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Beckwith-Wiedemann syndrome (BWS) is a rare genetic disorder characterized by genetic and epigenetic changes on the chromosome 11p15.5 region, which includes genes that are important for fetal and postnatal growth. Children with BWS have a higher chance of having hypoglycemia, hyperinsulinemia, and malignancies early in life, although hypoglycemia caused by an insulinoma that develops later in life has not been reported. We describe the diagnosis of insulinoma in a 53-year-old man with BWS in this case report. This is the first case report of insulinoma in an adult with this syndrome. [ABSTRACT FROM AUTHOR]

Diabetes and its major key determinants insulin resistance and hyperglycemia are known risk factors for calcific aortic valve disease (CAVD). The processes leading to molecular and structural alterations of the aortic valve are yet not fully understood. In previous studies, we could show that valvular interstitial cells (VIC) display canonical elements of classical insulin signaling and develop insulin resistance upon hyperinsulinemia and hyperglycemia accompanied by impaired glucose metabolism. Analyses of cultured VIC and aortic valve tissue revealed extracellular matrix remodeling and degenerative processes. Since PI3K signaling through mammalian target of rapamycin (mTOR) is involved in fibrotic processes of the heart, we aim at further functional investigation of this particular Akt-downstream signaling pathway in the context of diabetes-induced CAVD. Primary cultures of VIC were treated with hyperinsulinemia and hyperglycemia. Phosphorylation of mTOR(Ser2448) was determined by Western blot analysis after acute insulin stimulus. Inhibition of mTOR phosphorylation was performed by rapamycin. Phosphorylation of mTOR complex 1 (MTORC1) downstream substrates 4E-BP1(Thr37/46) and P70S6K(Thr389), and MTORC2 downstream substrate Akt(Ser473) as well as the PDK1-dependent phosphorylation of Akt(Thr308) was investigated. Markers for extracellular matrix remodeling, cell differentiation and degenerative changes were analyzed by Western blot analysis, semi-quantitative real-time PCR and colorimetric assays. Hyperinsulinemia and hyperglycemia lead to alterations of VIC activation, differentiation and matrix remodeling as well as to an abrogation of mTOR phosphorylation. Inhibition of mTOR signaling by rapamycin leads to a general downregulation of matrix molecules, but to an upregulation of α-smooth muscle actin expression and alkaline phosphatase activity. Comparison of expression patterns upon diabetic conditions and rapamycin treatment reveal a possible regulation of particular matrix components and key degeneration markers by MTORC1 downstream signaling. The present findings broaden the understanding of mitogenic signaling pathways in VIC triggered by hyperinsulinemia and hyperglycemia, supporting the quest for developing strategies of prevention and tailored treatment of CAVD in diabetic patients.

Objective: Cellular senescence, an irreversible proliferative cell arrest, is caused by excessive intracellular or extracellular stress/damage. Increased senescent cells have been identified in multiple tissues in different metabolic and other aging-related diseases. Recently, several human and mouse studies emphasized the involvement of senescence in development and progression of NAFLD. Hyperinsulinemia, seen in obesity, metabolic syndrome, and other conditions of insulin resistance, has been linked to senescence in adipocytes and neurons. Here, we investigate the possible direct role of chronic hyperinsulinemia in the development of senescence in human hepatocytes. Methods: Using fluorescence microscopy, immunoblotting, and gene expression, we tested senescence markers in human hepatocytes subjected to chronic hyperinsulinemia in vitro and validated the data in vivo by using liver-specific insulin receptor knockout (LIRKO) mice. The consequences of hyperinsulinemia were also studied in senescent hepatocytes following doxorubicin as a model of stress-induced senescence. Furthermore, the effects of senolytic agents in insulin- and doxorubicin-treated cells were analyzed. Results: Results showed that exposing the hepatocytes to prolonged hyperinsulinemia promotes the onset of senescence by increasing the expression of p53 and p21. It also further enhanced the senescent phenotype in already senescent hepatocytes. Addition of insulin signaling pathway inhibitors prevented the increase in cell senescence, supporting the direct contribution of insulin. Furthermore, LIRKO mice, in which insulin signaling in the liver is abolished due to deletion of the insulin receptor gene, showed no differences in senescence compared to their wild-type counterparts despite having marked hyperinsulinemia indicating these are receptor-mediated effects. In contrast, the persistent hyperinsulinemia in LIRKO mice enhanced senescence in white adipose tissue. In vitro, senolytic agents dasatinib and quercetin reduced the prosenescent effects of hyperinsulinemia in hepatocytes. Conclusion: Our findings demonstrate a direct link between chronic hyperinsulinemia and hepatocyte senescence. This effect can be blocked by reducing the levels of insulin receptors or administration of senolytic drugs, such as dasatinib and quercetin.

BackgroundInsulin resistance and/or hyperinsulinemia are closely linked to adiposity, metabolic syndrome (MetS) and prolonged inflammatory processes.MethodsWe retrospectively analyzed 1,018 adult individuals with a mean age of 46 years (74% male) and classified them as: Metabolically normal: without any of the five criteria of the International Diabetes Federation (IDF) used for the diagnosis of MetS, plus normal fasting insulin (Men < 8 mU/L, Women < 10 mU/L); Level 1 MetS: with one or two IDF criteria, plus hyperinsulinemia (Men: ≥ 8 mU/L), and Women: ≥ 10 mU/L); Level 2 MetS: with three or more IDF criteria, plus hyperinsulinemia.ResultsThe mean values for fasting insulinemia in metabolically normal individuals was 4.6 ± 1.8 mU/L and 5.6 ± 2.3 mU/L, while their means for the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) were 1.0 and 1.2 for men and women, respectively. In addition, the mean values for insulin (and HOMA-IR) for individuals with two normal anthropometric parameters (body mass index and waist girth), or two normal anthropometric parameters plus no IDF criteria, were similar to the metabolically normal group. Based on the obtained mean + 2 SD, we established the following insulin (and HOMA-IR) values as diagnostic cut-offs for hyperinsulinemia: Men: ≥ 8 mU/L (≥ 1.5), and Women: ≥ 10 mU/L (≥ 2.0). The mean serum insulin was significantly higher for individuals with Level 1 MetS (approx. 9 mU/L for both genders) compared with metabolically normal individuals, as was the prevalence of hepatic steatosis, which was more evident in men. Thus, the presence of one or two abnormal IDF criteria, combined with hyperinsulinemia and/or raised HOMA-IR, suggests the presence of MetS and insulin resistance. Patients of both genders with Level 2 MetS had higher serum insulin and/or HOMA-IR values than Level 1, as well as a higher prevalence of hypertension and hepatic steatosis, being more pronounced among men. The process was progressive and proportional to the degree of hyperinsulinemia.ConclusionIt is proposed that intervention against MetS progression should be started in individuals with Level 1 MetS, rather than waiting for more criteria for diagnostic confirmation, which this should help to reduce the occurrence of known complications such as type 2 diabetes, atherosclerosis, hypertension, and chronic kidney disease, among others.

Abstract Background We aim to assess the association of empirical dietary (EDIH) and lifestyle (ELIH) index for hyperinsulinemia with the risk of insulin resistance, hyperinsulinemia, insulin sensitivity, and β-cell dysfunction in Iranian adults. Methods In this prospective study, a total of 1244 men and women aged ≥ 20 years were selected among participants of the Tehran lipid and glucose study and followed for 3.2 years. Dietary intakes were assessed using a valid semi-quantitative food frequency questionnaire. Dietary and lifestyle insulinemic potential indices were calculated using dietary intake, body mass index, and physical activity information. Multivariable logistic regression was used to estimate the associated risk of a 3-year incidence of insulin-related disorders. Results The mean ± SD age and BMI of all eligible participants (42.7% males) were 43.0 ± 13.0 and 27.4 ± 4.9 in the study's baseline. After adjusting for all potential confounders, participants in the highest tertile of ELIH score had a greater risk of developing hyperinsulinemia (OR:2.42, 95%CI:1.52–3.86, P for trend =

ABSTRACT Objective: To study the association of SLC16A11 gene variants with obesity and metabolic markers in nondiabetic Chilean adults. Materials and methods: This cross-sectional study included 263 non-diabetic adults. The genotype of the rs75493593 polymorphism of SLC16A11 gene was performed by real-time PCR. It's association with adiposity markers (body weight, BMI, waist circumference and fat mass percentage), metabolic markers (glucose, insulin, HOMAIR, leptin, total cholesterol, LDLc, HDLc, triglycerides, ALT, GGT and hsCRP) and blood pressure was analyzed by linear regression. Results: The minor allele (T) of the SLC16A11 gene (rs75493593) has a frequency of 29.7% among Chileans. Risk genotypes (GT and TT) were associated with a significant 1.49 mU/l increase in plasmatic insulin for each copy of the minor allele (95% CI: 0.12, 2.87, p < 0.05). This association remained significant after adjusting for socio-demographic variables, physical activity and smoking (1.36 mU/l, 95% CI: 0.16, 2.58 p < 0.05), but was lost when BMI was included as a confounding factor. Higher BMI was also significantly associated with polymorphic genotypes in SLC16A11, independent of socio-demographic variables. Conclusion: The minor allele of the SLC16A11 gene (T) is highly prevalent among Chileans and is associated with increased insulin and BMI in nondiabetic individuals. These findings suggest that the genetic variant in SLC16A11 is not only associated with type 2 diabetes as previously shown in Mexicans, but is also related to early metabolic alterations in healthy subjects that may lead to type 2 diabetes.

Obesity is a multifactorial disease whose onset and development are shaped by the individual genetic background. The melanocortin 4 receptor gene (MC4R) is involved in the regulation of food intake and energy expenditure. Some of the single nucleotide polymorphisms (SNPs) of this gene are related to obesity and metabolic risk factors. The present study was undertaken to assess the relationship between three polymorphism SNPs, namely, rs17782313, rs17773430 and rs34114122, and obesity and metabolic risk factors. One hundred seventy-eight children with obesity aged between 7 and 16 years were studied to determine anthropometric variables and biochemical and inflammatory parameters. Our results highlight that metabolic risk factors, especially alterations in carbohydrate metabolism, were related to rs17782313. The presence of the minor C allele in the three variants (C–C–C) was significantly associated with anthropometric measures indicative of obesity, such as the body mass and fat mass indexes, and increased the values of insulinemia to 21.91 µIU/mL with respect to the wild type values. Our study suggests that the C–C–C haplotype of the SNPs rs17782313, rs17773430 and rs34114122 of the MC4R gene potentiates metabolic risk factors at early ages in children with obesity.

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. Figure illustrating the Sequential Milestones in the Emergence of Hepatogenous Diabetes in Liver Cirrhosis Patients. The cascade begins with insulin resistance induced by liver cirrhosis, subsequently leading to β-cell dysfunction. This dual mechanism triggers a progressive deterioration in glucose tolerance, ultimately culminating in the onset of hepatogenous diabetes. The intricate interplay of these events mirrors the complex pathophysiological changes associated with liver cirrhosis. Noteworthy stages include transitions from Normal Glucose Tolerance (NGT) to Impaired Glucose Tolerance (IGT) and finally to Diabetes Mellitus (DM). This comprehensive visualization underscores the dynamic and interconnected nature of the processes contributing to hepatogenous diabetes in the context of liver cirrhosis. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Betaxanthin reduces metabolic dysfunction in postmenopausal mouse models. • Betaxanthin decreases lung tumor growth in postmenopausal mouse models Betaxanthin mitigates pre-existing lung tumor growth in postmenopausal obese mouse model. • Betaxanthin inhibits lung cancer cell proliferation and migration in response to insulin challenge. • Betaxanthin suppresses tumor growth in the setting of hyperinsulinemia. • Betaxanthin improves SIRT3 expression levels in the lung tumor. Metabolic disturbances associated with obesity increase the risk and advancement of various tumor forms, including postmenopausal lung cancer, in humans. Betaxanthin, a type of yellow-orange pigment found in certain plants, particularly in some flowers, fruits, and vegetables, can be utilized to inhibit the growth of tumors and lessen the metabolic dysfunctions brought on by obesity. However, the functional role of betaxanthin (BET) in suppressing lung cancer progression and its potential mechanisms are still not fully understood. In this study, we examined the regulation of BET in obese mice with postmenopausal lung cancer receiving a high-fat diet (HFD). Initially, we found that BET could significantly mitigate the metabolic dysfunction that a high-fat diet causes in mice. Improved histological changes in the mammary fat pad, lower hepatic lipid deposition, and improved glucose tolerance and insulin resistance demonstrated this. Following that, BET treatment inhibited the formation of lung neoplasms in in-situ cancer animal models that were stimulated by HFD. Furthermore, in a postmenopausal mouse model fed HFD, BET significantly reduced the growth of pre-existing lung tumors, as well as attenuating metabolic abnormalities. Notably, in vitro research revealed that BET co-culture significantly reduced the proliferation and migration of mouse lung cancer cells, whereas insulin exposure increased these processes. Research on animals verified that lung cancer progressed due to hyperinsulinemia; however, BET treatment might inhibit this condition in postmenopausal mice on a high-fat diet. BET could up-regulate sirtuin 3 (SIRT3) expression levels in tumor, liver, and mammary fat pad tissues in postmenopausal mice with HFD-induced obesity, according to a bioinformatic and molecular biology study. Crucially, eradicating SIRT3 expression completely eliminated BET's inhibitory effects on insulin-stimulated cancer cell proliferation and migration. This suggests that increasing SIRT3 expression may be required for BET to perform its anti-tumor function against lung cancer in conditions of hyperinsulinemia. Our findings showed that by modifying SIRT3 signaling, BET consumption is probably effective in the prevention and treatment of obesity-related lung cancer. [ABSTRACT FROM AUTHOR]

Insulin, a principal anabolic hormone produced by pancreatic β-cells, has a primary function of storage of nutrients following excessive energy intake. Pre- or early type 2 diabetes stages present hyperinsulinemia (β-cell dysfunction) and insulin resistance. Initiation of hyperinsulinemia is triggered by a loss of first-phase glucose-stimulated insulin secretion with altered membrane ion channel distribution. More factors, including insulin resistance and excessive proliferation of β-cells, deteriorate the hyperinsulinemia, whereas the hyperinsulinemia contributes to further development of insulin resistance and type 2 diabetes; to develop eventually late-stage diabetes with absolute insulin deficiency. In this mini-review, the major focus was put on the causes and pathophysiology of hyperinsulinemia, and the metabolic consequences and current treatment of hyperinsulinemia were discussed. The data used in this narrative review were collected mainly from relevant discoveries in the past 3 years. [ABSTRACT FROM AUTHOR]

Obesity is a global epidemic that drives morbidity and mortality through cardiovascular disease, diabetes, and non‐alcoholic fatty liver disease (NAFLD). No definitive therapy has been approved to improve glycemic control and treat NAFLD in obese patients. Here, we investigated a semi‐synthetic, long chain, structurally‐engineered fatty acid‐1024 (SEFA‐1024), as a treatment for obesity‐induced hyperglycemia, insulin‐resistance, and fatty liver disease in rodent models. A single dose of SEFA‐1024 was administered to evaluate glucose tolerance and active glucagon‐like peptide 1 (GLP‐1) in lean rats in the presence and absence of a DPP‐4 inhibitor. The effects of SEFA‐1024 on weight loss and glycemic control were assessed in genetic (ob/ob) and environmental (high‐fat diet) murine models of obesity. Liver histology, serum liver enzymes, liver lipidomics, and hepatic gene expression were also assessed in the high‐fat diet murine model. SEFA‐1024 reversed obesity‐associated insulin resistance and improved glycemic control. SEFA‐1024 increased active GLP‐1. In a long‐term model of diet‐induced obesity, SEFA‐1024 reversed excessive weight gain, hepatic steatosis, elevated liver enzymes, hepatic lipotoxicity, and promoted fatty acid metabolism. SEFA‐1024 is an enterohepatic‐targeted, eicosapentaenoic acid derivative that reverses obesity‐induced dysregulated glucose metabolism and hepatic lipotoxicity in genetic and dietary rodent models of obesity. The mechanism by which SEFA‐1024 works may include increasing aGLP‐1, promoting fatty acid oxidation, and inhibiting hepatic triglyceride formation. SEFA‐1024 may serve as a potential treatment for obesity‐related diabetes and NAFLD. [ABSTRACT FROM AUTHOR]

Background: Previous studies have cited insulin-related disorders, including hyperinsulinemia, as one of the main causes of obesity risk and metabolic disorders. We aimed to investigate the association of the Empirical Dietary Index for Hyperinsulinemia (EDIH) and Empirical Lifestyle Index for Hyperinsulinemia (ELIH) with the risk of obesity phenotypes among Iranian adults.Methods: Present study was conducted on 2705 subjects, including 1604 metabolically healthy normal weights (MHNW) and 1101 metabolically healthy obesity (MHO) individuals. Obesity phenotypes, including MHNW, MHO, metabolically unhealthy normal weights (MUNW), and metabolic unhealthy obesity (MUO), were determined using the criteria of the Joint International statement (JIS) for metabolic syndrome. Dietary intake data from the previous year was gathered using a food frequency questionnaire. Cox proportional hazard regression was used to estimate the hazard ratio and 95% confidence intervals (HRs and 95% CIs) of obesity phenotypes incident across tertiles of EDIH and ELIH scores.Results: The mean ± SD of age and BMI of all participants were 33.5 ± 12.2 years and 24.3 ± 3.8 kg/m2, respectively. In the multivariable-adjusted model, a higher ELIH score was associated with a greater risk for incidence of MUO (HR: 3.47, 95%CI: 2.54-4.74; Ptrend =  < 0.001) and MHO (HR: 3.61, 95%CI: 2.73-4.77; Ptrend =  < 0.001). Also, a higher score of EDIH was related to an increased risk of MUO incidence (HR: 1.35, 95%CI: 1.02-1.79; P for trend = 0.046). However, there was no significant association between a higher score of EDIH and the risk of MHO.Conclusion: Our findings revealed that a high insulinemic potential of diet and lifestyle, determined by EDIH and ELIH indices, may be related to an increase in the simultaneous occurrence of obesity with metabolic disorders in Iranian adults. [ABSTRACT FROM AUTHOR]

Hyperinsulinemia is a condition with extremely high levels of insulin in the blood. Various factors can lead to hyperinsulinemia in children and adolescents. Puberty is a period of significant change in children and adolescents. They do not have to have explicit symptoms for prediabetes, and certain health indicators may indicate a risk of developing this problem. The scientific study is designed as a cross-sectional study. In total, 674 children and adolescents of school age from 12 to 17 years old participated in the research. They received a recommendation from a pediatrician to do an OGTT (Oral Glucose Tolerance test) with insulinemia at a regular systematic examination. In addition to factor analysis, the study of the influence of individual factors was tested using RBF (Radial Basis Function) and SVM (Support Vector Machine) algorithm. The obtained results indicated statistically significant differences in the values of the monitored variables between the experimental and control groups. The obtained results showed that the number of adolescents at risk is increasing, and, in the presented research, it was 17.4%. Factor analysis and verification of the SVM algorithm changed the percentage of each risk factor. In addition, unlike previous research, three groups of children and adolescents at low, medium, and high risk were identified. The degree of risk can be of great diagnostic value for adopting corrective measures to prevent this problem and developing potential complications, primarily type 2 diabetes mellitus, cardiovascular disease, and other mass non-communicable diseases. The SVM algorithm is expected to determine the most accurate and reliable influence of risk factors. Using factor analysis and verification using the SVM algorithm, they significantly indicate an accurate, precise, and timely identification of children and adolescents at risk of hyperinsulinemia, which is of great importance for improving their health potential, and the health of society as a whole. [ABSTRACT FROM AUTHOR]

Background: Androgens excess results in endoplasmic reticulum (ER) stress, which is an important cause of β cells dysfunction. Here, we investigated the molecular regulation of androgens excess, ER stress, and β-cell function in polycystic ovary syndrome (PCOS). Methods: PCOS mouse model was established by injection of DHEA. Primary cultured mouse islets were used to detect testosterone (TE)-induced ER stress. The response of ER stress, apoptosis, and hyperinsulinemia were analyzed in INS-1 cells with or without TE exposure. Androgen receptor (AR) antagonist and ER stress inhibitor treatment was performed to evaluate the role of TE in ER stress and proinsulin secretion of PCOS mice. Results: PCOS mice had higher ER stress in islets. TE exposure induced ER stress and apoptosis significantly through sustaining insulin overexpression in β cells, which in turn impaired proinsulin maturation and secretion. Blocking this pro cess could significantly relieve ER stress and apoptosis and improve insulin homeostasis. Conclusion: ER stress activated by androgens excess in PCOS contributes to β cell dysfunction and hyperinsulinemia.

Abstract Background Neuromyelitis optica spectrum disorder (NMOSD) is associated with inflammatory mediators that may also trigger downstream signaling pathways leading to reduce insulin sensitivity. Methods We aimed to determine the risk association of hyperinsulinemia in NMOSD patients with seropositive AQP4-IgG and the serum levels of interleukin (IL)-6 and IL-17A compared with the control group. Serum levels of metabolic (Insulin, Fasting Blood Sugar (FBS), lipid profile) and inflammatory (IL-6 and IL-17) markers were assessed in 56 NMOSD patients and 100 controls. Results Hyperinsulinemia was more prevalent in NMOSD patients independent of age, sex and body mass index (BMI) (48.2% vs. 26%, p = 0.005) compared to control group. After adjusting age, sex and BMI, there was significant association between lower insulin sensitivity (IS) and NMOSD risk (95% CI: Beta = 0.73, 0.62 to 0.86, p = 0.0001). Circulating levels of IL-6 and IL-17 were higher in NMOSD patients, and only IL-6 had an effect modifier for the association between lower insulin sensitivity and NMOSD risk. Conclusions Our data suggests that inflammatory pathogenesis of NMOSD leads to hyperinsulinemia and increases the risk of insulin resistance.

Abstract Background We aimed to assess the associations between insulinemic potential of diet and lifestyle and the risk of diabetes incident, using four empirical indices including the empirical dietary index for hyperinsulinemia (EDIH), the empirical dietary index for insulin resistance (EDIR), empirical lifestyle index for hyperinsulinemia (ELIH), and empirical lifestyle index for insulin resistance (ELIR). Methods A total of 3734 individuals, aged ≥ 20 years old, who were free of diabetes at baseline (2008–2011), were followed for 6.2 years (2015–2018) to ascertain incident diabetes. The food frequency questionnaire was used to collect dietary intakes at baseline. Odds ratio (OR) of diabetes were calculated across quartiles of EDIH, EDIR, ELIH, and ELIR using logistic regression, which controlled for confounding factors. Results The mean ± SD age and BMI of individuals (45.1 % male) were 40.9 ± 12.0 years and 27.1 ± 4.1 kg/m2, respectively. At the end of follow-up, 253 (6.8 %) diabetes cases were identified. In the multivariable-adjusted model, individuals in the highest quartile of EDIR (1.58;95 %CI:1.03–2.44, P for trend = 0.025), ELIH (1.89;95 %CI:1.20–2.97, P for trend = 0.004), and ELIR (1.74; 95 %CI:1.11–2.72, P for trend = 0.031) had increased the risk of diabetes. However, no significant associations were found between the score of EDIH and diabetes incident. Conclusions Higher adherence to EDIR, ELIH, and ELIR scores were associated with increased risk of diabetes, while no significant association was found between EDIH score and diabetes incident.

Introduction. Pre-eclampsia (PE) continues to be the leading problem in obstetrics. The existing methods for predicting PE show insufficient efficiency, and therefore the search for new predictors of PE remains relevant.The goal of the study. To develop a method for staged stratification of pregnant women to the risk of PE according on the basis of the revealed dismetabolic features of the pathogenesis of this complication of gestation.Material and methods. A dynamic clinical and laboratory examination of 180 pregnant women with independent factors of high risk of PE was carried out. PE was revealed in 89 women who made up group I. Group II (control) consisted of 30 healthy pregnant women with the physiological gestation.Results and discussion. A statistically significant increase in diabetogenic and atherogenic changes characteristic of physiological pregnancy, changes in hormonal, endothelial-hemostasiological, pro-inflammatory and placental parameters aimed at the energy and plastic supply of the fetus was revealed in women with PE. The results of laboratory examination, statistical data processing showed that the most significant pathogenetic mechanisms of development of PE are pathological insulin resistance (IR) and hyperinsulinemia (HI), which act as the basic link and initiate atherogenic transformation of the lipid profile, pro-inflammatory and immunometabolic disorders, prothrombotic status, hyperleptinemia, hyperuricemia, antiangiogenic state and endothelial dysfunction, which indicates a pronounced pathogenetic and clinical similarity of PE and metabolic syndrome. The revealed features of the pathogenesis of PE were reflected in the method of staged risk stratification of pregnant women: the models for assessing the individual risk of PE implementation included the levels of insulin, PlGF, PAMG-1, and TNF-α at 11–14 weeks of gestation; levels of insulin, uric acid, TNF-α, and mean platelet volume at 18-21 weeks of gestation (I trimester – AUC = 0.886, Se = 86.7%, Sp = 84.3%; II trimester - AUC = 0.874, Se = 83.3%, Sp = 87.2%, р < 0.001).Conclusion. Practical application of the developed pathogenetically substantiated method of staged stratification of pregnant women by the risk of PE implementation will justify the appointment and enhancement of preventive measures, reduce the incidence of severe and complicated forms of PE, and improve gestational and perinatal outcomes.

Abstract Diet‐induced obesity, the metabolic syndrome, type 2 diabetes (DIO/MetS/T2DM), and their adverse sequelae have reached pandemic levels. In mice, DIO/MetS/T2DM initiation involves diet‐dependent increases in lipids that activate hepatic atypical PKC (aPKC) and thereby increase lipogenic enzymes and proinflammatory cytokines. These or other hepatic aberrations, via adverse liver‐to‐muscle cross talk, rapidly impair postreceptor insulin signaling to glucose transport in muscle. The ensuing hyperinsulinemia further activates hepatic aPKC, which first blocks the ability of Akt to suppress gluconeogenic enzyme expression, and later impairs Akt activation, further increasing hepatic glucose production. Recent findings suggest that hepatic aPKC also increases a proteolytic enzyme that degrades insulin receptors. Fortunately, all hepatic aberrations and muscle impairments are prevented/reversed by inhibition or deficiency of hepatic aPKC. But, in the absence of treatment, hyperinsulinemia induces adverse events, some by using “spare receptors” to bypass receptor defects. Thus, in brain, hyperinsulinemia increases Aβ‐plaque precursors and Alzheimer risk; in kidney, hyperinsulinemia activates the renin–angiotensin–adrenal axis, thus increasing vasoconstriction, sodium retention, and cardiovascular risk; and in liver, hyperinsulinemia increases lipogenesis, obesity, hepatosteatosis, hyperlipidemia, and cardiovascular risk. In summary, increases in hepatic aPKC are critically required for development of DIO/MetS/T2DM and its adverse sequelae, and therapeutic approaches that limit hepatic aPKC may be particularly effective.

Background: Pathological insulin resistance in pregnancy is associated with an increased risk for complications such as gestational diabetes mellitus and pre-eclampsia. Individuals with pathological insulin resistance also exhibit hyperinsulinaemia. Currently, there are no diagnostic criteria for pathological hyperinsulinaemia in pregnancy that may be used to indicate risk of adverse outcomes. Aim: This case series aimed to explore the relationship between first trimester insulin response patterns and gestational outcomes. Setting: Auckland, New Zealand. Methods: Participants included four pregnant women with prepregnancy body mass index ≥ 25 kg/m2 and aged 25–35 years. Glucose and insulin response patterns were examined following a 120 min oral glucose tolerance test (OGTT) at 12–15 weeks of gestation using a modified Kraft methodology. Outcomes assessed at 25 and 35 weeks of gestation included gestational weight gain (GWG), blood pressure, fasting capillary blood glucose and foetal growth. Lifestyle and medical information were collected at each trimester. After delivery, total GWG, infant size, delivery method and clinical outcomes were recorded. Results: Kraft pattern IIB hyperinsulinaemia was identified in two cases. Amongst them, Case #1 experienced excessive GWG, induction of labour and surgically assisted delivery. Case #4 delivered by emergency caesarean, and the neonate required intensive care admission for 17 h. No cases developed hyperglycaemia or hypertension. Infant weights were between 3.75 kg and 3.86 kg. Conclusion: Dynamic insulin assay provides a promising template to assess metabolic risk in the first trimester of pregnancy. Diagnosing hyperinsulinaemia early in pregnancy means that lifestyle-based initiatives could be introduced earlier to mitigate excess GWG and potential adverse outcomes.

Background: Women with polycystic ovarian syndrome (PCOS) have insulin resistance and hyperinsulinemia that may play a key role in the pathogenesis of PCOS. Objectives: To determine and compare glucose-insulin ratio in hyper-insulinemic women with the polycystic ovarian syndrome and healthy controls. Materials & Methods: A cross-sectional comparative study was conducted at Lahore General Hospital. A total of 80 women 24-35 years of age were recruited from Lahore General Hospital. 50 women had PCOS, and 30 were healthy controls. PCOS was diagnosed by using the Rotterdam criteria. Height, weight, and waist circumference were measured. Glucose and insulin were estimated by the glucose oxidase method and ELISA, respectively. HOMA-IR was calculated to determine insulin resistance (IR). HOMA- β was calculated to assess the β-cell function. Fasting glucose and insulin ratio were also calculated. Results: Mean age of the women with PCOS and healthy controls was 29.89±3.54 and 28.60±1.12 years, respectively (p>0.54). BMI and waist circumference of women with PCOS were higher compared to healthy controls (p>0.45). Fasting glucose, fasting insulin, HOMA- β, and IR were significantly higher in women with PCOS compared to healthy controls (p

BackgroundThere is a limited number of studies on the dose-response relationship between serum uric acid and impaired glucose metabolism in people without diabetes, and no large-scale research exploring the relationship in women without diabetes is based on menopausal status. Consequently, the present study aimed to investigate the above relationship in United States adults without diabetes.Materials and MethodsData from 2,498 men and 2,650 women aged ≥20 years were obtained from the National Health and Nutrition Examination Survey 2011–2016 conducted in the United States. Binary logistic regression analysis was applied to evaluate the association between uric acid and impaired glucose metabolism. Restricted cubic spline analysis, sensitivity analysis, and stratified analysis by menopausal status were performed to explore the above relationships.ResultsA positive correlation was found between uric acid and the risk of insulin resistance in all participants (P < 0.05). In binary logistic regression analysis, after adjusting for confounding factors, compared with the lowest quartile of uric acid, the odds ratio (95% confidence intervals) of insulin resistance in the highest quartile was 1.9 (1.1–3.1) and 2.2 (1.2–4.3) in men and women, respectively. A significant positive relationship was also observed between uric acid and impaired fasting glucose and hyperinsulinemia in women, while in men, uric acid was positively associated with the risk of hyperinsulinemia but not impaired fasting glucose. Restricted cubic spline showed that the odds ratios of insulin resistance and hyperinsulinemia increased with elevating uric acid levels in both men and women. When stratified by menopause, the association remained significant in pre-menopausal women aged ≥20, but insignificant in post-menopausal women.ConclusionUric acid was positively associated with the risk of impaired glucose metabolism in a cohort of United States adults, and uric acid increased the risk of insulin resistance in pre-menopausal, but not in post-menopausal women.

Introduction and purpose: Insulin resistance (IR) is a health problem as it can accompany obesity and lead to serious metabolic complications. In recent years, it has been "overdiagnosed" in clinical practice due to the lack of specific diagnostic criteria. The article summarizes the current knowledge in the field of pathophysiology, clinical picture and diagnostics. State of knowledge: Obesity remains the leading cause of IR, especially in the 21st century. In a positive energy balance, the adipocyte overloaded with fat protects itself against further influx of glucose and fats and becomes insulin insensitive. A component of IR development is subclinical inflammation of macrophage-rich adipose tissue which is exacerbated by an adipocytokine imbalance, which in turn generates IR. The markers of cellular resistance to insulin are free fatty acids in the bloodstream which are responsible for the lipotoxicity in hepatocytes and myocytes. Compensatory fasting hyperinsulinemia, which is currently considered the most sensitive diagnostic criterion, provides evidence of IR. An effective method of sensitizing cells to insulin is lifestyle modification, including a low-energy diet with regular physical activity in the form of aerobic-resistance exercise. Literature recommends no pharmacological treatment of IR alone, without obesity or other concomitant diseases. Conclusions: IR is not a separate disease, but only a pathological expression of cells' adaptation to excess of consumed energy. However, in its systemic form, when the protective mechanisms become ineffective, it induces metabolic disturbances. Only the causal treatment of IR guarantees therapeutic success.

Insulin resistance is a risk factor for Alzheimer's disease (AD), although its role in AD etiology is unclear. We assessed insulin resistance using fasting and insulin-stimulated measures in 51 elderly subjects with no dementia (ND; n = 37) and with cognitive impairment (CI; n = 14). CI subjects exhibited either mild CI or AD. Fasting insulin resistance was measured using the homeostatic model assessment of insulin resistance (HOMA-IR). Insulin-stimulated glucose disposal was assessed using the hyperinsulinemic-euglycemic clamp to calculate glucose disposal rate into lean mass, the primary site of insulin-stimulated glucose disposal. Because insulin crosses the blood-brain barrier, we also assessed whether insulin infusion would improve verbal episodic memory compared to baseline. Different but equivalent versions of cognitive tests were administered in counterbalanced order in the basal and insulin-stimulated state. Groups did not differ in age or body mass index. Cognitively impaired subjects exhibited greater insulin resistance as measured at fasting (HOMA-IR; ND: 1.09 [1.1] vs. CI: 2.01 [2.3], p = 0.028) and during the hyperinsulinemic clamp (glucose disposal rate into lean mass; ND: 9.9 (4.5) vs. AD 7.2 (3.2), p = 0.040). Cognitively impaired subjects also exhibited higher fasting insulin compared to ND subjects, (CI: 8.7 [7.8] vs. ND: 4.2 [3.8] μU/mL; p = 0.023) and higher fasting amylin (CI: 24.1 [39.1] vs. 8.37 [14.2]; p = 0.050) with no difference in fasting glucose. Insulin infusion elicited a detrimental effect on one test of verbal episodic memory (Free and Cued Selective Reminding Test) in both groups (p < 0.0001) and no change in performance on an additional task (delayed logical memory). In this study, although insulin resistance was observed in cognitively impaired subjects compared to ND controls, insulin infusion did not improve memory. Furthermore, a significant correlation between HOMA-IR and glucose disposal rate was present only in ND (p = 0.0002) but not in cognitively impaired (p = 0.884) subjects, indicating potentially important physiological differences between these cohorts.

Abstract Background Conflicting information exists regarding the association between insulin resistance (IR) and left ventricular hypertrophy (LVH). We described the associations between obesity, fasting insulinemia, homeostasis model assessment of insulin resistance (HOMA-IR), and LVH in Black patients with essential hypertension. Methods A case–control study was conducted at the Centre Médical de Kinshasa (CMK), the Democratic Republic of the Congo, between January and December 2019. Cases and controls were hypertensive patients with and without LVH, respectively. The relationships between obesity indices, physical inactivity, glucose metabolism and lipid disorder parameters, and LVH were assessed using linear and logistic regression analyses in simple and univariate exploratory analyses, respectively. When differences were observed between LVH and independent variables, the effects of potential confounders were studied through the use of multiple linear regression and in conditional logistic regression in multivariate analyses. The coefficients of determination (R2), adjusted odds ratios (aORs), and their 95% confidence intervals (95% CIs) were calculated to determine associations between LVH and the independent variables. Results Eighty-eight LVH cases (52 men) were compared against 132 controls (81 men). Variation in left ventricular mass (LVM) could be predicted by the following variables: age (19%), duration of hypertension (31.3%), body mass index (BMI, 44.4%), waist circumference (WC, 42.5%), glycemia (20%), insulinemia (44.8%), and HOMA-IR (43.7%). Hypertension duration, BMI, insulinemia, and HOMA-IR explained 68.3% of LVM variability in the multiple linear regression analysis. In the logistic regression model, obesity increased the risk of LVH by threefold [aOR 2.8; 95% CI (1.06–7.4); p = 0.038], and IR increased the risk of LVH by eightfold [aOR 8.4; 95 (3.7–15.7); p

Background: Hyperinsulinemia and insulin resistance occurs in obese patients with primary hypertension independent of diabetes and obesity. This study was aimed at assessing serum fasting insulin levels, the homeostatic model assessment for insulin resistance (HOMA-IR), and serum lipid levels in non-obese patients with primary hypertension when compared to normotensive subjects. Methods: This observational study comprised 100 patients over 18 years of age, divided into two groups. The hypertensive group comprised non-obese patients with primary hypertension (n=50); the normotensive group comprised normotensive age- and sex-matched individuals (n=50). Patients with diabetes, impaired fasting glucose, obesity, and other causative factors of insulin resistance were excluded from the study. Serum fasting insulin levels and fasting lipid profiles were measured, and insulin resistance was calculated using HOMA-IR. These data were compared between the two groups. Pearson's correlation coefficient was used to assess the extent of a linear relationship between HOMA-IR and to evaluate the association between HOMA-IR and systolic and diastolic blood pressures. Results: Mean serum fasting insulin levels (mIU/L), mean HOMA-IR values, and fasting triglyceride levels (mg/dL) were significantly higher in the hypertensive versus normotensive patients (10.32 versus 6.46, P<0.001; 1.35 versus 0.84, P<0.001; 113.70 versus 97.04, P=0.005, respectively). The HOMA-IR levels were associated with systolic blood pressure (r value 0.764, P=0.0005). Conclusion: We observed significantly higher fasting insulin levels, serum triglyceride levels, and HOMA-IR reflecting hyperinsulinemia and possibly an insulin-resistant state among primary hypertension patients with no other causally linked factors for insulin resistance. We observed a significant correlation between systolic blood pressure and HOMA-IR. [ABSTRACT FROM AUTHOR]

Purpose of Review: Herein, we summarize recent advances which provide new insights into the role of the autonomic nervous system in the control of blood flow and blood pressure during hyperinsulinemia. We also highlight remaining gaps in knowledge as it pertains to the translation of findings to relevant human chronic conditions such as obesity, insulin resistance, and type 2 diabetes. Recent Findings: Our findings in insulin-sensitive adults show that increases in muscle sympathetic nerve activity with hyperinsulinemia do not result in greater sympathetically mediated vasoconstriction in the peripheral circulation. Both an attenuation of α-adrenergic-receptor vasoconstriction and augmented β-adrenergic vasodilation in the setting of high insulin likely explain these findings. In the absence of an increase in sympathetically mediated restraint of peripheral vasodilation during hyperinsulinemia, blood pressure is supported by increases in cardiac output in insulin-sensitive individuals. Summary: We highlight a dynamic interplay between central and peripheral mechanisms during hyperinsulinemia to increase sympathetic nervous system activity and maintain blood pressure in insulin-sensitive adults. Whether these results translate to the insulin-resistant condition and implications for long-term cardiovascular regulation warrants further exploration. [ABSTRACT FROM AUTHOR]

Donohue syndrome, previously (but no longer) described as Leprechaunism, is a rare autosomal recessive trait. The primary defect in the insulin receptor causes extreme insulin resistance and failure to thrive with hyperinsulinemia, intermittent preprandial hypoglycemia, and persistent postprandial hyperglycemia. Impaired glucose metabolism causes prenatal and postnatal growth deficiency, dysmorphic facial features, visceromegaly, and lipoatrophy. A preterm male was born following an uneventful prenatal course with a birth weight of 1450 g, length of 40.5 cm, and head circumference of 32 cm. Apgar scores were 9 at one and 9 at five minutes. His postnatal course was complicated by recurrent episodes of abdominal distension and emesis with appropriate stooling, intermittent fasting hypoglycemia, and persistent postprandial hyperglycemia despite daily titrations in total parenteral nutrition. Glycemic fluctuations (20-230 mg/dl) were wide. The maximum serum insulin level was 1388 uIU/ml. With time, his dysmorphic features became more prominent. Echocardiogram identified a moderate ostium secundum atrial septal defect, mild dilation of the right ventricle, mild hypertrophy of the right ventricle, and mild pulmonary stenosis with doming. Gene testing for INSR identified two novel variants of uncertain significance. [ABSTRACT FROM AUTHOR]

Study Question: Is the severity of menstrual cyclicity related to hyperinsulinemia and dysglycemia in women with hyperandrogenic polycystic ovary syndrome (PCOS)?Summary Answer: Hyperandrogenic PCOS women with amenorrhea, compared to those with oligomenorrhea or eumenorrhea, had a greater risk of post-challenge hyperinsulinemia, which may explain their higher prevalence of dysglycemia.What Is Known Already: PCOS is associated with metabolic dysregulation including insulin resistance (IR) and hyperinsulinemia, risk factors for type 2 diabetes mellitus (T2DM) and other vascular-metabolic morbidities. Although the severity of menstrual cyclicity is associated with IR in PCOS, it is unclear whether, and to what extent, it is related to hyperinsulinemia and glycemic abnormalities.Study Design, Size, Duration: We prospectively compared the degree of menstrual cyclicity with the presence of dysglycemia (elevated 1-h plasma glucose ≥155 mg/dl; abnormal glucose tolerance [AGT], including prediabetes and T2DM; and AUC for glucose [G-AUC]) or dynamic state hyperinsulinemia (peak insulin levels either at 1 or 2 h of the oral glucose tolerance test (oGTT) and AUC for insulin [I-AUC]) in 333 hyperandrogenic PCOS women.Participants/materials, Setting, Methods: In a tertiary care setting, hyperandrogenic PCOS participants with ovulatory eumenorrhea (Ov-Eumeno, n = 25), anovulatory eumenorrhea (Anov-Eumeno, n = 33), oligomenorrhea (Oligo, n = 150) and amenorrhea (Ameno, n = 125) underwent comprehensive phenotyping and a 2-h 75 g oGTT.Main Results and the Role Of Chance: Mean BMI was greater among Ameno women than among Oligo, Anov-Eumeno or Ov-Eumeno women. Adjusting for BMI, the Ameno group demonstrated higher mean 1- and 2-h insulin and glucose, peak insulin and I-AUC and G-AUC, and either had a higher, or tended toward having a higher, prevalence of elevated 1-h glucose level and prevalence of AGT than the Oligo, Anov-Eumeno or Ov-Eumeno groups. In logistic regression, adjusting for BMI, Ameno women were more likely to have: AGT than Oligo women (odds ratio [OR]: 2.3; 95% CI: 1.3 to 4.2); elevated 1-h glucose (OR: 10.2; CI: 1.3-79.7) than those with Ov-Eumeno; and both AGT (OR: 1.7; CI: 1.1-2.6) and elevated 1-h glucose (OR: 1.8; CI: 1.1-2.8) than those with Anov-Eumeno or Ov-Eumeno when combined. Race/ethnicity, age, waist-to-hip ratio, fasting insulin and glucose, and biochemical or clinical measures of hyperandrogenism were similar across the four menstrual categories.Limitations, Reasons For Caution: Our study was limited by its cross-sectional nature and by studying women affected by PCOS as defined by the Androgen Excess & PCOS Society criteria (i.e. Rotterdam Phenotypes A, B and C) who were identified in the clinical setting. Consequently, extrapolation of the present data to other PCOS phenotypes (e.g. PCOS Phenotype D) should be made with caution.Wider Implications Of the Findings: In hyperandrogenic PCOS phenotypes, a history of amenorrhea, compared to oligomenorrhea or eumenorrhea, suggests a more severe cardiometabolic risk, including a higher degree of hyperinsulinemia and greater prevalence of glycemic abnormalities. These findings may assist in refining the treatment and screening guidelines for glycemic abnormalities in PCOS.Study Funding/competing Interest(s): This work was supported in part by grants R01-DK073632 and R01-HD29364 from the NIH and an endowment of the Helping Hand of Los Angeles, Inc. (to R.A.). M.D.P. has no competing interests to declare. U.E. is an investor in Concentric Analgesics, Inc. R.A. serves as a consultant for Spruce Biosciences and Fortress Biotech and an advisor for Aurora Forge.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Hyperinsulinemia is often observed in obese subjects because of insulin resistance, but it may occur in nonobese subjects with unknown etiology. A 72-year-old man was admitted to our hospital for the examination of hyperinsulinemia, reactive hypoglycemia, and liver dysfunction. The patient's body mass index was 23.7 kg/m2, but he had an elevated visceral fat area (125 cm2). His laboratory data showed mildly elevated liver enzymes, whereas plasma fasting glucose and serum insulin levels were 91 mg/dL and 52.3 μU/mL, respectively. In a 75-g oral glucose tolerance test, the serum insulin level reached the highest value of 1124 μU/mL at 180 minutes. There was no obvious etiology except for mild liver steatosis shown by liver biopsy. We suspected genetic abnormalities related to hyperinsulinemia. We performed whole-exome sequencing (WES) analyses and identified a heterozygous nonsense variant p.R924X in the insulin receptor (INSR) gene, a novel heterozygous missense variant p.V416M in the AKT1 gene, and a novel hemizygous missense variant p.R310Q in the PHKA2 gene, which is the causative gene of hepatic injury as glycogen storage disease type IX. It was speculated that the INSR gene variant, in addition to visceral fat accumulation, was the main cause of hyperinsulinemia and reactive hypoglycemia, and the remaining 2 variants were also partly responsible for hyperinsulinemia. WES analysis revealed candidate gene variants of hyperinsulinemia and hepatic-type glycogenosis. Thus, WES analysis may be a useful tool for clarifying the etiology when unexplained genetic pathophysiological conditions are suspected. [ABSTRACT FROM AUTHOR]

Background: Hypertrophic cardiomyopathy (HCM) in newborns is a rare condition with heterogeneous etiologies. While the relationship between hyperinsulinism and cardiac hypertrophy (CH) is known, hyperinsulinism has not been reported as cause of HCM. Case presentation: We report the case of cardiac hypertrophy (CH) in an Extremely Low Birth Weight (ELBW) infant; this patient underwent insulin therapy after the onset of persistent hyperglycemia due to parenteral nutrition (PN), supporting the hypothesis of a role of iatrogenic hyperinsulinemia in the development of HCM. Conclusions: The present case underlines the importance of a close cardiological follow-up in infants undergoing insulin infusion for an alteration in the glucose metabolism. [ABSTRACT FROM AUTHOR]

Background and Aims: This study examined the effect of moderate intensity stair stepping exercise on the glycemic response, and antioxidant capacity (TAC) during an oral glucose tolerance test (OGTT).Methods and Results: Thirty participants (women = 12) completed 4 OGTTs during rest or stair walking bouts of 1, 3, and 10 min in a randomized order. Blood was collected at baseline and 30 min during the OGTTs and analyzed for glucose, insulin, TAC, and lactate. Glucose concentrations were decreased following the 10 min (-22.69 (-34.66 to -10.72) mg/dL, p < 0.002) and 3 min (-15.37 (-25.05 to -5.69) mg/dL, p < 0.004) bouts but not the 1 min bout (-6.18 (-19.54 to 7.18) mg/dL, p = 0.352). Insulin concentrations were decreased following the 10 min (-6.11 (-8.86 to -3.36 μIU/dL), p < 0.001) and 3 min (-2.589 (-4.54 to -0.63) μIU/dL, p < 0.012) bouts but not the 1 min bout (-0.37 (-1.87 to 1.13) μIU/dL, p = 0.616). Insulin sensitivity index values showed a significant increase in the 10-min trial (1.81 (0.03-3.58), p < 0.048), but not during the 3 min (0.65 (-0.66 to 1.96) p = 0.317) or 1 min trial (0.13 (-1.58 to 1.84) p = 0.878). There was no omnibus effect for trial in TAC (p = 0.132, η2 = 0.07). There was no interaction between trial and time for blood lactate (p = 0.621, η2 = 0.02).Conclusion: This study provides evidence bouts as short as 3 min decrease postprandial blood glucose and insulin levels but longer bouts are needed to affect insulin sensitivity. [ABSTRACT FROM AUTHOR]

Background: An in-depth study of dismetabolic mechanisms in the genesis of pre-eclampsia (PE) has been updated because pregnancy is considered as a natural model of metabolic syndrome (MS), as well as the metabolic disorders are important in development of essential hypertension.Aims: to reveal clinical and laboratory parallels in pregnancy complicated by PE without MS and pregnancy proceeding on the background of MS to assess the role of metabolic disturbances in the development of PE.Materials and methods: 82 women with MS were examined in the dynamics of pregnancy and were divided into 2 groups depending on the implementation of PE: group I consisted of 50 women with PE on the background of MS, group II 32 women with MS without PE. We formed group III consisting of 44 pregnant women with PE without accompanying diseases to assess the pathogenetic value of metabolic disorders in the development of PE. The IV (control) group consisted of 30 healthy women with physiological pregnancy. Metabolic, hematological parameters, hormones, markers of the proinflammatory state, endothelial hemostasiological dysfunction, decidualization and placental angiogenesis, accumulation dynamics and distribution loci of adipose tissue were determined in all pregnant women.Results: In the groups of pregnant women with PE, changes similar to MS were revealed: pronounced diabetic and atherogenic disorders with the development of pathological insulin resistance, hyperinsulinemia and leptinemia, endothelial-platelet link hyperactivation, thrombotic and inflammatory status, visceral type of fat deposition, hyperuricemia, hypersympathicotonia. It is proved that in the hierarchy of mechanisms of PE formation, placental dysfunction is a secondary alteration factor, which additionally potentiates the insulin resistance increase and the effects of structural and functional destabilization of the vascular endothelium.Conclusions: The direction of metabolic changes during pregnancy, the common development of PE and MS indicate the important role of dismetabolic mechanisms in the formation of PE.

Wolfgang Kopp Diagnostikzentrum Graz, Graz, 8043, AustriaCorrespondence: Wolfgang KoppFormer Head of Diagnostikzentrum (retired), Mariatrosterstraße 41, Graz 8043, AustriaEmail w.kopp@weiz.ccAbstract: Obesity has reached epidemic proportions and is one of the greatest challenges for public health in the twenty-first century. The macronutrient composition of diets, in particular the amount and ratio of carbohydrates, fat and protein, have received considerable attention in recent decades due to its potential relevance to the development of obesity and weight loss. The effects of various macronutrients on body weight regulation are still under debate. High-carbohydrate diets, and particularly high-fat diets, have been blamed for the increase in the prevalence of obesity. This paper shows that neither fat nor carbohydrates are fattening per se. Mixed diets with substantial amounts of fat and high-glycemic carbohydrates, like current WDs, are required to promote weight gain and obesity. High-glycemic carbohydrates are the active partner (the “driver”), which promotes fat storage through its insulinogenic effect, while fat is the passive partner (the “passenger”) on the way to obesity. Elevated insulin levels (postprandial, but more importantly due to hypersecretion and hyperinsulinemia) promote fat storage and play a key role in obesogenesis and the obesity epidemic. Furthermore, mixed diets high in high-glycemic carbohydrates and fat promote fetal programming, with long-term adverse impacts on the offspring, including insulin hypersecretion, (childhood) obesity and metabolic diseases. Maternal obesity and high weight gain during pregnancy have also been linked to deleterious effects on fetal programming. As the global obesity epidemic increasingly affects women of reproductive age, a significant percentage of fetuses will experience fetal programming with a tendency towards obesity – a self-reinforcing process that further fuels the epidemic. A change in lifestyle and diet composition is needed to prevent or limit the development of obesity and related diseases.Keywords: hypersecretion, hyperinsulinemia, fetal programming, weight gain, insulinogenic Western diet

Aim: to assess dynamic changes in insulin resistance (IR), hyperinsulinemia (HI) and related parameters of carbohydrate and lipid metabolism, endothelial dysfunction, pro-inflammatory and prothrombotic states in pregnancy complicated with preeclampsia (PE).Materials and Methods. A prospective observational study was conducted consisting of laboratory monitoring 148 high-PE-risk pregnant women comprising Group I - 72 women with overt PE; 36 healthy women with physiological course of pregnancy were included into Group II. All women were assessed level of venous blood glucose, insulin, total cholesterol, high-density lipoproteins (HDL), triglycerides (TG), leptin, placental lactogen, uric acid, tumor necrosis factor-a, C-reactive protein, circulating endothelial cells, fibronectin, nitric oxide metabolites, platelet aggregation at gestational periods 11-14 weeks, 18-21 weeks and 30-34 weeks. We also calculated insulin resistance index, atherogenic coefficient, and TG/HDL ratio, estimating accumulation and distribution of adipose tissue.Results. There were found physiological changes in IR and HI, lipid, endothelial-hemostasis axis, pro-inflammatory, placental parameters supposed to provide proper fetal energy supply during normal pregnancy. During PE, these parameters were aberrantly elevated starting from early pregnancy stage due to failure of gestational adaptation mechanisms, which acquire important pathogenetic significance therein.Conclusion. A holistic view at the mechanisms of forming atherogenic transformation of the lipid profile, endothelial dysfunction, pro-inflammatory and prothrombotic status, oxidative stress, hyperuricemia, visceral type of abdominal wall fat deposition as well as correlation analysis data indicate that all such changes were associated with unified pathogenetic arm consisting of pathological IR and HI serving as early baseline mechanisms in PE development.

Objective To investigate if insulin resistance per se or the accompanying hyperinsulinemia induced hypertension and its underlying mechanisms. Methods Sprague-Dawley rats were randomized into normal diet-fed group (ND group) and high-fat diet-fed group (HFD group). Then, the HFD group was further randomly divided into the control group (HFD_C group), the PIO group (treated with pioglitazone), the STZ_DM group (to induce diabetes with streptozotocin) and the DM+Ins group (streptozotocin injection followed by insulin treatment). Insulin sensitivity, plasma insulin, endothelin-1, norepinephrine, aldosterone, angiotensinⅡ and 24-h urinary sodium excretion (USE) levels of the groups were measured and analyzed. A multiple stepwise regression analysis method was applied to exam our hypothesis. Results Compared to HFD_C group, the groups with lower plasma insulin, the PIO group and STZ_DM group, showed higher USE and lower blood pressure. The groups with higher plasma insulin (but same level of insulin resistance), the HFD_C group and DM+Ins group, showed lower USE and higher blood pressure. The 24-h urinary sodium excretion was the most important contributor to the significant changes of blood pressure with an R2 of 25.2% in this animal experiment. Conclusions It is the compensatory hyperinsulinemia rather than insulin resistance per se that causes blood pressure elevation. The urinary sodium excretion is the key mediator among the multiple mechanisms. Therapies targeting hyperinsulinemia and restricting salt intake may favor a better control of hypertension associated with insulin resistance.

Background: Polycystic ovary syndrome (PCOS), with a prevalence of 4-12 percent, is the most common endocrine-metabolic disorder in reproductive age of women. Reproductive disorders in women with PCO include hyperinsulinemia, hyperandrogenism, chronic anovulation, and infertility. The purpose of this paper was to review and confirm the important role of oxidative stress in creating insulin resistance in this syndrome. Methods: All relevant information was collected through databases such as PubMed and Google Scholar, which was extracted from a total of 100 articles between 1989-2020. Today, the assessment of oxidative stress in women with PCO is performed using circulatory markers such as malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPX). Findings: Insulin resistance can be associated with the conditions of oxidative stress in women with PCO. Therefore, obtaining oxidative stress index can be considered valuable, and represent the occurrence of metabolic disorders in this syndrome. Conclusion: Oxidative stress can play a key role in insulin resistance. Therefore, the oxidative stress index can help to understand unknown metabolic causes of this syndrome.

Abstract Background Insulin shares a limited physiological concentration range with other endocrine hormones. Not only too low, but also too high systemic insulin levels are detrimental for body functions. Main body The physiological function and clinical relevance of insulin are usually seen in association with its role in maintaining glucose homeostasis. However, insulin is an anabolic hormone which stimulates a large number of cellular responses. Not only too low, but also excess insulin concentrations are detrimental to the physiological balance. Although the glucoregulatory activity of insulin is mitigated during hyperinsulinemia by dampening the efficiency of insulin signaling (“insulin resistance”), this is not the case for most other hormonal actions of insulin, including the promotion of protein synthesis, de novo lipogenesis, and cell proliferation; the inhibition of lipolysis, of autophagy-dependent cellular turnover, and of nuclear factor E2-related factor-2 (Nrf2)-dependent antioxidative; and other defense mechanisms. Hence, there is no general insulin resistance but selective impairment of insulin signaling which causes less glucose uptake from the blood and reduced activation of endothelial NO synthase (eNOS). Because of the largely unrestricted insulin signaling, hyperinsulinemia increases the risk of obesity, type 2 diabetes, and cardiovascular disease and decreases health span and life expectancy. In epidemiological studies, high-dose insulin therapy is associated with an increased risk of cardiovascular disease. Randomized controlled trials of insulin treatment did not observe any effect on disease risk, but these trials only studied low insulin doses up to 40 IU/day. Proof for a causal link between elevated insulin levels and cardiovascular disease risk comes from Mendelian randomization studies comparing individuals with genetically controlled low or high insulin production. Conclusions The detrimental actions of prolonged high insulin concentrations, seen also in cell culture, argue in favor of a lifestyle that limits circadian insulin levels. The health risks associated with hyperinsulinemia may have implications for treatment regimens used in type 2 diabetes.

Oana Albai,1,2 Mirela Frandes,3 Bogdan Timar,2,3 Diana-Loreta Paun,4 Deiana Roman,1 Romulus Timar1,2 1Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania; 2Department of Diabetes and Metabolic Diseases, “Pius Brinzeu” Emergency Hospital, Timisoara, Romania; 3Department of Functional Sciences, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania; 4Department of Public Health, Department of Endocrinology, “Carol Davila” University of Medicine and Pharmacy, Bucuresti, RomaniaCorrespondence: Mirela FrandesDepartment of Functional Sciences, “Victor Babes” University of Medicine and Pharmacy, 2 Eftimie Murgu, Timisoara 300041, RomaniaTel +40 731117020Fax +40 256462856Email mirela.frandes@umft.roBackground: In developing countries, cancer incidence has progressively increased, becoming the second cause of mortality after cardiovascular diseases. Type 2 diabetes mellitus (T2DM) is associated with an increased risk of malignant neoplastic disorders, especially pancreatic cancer, colorectal cancer, and breast cancer.Aim: The main aim of our study was to establish the prevalence of malignant neoplastic disorders in patients previously diagnosed with T2DM. Also, we have investigated the association between the components of the metabolic syndrome (MetS) and the different types of diagnosed malignant neoplasms.Methods: We performed a retrospective, population-based cohort study of 1,027 patients with T2DM from the Center for Diabetes Treatment of the “Pius Brînzeu” Emergency Hospital in Timisoara, Romania. The patients were followed up every three or six months, depending on their antidiabetic treatment. The patients who developed malignant neoplasms were registered and referred to oncology centers. The potential risk factors for malignancies in patients with T2DM were evaluated using logistic regression adjusting for possible confounders.Results: The prevalence of malignant neoplastic disorders in our study group was 7.1%; more precisely, we found 2.2% colon neoplasm, 2.9% mammary neoplasm, 0.7% lymphomas, 0.6% pulmonary neoplasm, 0.3% pancreatic neoplasm, and 0.4% prostate neoplasm. The presence of malignant neoplastic disorders was associated in our cohort of patients with T2DM with higher cholesterol (237.71± 47.82 vs 202.52± 52.16 mg/dL; p=0.005) and triglycerides levels (215.91± 52.41 vs 180.75± 54.32 mg/dL; p< 0.001), as well as higher body mass index (33.37± 3.87 vs 28.42± 3.56 kg/m2; p< 0.001) and abdominal circumference (110.11± 14.48 vs 98.12± 15.73 cm; p< 0.001). Also, we found that insulin-based treatment was an independent risk factor, the patients presenting ten times higher odds of developing malignant neoplastic disorders.Conclusion: The prevalence of malignant neoplastic disorders in our study group was 7.1%. Also, the prevalence of malignant neoplastic disorders was higher in patients with T2DM and MetS as compared to the general population of T2DM patients.Keywords: malignant neoplastic disorders, type 2 diabetes mellitus, hyperinsulinemia, metabolic syndrome, insulin resistance

Abstract Background Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women during reproductive age. It is characterised clinically by oligo-ovulation or anovulation, hyper-androgenism, and the presence of polycystic ovaries. It is associated with an increased prevalence of metabolic syndrome, cardiovascular disease and type 2 diabetes. The onset of PCOS has been associated to several hereditary and environmental factors, but insulin resistance plays a key pathogenetic role. We sought to investigate the effects of a ketogenic diet (KD) on women of childbearing age with a diagnosis of PCOS. Methods Fourteen overweight women with diagnosis of PCOS underwent to a ketogenic Mediterranean diet with phyoextracts (KEMEPHY) for 12 week. Changes in body weight, body mass index (BMI), fat body mass (FBM), lean body mass (LBM), visceral adipose tissue (VAT), insulin, glucose, HOMA-IR, total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides (TGs), total and free testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH); dehydroepiandrosterone sulfate (DHEAs), estradiol, progesterone, sex hormone binding globulin (SHBG) and Ferriman Gallwey score were evaluated. Results After 12 weeks, anthropometric and body composition measurements revealed a significant reduction of body weight (− 9.43 kg), BMI (− 3.35), FBM (8.29 kg) and VAT. There was a significant, slightly decrease of LBM. A significant decrease in glucose and insulin blood levels were observed, together with a significant improvement of HOMA-IR. A significant decrease of triglycerides, total cholesterol and LDL were observed along with a rise in HDL levels. The LH/FSH ratio, LH total and free testosterone, and DHEAS blood levels were also significantly reduced. Estradiol, progesterone and SHBG increased. The Ferriman Gallwey Score was slightly, although not significantly, reduced. Conclusions Our results suggest that a KD may be considered as a valuable non pharmacological treatment for PCOS. Longer treatment periods should be tested to verify the effect of a KD on the dermatological aspects of PCOS. Trial registration Clinicaltrial.gov, NCT04163120, registrered 10 November 2019, retrospectively registered, https://clinicaltrials.gov .

Background: Hyperinsulinemia and insulin resistance occurs in obese patients with primary hypertension independent of diabetes and obesity. This study was aimed at assessing serum fasting insulin levels, the homeostatic model assessment for insulin resistance (HOMA-IR), and serum lipid levels in non-obese patients with primary hypertension when compared to normotensive subjects. Methods: This observational study comprised 100 patients over 18 years of age, divided into two groups. The hypertensive group comprised non-obese patients with primary hypertension (n=50); the normotensive group comprised normotensive age- and sex-matched individuals (n=50). Patients with diabetes, impaired fasting glucose, obesity, and other causative factors of insulin resistance were excluded from the study. Serum fasting insulin levels and fasting lipid profiles were measured, and insulin resistance was calculated using HOMA-IR. These data were compared between the two groups. Pearson’s correlation coefficient was used to assess the extent of a linear relationship between HOMA-IR and to evaluate the association between HOMA-IR and systolic and diastolic blood pressures. Results: Mean serum fasting insulin levels (mIU/L), mean HOMA-IR values, and fasting triglyceride levels (mg/dL) were significantly higher in the hypertensive versus normotensive patients (10.32 versus 6.46, P

Increased insulin level (or “hyperinsulinemia”) is a common phenomenon in pancreatic ductal adenocarcinoma (PDA) patients and signals poor clinical outcomes. Insulin is safe in low PDA risk population, while insulin significantly promotes PDA risk in high PDA risk population. The correlation between insulin and PDA is a reciprocal self-reinforcing relationship. On the one hand, pancreatic cancer cells synthesize multiple molecules to cause elevated peripheral insulin resistance, thus enhancing hyperinsulinemia. On the other hand, insulin promotes pancreatic cancer initiation and sustains PDA development by eliciting tumorigenic inflammation, regulating lipid and glucose metabolic reprogram, overcoming apoptosis through the crosstalk with IGF-1, stimulating cancer metastasis, and activating tumor microenvironment formation (inflammation, fibrosis, and angiogenesis). Currently, taking glucose sensitizing agents, including metformin, SGLT-2 inhibitor, and GLP-1 agonist, is an effective way of lowering insulin levels and controlling PDA development at the same time. In the future, new drugs targeting insulin-related signal pathways may pave a novel way for suppressing PDA initiation and progression.

Metabolic syndrome (MetS) is defined by a cluster of several cardio-metabolic risk factors, specifically visceral obesity, hypertension, dyslipidemia, and impaired glucose metabolism, which together increase risks of developing future cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D). This article is a narrative review of the literature and a summary of the main observations, conclusions, and perspectives raised in the literature and the study projects of the Working Group of Childhood Obesity (WGChO) of the Italian Society of Paediatric Endocrinology and Diabetology (ISPED) on MetS in childhood obesity. Although there is an agreement on the distinctive features of MetS, no international diagnostic criteria in a pediatric population exist. Moreover, to date, the prevalence of MetS in childhood is not certain and thus the true value of diagnosis of MetS in youth as well as its clinical implications, is unclear. The aim of this narrative review is to summarize the pathogenesis and current role of MetS in children and adolescents with particular reference to applicability in clinical practice in childhood obesity.

Polycystic ovary syndrome (PCOS) is increasingly being characterized as an evolutionary mismatch disorder that presents with a complex mixture of metabolic and endocrine symptoms. The Evolutionary Model proposes that PCOS arises from a collection of inherited polymorphisms that have been consistently demonstrated in a variety of ethnic groups and races. In utero developmental programming of susceptible genomic variants are thought to predispose the offspring to develop PCOS. Postnatal exposure to lifestyle and environmental risk factors results in epigenetic activation of developmentally programmed genes and disturbance of the hallmarks of health. The resulting pathophysiological changes represent the consequences of poor-quality diet, sedentary behaviour, endocrine disrupting chemicals, stress, circadian disruption, and other lifestyle factors. Emerging evidence suggests that lifestyle-induced gastrointestinal dysbiosis plays a central role in the pathogenesis of PCOS. Lifestyle and environmental exposures initiate changes that result in disturbance of the gastrointestinal microbiome (dysbiosis), immune dysregulation (chronic inflammation), altered metabolism (insulin resistance), endocrine and reproductive imbalance (hyperandrogenism), and central nervous system dysfunction (neuroendocrine and autonomic nervous system). PCOS can be a progressive metabolic condition that leads to obesity, gestational diabetes, type two diabetes, metabolic-associated fatty liver disease, metabolic syndrome, cardiovascular disease, and cancer. This review explores the mechanisms that underpin the evolutionary mismatch between ancient survival pathways and contemporary lifestyle factors involved in the pathogenesis and pathophysiology of PCOS.

Metabolic syndrome (MetS) is considered a metabolic disorder that has been steadily increasing globally and seems to parallel the increasing prevalence of obesity. It consists of a cluster of risk factors which traditionally includes obesity and hyperlipidemia, hyperinsulinemia, hypertension, and hyperglycemia. These four core risk factors are associated with insulin resistance (IR) and, importantly, the MetS is known to increase the risk for developing cerebrocardiovascular disease and type 2 diabetes mellitus. The MetS had its early origins in IR and syndrome X. It has undergone numerous name changes, with additional risk factors and variables being added over the years; however, it has remained as the MetS worldwide for the past three decades. This overview continues to add novel insights to the MetS and suggests that leptin resistance with hyperleptinemia, aberrant mitochondrial stress and reactive oxygen species (ROS), impaired folate-mediated one-carbon metabolism with hyperhomocysteinemia, vascular stiffening, microalbuminuria, and visceral adipose tissues extracellular vesicle exosomes be added to the list of associated variables. Notably, the role of a dysfunctional and activated endothelium and deficient nitric oxide bioavailability along with a dysfunctional and attenuated endothelial glycocalyx, vascular inflammation, systemic metainflammation, and the important role of ROS and reactive species interactome are discussed. With new insights and knowledge regarding the MetS comes the possibility of new findings through further research.

Hyperinsulinemia is a condition characterized by excessively high levels of insulin in the bloodstream. It can exist for many years without any symptomatology. The research presented in this paper was conducted from 2019 to 2022 in cooperation with a health center in Serbia as a large cross-sectional observational study of adolescents of both genders using datasets collected from the field. Previously used analytical approaches of integrated and relevant clinical, hematological, biochemical, and other variables could not identify potential risk factors for developing hyperinsulinemia. This paper aims to present several different models using machine learning (ML) algorithms such as naive Bayes, decision tree, and random forest and compare them with a new methodology constructed based on artificial neural networks using Taguchi’s orthogonal vector plans (ANN-L), a special extraction of Latin squares. Furthermore, the experimental part of this study showed that ANN-L models achieved an accuracy of 99.5% with less than seven iterations performed. Furthermore, the study provides valuable insights into the share of each risk factor contributing to the occurrence of hyperinsulinemia in adolescents, which is crucial for more precise and straightforward medical diagnoses. Preventing the risk of hyperinsulinemia in this age group is crucial for the well-being of the adolescents and society as a whole.

Insulin autoimmune syndrome (IAS) is a rare cause of endogenous hyperinsulinemic hypoglycemia triggered by insulin autoantibodies. Through extensive research on IAS in recent years, it has been revealed that the use of exogenous insulin by diabetic patients can result in clinical manifestations similar to those of IAS. This phenomenon is known as exogenous IAS (EIAS). This article describes a case of a patient with EIAS who presented with atypical clinical manifestations. The patient, a middle-aged female with a 17-year history of type 2 diabetes, had been using Insulin Aspart 30 Injection for almost 10 years. She developed severe hyperinsulinemia, low C-peptide levels, positive insulin antibodies, poor postprandial glycemic control, and occasional autonomic nervous system symptoms such as hunger, palpitations, fatigue, and excessive sweating. Despite these symptoms, hypoglycemia was not detected. Switching the type of insulin for two weeks resulted in a significant reduction in insulin dosage, leading to stabilization of fasting and two-hour postprandial blood glucose levels within the target range. This article aims to alert medical professionals about diabetic patients who have hyperinsulinemia, insulin antibodies, and difficulty controlling blood sugar due to EIAS. It is crucial to prevent missed diagnoses, misdiagnoses, and potentially unnecessary surgical interventions through increased awareness., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Wang et al.)

Despite all the progress made by science in the prevention and treatment of cardiovascular diseases and cancers, these are still the main reasons for hospitalizations and death in the Western world. Among the possible causes of this situation, disorders related to hyperinsulinemia and insulin resistance (Hyperin/IR) are still little-known topics. An analysis of the literature shows that this condition is a multiple risk factor for type 2 diabetes, cardiovascular diseases, cellular senescence and cancer, and neurodegenerative diseases. Hyperin/IR is progressively increasing worldwide, and its prevalence has now exceeded 50% of the general population and in overweight children. Asymptomatic or poorly symptomatic, it can last for many years before manifesting itself as diabetes, cardiovascular disease, neoplasm, cognitive deficit, or dementia, therefore leading to enormous social and healthcare costs. For these reasons, a screening plan for this pathology should be implemented for the purpose of identifying people with Hyperin/IR and promptly starting them on preventive treatment.

Insulin resistance describes the lack of activity of a known quantity of insulin (exogenous or endogenous) to promote the uptake of glucose and its utilization in an individual, as much as it does in metabolically normal individuals. On the cellular level, it suggests insufficient power of the insulin pathway (from the insulin receptor downstream to its final substrates) that is essential for multiple mitogenic and metabolic aspects of cellular homeostasis. Atherosclerosis is a slow, complex, and multifactorial pathobiological process in medium to large arteries and involves several tissues and cell types (immune, vascular, and metabolic cells). Inflammatory responses and immunoregulation are key players in its development and progression. This paper examines the possible pathophysiological mechanisms that govern the connection of insulin resistance, hyperinsulinemia, and the closely associated cardiometabolic syndrome with atherosclerosis, after exploring thoroughly both in vitro and in vivo (preclinical and clinical) evidence. It also discusses the importance of visualizing and developing novel therapeutic strategies and targets for treatment, to face this metabolic state through its genesis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)