Dyslipidemia, insulin resistance, and impairment of placental metabolism in the offspring of obese mothers

2020 ◽  
pp. 1-10
Author(s):  
Matthew Bucher ◽  
Kim Ramil C. Montaniel ◽  
Leslie Myatt ◽  
Susan Weintraub ◽  
Hagai Tavori ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cord Blood ◽  
Metabolic Flux ◽  
Maternal Obesity ◽  
Plasma Lipids ◽  
Normal Weight ◽  
Dependent Manner ◽  
Blood Insulin ◽  
Insulin Resistant ◽  
Health And Wellbeing

Abstract Obesity is a chronic condition associated with dyslipidemia and insulin resistance. Here, we show that the offspring of obese mothers are dyslipidemic and insulin resistant from the outset. Maternal and cord blood and placental tissues were collected following C-section at term. Patients were grouped as being normal weight (NW, BMI = 18–24.9) or obese (OB, BMI ≥ 30), and separated by fetal sex. We measured plasma lipids, insulin, and glucose in maternal and cord blood. Insulin resistance was quantified using the HOMA-IR. Placental markers of lipid and energy metabolism and relevant metabolites were measured by western blot and metabolomics, respectively. For OB women, total cholesterol was decreased in both maternal and cord blood, while HDL was decreased only in cord blood, independent of sex. In babies born to OB women, cord blood insulin and insulin resistance were increased. Placental protein expression of the energy and lipid metabolism regulators PGC1α, and SIRT3, ERRα, CPT1α, and CPT2 decreased with maternal obesity in a sex-dependent manner (P < 0.05). Metabolomics showed lower levels of acylcarnitines C16:0, C18:2, and C20:4 in OB women’s placentas, suggesting a decrease in β-oxidation. Glutamine, glutamate, alpha-ketoglutarate (αKG), and 2-hydroxyglutarate (2-HG) were increased, and the glutamine-to-glutamate ratio decreased (P < 0.05), in OB placentas, suggesting induction of glutamate into αKG conversion to maintain a normal metabolic flux. Newly-born offspring of obese mothers begin their lives dyslipidemic and insulin resistant. If not inherited genetically, such major metabolic perturbations might be explained by abnormal placental metabolism with potential long-term adverse consequences for the offspring’s health and wellbeing.

scholarly journals A Complex Relationship between Immunity and Metabolism inDrosophilaDiet-Induced Insulin Resistance

2017 ◽  
Vol 38 (2) ◽  
Author(s):  
Laura Palanker Musselman ◽  
Jill L. Fink ◽  
Ana R. Grant ◽  
Jared A. Gatto ◽  
Bryon F. Tuthill ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Innate Immunity ◽  
Differential Expression ◽  
Insulin Signaling ◽  
Drug Targets ◽  
Fat Body ◽  
Dependent Manner ◽  
Content Type ◽  
Insulin Resistant ◽  
Fat Bodies

ABSTRACTBoth systemic insulin resistance and tissue-specific insulin resistance have been described inDrosophilaand are accompanied by many indicators of metabolic disease. The downstream mediators of insulin-resistant pathophysiology remain unclear. We analyzed insulin signaling in the fat body studying loss and gain of function. When expression of the soleDrosophilainsulin receptor (InR) was reduced in larval fat bodies, animals exhibited developmental delay and reduced size in a diet-dependent manner. Fat body InR knockdown also led to reduced survival on high-sugar diets. To look downstream of InR at potential mediators of insulin resistance, transcriptome sequencing (RNA-seq) studies in insulin-resistant fat bodies revealed differential expression of genes, including those involved in innate immunity. Obesity-associated insulin resistance led to increased susceptibility of flies to infection, as in humans. Reduced innate immunity was dependent on fat body InR expression. The peptidoglycan recognition proteins (PGRPs) PGRP-SB2 and PGRP-SC2 were selected for further study based on differential expression studies. Downregulating PGRP-SB2 selectively in the fat body protected animals from the deleterious effects of overnutrition, whereas downregulating PGRP-SC2 produced InR-like phenotypes. These studies extend earlier work linking the immune and insulin signaling pathways and identify new targets of insulin signaling that could serve as potential drug targets to treat type 2 diabetes.

Maternal insulin resistance, triglycerides and cord blood insulin in relation to post-natal weight trajectories and body composition in the offspring up to 2 years

2013 ◽  
Vol 30 (12) ◽  
pp. 1500-1507 ◽  
Author(s):  
S. Brunner ◽  
D. Schmid ◽  
K. Hüttinger ◽  
D. Much ◽  
E. Heimberg ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Composition ◽  
Cord Blood ◽  
Blood Insulin ◽  
Weight Trajectories

Insulin resistance and lung function in obese asthmatic pre-pubertal children

2018 ◽  
Vol 31 (1) ◽  
pp. 45-51 ◽  
Author(s):  
Paola Di Filippo ◽  
Alessandra Scaparrotta ◽  
Daniele Rapino ◽  
Tommaso de Giorgis ◽  
Marianna Immacolata Petrosino ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lung Function ◽  
Statistical Significance ◽  
Serum Levels ◽  
Forced Expiratory Volume ◽  
Normal Weight ◽  
Model Assessment ◽  
Obese Children ◽  
Asthmatic Children ◽  
Insulin Resistant

AbstractBackground:Recent findings have supposed that the underlying association between the increased prevalence of both asthma and obesity may be insulin resistance (IR).Methods:Insulin and glucose serum levels were analyzed to calculate the homeostatic model assessment of insulin resistance (HOMA-IR) for IR in 98 pre-pubertal children. Lung function and allergy status evaluation were performed. The study population was divided into four groups: (1) obese asthmatic children (ObA); (2) normal-weight asthmatic children (NwA); (3) normal-weight non-asthmatic children (Nw) and (4) obese non-asthmatic children (Ob).Results:Forced expiratory volume in 1 s (FEV1) was slightly lower in obese subjects compared with normal-weight subjects and forced vital capacity (FVC) appeared lower in asthmatics, whereas between non-asthmatics subjects, it was lower in the obese group than in the normal-weight one. The post hoc analysis revealed a statistically significant reduction in FEV1, peak expiratory flow (PEF), forced expiratory flows (FEF) between 50% and 25% of the FVC (FEF50and FEF25) between ObA and Nw and in FEV1, FVC, PEF, FEF50and FEF25between NwA and Nw, but no statistically significant differences of lung function parameters were observed between ObA and NwA. We found an inverse relationship between HOMA-IR and all spirometric parameters, although without any statistical significance. We also observed a significantly lower FVC in insulin-resistant children (HOMA-IR>95th percentile) (p=0.03).Conclusions:This study suggests that lung function could be early altered in obese children, already in pre-pubertal age. Although IR should not manifest its effects on lungs in pre-pubertal obese children, the prevention or treatment of obesity in the pre-pubertal period may prevent definitive negative effects on lungs.

scholarly journals Arginine 16 Glycine Polymorphism inβ2-Adrenergic Receptor Gene Is Associated with Obesity, Hyperlipidemia, Hyperleptinemia, and Insulin Resistance in Saudis

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Maha H. Daghestani ◽  
Arjumand Warsy ◽  
Mazin H. Daghestani ◽  
Ali N. Al-odaib ◽  
Abdelmoneim Eldali ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Plasma Lipids ◽  
Receptor Gene ◽  
Normal Weight ◽  
Overweight And Obesity ◽  
Hip Circumference ◽  
Anthropometric Parameters ◽  
Obese Subjects ◽  
Arg16gly Polymorphism ◽  
Adrenergic Receptor Gene

Background. Several studies have shown an association between codon 16 polymorphism of theβ2AR gene and obesity.Methods. We studied the association between Arg16Gly polymorphism and obesity and its influence on anthropometric parameters, lipids, insulin resistance and leptin in Saudi individuals. The study group included 329 individuals (males: 109 and females: 220). Metabolic parameters, including glucose, lipids, insulin, and leptin were analyzed and anthropometric parameters including waist and hip circumference, waist/hip (W/H) ratio, and body mass index (BMI) were measured and HOMA-IR was calculated. Genotyping was conducted by DNA sequencing of 353 bp fragments, carrying the Arg16Gly polymorphic site.Results and Conclusion. Overweight and obese subjects had a significantly higher frequency of Gly16 (0.375 and 0.38, resp.) compared with normal-weight subjects (0.200). In addition, subjects carrying Gly16 allele regardless of their BMI had greater waist and hip circumference, W/H ratio, plasma lipids, leptin, glucose level, and insulin resistance as judged from the HOMA-IR, compared to those with the wild-type allele. The findings of this study show a significant association between the Arg16Gly polymorphism inβ2AR gene and the development of insulin resistance, overweight, and obesity in Saudi populations with an influence on the levels of lipid and leptin.

scholarly journals Metabolic syndrome identifies normal weight insulin-resistant stroke patients at risk for recurrent vascular disease

2018 ◽  
Vol 14 (6) ◽  
pp. 639-645 ◽  
Author(s):  
Jennifer L Dearborn ◽  
Catherine M Viscoli ◽  
Silvio E Inzucchi ◽  
Lawrence H Young ◽  
Walter N Kernan
Keyword(s):  
Myocardial Infarction ◽  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Obesity Paradox ◽  
Normal Weight ◽  
Diabetic Patients ◽  
Insulin Resistant ◽  
Increased Risk ◽  
All Cause Mortality ◽  
Patients At Risk

Background The obesity paradox refers to the finding in observational studies that patients with obesity have a better prognosis after stroke than normal weight patients. Aim To test the hypothesis that there might be important heterogeneity within the obese stroke population, such that those with metabolic syndrome would be at higher risk for stroke or myocardial infarction and all-cause mortality compared to patients without metabolic syndrome. Methods The Insulin Resistance Intervention after Stroke trial enrolled non-diabetic patients with a recent ischemic stroke or transient ischemic attack and insulin resistance. We examined the association between metabolic syndrome and outcome risk in patients with normal weight at entry (body mass index (BMI) = 18.5–24.9 kg/m2), overweight (BMI = 25–29.9 kg/m2), or obesity (BMI ≥ 30 kg/m2). Analyses were adjusted for demographic features, treatment assignment, smoking, and major comorbid conditions. Results Metabolic syndrome was not associated with greater risk for stroke or myocardial infarction among 1536 patients who were overweight (adjusted hazard ratio (HR), 0.95; 95% confidence interval (CI): 0.69–1.31) or 1626 obese patients (adjusted HR, 1.00; 95% CI: 0.70–1.41). However, among 567 patients with a normal BMI, metabolic syndrome was associated with increased risk for stroke or myocardial infarction (adjusted HR, 2.05; 95% CI: 1.25–3.37), and all-cause mortality (adjusted HR, 1.70; 95% CI: 1.03–2.81) compared to patients without metabolic syndrome. Conclusions The presence of metabolic syndrome identified normal weight patients with insulin resistance but no diabetes who have a higher risk of adverse cardiovascular outcomes, compared with patients without metabolic syndrome.

Abstract 630: Novel Chimeric Anti-proteoglycan Antibody Inhibits Arterial Retention of Proatherogenic Lipoproteins in a Rat Model of Insulin Resistance

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Yosdel Soto ◽  
Rabban Mangat ◽  
Ana M Vázquez ◽  
Spencer D Proctor
Keyword(s):  
Insulin Resistance ◽  
Monoclonal Antibody ◽  
Ex Vivo ◽  
Dependent Manner ◽  
Insulin Resistant ◽  
Remnant Lipoproteins ◽  
Preferential Binding ◽  
Carotid Vessels

Background: The response-to-retention hypothesis for atherosclerosis describes subendothelial retention of apolipoprotein B-containing lipoproteins mediated by proteoglycans (PG). Further we know that diabetes is also associated with both increased circulating chylomicron remnants and remodeling of proatherogenic PGs. We have recently reported antiatherogenic properties of a novel chimeric monoclonal antibody (chP3R99) that recognizes PG sulfated molecules. Hypothesis: chP3R99 monoclonal antibody may interfere with the interaction of atherogenic lipoproteins with arterial sulfated PGs during insulin resistance. Methods and Results: chP3R99 antibody recognized sulfated glycosaminoglycans by ELISA showing a preferential binding to chondroitin sulfate. Also, chP3R99 blocked the interaction of proatherogenic lipoproteins with this glycosaminoglycan in vitro in a dose-dependent manner and its intravenous injection into healthy Sprague-Dawly rats (n=6, 1 mg/animal) inhibited LDL (4 mg/kg; intraperitoneally) aortic retention. To further assess this property in an insulin resistant condition, carotid arteries from control and JCR:LA-cp rats (n=4) were perfused ex vivo with apoB48 containing remnant lipoproteins (prepared via rabbit hepatectomy procedure), with or without Cy3-LDL (150 μg/mL) for 20 minutes. Confocal microscopy analysis revealed an increased arterial retention of both remnants (3.6 fold) and LDL (2.8 fold) in carotid vessels from insulin resistant rats relative to control. However, chP3R99 pre-perfusion resulted in decreased retention of remnants (-30%) and LDL (-60%) associated arterial cholesterol. Data suggests that the chP399 antibody may interfere with the arterial attachment of both remnants and LDL in vivo, but with differential efficacy. Conclusions: Relative to LDL, remnant lipoproteins had preferential accumulation in arterial vessels from insulin resistant rats ex vivo , which could then be inhibited by acute pre-exposure to the chP3R99 antibody. These in vivo data support the concept for an innovative approach to target the retention of proatherogenic lipoproteins in a pre-clinical setting.

scholarly journals Mitochondrial Function and Insulin Resistance in Overweight and Normal-Weight Children

2009 ◽  
Vol 94 (12) ◽  
pp. 4923-4930 ◽  
Author(s):  
Amy Fleischman ◽  
Matthew Kron ◽  
David M. Systrom ◽  
Mirko Hrovat ◽  
Steven K. Grinspoon
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Energy Expenditure ◽  
Mitochondrial Function ◽  
Resting Energy Expenditure ◽  
Normal Weight ◽  
Metabolic Phenotype ◽  
Overweight Children ◽  
Insulin Resistant ◽  
Resting Energy

Background: Obesity has become an epidemic in children, associated with an increase in insulin resistance and metabolic dysfunction. Mitochondrial function is known to be an important determinant of glucose metabolism in adults. However, little is known about the relationship between mitochondrial function and obesity, insulin resistance, energy expenditure, and pubertal development in children. Methods: Seventy-four participants, 37 overweight (≥85th percentile body mass index for age and sex) and 37 normal-weight (&lt;85th percentile) without personal or family history of diabetes mellitus were enrolled. Subjects were evaluated with an oral glucose tolerance test, metabolic markers, resting energy expenditure, Tanner staging, and 31P magnetic resonance spectroscopy of skeletal muscle for mitochondrial function. Results: Overweight and normal-weight children showed no difference in muscle ATP synthesis [phosphocreatine (PCr) recovery after exercise] (32.4 ± 2.3 vs. 34.1 ± 2.1, P = 0.58). However, insulin-resistant children had significantly prolonged PCr recovery when compared with insulin-sensitive children, by homeostasis model assessment for insulin resistance quartile (ANOVA, P = 0.04). Similarly, insulin-resistant overweight children had PCr recovery that was prolonged compared with insulin-sensitive overweight children (P = 0.01). PCr recovery was negatively correlated with resting energy expenditure in multivariate modeling (P = 0.03). Mitochondrial function worsened during mid-puberty in association with insulin resistance. Conclusion: Reduced skeletal muscle mitochondrial oxidative phosphorylation, assessed by PCr recovery, is associated with insulin resistance and an altered metabolic phenotype in children. Normal mitochondrial function may be associated with a healthier metabolic phenotype in overweight children. Further studies are needed to investigate the long-term physiological consequences and potential treatment strategies targeting children with reduced mitochondrial function.

scholarly journals PPARα activation elevates blood pressure and does not correct glucocorticoid-induced insulin resistance in humans

2006 ◽  
Vol 291 (6) ◽  
pp. E1365-E1371 ◽  
Author(s):  
Savitha Subramanian ◽  
Michael A. DeRosa ◽  
Carlos Bernal-Mizrachi ◽  
Nicholas Laffely ◽  
William T. Cade ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Vascular Function ◽  
Hepatic Glucose Production ◽  
Ambulatory Monitoring ◽  
Glucose Production ◽  
Normal Weight ◽  
Glucose Disposal ◽  
Insulin Resistant

Fibrates, activators of the nuclear receptor PPARα, improve dyslipidemia, but their effects on insulin resistance and vascular disease are unresolved. To test the hypothesis that PPARα activation improves insulin resistance and vascular function, we determined the effects of fenofibrate in healthy adults with insulin resistance induced by short-term glucocorticoid administration. Eighteen normal-weight subjects were studied in four stages: at baseline, after 21 days of fenofibrate (160 mg/day) alone, after 3 days of dexamethasone (8 mg/day) added to fenofibrate, and after 3 days of dexamethasone added to placebo (dexamethasone alone). Dexamethasone alone caused hyperinsulinemia, increased glucose, decreased glucose disposal, and reduced insulin-induced suppression of hepatic glucose production as determined by hyperinsulinemic euglycemic clamp and increased systolic blood pressure as determined by ambulatory monitoring, features associated with an insulin-resistant state. Fenofibrate improved fasting LDL and total cholesterol in the setting of dexamethasone treatment but had no significant effect on levels of insulin or glucose, insulin-stimulated glucose disposal, or insulin suppression of glucose production during clamps, or ambulatory monitored blood pressure. In the absence of dexamethasone, fenofibrate lowered fasting triglycerides and cholesterol but unexpectedly increased systolic blood pressure by ambulatory monitoring. These data suggest that PPARα activation in humans does not correct insulin resistance induced by glucocorticoids and may adversely affect blood pressure.

Abstract 297: Increased ETA Receptor-Mediated Contractility of Thoracic Aorta by Endothelin-1 in High-Fat-Diet--Fed Insulin-Resistant Rats

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Ramarao Poduri ◽  
Payal Gupta ◽  
Anil Gulati
Keyword(s):  
Insulin Resistance ◽  
Thoracic Aorta ◽  
High Fat Diet ◽  
Specific Binding ◽  
Dependent Manner ◽  
High Fat ◽  
Contractile Responses ◽  
Endothelin 1 ◽  
Insulin Resistant ◽  
Eta Receptor

Abstract: Increased incidences of cardio-vascular complications in diabetic conditions are a major concern. Endothelin-1 (ET-1) is an important regulator of vascular contractility, and its effects are mediated through ETA and ETB. Previous data from the lab indicates that GPCR mediate contractile responses are enhanced and the present study is aimed to extend the hypothesis that ETA receptor mediated contractile responses of ET-1 under insulin-resistant condition are enhanced. Methods: Male Sprague-Dawley (SD) rats were kept on high-fat diet (HFDIRR, 8 weeks) for inducing insulin-resistance. Further, b-cell specific toxin streptozotocin (STZ, 50 mg/kg; i.p.) was used to induce hypoinsulinemia in rats. The responses of ET-1, ACh, KCl and Ang -II were recorded in the concentration-dependent manner in the thoracic aorta of rats. Specific ETA receptor antagonist, BMS182874 was used to confirm the findings. Specific binding of [3H]-BQ123 was performed to determine the characteristics of ETA receptors. Biochemical parameters were measured and induction of insulin-resistance was confirmed by intra-peritoneal glucose tolerance test (IPGTT). Results: ET-1 mediated contractile response (4541 ± 274 mg/mm2 (mean ± s.e.m. (n=8)) was significantly higher in insulin-resistant rats, while that of KCl unchanged. Tempol (100μM) restored the ET-1 mediated contractions in HFDIRR (4541 ± 274 vs 3406 ± 252.8 mg/mm2; p < 0.001; (n=5)). BMS182874 restored NO-mediated endothelium-dependent ACh relaxation in HFDIRR. The specific binding of [3H]-BQ123 to ETA receptors (112.35 ± 5.19 vs. 39.74 ± 4.04 f mol/mg; P < 0.001; (n=5)) was increased in HFDIRR. Conclusions: Insulin-resistance up-regulates ETA receptor may be responsible enhanced ET-1 mediated contractility of the thoracic aorta.

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