Insulin-resistant Phenotype Research Articles

P-735 Are there any differences in preimplantation blastocyst chromosomal abnormalities between polycystic ovary syndrome patients and controls? A multi-center retrospective cohort study

Abstract Study question Are there possible differences in the preimplantation blastocyst chromosome aberrations between polycystic ovary syndrome (PCOS) patients and controls? Summary answer PCOS lowers aneuploidy risk but increases mosaicism risk in preimplantation embryos, and PCOS-related insulin resistance should be investigated as a potential cause. What is known already PCOS is thought to alter granulosa cell functions and effects on oocyte development, potentially leading to chromosomal abnormalities and increasing the risk of pregnancy loss. However, few studies have compared the chromosomal status of preimplantation embryos from PCOS patients to those from healthy controls. Study design, size, duration This was a multi-center retrospective cohort study conducted at 3 IVF centers. A total of 707 blastocysts from 147 PCOS patients and 3006 blastocysts from 821 control women receiving preimplantation genetic testing (PGT) between 2015 and 2021. Participants/materials, setting, methods PGT was performed using next-generation sequencing (NGS). Differences in the chromosome aberrations were compared. Multivariate and subgroup analyses were conducted to control for confounders. Influences of insulin resistance and PCOS phenotype on the risks of specific chromosomal abnormalities were also examined. Main results and the role of chance Compared to controls, blastocysts from PCOS patients demonstrated lower aneuploidy rate (14.7% vs. 25.4%, P < 0.001) but greater mosaicism rate (16.5% vs. 8.7%, P < 0.001). Multivariable analysis adjusting for age, IVF center, body mass index (BMI), total gonadotropin (Gn) dose, and peak serum estradiol (E2) on trigger day, identified PCOS as an independent protective factor against embryonic aneuploidy (adjusted OR = 0.56, 95% CI, 0.42–0.76, P<0.001) but a risk factor for embryonic mosaicism (adjusted OR = 2.05, 95% CI 1.48–2.85, P<0.001). These differences in chromosomal spectrum were also observed in subgroups stratified by age, IVF center and BMI. Further multivariate analysis suggested that insulin resistance could be responsible for the increased risk of embryonic mosaicism among PCOS patients (OR = 1.89, 95% CI, 1.06–3.34, P=0.03). Limitations, reasons for caution The main limitation is the retrospective design. Besides, methodological uncertainties still exist in detecting mosaicism in current reproductive medicine. A longer-term, multiple-center prospective study with greater methodological standardization is warranted to confirm the present results. Wider implications of the findings These results suggest that PCOS pathology may increase the risk of mitosis errors but not the risk of meiosis errors during oocyte development, and PCOS-related insulin resistance should be investigated as a potential cause. Trial registration number 2020[325]

1177-P: Maternal Insulin Intervention Improves Offspring Glucose Metabolism via Long Noncoding RNA

Maternal high fat (HF) during pregnancy is known to have numerous adverse effects on offspring, including increased adiposity and impaired glucose tolerance later in life. The aim of this study was to determine if prebiotic early intervention could mitigate some of the negative effects of maternal HF and involved mechanism. C57BL mice were fed a HF diet, normal diet or a HF diet with prebiotic supplementation during pregnancy and lactation. At 8 weeks of age, glucose tolerance were measured in the offspring. And offspring livers were obtained to assay lncRNA and mRNA profiles to investigate the effects of early maternal inulin intervention on offspring. Offspring from HF-fed dams displayed glucose intolerance and an insulin resistance phenotype at 8 weeks of age. Early maternal inulin intervention improved glucose metabolism in male offspring of mothers fed a HF during gestation and lactation. The lncRNA and mRNA profile data revealed that compared with the offspring from HF dams, offspring from the early inulin intervention dams had 99 differentially expressed hepatic lncRNAs and 529 differentially expressed mRNAs. The differentially expressed lncRNA-mRNA coexpression analysis demonstrated that early maternal inulin intervention may change hepatic lncRNA expression in offspring. These lncRNAs are involved in metabolic pathways and the AMP-activated protein kinase signaling pathway. Importantly, the early maternal inulin intervention alleviated glucose metabolism by inhibiting the lncRNA Serpina4-ps1/let-7b-5p/Ppargc1a as a competing endogenous RNA in male offspring. Disclosure Q.Zhang: None. X.Xiao: None. M.Li: None. Funding National Natural Science Foundation of China (82170854, 81870579, 81870545, 81570715, 81170736); Beijing Natural Science Foundation (7202163); Beijing Municipal Science & Technology Commission (Z201100005520011); National High Level Hospital Clinical Research Funding (2022-PUMCH-C-019); National Key Research and Development Program of China (2018YFC2001100); CAMS Innovation Fund for Medical Sciences (CIFMS2021-1-I2M-002, CIFMS2017-I2M-1-008)

1203-P: Elevated HOMA-IR and IL-6 in Pregnant Women with Metabolic-Dysfunction–Associated Fatty Liver Disease and Gestational Diabetes Mellitus

Background: It is uncertain whether biomarkers differ in singleton pregnant women with metabolic dysfunction-associated fatty liver disease (MAFLD) and gestational diabetes mellitus (GDM). Methods: A prospective cohort study was conducted. A FibroScan® was performed between 10-24 weeks. A controlled attenuation parameter score ≥233.5dB/m indicated MAFLD. GDM was diagnosed with IADPSG criteria. Between 24-30 weeks, fasting blood was collected to determine serum levels of tumour necrosis factor alpha (TNF-α), interleukin 6 (IL-6), fibroblast growth factor 21 (FGF-21), high molecular weight adiponectin (HMW-APN), glucose and insulin. HOMA-IR was calculated: [insulin (mU/L) × glucose (mmol/L)]/22.5. Four groups of control (no GDM/MAFLD), MAFLD only, GDM only, MAFLD & GDM were formed. Biomarkers were analyzed by general linear models after log transformation, adjusted for age, body mass index, ethnicity and nulliparity. Results: Of 120 women, 47 were control, 37 MAFLD only, 14 GDM only and 22 MAFLD & GDM. Compared to controls, MAFLD & GDM had 1.8-fold higher HOMA-IR and IL-6, significantly elevated over GDM only and MAFLD only (Table 1). No significant differences in TNF-α, FGF-21 or HMW-APN occurred (Table 1). Conclusions: Significantly elevated HOMA-IR and IL-6 in pregnant women with MAFLD & GDM suggests a more insulin resistant and inflammatory phenotype. Disclosure T.Y.L.Chai: None. D.Pasupathy: None. J.George: None. N.Cheung: None. Funding Diabetes Australia Research Program (Y21GCHEW)

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.

Association between serum leptin concentrations and homeostasis model assessment-insulin resistance of 2.5 and higher in normal weight Japanese women

Normal weight insulin resistant phenotype was characterized in 251 Japanese female university students using homeostasis model assessment-insulin resistance. Birth weight, body composition at age 20, cardiometabolic traits and dietary intake were compared cross-sectionally between insulin sensitive (< 1.6, n = 194) and insulin resistant (2.5 and higher, n = 16) women. BMI averaged < 21 kg/m2 and waist < 72 cm and did not differ between two groups. The percentage of macrosomia and serum absolute and fat-mass corrected leptin concentrations were higher in insulin resistant women although there was no difference in birth weight, fat mass index, trunk/leg fat ratio and serum adiponectin. In addition, resting pulse rate, serum concentrations of free fatty acids, triglycerides and remnant-like particle cholesterol were higher in insulin resistant women although HDL cholesterol and blood pressure did not differ. In multivariate logistic regression analyses, serum leptin (odds ratio:1.68, 95% confidential interval:1.08–2.63, p = 0.02) was associated with normal weight insulin resistance independently of macrosomia, free fatty acids, triglycerides, remnant-like particle cholesterol and resting pulse rate. In conclusion, normal weight IR phenotype may be associated with increased plasma leptin concentrations and leptin to fat mass ratio in young Japanese women, suggesting higher leptin production by body fat unit.

Distal inflammatory priming of normal mammary tissue by the gut microbiome drives breast tumor metastasis via metabolic dysregulation

Abstract Hormone receptor-positive (HR +), HER2 −is the most prevalent metastatic breast cancer subtype, constituting 73.1% of the metastatic disease population in the US. Despite targeted therapies that have increased long-term survival, many patients develop and eventually succumb to metastatic disease. Tumor dissemination occurs early during disease progression and is driven by cellular and molecular changes in the tissue. Though host-intrinsic factors that preferentially predispose certain individuals to metastatic disease are poorly defined, gut microbial health has become increasingly recognized as a determinant of the metastatic potential of breast tumors. We demonstrated that commensal dysbiosis, an inflammatory gut microbiome with low biodiversity, drives HR +tumor metastasis. Our work identified that a dysbiosis-induced CCL2/mast cell axis in normal (non-tumor-bearing) mammary tissues acts as a master regulator of early metastasis. Our present goal is to define how gut dysbiosis triggers tissue inflammation. We present evidence that dysbiosis-induced metabolic dysregulation increases early dissemination of HR +tumors by initiating cellular and molecular changes in normal mammary tissue. Dysbiosis results in systemic insulin-glucose dynamics that resemble an insulin resistant phenotype. Additionally, we find that acylcarnitine species, byproducts of incomplete fatty acid β-oxidation which we hypothesize promote local tissue inflammation, accumulate in normal mammary tissues of dysbiotic mice. Altogether, we propose that commensal dysbiosis triggers a systemic metabolic shift that enhances the metastatic potential of HR +tumors by shaping the immune landscape of the pre-cancerous mammary tissues. Supported by grants from NIH (1RO1 CA253285, 2T32AI007496-26A1)

GRK2-Targeted Knockdown as Therapy for Multiple System Atrophy.

Multiple system atrophy (MSA) is a sporadic adult-onset rare neurodegenerative synucleinopathy for which counteracting central nervous system insulin resistance bears the potential of being neuroprotective. G-protein-(heterotrimeric guanine nucleotide-binding protein)-coupled receptor kinase 2 (GRK2) is emerging as a physiologically relevant inhibitor of insulin signaling. We tested whether lowering brain GRK2 abundance may reverse insulin-resistance. We lowered brain GRK2 abundance through viral-mediated delivery of a GRK2-specific miRNA and quantified the reversion of a developing or an established insulin-resistant phenotype using the transgenic PLP-SYN mouse model of MSA. Viral vector delivery of a GRK2 miRNA demonstrated a neuroprotective capacity when administered (1) in utero intracerebroventricularly in developing PLP-SYN mice and (2) intrastriatally in adult PLP-SYN mice. Decreased striatal GRK2 levels correlated in both designs with neuroprotection of the substantia nigra dopamine neurons, reduction in high-molecular-weight species of α-synuclein, and reduced insulin resistance. These data support GRK2 as a potential therapeutic target in MSA. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Impaired white adipose tissue fatty acid metabolism in mice fed a high-fat diet worsened by arsenic exposure, primarily affecting retroperitoneal adipose tissue

Fatty acid (FA) metabolism dysfunction of white adipose tissue (WAT) underlies obesity and insulin resistance in response to high calorie intake and/or endocrine-disrupting chemicals (EDCs), among other factors. Arsenic is an EDC that has been associated with metabolic syndrome and diabetes. However, the combined effect of a high-fat diet (HFD) and arsenic exposure on WAT FA metabolism has been little studied.FA metabolism was evaluated in visceral (epididymal and retroperitoneal) and subcutaneous WAT of C57BL/6 male mice fed control or HFD (12 and 40% kcal fat, respectively) for 16 weeks together with an environmentally relevant chronic arsenic exposure through drinking water (100 μg/L) during the second half of the study.In mice fed HFD, arsenic potentiated the increase of serum markers of selective insulin resistance in WAT and fatty acid re-esterification and the decrease of the lipolysis index. Retroperitoneal was the WAT most affected, where the combination of arsenic and HFD in contrast to HFD, generated higher adipose weight, larger adipocytes, increased triglyceride content, and decreased fasting stimulated lipolysis evidenced by lower phosphorylation of HSL and perilipin. At the transcriptional level, arsenic in mice fed either diet downregulated genes involved in fatty acid uptake (LPL, CD36), oxidation (PPARα, CPT1), lipolysis (ADRß3) and glycerol transport (AQP7 and AQP9). Additionally, arsenic potentiated hyperinsulinemia induced by HFD, despite a slight increase in weight gain and food efficiency.Thus, the second hit of arsenic in sensitized mice by HFD worsens fatty acid metabolism impairment in WAT, mainly retroperitoneal, along with an exacerbated insulin resistance phenotype.

Cardiometabolic health improvements upon dietary intervention are driven by tissue-specific insulin resistance phenotype: A precision nutrition trial

Precision nutrition based on metabolic phenotype may increase the effectiveness of interventions. In this proof-of-concept study, we investigated the effect of modulating dietary macronutrient composition according to muscle insulin-resistant (MIR) or liver insulin-resistant (LIR) phenotypes on cardiometabolic health. Women and men with MIR or LIR (n= 242, body mass index [BMI] 25-40kg/m2, 40-75 years) were randomized to phenotype diet (PhenoDiet) group A or B and followed a 12-week high-monounsaturated fatty acid (HMUFA) diet or low-fat, high-protein, and high-fiber diet (LFHP) (PhenoDiet group A, MIR/HMUFA and LIR/LFHP; PhenoDiet group B, MIR/LFHP and LIR/HMUFA). PhenoDiet group B showed no significant improvements in the primary outcome disposition index, but greater improvements in insulin sensitivity, glucose homeostasis, serum triacylglycerol, and C-reactive protein compared with PhenoDiet group A were observed. We demonstrate that modulating macronutrient composition within the dietary guidelines based on tissue-specific insulin resistance (IR) phenotype enhances cardiometabolic health improvements. Clinicaltrials.gov registration: NCT03708419, CCMO registration NL63768.068.17.

In-frame deletion of SMC5 related with the phenotype of primordial dwarfism, chromosomal instability and insulin resistance.

SMC5/6 complex plays a vital role in maintaining genome stability, yet the relationship with human diseases has not been described. SMC5 variation was identified through whole-exome sequencing (WES) and verified by Sanger sequencing. Immunoprecipitation, cytogenetic analysis, fluorescence activated cell sorting (FACS) and electron microscopy were used to elucidate the cellular consequences of patient's cells. smc5 knockout (KO) zebrafish and Smc5K371del knock-in mouse models were generated by CRISPR-Cas9. RNA-seq, quantitative real-time PCR (qPCR), western blot, microquantitative computed tomography (microCT) and histology were used to explore phenotypic characteristics and potential mechanisms of the animal models. The effects of Smc5 knockdown on mitotic clonal expansion (MCE) during adipogenesis were investigated through Oil Red O staining, proliferation and apoptosis assays in vitro. We identified a homozygous in-frame deletion of Arg372 in SMC5, one of the core subunits of the SMC5/6 complex, from an adult patient with microcephalic primordial dwarfism, chromosomal instability and insulin resistance. SMC5 mutation disrupted its interaction with its interacting protein NSMCE2, leading to defects in DNA repair and chromosomal instability in patient fibroblasts. Smc5 KO zebrafish showed microcephaly, short length and disturbed glucose metabolism. Smc5 depletion triggers a p53-related apoptosis, as concomitant deletion of the p53 rescued growth defects phenotype in zebrafish. An smc5K371del knock-in mouse model exhibited high mortality, severe growth restriction and fat loss. In 3T3-L1 cells, the knockdown of smc5 results in impaired MCE, a crucial step in adipogenesis. This finding implies that defective cell survival and differentiation is an important mechanism linking growth disorders and metabolic homeostasis imbalance.

Do diabetes phenotypes in US women differ by race/ethnicity? A population-based cluster analysis

ObjectiveUS women exhibit racial disparities in the lifetime risk of diabetes and related outcomes. Identifying heterogeneity in clinical presentation may assist with reducing racial disparities in diabetes outcomes. We identified clinical phenotypes of diabetes and examined their racial and ethnic distribution in US women. Research design and methodsWe conducted cluster analysis based on five factors in US women with diagnosed diabetes assessed in the National Health and Nutrition Examination Surveys 1999–2018 (n = 825). Multinomial logistic regression analysis was performed to identify racial and ethnic differences in the distribution of phenotypes. ResultsWe identified four distinct clinical phenotypes. Two phenotypes, mild age-related and severe insulin-deficient diabetes, each included approximately a third of women. Mild insulin-resistant and severe insulin-resistant diabetes phenotypes accounted for 19.9% and 13.7%, respectively. The distribution of clusters did not differ by race and ethnicity. ConclusionsThe prevalence of four clinically distinct diabetes phenotypes identified in US women did not differ by race and ethnicity.

Insulin resistance phenotype is associated with vascular risk phenotype at the end of the second decade of life: a population-based study

We hypothesize that early events of diabetes and cardiovascular disease continuums would be ongoing and associated in adolescents. We investigated the association between the Insulin Resistance Phenotype and the Vascular Risk Phenotype at the end of the second decade of life and indirect pathways from social vulnerability, alcohol consumption, and body fat mass. It is a population-based study in the RPS cohort of 18–19 years (n = 2,515), São Luís, Brazil. The theoretical model analyzed the association between Insulin Resistance Phenotype and Vascular Risk Phenotype by sex, using structural equation modeling (SEM). The Insulin Resistance Phenotype was a latent variable deduced from the correlations of Triglyceride to HDL ratio, Triglyceride Glycemic index, and VLDL; the Vascular Risk Phenotype was deduced from Systolic Blood Pressure, Diastolic Blood Pressure, and Pulse Wave Velocity. The Insulin Resistance Phenotype was directly associated with the Vascular Risk Phenotype in males (standardized coefficient SC = 0.183; p < 0.001) and females (SC = 0.152; p < 0.001). The Insulin Resistance Phenotype was an indirect pathway in the association of alcohol consumption and higher values of fat mass index with the Vascular Risk Phenotype. VLDL presented the highest factor loading, appearing as a marker of insulin resistance linked to cardiovascular risk in young people. Lower values of socioeconomic status, harmful use of alcohol, and high body fat values were also associated with higher values of the two phenotypes. The association of the Insulin Resistance Phenotype with the Vascular Risk Phenotype suggests common pathophysiological mechanisms present in early events in the continuums of diabetes and cardiovascular disease in adolescence.

Metabolomics and Lipidomics Signatures of Insulin Resistance and Abdominal Fat Depots in People Living with Obesity.

The liver, skeletal muscle, and adipose tissue are major insulin target tissues and key players in glucose homeostasis. We and others have described diverse insulin resistance (IR) phenotypes in people at risk of developing type 2 diabetes. It is postulated that identifying the IR phenotype in a patient may guide the treatment or the prevention strategy for better health outcomes in populations at risk. Here, we performed plasma metabolomics and lipidomics in a cohort of men and women living with obesity not complicated by diabetes (mean [SD] BMI 36.0 [4.5] kg/m2, n = 62) to identify plasma signatures of metabolites and lipids that align with phenotypes of IR (muscle, liver, or adipose tissue) and abdominal fat depots. We used 2-step hyperinsulinemic-euglycemic clamp with deuterated glucose, oral glucose tolerance test, dual-energy X-ray absorptiometry and abdominal magnetic resonance imaging to assess muscle-, liver- and adipose tissue- IR, beta cell function, body composition, abdominal fat distribution and liver fat, respectively. Spearman's rank correlation analyses that passed the Benjamini-Hochberg statistical correction revealed that cytidine, gamma-aminobutyric acid, anandamide, and citrate corresponded uniquely with muscle IR, tryptophan, cAMP and phosphocholine corresponded uniquely with liver IR and phenylpyruvate and hydroxy-isocaproic acid corresponded uniquely with adipose tissue IR (p &lt; 7.2 × 10-4). Plasma cholesteryl sulfate (p = 0.00029) and guanidinoacetic acid (p = 0.0001) differentiated between visceral and subcutaneous adiposity, while homogentisate correlated uniquely with liver fat (p = 0.00035). Our findings may help identify diverse insulin resistance and adiposity phenotypes and enable targeted treatments in people living with obesity.

Differential IL18 signaling via IL18 receptor and Na-Cl co-transporter discriminating thermogenesis and glucose metabolism regulation.

White adipose tissue (WAT) plays a role in storing energy, while brown adipose tissue (BAT) is instrumental in the re-distribution of stored energy when dietary sources are unavailable. Interleukin-18 (IL18) is a cytokine playing a role in T-cell polarization, but also for regulating energy homeostasis via the dimeric IL18 receptor (IL18r) and Na-Cl co-transporter (NCC) on adipocytes. Here we show that IL18 signaling in metabolism is regulated at the level of receptor utilization, with preferential role for NCC in brown adipose tissue (BAT) and dominantly via IL18r in WAT. In Il18r-/-Ncc-/- mice, high-fat diet (HFD) causes more prominent body weight gain and insulin resistance than in wild-type mice. The WAT insulin resistance phenotype of the double-knockout mice is recapitulated in HFD-fed Il18r-/- mice, whereas decreased thermogenesis in BAT upon HFD is dependent on NCC deletion. BAT-selective depletion of either NCC or IL18 reduces thermogenesis and increases BAT and WAT inflammation. IL18r deletion in WAT reduces insulin signaling and increases WAT inflammation. In summary, our study contributes to the mechanistic understanding of IL18 regulation of energy metabolism and shows clearly discernible roles for its two receptors in brown and white adipose tissues.

Higher fasting glucose, triglycerides, resting pulse rate and high-sensitivity C reactive protein in adipose insulin-resistant but normal weight young Japanese women

IntroductionAdipose insulin-resistant but normal weight phenotype has not been reported and hence was characterized in young Japanese women.Research design and methodsBody composition, a broad range of cardiometabolic health and dietary...

Effects of distinct n-6 to n-3 polyunsaturated fatty acid ratios on insulin resistant and AD-like phenotypes in high-fat diets-fed APP/PS1 mice

Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are prevalent diseases with similar pathophysiological characteristics and genetic predispositions. Polyunsaturated fatty acids (PUFAs) are essential in maintaining normal brain function. However, little is known about the effect of dietary n-6/n-3 PUFA ratio on AD-like pathology, particularly in high-fat diet (HFD)-fed AD model mice. In the present study, the APP/PS1 mice were fed with 60 % HFD for 3.5 months to induce insulin resistance. After that, 45 % HFD with various n-6/n-3 PUFA ratios (n-6/n-3 = 1:1, 5:1 or 16:1) was applied for an additional 3.5 months of treatment. The behavior of mice was observed using the water maze after dietary intervention. The animals were euthanized after behavioral testing, and serum and tissue samples were collected for biochemical, histological, and pathological tests and evaluation. HFD caused insulin resistance, increased serum IL-6 and TNF-α levels, cortical soluble Aβ1-40, Aβ1-42 content, and cortical n-6/n-3 PUFA ratio in APP/PS1 mice. Increased APP and BACE1 protein expression and p-IR/IR ratio but decreased pro-inflammatory cytokines mRNA expression was detected in the cortex of 60 % HFD-fed APP/PS1 mice. N-3 PUFAs-rich diet (n-6/n-3 = 1:1) alleviated insulin resistance and hyperlipidemia caused by 60 % HFD. Cortical soluble Aβ1-40 and Aβ1-42 contents, as well as the expression of cortical APP, GLUT1, GLUT3, insulin metabolism-related molecules, and NF-κB pathway downstream pro-inflammatory cytokines, were found to be n-6/n-3 PUFAs ratio-dependent, indicating that dietary n-6/n-3 PUFA ratio plays a critical role in modifying the responses of serum inflammatory cytokines, AD pathology, cortical n-6/n-3 PUFAs ratio, insulin signaling, and neuroinflammation to HFD treatment.

PMON209 Ceramides Predict Metabolic Response to Metformin in Women with PCOS

Abstract Polycystic ovarian syndrome (PCOS) is a complex disorder in which metabolic abnormalities are associated with reproductive dysfunction. Women with PCOS have been shown to have increased ceramide concentrations with the obese, insulin resistant phenotype having even higher levels. Ceramides modulate insulin signaling, promoting insulin resistance, and are markers of diabetes risk and cardiovascular mortality. Previous studies demonstrate that treating metabolic abnormalities of PCOS with metformin improved glucose effectiveness, caused weight loss, and restored ovulation in 61% of women after 12 weeks. However, these metabolic improvements did not explain improved ovulation experienced by some women. Hypothesis We hypothesized that in women with PCOS, baseline ceramide, diacylglycerol (DAG) and triacylyglycerol (TAG) concentrations are associated with an improved metabolic response to metformin.Subjects: Women (n=29), aged 29±5 years and diagnosed with PCOS by the NIH criteria were studied. Methods Individuals underwent an intravenous glucose tolerance test (IVGTT) and hCG-stimulation before and after 12-weeks of treatment with metformin (1500 mg per day). Metabolic responders were defined by improved glucose effectiveness after metformin treatment. Results Among predominantly white women with an average body mass index 29.4±6.1 kg/m2, 12-weeks of metformin resulted in weight loss (-1.7±2.6 kg, p&amp;lt;0.01) and a reduction in BMI (-0.6±0.9 kg/m2, p&amp;lt;0.01) with no change in HbA1c (5.5%±0.3 vs 5.5%±0.3, p=0.7). The concentrations of ceramides with acyl chain length at 22 and 24 (C22 and C24), total ceramides, dihydroceramides (C16: 0), C18: 2, DAG, dihydrosphingomyelin (DHSM), and TAG decreased after metformin treatment (p&amp;lt;0.05). Baseline total dihydroceramides (C16: 0) and DHSM were lower in metabolic responders compared to metabolic non-responders (C16: 0 172±11 vs 232±14 pmol/ml, p&amp;lt;0.01; DHSM 36650±2642 vs 48842±3379 pmol/ml, p&amp;lt;0.01). Total C16: 0 concentrations of &amp;lt;204 pmol/ml was 83% sensitive (AUC 0.79, p&amp;lt;0.01) and total DHSM concentrations of &amp;lt;51705 pmol/ml was 100% sensitive (AUC 0.73, p=0.02) in predicting improved metabolic response to metformin, as measured by IVGTT. After adjusting for multiple comparisons, baseline DAG and TAG concentrations were associated with baseline ß-cell function (DAG r2=0.47, p&amp;lt;0.01; TAG r2=0.32, p&amp;lt;0.01), basal insulin concentrations (DAG r2=0.48, p&amp;lt;0.01; TAG r2=0.33, p&amp;lt;0.01) and decreased insulin sensitivity (DAG r2= 0.45, p&amp;lt;0.01; TAG r2=0.3,p&amp;lt;0.01). Baseline ceramide concentrations were not associated with improved ovulation. Conclusion Ceramide concentrations predict metabolic disruption and lower levels are associated with a beneficial metabolic response to metformin in women with PCOS. Based on the known association between higher ceramide levels and type 2 diabetes, the data suggest that metformin improves metabolic parameters in women with mild metabolic derangements but not in those with severe insulin resistance. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Exogenous detection of 13C-glucose metabolism in tumor and diet-induced obesity models.

Metabolic rewiring is a hallmark feature prevalent in cancer cells as well as insulin resistance (IR) associated with diet-induced obesity (DIO). For instance, tumor metabolism shifts towards an enhanced glycolytic state even under aerobic conditions. In contrast, DIO triggers lipid-induced IR by impairing insulin signaling and reducing insulin-stimulated glucose uptake. Based on physiological differences in systemic metabolism, we used a breath analysis approach to discriminate between different pathological states using glucose oxidation as a readout. We assessed glucose utilization in lung cancer-induced cachexia and DIO mouse models using a U-13C glucose tracer and stable isotope sensors integrated into an indirect calorimetry system. Our data showed increased 13CO2 expired by tumor-bearing (TB) mice and a reduction in exhaled 13CO2 in the DIO model. Taken together, our findings illustrate high glucose uptake and consumption in TB animals and decreased glucose uptake and oxidation in obese mice with an IR phenotype. Our work has important translational implications for the utility of stable isotopes in breath-based detection of glucose homeostasis in models of lung cancer progression and DIO.

Troxerutin attenuates insulin resistance via pancreatic IL-22/JAK1/STAT3 signaling activation in dihydrotestosterone-induced polycystic ovary syndrome rats.

Polycystic ovary syndrome (PCOS) is an extremely common endocrine-metabolic disorder and the main cause of infertility in premenopausal women, thus targeted treatments are sorely needed. Accumulative evidence showed that exogenous supplementation of IL-22 in PCOS mice may be of significant positive effect on insulin resistance (IR), a root causative factor for this condition, but much remained unknown about its mechanism. According to our previous study, troxerutin, a common anticoagulant and thrombolytic agent in clinic, alleviated various PCOS-like phenotypes in dihydrotestosterone (DHT)-treated rat model with unclear mechanism. Here, glucose tolerance tests (GTTs), insulin tolerance tests (ITTs), and homeostatic model assessment of insulin resistance (HOMA-IR) analyses revealed that troxerutin treatment in DHT-treated rats also significantly improved insulin resistance and enhanced serum IL-22 levels, which thereby activated IL-22R1/Janus kinase 1 (JAK1)/signal transducer and activator of transcription-3 (STAT3) signaling pathway in pancreatic islet. This protective effect of troxerutin on insulin resistance improvement was blocked by an inhibitor of p-STAT3, S3I-201. Troxerutin administration to DHT rats decreased the relative abundance of Bifidobacterium and enhanced secondary bile acid profiles, which were positively correlated with serum IL-22 concentration. Conclusively, the present study reported that troxerutin is an endogenous enhancer of IL-22 and the effect of troxerutin on insulin resistance improvement was via IL-22R1/JAK1/STAT3 signaling activation in a DHT-induced PCOS rat model. These insights may be translated into a primary therapeutic agent for PCOS with insulin resistance and hyperandrogenism.NEW & NOTEWORTHY Troxerutin decreased the relative abundance of Bifidobacterium, along with enhancement of secondary bile acids/IL-22 system, which thereby activated its downstream IL-22R1/JAK1/STAT3 signaling pathway in pancreatic β cells, subsequently attenuated insulin resistance (IR), hyperandrogenism and PCOS-like phenotypes in DHT-induced PCOS rat models. Troxerutin is an endogenous IL-22 enhancer and may be of therapeutic value for PCOS with insulin resistance.

Abstract P234: Arterial Hypertension, Insulin Resistance And Depressive-like Behavior In Crtc1 -deficient Mice

Background: Epidemiological evidence has demonstrated a link between cardiovascular disease, metabolic syndrome and depression. Whether this association is causal and what mechanisms may be involved is still unknown. Studies in humans and mice suggest that alterations of the CREB-BDNF pathway can contribute to the development of both, eating disorders and major depressive disorders. Mice deficient in the CREB-regulated transcriptional coactivator 1 (Crtc1) have been shown to become overweight and display depressive-like behavior. Here, we investigated whether Crtc1 -deficient mice concomitantly exhibit a hypertensive, insulin resistant and depression-like phenotype. Methods: Mean arterial blood pressure and heart rate were measured by radiotelemetry in unrestrained Crtc1 -deficient mice (KO) and wildtype littermates (WT). Renal renin expression was quantified by qPCR. Insulin resistance was determined by the i.p. glucose tolerance test, and depressive-like behavior was assessed by the soiled bedding preference test. Results: Crtc1 -deficient mice had higher arterial blood pressures (dark: KO 117±2 mm Hg, WT 107±2 mm Hg, p&lt;0.05; light: KO 102±2 mm Hg, WT 94±2 mm Hg, p&lt;0.05, 1-way ANOVA, n=8-11) and heart rates (dark: KO 593±11 bpm, WT 596±7 bpm; light: KO 529±12 bpm, WT 494±8 bpm, p&lt;0.05, 1-way ANOVA, n=8-11). Relative renin mRNA expression was not different between genotypes (KO 0.86±0.07, WT 1.00±0.10, n=10). Glucose tolerance was significantly impaired in Crtc1 -deficient mice (maximum plasma glucose concentrations KO 423±27 mg/dl, WT 295±27 mg/dl, p&lt;0.0001, 2-way ANOVA, n=9). In the soiled bedding preference test, male Crtc1 -deficient mice exhibited a lack of preference for female-soiled bedding over clean bedding (female vs. clean KO 75.3±11.2 s vs 79.0±11.0 s, WT 119.5±13.5 s vs. 51.5±10.5 s, n=2-3). Conclusions: Crtc1 might be a molecular component of a pathway that connects arterial hypertension, metabolic syndrome and depression.