs. Currently, no definitive guidelines exist for managing IAS. Most management strategies involve supportive measures due to the high rate of spontaneous remission, with hypoglycemia often managed through dietary interventions. However, a few medications have shown benefit. Although predominantly observed in the Japanese population, IAS cases have been reported in other ethnicities, including Caucasians. This report presents a unique case of IAS in an African American male.

The association of dietary indices for hyperinsulinemia and insulin resistance with the risk of metabolic syndrome: a population-based cross-sectional study.

We aimed to investigate the association between an empirical dietary index for hyperinsulinemia (EDIH), empirical dietary index for insulin resistance (EDIR), and MetS and its components in an adult Iranian population. In this cross-sectional study, a total of 6482 participants aged 35-65 years were recruited as part of the MASHAD cohort study. Dietary intakes were assessed using a validated food frequency questionnaire (FFQ). The International Diabetes Federation (IDF) criteria were used to define MetS. Multivariable logistic regression models were applied to determine the association between EDIH, EDIR, and MetS and its components. The mean age and BMI of participants were 48.44±8.20 years, and 27.98±4.73 kg/m2, respectively. Around 59% of the population was female. Of the total population, 35.4% had MetS. According to the full-adjusted model, there was no significant association between higher quartiles of EDIH and EDIR and odds of MetS (Q4 EDIH; OR (95%CI):0.93 (0.74-1.18), Q4 EDIR; OR (95%CI):1.14 (0.92-1.40). Regarding MetS components, EDIR was associated with increased odds of hypertension and diabetes (Q4 EDIR; OR (95%CI):1.22 (1.04-1.44) and 1.22 (1.01-1.47), respectively). EDIH was also associated with decreased odds of hypertriglyceridemia (Q4 EDIH; OR (95%CI): 0.72 (0.60-0.87)). This study showed no significant association between hyperinsulinemia and insulin resistance potential of diet and odds of MetS among Iranian adults. However, EDIR was significantly associated with increased odds of hypertension and diabetes as MetS components.