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.

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.

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.

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.

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.

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.

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.

Sweet Saboteur: Insulinoma Presenting As Recurrent Hypoglycemic Seizures.

Insulinoma, a rare neuroendocrine tumor of the pancreas, often presents diagnostic challenges due to its diverse clinical manifestations. We present the case of a 25-year-old female with recurrent hypoglycemic seizures and neuroglycopenic symptoms, ultimately diagnosed with insulinoma. Despite an initial asymptomatic period, the patient experienced progressively worsening symptoms over three years, culminating in eight episodes of generalized tonic-clonic seizures per week. Biochemical investigations during hypoglycemic episodes revealed elevated C-peptide and insulin levels, consistent with endogenous hyperinsulinemia. Imaging studies, including contrast-enhanced computed tomography (CECT) and Ga-DOTATATE scan, confirmed a hyper-enhancing lesion in the distal body of the pancreas, indicative of insulinoma. Histopathological examination (HPE) further corroborated the diagnosis. Prompt recognition and surgical excision led to the complete resolution of symptoms and improved long-term prognosis. This case underscores the importance of considering insulinoma in young individuals presenting with recurrent hypoglycemic episodes and highlights the significance of early diagnosis and intervention in preventing morbidity and mortality associated with this condition.

Inhibiting arachidonic acid generation mitigates aging-induced hyperinsulinemia and insulin resistance in mice.

BACKGROUND: Aging-related type 2 diabetes (T2DM) is characterized by hyperinsulinemia, insulin resistance, and ß-cell dysfunction. However, the underlying molecular mechanisms remain to be unclear. METHODS: We conducted non-targeted metabolomics to compare human serum samples from young adults (YA), elderly adults (EA), and elderly adults with diabetes (EA + DM) of Chinese population. Adult mice and aged mice were intragastrically administered with varespladib every day for two weeks and metabolic characteristics were monitored. Serum levels of arachidonic acid, insulin, and C-peptide, as well as serum activity of secretory phospholipase A2 (sPLA2) were detected in mice. Mouse islet perfusion assays were used to assess insulin secretion ability. Phosphorylated AKT levels were measured to evaluate insulin sensitivities of peripheral tissues in mice. RESULTS: Non-targeted metabolomics analysis of human serum samples revealed differential metabolic signatures among the YA, EA, and EA + DM groups. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed significant enhancement of arachidonic acid metabolism and glycerophospholipid metabolism in the EA group compared with the YA group. Further analysis identified two metabolic fluxes that favored the accumulation of arachidonic acid in the elderly. Increased levels of arachidonic acid were also confirmed in aged mice with hyperinsulinemia and insulin resistance, together with subsequent glucose intolerance. Conversely, inhibiting the generation of arachidonic acid with varespladib, an inhibitor of sPLA2, reduced aging-associated diabetes by improving hyperinsulinemia and hepatic insulin resistance in aged mice but not in adult mice. Islet perfusion assays also showed that varespladib treatment suppressed the enhanced insulin secretion observed in aged islets. CONCLUSIONS: Collectively, our findings uncover that arachidonic acid serves as a metabolic hub in Chinese elderly population. Our results also suggest that arachidonic acid plays a fundamental role in regulating ß-cell function during aging and point to a novel therapy for aging-associated diabetes.

Phthalate and gallstones: the mediation of insulin.

Background: Exposure to a mixture of environmental chemicals may cause gallstone, but the evidence remains equivocal. The current study aims to investigate the association between phthalate metabolites and gallstones, and to explore their mediators. Methods: Data from the National Health and Nutrition Examination Survey 2017-2018 on U.S. adults (≥20 years) were analyzed to explore the association between phthalate metabolites and gallstones by employed survey-weighted logistic regression, restricted cubic spline (RCS), weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR). Mediation analyses examined the role of oxidative stress markers, inflammatory markers, metabolic syndrome, body composition, diabetes, and insulin. Results: The current study included 1,384 participants, representing 200.6 million U.S. adults. Our results indicated a significant association between phthalate metabolites, particularly high molecular weight metabolites such as Di(2-ethylhexyl) phthalate (DEHP) and 1,2-Cyclohexane dicarboxylic acid diisononyl ester (DINCH), and gallstones. Furthermore, mediation analyses indicated that phthalate metabolites may play a role in the development of gallstones by influencing insulin secretion. Subgroup analyses did not reveal significant interaction. Conclusion: The association between exposure to phthalates and the occurrence of gallstones, potentially mediated by hyperinsulinemia from a nationally representative epidemiological perspective. These insights contribute to a better understanding of the potential health implications of plasticizers, emphasizing the need for proactive management measures.

Dietary Cholest-4-en-3-one, a Cholesterol Metabolite of Gut Microbiota, Alleviates Hyperlipidemia, Hepatic Cholesterol Accumulation, and Hyperinsulinemia in Obese, Diabetic db/db Mice.

Previous studies have shown that dietary cholest-4-en-3-one (4-cholestenone, 4-STN) exerts anti-obesity and lipid-lowering effects in mice. However, its underlying mechanisms are not fully understood. In the present study, we evaluated whether 4-STN supplementation would protect obese diabetic db/db mice from obesity-related metabolic disorders. After four weeks of feeding of a 0.25% 4-STN-containing diet, dietary 4-STN was found to have significantly alleviated hyperlipidemia, hepatic cholesterol accumulation, and hyperinsulinemia; however, the effect was not sufficient to improve hepatic triglyceride accumulation or obesity. Further analysis demonstrated that dietary 4-STN significantly increased the content of free fatty acids and neutral steroids in the feces of db/db mice, indicating that the alleviation of hyperlipidemia by 4-STN was due to an increase in lipid excretion. In addition, dietary 4-STN significantly reduced the levels of desmosterol, a cholesterol precursor, in the plasma but not in the liver, suggesting that normalization of cholesterol metabolism by 4-STN is partly attributable to the suppression of cholesterol synthesis in extrahepatic tissues. In addition, dietary 4-STN increased the plasma and hepatic levels of 4-STN metabolites cholestanol (5α-cholestan-3ß-ol) and coprostanol (5ß-cholestan-3ß-ol). Our results show that dietary 4-STN alleviates obesity-related metabolic disorders, such as hyperlipidemia, hepatic cholesterol accumulation, and hyperinsulinemia, in db/db mice.

Hyperinsulinemic State and Hypokalemic Quadriparesis in Tropical Fever: Is There a Link?

It is rare for quadriparesis to manifest as a symptom of tropical illnesses. With a history of only one fever episode one week prior, our patient, a 48-year-old male with obesity and prediabetes, who was also known to have ankylosing spondylitis, presented with acute onset flaccid quadriparesis. He did not exhibit any additional symptoms of dengue, such as bleeding tendencies, petechial rashes, thrombocytopenia, or febrile episodes. Upon examination, it was discovered that he had extremely low serum potassium levels and was dengue non-specific antigen 1 (NS1) positive. His hyperinsulinemia, as seen by elevated C peptide levels, most likely caused a transcellular shift that was then triggered by the dengue infection, leading to hypokalemic paralysis.

Disentangling fetal insulin hypersecretion and insulin resistance.

Disentangling which of insulin hypersecretion and insulin resistance is upstream in obesity-related type 2 diabetes (T2D) is challenging. Here, we consider the dynamics of insulin secretion and action in the fetuses of mothers with diabetes. We argue that fetal insulin hypersecretion occurs first, with insulin resistance being an adaptive protective response.

Overnutrition, Hyperinsulinemia and Ectopic Fat: It Is Time for A Paradigm Shift in the Management of Type 2 Diabetes.

The worldwide incidence of prediabetes/type 2 has continued to rise the last 40 years. In the same period, the mean daily energy intake has increased, and the quality of food has significantly changed. The chronic exposure of pancreatic ß-cells to calorie excess (excessive energy intake) and food additives may increase pancreatic insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing chronic hyperinsulinemia and peripheral insulin resistance. Chronic calorie excess and hyperinsulinemia may promote lipogenesis, inhibit lipolysis and increase lipid storage in adipocytes. In addition, calorie excess and hyperinsulinemia can induce insulin resistance and contribute to progressive and excessive ectopic fat accumulation in the liver and pancreas by the conversion of excess calories into fat. The personal fat threshold hypothesis proposes that in susceptible individuals, excessive ectopic fat accumulation may eventually lead to hepatic insulin receptor resistance, the loss of pancreatic insulin secretion, hyperglycemia and the development of frank type 2 diabetes. Thus, type 2 diabetes seems (partly) to be caused by hyperinsulinemia-induced excess ectopic fat accumulation in the liver and pancreas. Increasing evidence further shows that interventions (hypocaloric diet and/or bariatric surgery), which remove ectopic fat in the liver and pancreas by introducing a negative energy balance, can normalize insulin secretion and glucose tolerance and induce the sustained biochemical remission of type 2 diabetes. This pathophysiological insight may have major implications and may cause a paradigm shift in the management of type 2 diabetes: avoiding/reducing ectopic fat accumulation in the liver and pancreas may both be essential to prevent and cure type 2 diabetes.

Association between insulin resistance and multiple sclerosis: a systematic review and meta-analysis.

There is increasing evidence of metabolic perturbations in multiple sclerosis (MS) patients, and insulin is an important parameter that has controversial effects on neurological disease. Therefore, this systematic review and meta-analysis study aimed to explore the association between insulin resistance (IR) and MS as well as insulin levels and MS. Three electronic databases, including Medline, Scopus, and the Web of Science, were examined up to 26 May 2023 for observational studies. Two independent reviewers assessed the studies according to a pre-specified protocol. Random-effects model using a Restricted-maximum Likelihood (REML) estimator was used to meta-analyze the association between IR [assessed by Homeostatic Model Assessment (HOMA-IR)], insulin and MS. Eighteen datasets from 2012 to 2022 were included in this meta-analysis. The standardized mean difference (SMD) for comparison IR and insulin between MS and healthy control group as outcomes 1 and 2 were 0.78 and 0.72 respectively. Furthermore, for outcome 1, we observed a greater effect size in studies that recruited different types of MS (Mix) (SMD: 1.09) than in those that included only relapsing-remitting MS (RRMS) (SMD: 0.59). The meta-analysis revealed a significant association between IR, insulin and MS, with stronger associations in studies that recruited mixed patients. However, high heterogeneity has been observed in the present study. Therefore, more studies are needed to confirm the association between these parameters and MS.

Therapeutic potential of acarbose in ameliorating the metabolic and endocrinological complications of polycystic ovarian syndrome: a review.

Polycystic ovarian syndrome is a perplexed condition addressing endocrinal, cardiometabolic and gynaecological issues. It affects women of adolescent age and is drastically increasing in the Indo-Asian ethnicity over the recent years. According to Rotterdam criteria, PCOS is characterized by clinical or biochemical excess androgen and polycystic ovarian morphology; however, it has been established in the recent years that PCOS exacerbates to further serious metabolic conditions on the long term. This is a narrative literature review and not systematic review and is based on PubMed searches with relevant keywords "Polycystic ovarian syndrome AND acarbose OR metformin OR myoinositol; PCOS AND metabolic syndrome OR cardiovascular disease OR menstrual irregularity OR infertility OR chronic anovulation OR clinical hyperandrogenism" used in the title and are limited to articles published in English language with no time limits. A prominent aspect of PCOS is hyperandrogenaemia and hyperinsulinemia. About 50-70% of afflicted women have compensatory hyperinsulinemia and close to one tierce suffer from anovulation and infertility. Insulin resistance leads to metabolic complications and works with luteinizing hormone in increasing the ovarian androgen production. This excess androgen leads to clinical manifestations, irregular menstrual cycles and infertility. There isn't an entire cure, only the symptomatic clinical factors are considered rather than focusing on the underlying long-term complications. Therefore, the article focuses on a potent alpha glucosidase inhibitor, acarbose which suppresses the post meal glucose and insulin by delaying the absorption of complex carbs. It exhibits cardio-metabolic and hormonal benefits and is well tolerable in the south asian population. This review highlights the safety, effectiveness of acarbose in ameliorating the long-term complications of PCOS.

Acne Keloidalis Nuchae in a Caucasian Non-Hispanic Woman With Metabolic Syndrome and Autoimmune Thyroiditis: A Case Report.

Acne keloidalis nuchae (AKN) is a rare dermatological condition primarily observed in men of African descent. We present a remarkable case of AKN in a 38-year-old Caucasian non-Hispanic woman with metabolic syndrome and autoimmune thyroiditis. After appropriate treatment during the one-year follow-up (including oral antibiotics, insulin sensitizers, levothyroxine, spironolactone and liraglutide), the patient demonstrated a visible reduction in plaque size and improvement of overall symptoms. Importantly, this improvement persisted even in the absence of topical treatment, further supporting the notion that hormonal abnormalities may play a significant role in the pathogenesis of AKN. This case report highlights the potential link between AKN and endocrinologic disorders, such as metabolic syndrome and autoimmune thyroiditis. However, further research is warranted to elucidate the underlying mechanisms and establish the causative relationship. Early recognition, appropriate management of associated conditions, and tailored treatment strategies may lead to better outcomes and improved quality of life.

Insulin Resistance/Hyperinsulinemia, Neglected Risk Factor for the Development and Worsening of Heart Failure with Preserved Ejection Fraction.

Heart failure (HF) has become a subject of continuous interest since it was declared a new pandemic in 1997 because of the exponential increase in hospitalizations for HF in the latest years. HF is the final state to which all heart diseases of different etiologies lead if not adequately treated. It is highly prevalent worldwide, with a progressive increase with age, reaching a prevalence of 10% in subjects over the age of 65 years. During the last two decades, it was possible to see that the prevalence of heart failure with preserved ejection fraction (HFpEF) was increasing while that of heart failure with reduced ejection fraction (HFrEF) was decreasing. HFpEF is typically characterized by concentric remodeling of the left ventricle (LV) with impaired diastolic function and increased filling pressures. Over the years, also the prevalence of insulin resistance (IR)/hyperinsulinemia (Hyperins) in the general adult population has progressively increased, primarily due to lifestyle changes, particularly in developed and developing countries, with a range that globally ranges between 15.5% and 46.5%. Notably, over 50% of patients with HF also have IR/Hyperins, and the percentage is even higher in those with HFpEF. In the scientific literature, it has been well highlighted that the increased circulating levels of insulin, associated with conditions of insulin resistance, are responsible for progressive cardiovascular alterations over the years that could stimulate the development and/or the worsening of HFpEF. The aim of this manuscript was to review the scientific literature that supports a pathophysiologic connection between IR/Hyperins and HFpEF to stimulate the scientific community toward the identification of hyperinsulinemia associated with insulin resistance as an independent cardiovascular risk factor in the development and worsening of HF, believing that its adequate screening in the general population and an appropriate treatment could reduce the prevalence of HFpEF and improve its progression.