Insulin-resistant States Research Articles

Short chain fatty acids and GIT hormones mitigate gut barrier disruption in high fat diet fed rats supplemented by synbiotics

High fat diet (HFD) predisposes to many metabolic changes; it may disrupt gut barrier integrity and gut microbiota composition. Synbiotic supplementation may promote host’s metabolic health by selective activation of the healthy microorganisms. This study aimed to probe the interaction between synbiotic supplementation, gut microbiota and gut hormones in HFD states. Twenty-seven adult male albino rats, 3 groups, group I: control, group II: HFD received HFD for 12 weeks and group III: synbiotic-supplemented HFD received synbiotic in the last 6 weeks. The anthropometric measurments were measured. Liver transaminases, lipid profile, parameters of insulin resistance, serum serotonin, glucagon like polypeptide-1 (GLP-1), oxidant/antioxidant markers (MDA/GPx), zonulin levels and quantitative cecal short chain fatty acids (SCFA) were assessed. Samples of liver and colon were employed for histopathological studies. Compared to HFD group, synbiotic led to a significant reduction in anthropometric measurements, liver enzymes, atherogenic index, HOMA-IR and MDA denoting improved dyslipidemia, insulin resistance and oxidative state. Moreover, synbiotic supplementation decreased serum zonulin and increased both serum serotonin, GLP-1 and cecal SCFAs. Synbiotic supplementation ameliorated the metabolic derangements and the disturbed integrity of the intestinal barrier induced by HFD. As synbiotics can increase gut hormones (serum GLP-1&serotonin) and SCFAs.

Raptor levels are critical for β-cell adaptation to a high-fat diet in male mice

ObjectiveThe essential role of raptor/mTORC1 signaling in β-cell survival and insulin processing has been recently demonstrated using raptor knock-out models. Our aim was to evaluate the role of mTORC1 function in adaptation of β-cells to insulin resistant state. MethodHere, we use mice with heterozygous deletion of raptor in β-cells (βraHet) to assess whether reduced mTORC1 function is critical for β-cell function in normal conditions or during β-cell adaptation to high-fat diet (HFD). ResultsDeletion of a raptor allele in β-cells showed no differences at the metabolic level, islets morphology, or β-cell function in mice fed regular chow. Surprisingly, deletion of only one allele of raptor increases apoptosis without altering proliferation rate and is sufficient to impair insulin secretion when fed a HFD. This is accompanied by reduced levels of critical β-cell genes like Ins1, MafA, Ucn3, Glut2, Glp1r, and specially PDX1 suggesting an improper β-cell adaptation to HFD. ConclusionThis study identifies that raptor levels play a key role in maintaining PDX1 levels and β-cell function during the adaptation of β-cell to HFD. Finally, we identified that Raptor levels regulate PDX1 levels and β-cell function during β-cell adaptation to HFD by reduction of the mTORC1-mediated negative feedback and activation of the AKT/FOXA2/PDX1 axis. We suggest that Raptor levels are critical to maintaining PDX1 levels and β-cell function in conditions of insulin resistance in male mice.

Inhibition of miR-543 alleviates cardiac fibroblast-to-myofibroblast transformation and collagen expression in insulin resistance via targeting PTEN

BackgroundMyocardial interstitial fibrosis is an important manifestation of diabetic heart disease, and insulin resistance is one of the mechanisms of myocardial interstitial fibrosis. Some studies have found that miR-543 is associated with insulin resistance, but whether it plays a role in diabetic myocardial interstitial fibrosis remains unclear. This study aimed to investigate the role of miR-543 in diabetic myocardial interstitial fibrosis. MethodsThe combination of high glucose and high insulin was used to establish an insulin-resistant myocardial fibroblast model. The expression levels of miR-543, α-SMA, collagen Ⅰ, collagen Ⅲ and PTEN were detected. Cell proliferation and migration were detected. Luciferase reporter gene assay was used to verify the targeting relationship between miR-543 and PTEN. ResultsThe expression of miR-543 was up-regulated in myocardial fibroblasts with insulin resistance, which was consistent with the results of bioinformatics analysis. The proliferation and migration levels of myocardial fibroblasts in insulin-resistant states were increased, and the expression levels of α-SMA, collagen Ⅰ and collagen Ⅲ were also increased. Inhibition of miR-543 expression could reverse the above changes. Target gene prediction and dual luciferase reporter assay demonstrated that miR-543 could bind to the 3′UTR region of PTEN. Moreover, the effect of miR-543 on insulin-resistant myocardial fibroblasts is mediated by targeting PTEN. ConclusionsInhibition of miR‐543 can reduce myocardial fibroblast-myofibroblast transformation and collagen expression in insulin-resistant states by targeting PTEN.

A Woman's Heart: Improving Uptake and Awareness of Cardiovascular Screening for Middle-Aged Populations.

Mid-life, the years leading up to and following the menopause transition, in women is accompanied by a change in cardiometabolic risk factors, including increases in body weight, changes in body composition, a more insulin-resistant state, and a shift towards a more atherogenic dyslipidemia pattern. Cardiovascular disease (CVD) risk assessment should be performed continually throughout the lifespan, as risk is not stagnant and can change throughout the life course. However, mid-life is a particularly important time for a woman to be evaluated for CVD risk so that appropriate preventive strategies can be implemented. Along with assessing traditional risk factors, ascertainment of a reproductive history is an integral part of a comprehensive CVD risk assessment to recognize unique female-specific or female-predominant factors that modify a woman's risk. When there is uncertainty about CVD risk and the net benefit of preventive pharmacotherapy interventions (such as statins), measuring a coronary artery calcium score can help further refine risk and guide shared decision-making. Additionally, there should be heightened sensitivity around identifying signs and symptoms of ischemic heart disease in women, as these may present differently than in men. Ischemia from coronary microvascular disease and/or vasospasm may be present even without obstructive coronary artery disease and is associated with a heightened risk for major cardiovascular events and reduced quality of life. Therefore, correctly identifying CVD in women and implementing preventive and treatment therapies is paramount. Unfortunately, women are underrepresented in cardiovascular clinical trials, and more data are needed about how to best incorporate novel and emerging risk factors into CVD risk assessment. This review outlines an approach to CVD screening and risk assessment in women using several methods, focusing on the middle-aged population.

P16-041-23 Combined Oral Contraceptive Use Alters the Effects of Egg Intake on Lipoprotein Profiles,Without Impacting Effects on Insulin Resistance, Inflammation, or Choline Status

P16-041-23 Combined Oral Contraceptive Use Alters the Effects of Egg Intake on Lipoprotein Profiles,Without Impacting Effects on Insulin Resistance, Inflammation, or Choline Status

Unveiling the Silent Danger of Childhood Obesity: Non-Invasive Biomarkers Such as Carotid Intima-Media Thickness, Arterial Stiffness Surrogate Markers, and Blood Pressure Are Useful in Detecting Early Vascular Alterations in Obese Children.

Obese children present a higher cardio-metabolic risk. Measuring vascular biomarkers that assess the evolution of arterial stiffness, subclinical atherosclerosis, and hypertension in such patients could be helpful in the long term. We studied 84 children, aged from 6 to 18 years: 50 obese subjects, versus 34 of normal weight. Clinical examination involved: BMI, waist circumference, waist-to-height ratio, and detection of the presence of acanthosis nigricans and irregular menstrual cycles (the latter in adolescent girls). The carotid intima-media thickness (CIMT) was measured with the Aixplorer MACH 30 echography device. The pulse wave velocity (PWV), augmentation index (AIx), and peripheral and central blood pressures (i.e., SBP, DBP, cSBP, cDBP, and cPP) were acquired through a Mobil-O-Graph device. Obese subjects underwent body composition analysis with a Tanita BC-418. Blood tests were: HOMA-IR, lipid panel, uric acid, and 25-OH vitamin D. All vascular biomarkers presented increased values in obese subjects versus controls. The following cut-off values were significant in detecting obesity: for PWV > 4.6 m/s, cSBP > 106 mmHg for the <12-year-olds, PWV > 4.5 m/s and cSBP > 115 mmHg for the 12-15-year-olds, and PWV > 5 m/s, cSBP > 123 mmHg for the >15-year-olds. AIx is higher in obese children, regardless of their insulin resistance status. Waist circumference and waist-to-height ratio correlate to all vascular parameters. HOMA-IR is an independent predictor for all vascular parameters except CIMT. Cut-off values for PWV of >4.8 m/s, SBP > 125 mmHg, and a cSBP > 117 mmHg predicted the presence of acanthosis nigricans. Obese girls with irregular menses displayed significantly higher PWV, SBP, and DPB. Elevated levels of uric acid, LDL-c, non-LDL-c, triglycerides, and transaminases, and low levels of HDL-c and 25-OH vitamin D correlated with higher arterial stiffness and CIMT values. We conclude that CIMT and the markers of arterial stiffness are useful in the early detection of vascular damage in obese children.

1563-P: Hepatic PHD3 Stimulates Gluconeogenesis and Aggravates Hyperglycemia and Type 2 Diabetes by Hydroxylating CRTC2 at Pro129 and Pro615

Hepatic gluconeogenesis is critical for metabolic adaption in response to fasting, and its abnormal elevation contributes to the pathogenesis of hyperglycemia and type 2 diabetes. However, whether and how protein hydroxylation regulates hepatic gluconeogenesis and glucose metabolism remains largely unknown. Here we report that PHD3 is identified as a fasting-induced factor and regulates hepatic gluconeogenesis through interaction and hydroxylation of CRTC2. Pro129 and Pro615 hydroxylation of CRTC2 following PHD3 activation is necessary for its nuclear translocation and association with CREB, and enhanced binding to promoters of gluconeogenic target genes in response to fasting or the cAMP activator forskolin. CRTC2 hydroxylation-stimulated gluconeogenic gene expression is independent of SIK-mediated phosphorylation of CRTC2. Liver-specific knockout of PHD3 (PHD3 LKO) mice or prolyl hydroxylase-deficient knockin mice with alanine mutation in PHD3 at Pro196 (PHD3 KI) show significant attenuated gluconeogenic genes, glycaemia and hepatic capacity to produce glucose during fasting or fed with high-fat, high-sucrose diet. The efficacies of glucagon or adenylyl cyclase activator forskolin on stimulating the expression of gluconeogenic enzymes, such as PEPCK and G6Pase, and on glucose output are abolished in PHD3-/- mouse primary hepatocytes. Importantly, Pro615 hydroxylation of CRTC2 by PHD3 is increased in livers of fasted mice, diet-induced insulin resistance or genetically obese ob/ob mice and humans with diabetes. Together, these findings increase our understanding of the molecular mechanisms linking protein hydroxylation to gluconeogenesis under physiological and insulin resistant conditions, and may offer therapeutic potential for treating sustained gluconeogenesis, hyperglycemia and type 2 diabetes. Disclosure Y.Xue: None. W.Su: None. J.Zhao: None. C.Gao: None. J.Wen: None. Y.Xu: None. W.Fu: None. J.C.Fang: None. Y.Li: None. A.Cui: None. S.Wei: None. F.Ma: None. Z.Liu: None. X.Fang: None. W.Li: None. Y.Liu: None. G.Cai: None. Funding National Key R&amp;D Program of China (2019YFA0802502); National Natural Science Foundation of China (81925008, 82073061, 82170587, 32100943); Ministry of Science and Technology of China (2020YFA0803301); Open Project Program of Metabolic Vascular Diseases Key Laboratory of Sichuan Province (2022MVDKL-K2); Shandong Natural Science Foundation (ZR2020MH206); China Postdoctoral Science Foundation (2021M693273)

1300-P: Glucagon-Like Peptide-1 Levels Mirror Insulin Resistant States in Treatment-Naïve Type 2 Diabetes Mellitus

Introduction: In some Asian populations incretin system has been shown to be preserved in type 2 diabetes mellitus (T2DM). The association between fasting and post-OGTT glucagon-like peptide-1 (GLP-1) levels and insulin resistance in treatment-naïve T2DM population has not been clearly defined. Aim: To assess the insulin resistant states (IRS) by means of insulin resistance index (HOMA-IR) and relate this to the fasting and post-OGTT GLP-1 responses in treatment-naïve T2DM. Methods : Thirty-one treatment-naive T2DM subject underwent a 75-g OGTT. Fasting plasma glucose and insulin levels were obtained for HOMA-IR analyses along with plasma total GLP-1 concentrations measured at 0, 30 and 120 min. Results: Majority of the treatment-naïve T2DM patients were newly-diagnosed (n=28, 96.6%). The GLP-1 levels at 0, 30- and 120-min were 25.59 ± 10.87 pmol/L, 46.86 ± 18.36 pmol/L and 27.02 ± 13.37 pmol/L respectively. Fasting GLP-1, incremental GLP-1 at 30 min (∆GLP-130min) and ∆GLP-1120min were positively correlated with HOMA-IR (r=0.654, p&amp;lt;0.001; r=0.421, p=0.018; r=0.574, p=0.001 respectively). Conclusions: The novel finding of this study is that fasting and post-OGTT GLP-1 levels increased proportionately to IRS. This suggests an adaptive compensatory GLP-1 responses to overcome the worsening insulin resistance in treatment-naïve newly-diagnosed T2DM patients. Disclosure S.Chong: None. N.Sukor: None. S.A.Robert: None. K.Ng: None. N.A.Kamaruddin: Advisory Panel; Zuellig Pharma Holdings Pte. Ltd., Other Relationship; American Association of Clinical Endocrinologists, Speaker's Bureau; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk. Funding National University of Malaysia (GUP-2017-066); Malaysian Endocrine &amp; Metabolic Society (L12-MEMS6)

1628-P: Role of CD38 in the Regulation of Muscle Stem Cell Functions in Aged Mice

Skeletal muscle repair and regeneration is a complex process and is known to be delayed with aging, diabetes and obesity. This is in part due to infiltration of inflammatory macrophages which can delay the recovery process. Both macrophages and satellite cells require nicotinamide adenine dinucleotide (NAD+) for their biological functions. Aging-induced decline in NAD+ have been shown to worsen insulin resistance and muscle dysfunction. CD38 is an ectoenzyme that degrades NAD+ and is increased in inflammatory macrophages in aging, obesity and other insulin-resistant states. However, how inhibition of CD38 affects satellite cell functions in aged or obese mice, remains unknown. Here, we utilized aged CD38 knockout mice to assess the role of this protein and NAD+ in the recovery process in injured muscle. CD38 KO mice were found to be resistant to diet-induced obesity and had improved insulin sensitivity. Our data show that genetic deletion of CD38 in aged mice increased NAD+ levels and thus enhanced muscle stem/satellite cells differentiation and promote myogenesis. Deletion of CD38 also resulted in an enhanced number of regenerating myofibers. Furthermore, we found that deletion of CD38 significantly reduces fibrosis of muscle and also improved limb grip strength. Pharmacological inhibition of CD38 in C2C12 myoblasts and ex-vivo primary myoblasts significantly increased NAD+ levels and also enhanced the differentiation of satellite cells into myoblasts and myofibers. We, therefore, examined the rescue effects of 78c (CD38i) on human recombinant CD38 (hCD38) inhibition of muscle stem cells. Administration of hCD38 inhibited expression of MyoD and MyoG in primary myoblasts, while this effect was rescued through 78c treatment. Taken together, these data demonstrate that restoration of NAD+ levels either through genetic deletion/pharmacological inhibition of CD38 can improve muscle stem cell functions and muscle regeneration and might promote muscle regeneration in obesity, type 2 diabetes, and aging. Disclosure A.Nawaz: None. K.Yaku: None. I.Jeelani: None. K.Tobe: Other Relationship; MSD K.K., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Suntory Global Corporation, Ltd.,, Taiho Pharmaceutical Co. Ltd., Japan Diabetes Foundation, Japan Association for Diabetes Education and Care. T.Nakagawa: None.

1610-P: Fatty Acid–Binding Protein 4 as a Biomarker for Remission of Type 2 Diabetes

Elevated levels of circulating Fatty Acid Binding Protein 4 (FABP4), also named adipocyte FABP (A-FABP), are associated with obesity, diabetes mellitus, insulin resistance, hypertension, and cardiovascular risk. FABP4 is a protein found in high levels in both macrophages and adipocytes. Release of FABP4 from adipocytes via lipolysis, and release from macrophages during inflammation, plays a key role in development of insulin resistance and diabetes mellitus. We studied the effect of a high protein (HP; 30% protein, 40% carbohydrate, 30% fat) diet vs high carbohydrate (HC;15% protein, 55% carbohydrate, 30% fat) diet in patients recently diagnosed with Type 2 Diabetes (T2D). We determined the levels of circulating FABP4 and metabolic parameters in the HP vs HC groups at baseline and 6 months after consuming the respective diets. Participants (14) were randomized to a HP or HC diet for 6 months. All food was provided and designed for weight loss. After 6 months on the HP diet, 100% of the subjects had remission of T2D to Normal Glucose Tolerance (NGT), whereas only 16.6% of subjects on HC diet had remission of T2D. The HP diet group exhibited significant improvement in a) insulin sensitivity (p=0.001), b) inflammatory cytokines (p=0.001), C) cardiovascular risk factors (p=0.004) compared to the HC diet group at 6 months. Although weight loss in both groups was around 10% at 6 months, the HP group lost % fat mass, whereas, the HC group lost both % muscle and fat mass. Average level of FABP4 decrease after 6 months was 12,831 pg/ml in the 8 participants on the HP diet, compared to only a 1183 pg/ml average decrease after 6 months for the 6 HC participants. Conclusions: These data showed a significant decrease of circulating FABP4 in the HP but not HC diet group and suggests that a high protein diet could be an optimal way to reduce FABP4 levels in the blood. This could subsequently lower the risk of development/progression of insulin resistance, T2D, inflammation and cardiovascular risk conditions and serve as a biomarker. Disclosure F.B.Stentz: None. Funding AD Baskin

Lights and shadows on the use of metformin in pregnancy: from the preconception phase to breastfeeding and beyond.

During pregnancy, the complex hormonal changes lead to a progressive decrease of insulin sensitivity that can drive the onset of gestational diabetes (GDM) or worsen an already-known condition of insulin resistance like type 2 diabetes, polycystic ovarian syndrome (PCOS), and obesity, with complications for the mother and the fetus. Metformin during pregnancy is proving to be safe in a growing number of studies, although it freely crosses the placenta, leading to a fetal level similar to maternal concentration. The aim of this literature review is to analyze the main available evidence on the use of metformin during, throughout, and beyond pregnancy, including fertilization, lactation, and medium-term effects on offspring. Analyzed studies support the safety and efficacy of metformin during pregnancy. In pregnant women with GDM and type 2 diabetes, metformin improves obstetric and perinatal outcomes. There is no evidence that it prevents GDM in women with pregestational insulin resistance or improves lipid profile and risk of GDM in pregnant women with PCOS or obesity. Metformin could have a role in reducing the risk of preeclampsia in pregnant women with severe obesity, the risk of late miscarriages and preterm delivery in women with PCOS, and the risk of ovarian hyperstimulation syndrome, increasing the clinical pregnancy rate in women with PCOS undergoing in vitro fertilization (IVF/FIVET). Offspring of mothers with GDM exposed to metformin have no significant differences in body composition compared with insulin treatment, while it appears to be protective for metabolic and cardiovascular risk.

Predictors of Nonalcoholic Steatohepatitis Severity in Obese Patients Undergoing Bariatric Surgery: A Cross-Sectional Study

Background: Nonalcoholic steatohepatitis (NASH) currently affects 3–5% of the general population and 10–50% of patients with obesity. Our aim was to determine the predictors of severity of NASH in patients with obesity undergoing sleeve gastrectomy. Methods: We conducted a retrospective study in patients with obesity who underwent sleeve gastrectomy from 2013 to 2016. Liver biopsy at the time of the surgery showed a histological grade of NASH in all the patients. Patients were stratified into two groups, mild and moderate-severe (MS) NASH. Predictors were evaluated with multivariate logistic regression. Results: We included 193 patients. Of these, 139 had mild, 22 moderate, and 36 severe NASH. Majority of patients were female (54.8%) and the mean body mass index was 40.30 ± 2.19 kg/m2. In the adjusted regression model, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (prevalence ratios [PR]: 1.06, confidence interval [95% CI]: 1.02–1.10) and alanine aminotransferase (ALT) (PR: 1.01, 95% CI: 1.00–1.01) were factors associated with MS NASH. Conclusions: Despite the high prevalence of NASH in the obese population, most patients presented mild severity. A higher severity of NASH among patients with obesity can be predicted by clinical abnormalities such as higher HOMA-IR and ALT levels. Higher HOMA-IR levels are potential predictors of MS NASH regardless of insulin resistance status and in patients without metabolic syndrome.

ASSESSMENT OF MACROPHAGE INFLAMMATORY ACTIVITY ON VISCERAL ADIPOSE TISSUE IN HIGH-FAT DIET-INDUCED OBESE MICE BY 18F- FDG PET/CT

Objective: Obesity induced inflamed visceral adipose tissue (VAT) secretes pro-inflammatory cytokines thereby promoting systemic inflammation and insulin resistance which further exacerbate obesity-related cardiovascular disease (CVD). Macrophages are the key players in the development of obesity-associated VAT inflammation. Extensive clinical studies have reported that 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) can be used to evaluate the macrophage inflammatory activity on VAT in human beings. However, due to difficulty in human VAT biopsy, pathologic correlations were lacking and there was a few study on preclinical animal models. Here, we investigated whether 18F-FDG PET/CT could reflect the macrophage inflammatory activity on VAT in high-fat diet-induced obese mice. Design and method: Obese animal models were induced by a high-fat diet (60% fat) for 20 weeks using the male C57BL/6 mice. Insulin tolerance test was performed to evaluate the status of insulin resistance and C-reactive protein (CRP) was measured to assess the status of systemic inflammation. All animals underwent 18F-FDG PET/CT before sacrifice. Macrophage inflammatory activity was evaluated using the maximum standardized uptake value (SUVmax). Flow cytometry-, histological-, and molecular analyses were performed on harvested VAT. Results: All obese animals showed insulin resistance which resembled the human metabolic syndrome, a key pathophysiological process that contributes to increase CVD risk. VAT SUVmax was increased in obese mice and significantly correlated with the levels of CRP. Furthermore, VAT from obese mice showed increased macrophage infiltration, compared to normal mice. Conclusions: 18F-FDG PET/CT could visualize and evaluate the macrophage inflammatory activity on obesity-driven inflamed VAT in obese mice model. Our preclinical study strongly supports the clinical application of 18F-FDG PET/CT in the assessment of VAT inflammation to patients who are vulnerable to CVD.

Study on the therapeutic effect and mechanism of Tangningtongluo Tablet on diabetic mice

AimsTo investigate the therapeutic effects of Tangningtongluo Tablet on diabetic mice and its mechanism. This study was established the scientific basis for the clinical application of Tangningtongluo Tablet in the treatment of diabetes mellitus and provided data supporting the transformation of Tangningtongluo Tablet from an in-hospital preparation to a new Chinese medicine. MethodsIn this study, a diabetic mouse model was established by high-glucose and high-fat diet feeding in combination with STZ injection for 4 weeks. Glucose metabolism, lipid metabolism, liver histomorphological changes and liver function related indexes were detected, pancreatic histomorphological changes and insulin resistance related indexes were observed, and the expression of pathway related proteins and inflammatory factors were examined. ResultsGlycemia and glycated hemoglobin were reduced in diabetic mice after the treatment of Tangningtongluo Tablet, and glucose tolerance and lipid results were modified. The insulin resistance status of the mice was diminished and tissue damage to the pancreas and liver was repaired. Expression of ERS/NF-κB related pathway proteins was reduced in liver tissues, and inflammatory factors such as TNF-α, IL-6 and IL-1β were reduced in serum. ConclusionsTangningtongluo Tablet could reduce blood glucose in diabetic mice, regulate the disorder of lipid metabolism, enhance insulin sensitivity, improve insulin resistance, repair pancreatic tissue damage and protect mouse liver in diabetic mice. The mechanism of action might be related to the regulation of ERS/NF-κB signaling pathway and the reduction of TNF-α, IL-6 and IL-1β production.

Serum HMGB1 levels are independently associated with glucose clamp-derived measures of insulin resistance in women with PCOS

PurposePCOS is associated with low grade inflammation which could play a role in insulin resistance and ovarian dysfunction. Preliminary findings suggested that serum levels of HMGB1, a cytokine involved in inflammation, might be altered in women with PCOS. Primary aim of this study was to assess whether HMGB1 serum concentrations are associated with PCOS and with the state of insulin resistance of these women.MethodsSixty women with PCOS, selected to have a similar proportion of subjects with altered or normal insulin sensitivity, and 29 healthy controls were studied. Serum HMGB1 levels were compared in subgroups of PCOS women and controls. In PCOS women, insulin sensitivity was assessed by the glucose clamp technique and HMGB1 was measured at baseline and after acute hyperinsulinemia.ResultsHMGB1 levels were similar in women with PCOS and controls and no elements used for diagnosing PCOS were associated with serum HMGB1. However, HMGB1 concentrations were higher in insulin-resistant vs insulin-sensitive PCOS women (p = 0.017), and inversely associated with insulin-induced total and non-oxidative glucose metabolism. In both subgroups of PCOS women, serum HMBG1 levels significantly increased after acute hyperinsulinemia.ConclusionsThese data suggest that HMGB1 levels are not associated with PCOS per se, but with insulin resistance. Further research should establish the underlying nature of this relationship, and whether this protein might play a role in the metabolic complications of PCOS.

AMPK Activation as a Protective Mechanism to Restrain Oxidative Stress in the Insulin-Resistant State in Skeletal Muscle of Rat Model of PCOS Subjected to Postnatal Overfeeding.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy in women of reproductive age, often associated with obesity and insulin resistance. Childhood obesity is an important predisposing factor for the development of PCOS later in life. Being particularly interested in the interplay between prepubertal obesity and hyperandrogenemia, we investigated the effects of early postnatal overfeeding, accomplished by reducing litter size during the period of suckling, on energy sensing and insulin signaling pathways in the gastrocnemius muscle of a rat model of PCOS-induced by 5α-dihydrotestosterone (DHT). The combination of overfeeding and DHT treatment caused hyperinsulinemia and decreased systemic insulin sensitivity. Early postnatal overfeeding induced defects at critical nodes of the insulin signaling pathway in skeletal muscle, which was associated with reduced glucose uptake in the presence of hyperandrogenemia. In this setting, under a combination of overfeeding and DHT treatment, skeletal muscle switched to mitochondrial β-oxidation of fatty acids, resulting in oxidative stress and inflammation that stimulated AMP-activated protein kinase (AMPK) activity and its downstream targets involved in mitochondrial biogenesis and antioxidant protection. Overall, a combination of overfeeding and hyperandrogenemia resulted in a prooxidative and insulin-resistant state in skeletal muscle. This was accompanied by the activation of AMPK, which could represent a potential therapeutic target in insulin-resistant PCOS patients.

Insulin Resistance and Impaired Branched-Chain Amino Acid Metabolism in Alzheimer's Disease.

The pathogenesis of Alzheimer's disease (AD) is complicated and involves multiple contributing factors. Mounting evidence supports the concept that AD is an age-related metabolic neurodegenerative disease mediated in part by brain insulin resistance, and sharing similar metabolic dysfunctions and brain pathological characteristics that occur in type 2 diabetes mellitus (T2DM) and other insulin resistance disorders. Brain insulin signal pathway is a major regulator of branched-chain amino acid (BCAA) metabolism. In the past several years, impaired BCAA metabolism has been described in several insulin resistant states such as obesity, T2DM and cardiovascular disease. Disrupted BCAA metabolism leading to elevation in circulating BCAAs and related metabolites is an early metabolic phenotype of insulin resistance and correlated with future onset of T2DM. Brain is a major site for BCAA metabolism. BCAAs play pivotal roles in normal brain function, especially in signal transduction, nitrogen homeostasis, and neurotransmitter cycling. Evidence from animal models and patients support the involvement of BCAA dysmetabolism in neurodegenerative diseases including Huntington's disease, Parkinson's disease, and maple syrup urine disease. More recently, growing studies have revealed altered BCAA metabolism in AD, but the relationship between them is poorly understood. This review is focused on the recent findings regarding BCAA metabolism and its role in AD. Moreover, we will explore how impaired BCAA metabolism influences brain function and participates in the pathogenesis of AD.

Role of Melatonin in the Onset of Metabolic Syndrome in Women.

Metabolic syndrome (MetS) is a constellation of several associated cardiometabolic risk factors that increase the risk of developing type 2 diabetes mellitus (T2DM), cardiovascular diseases, and mortality. The role of hormonal factors in the development of MetS is assumed. In women, an insulin-resistant state that is associated with polycystic ovarian syndrome and increased deposition of intra-abdominal adipose tissue promotes the development of MetS and increases cardiovascular risk. The neuroendocrine hormone melatonin is secreted mainly at night under the regulatory action of the suprachiasmatic nucleus in the hypothalamus. Melatonin secretion is influenced by exogenous factors such as light and seasons and endogenous factors such as age, sex, and body weight. At present, the role of melatonin in metabolic disorders in humans is not fully understood. In this review, we set out to analyze the relationship of melatonin with the main features of MetS in women. Data from experimental and clinical studies on the role of melatonin in glucose metabolism and on the involvement of melatonin in lipid disturbances in MetS are reviewed. The complex influence of melatonin on hypertension is discussed. The changes in melatonin, leptin, and ghrelin and their relation to various metabolic processes and vascular dysfunction are discussed.

PKN1 Kinase: A Key Player in Adipocyte Differentiation and Glucose Metabolism.

Adipocyte dysfunction is the driver of obesity and correlates with insulin resistance and the onset of type 2 diabetes. Protein kinase N1 (PKN1) is a serine/threonine kinase that has been shown to contribute to Glut4 translocation to the membrane and glucose transport. Here, we evaluated the role of PKN1 in glucose metabolism under insulin-resistant conditions in primary visceral adipose tissue (VAT) from 31 patients with obesity and in murine 3T3-L1 adipocytes. In addition, in vitro studies in human VAT samples and mouse adipocytes were conducted to investigate the role of PKN1 in the adipogenic maturation process and glucose homeostasis control. We show that insulin-resistant adipocytes present a decrease in PKN1 activation levels compared to nondiabetic control counterparts. We further show that PKN1 controls the adipogenesis process and glucose metabolism. PKN1-silenced adipocytes present a decrease in both differentiation process and glucose uptake, with a concomitant decrease in the expression levels of adipogenic markers, such as PPARγ, FABP4, adiponectin and CEBPα. Altogether, these results point to PKN1 as a regulator of key signaling pathways involved in adipocyte differentiation and as an emerging player of adipocyte insulin responsiveness. These findings may provide new therapeutic approaches for the management of insulin resistance in type 2 diabetes.

The Function of MondoA and ChREBP Nutrient-Sensing Factors in Metabolic Disease.

Obesity is a major global public health concern associated with an increased risk of many health problems, including type 2 diabetes, heart disease, stroke, and some types of cancer. Obesity is also a critical factor in the development of insulin resistance and type 2 diabetes. Insulin resistance is associated with metabolic inflexibility, which interferes with the body's ability to switch from free fatty acids to carbohydrate substrates, as well as with the ectopic accumulation of triglycerides in non-adipose tissue, such as that of skeletal muscle, the liver, heart, and pancreas. Recent studies have demonstrated that MondoA (MLX-interacting protein or MLXIP) and the carbohydrate response element-binding protein (ChREBP, also known as MLXIPL and MondoB) play crucial roles in the regulation of nutrient metabolism and energy homeostasis in the body. This review summarizes recent advances in elucidating the function of MondoA and ChREBP in insulin resistance and related pathological conditions. This review provides an overview of the mechanisms by which MondoA and ChREBP transcription factors regulate glucose and lipid metabolism in metabolically active organs. Understanding the underlying mechanism of MondoA and ChREBP in insulin resistance and obesity can foster the development of new therapeutic strategies for treating metabolic diseases.