Higher Insulin Resistance Research Articles

Neddylation-dependent protein degradation is a nexus between synaptic insulin resistance, neuroinflammation and Alzheimer\u2019s disease

BackgroundThe metabolic syndrome is a consequence of modern lifestyle that causes synaptic insulin resistance and cognitive deficits and that in interaction with a high amyloid load is an important risk factor for Alzheimer's disease. It has been proposed that neuroinflammation might be an intervening variable, but the underlying mechanisms are currently unknown.MethodsWe utilized primary neurons to induce synaptic insulin resistance as well as a mouse model of high-risk aging that includes a high amyloid load, neuroinflammation, and diet-induced obesity to test hypotheses on underlying mechanisms.ResultsWe found that neddylation and subsequent activation of cullin-RING ligase complexes induced synaptic insulin resistance through ubiquitylation and degradation of the insulin-receptor substrate IRS1 that organizes synaptic insulin signaling. Accordingly, inhibition of neddylation preserved synaptic insulin signaling and rescued memory deficits in mice with a high amyloid load, which were fed with a 'western diet'.ConclusionsCollectively, the data suggest that neddylation and degradation of the insulin-receptor substrate is a nodal point that links high amyloid load, neuroinflammation, and synaptic insulin resistance to cognitive decline and impaired synaptic plasticity in high-risk aging.

Process to insulin for type 2 diabetes mellitus therapy

In type 1 diabetes mellitus and in symptomatic and critical hyperglycemic states, insulin is a lifesaving drug; however, its value in long-term type 2 diabetes therapy, which represents more than 90% of diabetes, has not been assessed. This happens despite the fact that, in randomized studies on type 2 diabetes, insulin is used in two-thirds of cases when intensive hypoglycemic treatment is needed and in half of the patients when treatment is the standard one. This is a major issue from a clinical, economic and social-health organization point of view as insulin therapy is expensive and needs a complex organization. Observational and retrospective studies from the scientific literature show that in this type of diabetes insulin treatment is associated with increased cardiovascular and all-cause mortality. It is not clear whether this is due to a greater severity of the clinical picture, to the therapeutic target of blood glucose that may induce hypoglycemia, or to the intrinsic pharmacological activity of the drug that beyond reducing hyperglycemia can cause hypoglycemia, water retention, weight gain and hyperinsulinemia with proatherogenic effects. In particular, in patients with heart failure at high cardiovascular risk or with high insulin resistance, these clues are supported by meaningful data. Although there is no definitive evidence (the so-called "smoking gun") from randomized controlled trials, the high degree of suspicion induces the preferential choice of other drugs such as sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists and metformin beyond avoiding glycemic targets that induce hypoglycemia, especially in frail, elderly patients, or patients with cardiovascular diseases. These drugs, for their proven efficacy and the easy use within an outpatient setting (that favors their prescription and improves the inertia of the doctor and the adherence of patients), could help a more effective treatment of patients, both for quality and life expectancy beyond mere glycemic control.

Insulin resistance in various grades of acanthosis nigricans

Insulin resistance (IR) is a metabolism disorder that contributes to the pathophysiology of acanthosis nigricans (AN). In turn, AN is a self-determining risk factor and cutaneous marker of IR. However, conflicting evidence makes the AN-IR relationship debatable and open to exploration. If established, it could provide opportunities for early diagnosis and management of IR before the onset of diabetes mellitus and its complications by screening AN patients. This study investigates the prevalence of IR among AN patients and evaluates the association between IR and AN severity. Eighty-seven patients, 18 to 60 years old, with untreated AN and absence of diabetes mellitus, underwent detailed history, systemic, and cutaneous examinations, as well as measurement of their body mass index (BMI), waist and hip circumference and their ratio (WHR), fasting blood glucose (FBG) and lipid profile, fasting serum insulin levels, and quantitative insulin-sensitivity check index (QUICKI). Severity of the neck lesions was graded according to Burke et al.'s grading system. AN was noted most commonly in younger age groups with 93.1% of the cases younger than 45. All patients had lesions on the neck, and 63.3% of the cases had multiple site involvement. Nearly 84% of the cases were overweight or obese. AN grades exhibited a significant positive association with BMI (p = 0.002) and WHR (p = 0.016). High IR (< 0.35 QUICKI) was seen in 55 (63.2%) AN patients. IR, QUICKI, and triglyceride levels showed no significant association with AN severity and the number of AN lesion sites (p > 0.05). LDL levels (p = 0.02) and WHR (p = 0.049) showed a significant positive association with the number of AN lesion sites, but not with AN severity grading (p > 0.05). IR is present in AN patients, but the association between IR and AN severity is not significant enough to qualify AN as a screening tool for IR.

Elevated White Blood Cell Count Is Associated with an Increased Risk of Insulin Resistance among Non-Diabetic Taxi-Motorbike Drivers Working in Cotonou, Benin

High white blood cell count (WBC) and insulin resistance (IR) are interrelated events that contribute to non-communicable diseases (NCDs), including type-2 diabetes (T2D). However, associations between IR and hematological parameters have never been explored in populations of Benin. The aims of this study were to determine the prevalence of IR and associated hematological parameters in taxi-motorbike drivers (TMDs) working in Cotonou. A total of 133 participants were analyzed in this cross-sectional study. Complete blood count, including WBC and platelet, as well as fasting plasma glucose and insulin, were performed by standard procedures. IR was assessed using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Factors associated with IR, their odds ratios (ORs) and 95% confidence intervals (CIs) were determined by logistic regression analysis. The mean age of the study participants was 39.3 years. The HOMA-IR cut-off (75th percentile) for IR was 5.9. The overall prevalence of IR was 24.1%. IR increased with the increase of exposure duration and WBC levels. Logistic regression analysis revealed that the risk of IR increased significantly with higher total WBC, with adjusted ORs (95% CI) for the second and third tertiles of 3.56 (1.10 - 11.58) and 4.01 (1.21 - 13.31), respectively. Similar patterns of associations were observed in an analysis restricted to non-drinkers, although these estimates lacked statistical significance. BMI > 24.2 kg/m2 was independently associated with an increased risk of IR (OR = 3.82, 95% CI: 1.33 - 11.03, P = 0.013). In conclusion, the prevalence of IR in TMDs was 24.1%. IR was significantly associated with elevated WBC count and BMI. WBC may serve as a biomarker to identify individuals at the greatest IR risk.

A Noninvasive Scoring System for Liver Fibrosis in Patients With Metabolic Dysfunction-Associated Fatty Liver Disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is diagnosed in patients with hepatic steatosis who meet at least one of the following criteria: body mass index >25, diabetes mellitus type 2, and metabolic dysfunction. Given about one-third of Americans meet the criteria for MAFLD, there is an unmet need for a score to noninvasively triage patients who need transient elastography and possible biopsy. We determined the risk factors for advanced fibrosis (F3+ on transient elastography) in a cohort of 2671 MAFLD patients and developed the MAFLD fibrosis-4 (FIB-4) score to help clinicians predict the risk of advanced fibrosis. Multivariate logistic regression analysis and independent t-tests were used to evaluate the relationship between physical exam parameters, lab values, and interview responses and risk of advanced fibrosis. The most significant risk factors were used to build the MAFLD FIB-4 score, equivalent to-46.55+ (7.89∗log[waist circumference])+ (1.25∗log[fasting plasma glucose])+ (0.85∗FIB-4 score). Risk factors for advanced fibrosis in MAFLD patients are elevated body mass index (odds ratio [OR]= 5.90; P < .01), waist circumference (OR= 3.53; P < .01), high fasting plasma glucose (OR= 2.45; P < .01), high homeostasis model assessment-estimated insulin resistance score (OR= 2.18; P= .02), high triglycerides (OR= 1.94; P= .03), positive hepatitis C RNA (OR= 14.92; P= .02), high ferritin (OR= 1.58; P= .05), and alanine transaminase > aspartate aminotransferase (OR= 1.54; P= .04). The MAFLD FIB-4 score has a specificity of 80%, sensitivity of 97%, and receiver operating characteristic of 0.85 (compared to the receiver operating characteristic of 0.60 for FIB-4 and 0.68 for nonalcoholic fatty liver disease existing scores) for the detection of advanced fibrosis in MAFLD patients. Clinicians can utilize the MAFLD FIB-4 score to noninvasively identify patients with advanced fibrosis risk for further evaluation and management.

Association of Plasma Fibrinogen and Insulin Resistance in Women with Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is thought to be developed as a consequence of high insulin resistance (IR). It has been proposed that IR may involve in the pathogenesis of hyperfibrinogenemia in GDM. This study was aimed to evaluate the plasma fibrinogen levels and its association with insulin resistance in GDM. This cross sectional study was performed with 44 GDM women and 44 pregnant women with normal glucose tolerance (NGT) at or after 24 weeks of their gestation. Glucose was measured by glucose oxidase method, fasting insulin was measured by chemiluminescent immunoassay and plasma fibrinogen was measured by STA-fibrinogen kit with an automated coagulation analyzer. GDM women had significantly increased age and higher BMI than pregnant women with NGT (p=0.008). Plasma fibrinogen level was significantly higher in GDM (p<0.001). Fasting insulin level and Homeostasis Model Assessment of Insulin Resistance [HOMA-IR] were also significantly higher in GDM (p<0.001). Fibrinogen showed positive correlation with fasting insulin level (r=0.470, p<0.001) as well as with HOMA-IR (r=0.470, p<0.001) in GDM. Using HOMA-IR at cut-off value 2.89, it was observed that a significant number of GDM women had higher HOMA-IR values than pregnant women with NGT (p=0.002) and GDM women with HOMA-IR values ≥2.89 had significantly higher fibrinogen values (p=0.002). Gestational diabetes mellitus is associated with higher plasma fibrinogen level and increased insulin resistance, indicating a state of hypercoagulability than that of pregnant women with normal glucose tolerance. There is a clear association between hyperfibrinogenemia and insulin resistance.

Cardiovascular risk and insulin resistance in childhood leukemia survivors

Material and methods: a retrospective study of childhood acute leukemia survivors. Survivors with a diagnosis of leukemia before 16 years of age in a tertiary hospital, during the period of 1998-2018, were selected, who had completed their treatment at least two years earlier. We examined: blood adipokine levels and carbohydrate metabolism, body composition by bioimpedance, and carotid status by ultrasound. Somatometric measures were also taken. Results: the registry showed 82 children diagnosed with acute leukemia, aged between 6 and 16 years. Only 22 met the criteria to be included in the study. Results reveled that 32 % of the sample met the criteria for overweight-obesity, and 36 % had high insulin resistance indexes (IR). Leptin levels were higher in women (15.45 vs. 3.25; p = 0.044) and in obese and overweight subjects, as was the leptin/adiponectin ratio, which rises in the presence of IR (2.52 vs. 0.45; p = 0.037). We observed an increase in carotid intima-media thickness in relation to BMI (0.008; CI, -0.002 to 0.013; p = 0.007) without any association with an increase in fat mass in these patients (0.204; CI, -0.043 to 0.451; p = 0.101). Conclusions: childhood leukemia survivors have a high cardiovascular risk, characterized by an increase in IR, not associated with an increase in fat mass. This risk could justify the implementation of preventive actions in these long-lived patients.

Utility of Epicardial Fat Thickness in Subclinical Hypothyroid Children to Determine Existence of Subclinical Atherosclerosis in Them.

Adult studies have shown the association of subclinical hypothyroid (SCH) with various cardiovascular dysfunction, which indicates SCH may be a potentially modifiable risk factor of CV disease and mortality. However, there is still controversy about the association of cardiovascular dysfunction in children with SCH. Epicardial fat thickness (EFT) is a reliable and sensitive marker of cardiovascular risk and has become an emerging modality to predict CV risks. To measure the EFT in children with subclinical hypothyroidism and compare with healthy children. To find its correlation with subclinical atherosclerosis. To compare EFT between TPO positive and TPO negative subclinical hypothyroid patients. Children of subclinical hypothyroidism (TSH >5 mIU/ml with normal FT3, FT4, and age and sex matched control were included as per inclusion and exclusion criteria. Clinical data was collected from all study subjects. Thyroid function tests including FT3, FT4 and TSH, TPO antibody, fasting insulin, hsCRP, Lp(a), USG neck for carotid intima media thickness (CIMT), USG brachial artery for flow mediated dilation (FMD) and echocardiography for epicardial fat thickness (EFT) were done in all patients. A total 42 number of SCH and 50 age and sex matched controls were recruited and screened for various parameters of subclinical atherosclerosis. EFT was significantly higher in the cases than in the controls (6.27 mm vs 4.54 mm) with P value < 0.001. Brachial FMD was significantly lower in cases than the cohort (4.5% vs 8.93%, P < 0.001). Difference in CIMT was not significant amongst the cases and controls. EFT failed to correlate with the level of TSH though it had significant positive correlation with hsCRP. The patients who were TPO positive, had higher fasting insulin, HOMAIR, hsCRP, Lp(a) than those who were TPO negative. Results of this study show the presence of subclinical atherosclerosis in children with SCH regardless of the aetiologies. The patients of Hashimoto thyroiditis had significantly high insulin resistance and inflammation than the SCH patients of other aetiologies.

An Investigation of the Effect of Curcumin on Fructose-Induced Metabolic Syndrome Rat Models

Aim: This study aimed to evaluate the potential effect of curcumin on glucose homeostasis, insulin resistance, inflammation, and oxidative stress in a fructose-induced metabolic syndrome rat model. Material and Methods: 24 male adult Wistar albino rats were randomly separated in to 4 groups: control (Group 1), 20% fructose (Group 2), 20% fructose and 100 mg/kg curcumin (Group 3), and 20% fructose, and 200 mg/kg curcumin (Group 4). Serum glucose, insulin, and plasma lipoprotein levels were determined by an auto-analyzer. Other parameters were determined by the Elisa Assay Method. Mann-Whitney U test was performed using the Bonferroni Correction to determine the significance of the difference between the two group (p≤0.008). Spearman Correlation Analysis was performed among parameters. Results: Metabolic Syndrome (MetS) was successfully created by observing increased serum glucose, high blood pressure, insulin resistance, and dyslipidemia in Group 2 compared to Group 1 (p≤0.008). The significance of serum total antioxidant capacity (TAC) levels among the groups could not be determined. While serum total oxidant status (TOS) and oxidative stress index (OSI) levels of Group 2 increased significantly compared to Group 1, and the levels of these parameters were significantly decreased in Group 3 and Group 4 compared to Group 2 (p≤0.008). The serum tumor necrosis factor-α (TNF-α) level of Group 2 increased significantly compared to Group 1 (p≤0.008). It was determined that the serum TNF-α level of Group 3 and Group 4 decreased significantly compared to Group 2 (p≤0.008). There was a positive correlation between serum OSI and TNF-α levels and serum HOMA-IR and TNF-α levels (p≤0.01). Conclusion: Our findings indicated that curcumin has a healing effect against MetS in the rat experimental animal model.

LRG1 is an adipokine that mediates obesity-induced hepatosteatosis and insulin resistance.

Dysregulation in adipokine biosynthesis and function contributes to obesity-induced metabolic diseases. However, the identities and functions of many of the obesity-induced secretory molecules remain unknown. Here, we report the identification of leucine-rich alpha-2-glycoprotein 1 (LRG1) as an obesity-associated adipokine that exacerbates high fat diet-induced hepatosteatosis and insulin resistance. Serum levels of LRG1 were markedly elevated in obese humans and mice compared with their respective controls. LRG1 deficiency in mice greatly alleviated diet-induced hepatosteatosis, obesity, and insulin resistance. Mechanistically, LRG1 bound with high selectivity to the liver and promoted hepatosteatosis by increasing de novo lipogenesis and suppressing fatty acid β-oxidation. LRG1 also inhibited hepatic insulin signaling by downregulating insulin receptor substrates 1 and 2. Our study identified LRG1 as a key molecule that mediates the crosstalk between adipocytes and hepatocytes in diet-induced hepatosteatosis and insulin resistance. Suppressing LRG1 expression and function may be a promising strategy for the treatment of obesity-related metabolic diseases.

Gestational and pregestational diabetes in pregnant women with cystic fibrosis

As cystic fibrosis transmembrane regulator (CFTR) modulator therapies offer greater longevity and improved health quality, women living with cystic fibrosis (CF) are increasingly pursuing pregnancy. Maternal risks for pregnant women with CF largely depend on a woman’s baseline pulmonary and pancreatic function, and the majority of CF pregnancies will successfully end in live births.Diabetes, either gestational or pre-existing cystic fibrosis-related diabetes (CFRD), is highly prevalent in women with CF, affecting 18 to 62% of pregnancies in recent CF center reports. In addition to the rising incidence of CFRD with age, gestational diabetes is also more common in women with CF due to lower insulin secretion, higher insulin resistance, and increased hepatic glucose production as compared to pregnant women without CF. Diabetes occurring during pregnancy has important implications for maternal and fetal health. It is well established in women without CF that glycemic control is directly associated with risks of fetal malformation, neonatal-perinatal mortality, cesarean delivery and need for neonatal intensive care. Small studies in women with CF suggest that pregnancies affected by diabetes have an increased risk of preterm delivery, lower gestational age, and lower fetal birth weight compared to those without diabetes.Women with CF preparing for pregnancy should be counseled on the risks of diabetes and should undergo routine screening for CFRD with oral glucose tolerance testing (OGTT) if not already completed in the past six months. Glycemic control in those with pre-gestational CFRD should be optimized prior to conception. Insulin is preferred for the management of diabetes in pregnant women with CF via multiple daily injections or insulin pump therapy, and continuous glucose monitors (CGM) can be useful in mitigating hypoglycemia risks. Women with CF face many unique challenges impacting diabetes care during pregnancy and would benefit from support by a multidisciplinary care team, including nutrition and endocrinology, to ensure healthy pregnancies.

Insulin resistance and risk of vascular events, interventions and mortality in type 1 diabetes.

To identify determinants associated with insulin resistance and to assess the association between insulin resistance and cardiovascular events, vascular interventions and mortality in people with type 1 diabetes at high risk of cardiovascular disease. Prospective cohort study. One hundred and ninety-five people with type 1 diabetes from the Secondary Manifestations of ARTerial disease (SMART) cohort were included. Insulin resistance was quantified by the estimated glucose disposal rate (eGDR) with higher eGDR levels indicating higher insulin sensitivity (i.e. lower eGDR levels indicating higher insulin resistance). Linear regression models were used to evaluate determinants associated with eGDR. The effect of eGDR on cardiovascular events, cardiovascular events or vascular interventions (combined endpoint) and on all-cause mortality was analysed using Cox proportional hazards models adjusted for confounders. In 195 individuals (median follow-up 12.9 years, IQR 6.7-17.0), a total of 25 cardiovascular events, 26 vascular interventions and 27 deaths were observed. High eGDR as a marker for preserved insulin sensitivity was independently associated with a lower risk of cardiovascular events (HR: 0.75; 95% CI: 0.61-0.91), a lower risk of cardiovascular events and vascular interventions (HR: 0.74; 95% CI: 0.63-0.87) and a lower risk of all-cause mortality (HR: 0.81; 95% CI: 0.67-0.98). Insulin resistance as measured by eGDR is an additional risk factor for cardiovascular disease in individuals with type 1 diabetes. Modification of insulin resistance by lifestyle interventions or pharmacological treatment could be a viable therapeutic target to lower the risk of cardiovascular disease.

Aberrant protein palmitoylation: A new route involved in Alzheimer's disease.

Growing evidence points to altered metabolic signals as a risk factor for Alzheimer's disease (AD). The high fatty acid levels and brain insulin resistance (BIR) found in AD brains may impinge on protein palmitoylation (P-S-palm), a post-translational modification critically involved in the regulation of neuronal protein localization and synaptic function. Our previous findings highlighted the critical role of aberrant palmitoylation in BIR-dependent memory impairment (Spinelli et al., 2017). We tested the effect of chronic intranasal injection of the palmitoylation inhibitor 2-bromopalmitate (2BP) on a large cohort of male and female 3xTg-AD mice, starting from 3 months of age, by performing cognitive (novel object recognition and object displacement tests), electrophysiological (LTP), immunohistochemical (Abeta deposition) and molecular analyses (Abeta measurement by ELISA). We also analyzed the palmitoyl-proteome (by acyl biotin exchange assay and mass-spectrometry) in the hippocampus of 9-month-old wild type, 3xTg-AD and 2BP-treated 3xTg-AD mice. 2BP delayed the onset of memory deficits in both male and female 3xTg-AD mice. More importantly, 2BP significantly enhanced cognitive performances in 6-, 9- and 12-month-old animals. Accordingly, electrophysiological analyses on hippocampal brain slices from 2BP-treated 3xTg-AD mice revealed greater long-term potentiation at CA3-CA1 synapses. In addition, 2BP mice showed lower Abeta deposition in hippocampus. Finally, palmitoyl-proteome analysis revealed a large number of proteins involved in APP and tau metabolism, synaptic plasticity and brain metabolism aberrantly palmitoylated in the AD mouse model and reverted by 2BP. Our data indicate that aberrant palmitoylation plays a critical role in the onset and progression of AD and reveal novel targets of protein palmitoylation potentially involved in the development of neurodegeneration and dementia. This is also the first preclinical study on the effect of 2BP on AD-related cognitive decline.

Silencing TXNIP ameliorates high uric acid-induced insulin resistance via the IRS2/AKT and Nrf2/HO-1 pathways in macrophages

Insulin resistance (IR) promotes atherosclerosis and increases the risk of diabetes and cardiovascular diseases. Our previous studies have demonstrated that high uric acid (HUA) increased oxidative stress, leading to IR in cardiomyocytes and pancreatic β cells. However, whether HUA can induce IR in monocytes/macrophages, which play critical roles in all stages of atherosclerosis, is unclear. Recent findings revealed that thioredoxin-interacting protein (TXNIP) negatively regulates insulin signaling; however, the roles and mechanisms of TXNIP in HUA-induced IR remain unclear. Therefore, in this study, we investigated the function of TXNIP in macrophages treated with UA. Transcriptomic profiling revealed TXNIP as one of the most upregulated genes, and subsequent RT-PCR and Western blot analyses confirmed that TXNIP was upregulated by HUA. HUA treatment significantly increased mitochondrial reactive oxygen species (MtROS) levels and decreased insulin-stimulated glucose uptake. Silencing TXNIP by RNA interference significantly diminished HUA-induced oxidative stress and IR. Mechanistically, silencing TXNIP reversed the inhibition of the phosphorylation of insulin receptor substrate 2 (IRS2)/protein kinase B (AKT) pathway induced by HUA. Additional study revealed that HUA induced the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathway, but silencing TXNIP abolished it. Moreover, Nrf2 inhibitor (ML385) ameliorated HUA-induced IR independent of IRS2/AKT signaling. Probenecid, a well-known UA-lowering drug, significantly suppressed the activation of TXNIP and Nrf2/HO-1 signaling. Furthermore, RNA-seq revealed that activation of the TXNIP-related redox pathway may be a key regulator in patients with asymptomatic hyperuricemia. These data suggest that silencing TXNIP could ameliorate HUA-induced IR via the IRS2/AKT and Nrf2/HO-1 pathways in macrophages. Additionally, TXNIP might be a promising therapeutic target for preventing and treating oxidative stress and IR induced by HUA.

Lower B-type natriuretic peptide levels predict left ventricular concentric remodelling and insulin resistance.

AimsNatriuretic peptides have reportedly been associated with cardiac hypertrophy and insulin resistance; however, it has not been established if B‐type natriuretic peptide (BNP) is associated with either insulin resistance or cardiac remodelling in a population with normal plasma BNP levels. We investigated the relationship among plasma BNP levels, insulin resistance, and left ventricular (LV) remodelling in a population with normal physiological plasma BNP levels.Methods and resultsAmong 1632 individuals who participated in annual health checks between 2005 and 2008 in Arita‐cho, Saga, Japan, 675 individuals [median (interquartile range) for age 62 (51–69) years; 227 men (34%)] with LV ejection fraction 50% and BNP level <35 pg/mL were enrolled in this study. Insulin resistance was assessed using homeostatic model assessment of insulin resistance (HOMA‐IR). LV geometry, including LV concentric remodelling, was classified based on relative wall thickness (RWT) and LV mass index values derived from echocardiographic findings. Factors associated with insulin resistance and LV geometry were investigated using multiple logistic regression analysis. Tertiles of BNP were inversely associated with HOMA‐IR [1st tertile, 1.33 (0.76–1.74); 2nd tertile, 1.05 (0.72–1.59); 3rd tertile, 0.95 (0.66–1.58), P = 0.005]. Lower BNP was associated with the prevalence of insulin resistance, defined as HOMA‐IR ≥1.37, even after full multivariate adjustment [1 SD increment in BNP = adjusted odds ratio (aOR) 0.740; 95% confidence interval (CI) 0.601–0.912; P = 0.005]. LV concentric remodelling (RWT >0.42; LV mass index ≤115 g/m2 in men and ≤95 g/m2 in women) was observed in 107 (16%) participants, while normal LV geometry (RWT ≤0.42; LV mass index ≤115 g/m2 in men and ≤95 g/m2 in women) was seen in 423 (63%), and LV hypertrophy (LV mass index >115 g/m2 in men and >95 g/m2 in women) in 145 (21%). Both low BNP level and higher insulin resistance were independently linked to LV concentric remodelling after multivariate adjustment (1 SD increment in BNP = aOR 0.714, 95% CI 0.544–0.938, P = 0.015; HOMA‐IR ≥ 1.37 vs. <1.37: aOR 1.694, 95% CI 1.004–2.857, P = 0.048, respectively).ConclusionsLower BNP levels are linked to either insulin resistance or LV concentric remodelling in a population with normal plasma BNP levels, suggesting that participants with lower natriuretic peptide level might be vulnerable to the development of metabolic disorders and LV morphological abnormalities.

Association of Diabetes Mellitus and Alcohol Abuse with Cancer: Molecular Mechanisms and Clinical Significance.

Diabetes mellitus (DM), one of the metabolic diseases which is characterized by sustained hyperglycemia, is a life-threatening disease. The global prevalence of DM is on the rise, mainly in low- and middle-income countries. Diabetes is a major cause of blindness, heart attacks, kidney failure, stroke, and lower limb amputation. Type 2 diabetes mellitus (T2DM) is a form of diabetes that is characterized by high blood sugar and insulin resistance. T2DM can be prevented or delayed by a healthy diet, regular physical activity, maintaining normal body weight, and avoiding alcohol and tobacco use. Ethanol and its metabolites can cause differentiation defects in stem cells and promote inflammatory injury and carcinogenesis in several tissues. Recent studies have suggested that diabetes can be treated, and its consequences can be avoided or delayed with proper management. DM has a greater risk for several cancers, such as breast, colorectal, endometrial, pancreatic, gallbladder, renal, and liver cancer. The incidence of cancer is significantly higher in patients with DM than in those without DM. In addition to DM, alcohol abuse is also a risk factor for many cancers. We present a review of the recent studies investigating the association of both DM and alcohol abuse with cancer incidence.

Plumbagin attenuates high glucose-induced trophoblast cell apoptosis and insulin resistance via activating AKT/mTOR pathway

Plumbagin, a bioactive phytoconstituent, is isolated from the root of Plumbago zeylanica L. Plumbagin possesses antidiabetic effect to mediate glucose homeostasis, wound healing and diabetic nephropathy. However, the involvement of plumbagin in gestational diabetes mellitus (GDM) has not been reported yet. Trophoblast cell line (HTR8/SVneo) was incubated with high glucose to establish cell model of GDM. Cell viability and proliferation were detected by MTT and EdU staining. Flow cytometry was used to investigate cell apoptosis. Cell viability of HTR8/SVneo was reduced by high glucose or incubation of plumbagin. Plumbagin restored reduced cell viability and proliferation of HTR8/SVneo induced by high glucose. Plumbagin attenuated high glucose-induced cell apoptosis in HTR8/SVneo cells through upregulation of Bcl-2 and down-regulation of Bax, cleaved caspase-3 and cleaved caspase-9. Protein expression of glucose transporter type 4 (GLUT-4), insulin receptor (INSR)-B and INSR substrate (IRS1) was decreased in high glucose-induced HTR8/SVneo but increased by plumbagin. The suppressive effects of high glucose on phosphorylation of AKT and mTOR in HTR8/SVneo were reversed by plumbagin. Plumbagin improved high glucose-induced cell apoptosis and insulin resistance of HTR8/SVneo through activation of AKT/mTOR pathway, suggesting that plumbagin might be used as a potential strategy for the prevention of GDM.

Impaired glucose metabolism reduces the neuroprotective action of adipocytokines in cognitively normal older adults with insulin resistance.

Evidence suggests that aging-related dysfunctions of adipose tissue and metabolic disturbances increase the risk of diabetes and metabolic syndrome (MtbS), eventually leading to cognitive impairment and dementia. However, the neuroprotective role of adipocytokines in this process has not been specifically investigated. The present study aims to identify metabolic alterations that may prevent adipocytokines from exerting their neuroprotective action in normal ageing. We hypothesize that neuroprotection may occur under insulin resistance (IR) conditions as long as there are no other metabolic alterations that indirectly impair the action of adipocytokines, such as hyperglycemia. This hypothesis was tested in 239 cognitively normal older adults (149 females) aged 52 to 87 years (67.4 ± 5.9 yr). We assessed whether the homeostasis model assessment-estimated insulin resistance (HOMA-IR) and the presence of different components of MtbS moderated the association of plasma adipocytokines (i.e., adiponectin, leptin and the adiponectin to leptin [Ad/L] ratio) with cognitive functioning and cortical thickness. The results showed that HOMA-IR, circulating triglyceride and glucose levels moderated the neuroprotective effect of adipocytokines. In particular, elevated triglyceride levels reduced the beneficial effect of Ad/L ratio on cognitive functioning in insulin-sensitive individuals; whereas under high IR conditions, it was elevated glucose levels that weakened the association of the Ad/L ratio with cognitive functioning and with cortical thickness of prefrontal regions. Taken together, these findings suggest that the neuroprotective action of adipocytokines is conditioned not only by whether cognitively normal older adults are insulin-sensitive or not, but also by the circulating levels of triglycerides and glucose, respectively.

Low plasma levels of B-type natriuretic peptide predict the insulin resistance and left ventricular concentric remodeling in subjects without heart diseases: the observational arita cohort study

Abstract Introduction Although natriuretic peptides (NPs) are established as a biomarker of heart failure (HF), NPs have been attracting attention as a mediator in the metabolic sequences recently. On the other hand, metabolic disorders including insulin resistance have been suggested to be involved in left ventricular (LV) concentric remodeling, hinting us to the unexpected relationship among NPs, insulin resistance and LV concentric remodeling. Purpose To investigate whether the basal B-type natriuretic peptide (BNP) level is linked to insulin resistance or LV concentric remodeling in the participants independent of HF in the Japanese Arita-cho cohort study. Methods Among 1632 subjects who participated in annual health checks from 2005 to 2008 in Arita-cho, Saga, Japan as a cohort study, we studied 675 subjects without history of cardiovascular disease with LV ejection fraction≥50% and BNP level&amp;lt;35pg/ml (227 men; median 62 years old). Insulin resistance was assessed by homeostatic model assessment of insulin resistance (HOMA-IR) and LV geometry including LV concentric remodeling was classified based on relative wall thickness (RWT) and LV mass index from echocardiographic findings. Results The tertile levels of BNP were inversely associated with HOMA-IR (the 1st tertile 1.33 (0.76–1.74), the 2nd tertile 1.05 (0.72–1.59), the 3rd tertile 0.95 (0.66–1.58), p=0.005); in the logistic regression analysis, the lower BNP level was related to the prevalence of insulin resistance defined as HOMA-IR≥1.37 after full multivariate adjustment (1 SD increment of BNP: adjusted odds ratio [aOR] 0.740, 95% confidence interval 0.601–0.912, P=0.005. LV concentric remodeling (RWT &amp;gt;0.42 and LV mass index ≤115 g/m2 in men and ≤95 g/m2 in women) was observed in 170 (25%) subjects; both low BNP level and higher insulin resistance were independently linked with LV concentric remodeling after multivariate adjustment (1 SD increment of BNP: aOR 0.714, 95% CI 0.544–0.938, p=0.015, HOMA-IR≥1.37 vs. &amp;lt;1.37: aOR 1.694, 95% CI 1.004–2.857, p=0.048, respectively) (Figure). Conclusions In the cohort without HF, the low BNP level was linked to insulin resistance and LV concentric remodeling independently, suggesting that the subjects with low NPs levels may cause metabolic disorders and LV morphological abnormalities. Funding Acknowledgement Type of funding sources: None.

Insulin resistance in children with juvenile systemic lupus erythematosus and ınvestigation of the possibly responsible factors.

Insulin resistance (IR) has been described in adults with systemic lupus erythematosus (SLE), though its mechanism has not been fully clarified. In this study, it was aimed to investigate insulin sensitivity for the first time in children with juvenile SLE (jSLE) by considering the effect of the already known contributing factors of IR. This is a cross-sectional study including 43 patients with jSLE and the same number of healthy controls matched for age, gender, pubertal stage, body mass index, and physical activity level. IR, as calculated by both homeostatic model assessment for insulin resistance (HOMA-IR) and a relatively new method, triglyceride glucose (TyG) index, was compared between the patients and their matched controls, also among the patients stratified by disease duration, corticosteroid use, and disease activity. Insulin resistance in the patient group was higher than the controls according to both HOMA-IR and TyG index (p < 0.001 for both). In the patient group, no significant effect of disease duration, corticosteroid use, disease activity, and levels of anti-dsDNA, anti-cardiolipin IgM, anti-cardiolipin IgG, C3, and C4 on IR was demonstrated. Children with jSLE were found to have higher IR even after neutralizing the effects of the contributing factors which are expected to aggravate IR. This elevation in IR in jSLE seems not to be associated with corticosteroid use, disease duration, disease activity, or autoantibody levels. Thus, the presence of IR in jSLE cannot be explained solely with neither the already known contributing factors nor the increased inflammation of the disease. Key Points • In this study, insulin sensitivity was investigated for the first time in children with jSLE. • Children with jSLE have higher insulin resistance than healthy ones. • Insulin resistance in children with jSLE is independent of corticosteroid use, disease duration, disease activity or autoantibody, and complement levels.