Metabolic Insulin Research Articles

IMMU-32. DIPEPTIDYL PEPTIDASE-4 (DPP-4) MEDIATED CD8+ T-CELL REGULATION IN GLIOBLASTOMA

Abstract Glioblastoma (GBM) remains to be one of the deadliest cancers with poor prognosis and limited treatment options. While immunotherapies have revolutionized the field for other cancers, GBM remains resistant to these types of interventions partly due to its highly immunosuppressive tumor microenvironment, which is characterized by accumulation of exhausted CD8+ T cells. Therefore, there is a pressing need to identify molecular targets for improve anti-tumorigenic T cell response. Previous studies in our laboratory identified dipeptidyl peptidase-4 (DPP-4), an exopeptidase and a membrane-bound signaling receptor, as a potential marker of immunosuppression in GBM. While DPP-4 is well-drugged due to its role in insulin metabolism, the function of DPP-4 in immune regulation and cancer remains poorly defined. I observed that DPP-4 is highly expressed by CD8+ T cells GBM patients and preclinical models. Furthermore, DPP-4 levels increased with the exhaustion or memory differentiation of effector T cell. Pharmaceutical inhibition of DPP-4 enriched expression of genes related to lymphocyte activation and mitochondrial metabolism. These transcriptional changes were accompanied by enhanced T cell proliferation, cytotoxic function, and effector mediator production under exhaustion conditions. These findings suggest that pharmacological inhibition of DPP-4 promotes anti-tumorigenic function of CD8+ T-cell by preventing exhaustion and support future translational efforts to repurpose DPP-4 inhibitors as immunotherapy agents in GBM, given their favorable safety profiles.

Phosphate metabolism: its impact on disorders of mineral metabolism.

Regulatory molecules typically work cooperatively to ensure the efficient functioning of hormonal systems. Examples include LH and FSH in reproductive biology, insulin and glucagon in glucose metabolism. Similarly, calcium and phosphorus are important regulators of skeletal homeostasis. In the circulation, these molecules are under the control of PTH, 1,25(OHD), and FGF23. In turn, these hormones depend upon a mutual and complex interplay among themselves. For example, alterations in calcium metabolism influence phosphorus homeostasis, as occurs in primary hyperparathyroidism (PHPT). Not as well recognized is the influence that abnormalities in phosphorus metabolism can have on calcium homeostasis. In this review, we call attention to the impact that abnormalities in phosphorus can have on calcium metabolism.

Omentin increases glucose uptake, but not insulin sensitivity in human myotubes dependent on extracellular lactotransferrin.

Omentin (intelectin-1) is an adipokine produced by the stromal vascular fraction of visceral adipose tissue and has been positively associated with insulin sensitivity. The underlying mechanism of action, however, is largely unknown. It has been described that omentin may increase insulin sensitivity and glucose uptake of adipocytes, but effects on other insulin-sensitive tissues such as skeletal muscle are unexplored. We therefore investigated effects of omentin on insulin sensitivity and metabolism of primary human myotubes. Primary human myotubes were treated with 0.5 or 2 µg/mL omentin and subsequently protein detection, glucose uptake assay, lactate assay and lipidomics analysis were performed. Omentin did not affect skeletal muscle insulin signaling, as assessed by basal and insulin-stimulated phosphorylation of IRS1 and AKT. Omentin increased basal, but not insulin-stimulated glucose uptake. While increased glycolytic activity was confirmed by elevated lactate release after omentin treatment, effects on cellular lipid composition were limited to an increase in total triacylglycerol concentration. Increased glucose uptake by omentin was counteracted by addition of extracellular lactotransferrin, which can bind to omentin. Overall, increased basal glucose uptake in skeletal muscle cells suggests differential effects of omentin on insulin-sensitive tissues. Moreover, an involvement of lactotransferrin in omentin's mechanism of action may partially explain contradictory results of epidemiological studies on the role of omentin in different diseases.

Network transformation-based analysis of biochemical systems.

A dynamical system obtains a wide variety of kinetic realizations, which is advantageous for the analysis of biochemical systems. A reaction network, derived from a dynamical system, may or may not possess some properties needed for a thorough analysis. We improve and extend the work of Johnston and Hong et al. on network translations to network transformations, where the network is modified while preserving the dynamical system. These transformations can shrink, extend, or retain the stoichiometric subspace. Here, we show that a positive dependent network can be translated to a weakly reversible network. Using the kinetic realizations of (1) calcium signaling in the olfactory system and (2) metabolic insulin signaling, we demonstrate the benefits of transformed systems with positive deficiency for analyzing biochemical systems. Furthermore, we present an algorithm for a network transformation of a weakly reversible non-complex factorizable kinetic (NFK) system to a weakly reversible complex factorizable kinetic (CFK) system, thereby enhancing the Subspace Coincidence Theorem for NFK systems of Nazareno et al. Finally, using the transformed kinetic realization of monolignol biosynthesis in Populus xylem, we study the structural and kinetic properties of transformed systems, including the invariance of concordance and variation of injectivity and mono-/multi-stationarity under network transformation.

Assessing the validity of METS-IR for predicting the future onset of diabetes: an analysis using time-dependent receiver operating characteristics

BackgroundThe Metabolic Insulin Resistance Score (METS-IR) is a non-invasive proxy for insulin resistance (IR) that has been newly developed in recent years and has been shown to be associated with diabetes risk. Our aim was to assess the predictive value of METS-IR for the future development of diabetes and its temporal differences in people of different sex, age, and body mass index (BMI).MethodsThe current study included 15,453 baseline non-diabetic subjects in the NAGALA cohort and then grouped according to the World Health Organization’s (WHO) recommended criteria for age and BMI. Multivariate Cox regression and time-dependent receiver operator characteristics (ROC) curves were used to analyze the value of METS-IR in assessing and predicting the risk of diabetes in people of different sexes, ages, and BMIs.Results373 individuals developed diabetes during the observation period. By multivariate COX regression analysis, the development of future diabetes was significantly associated with increased METS-IR, and this positive association was stronger in women than in men and in individuals < 45 years than in individuals ≥ 45 years; while no significant differences were observed between non-obese and overweight/obesity individuals. Using time-dependent ROC analysis we also assessed the predictive value of METS-IR for future diabetes at a total of 11-time points between 2 and 12 years. The results showed that METS-IR had a higher predictive value for the future development of diabetes in women or individuals < 45 years of age compared to men or individuals ≥ 45 years of age for almost the entire follow-up period. Furthermore, across different BMI categories, we also found that in the short term (3–5 years), METS-IR had a higher predictive value for the development of diabetes in individuals with overweight/obesity, while in the medium to long term (6–12 years), METS-IR was more accurate in predicting the development of diabetes in non-obese individuals.ConclusionsOur study showed that METS-IR was independently associated with the development of future diabetes in a non-diabetic population. METS-IR was a good predictor of diabetes, especially for women and individuals < 45 years old for predicting the future risk of developing diabetes at all times.

Increased susceptibility to diet-induced obesity in female mice impairs ovarian steroidogenesis: the role of elevated leptin signalling on Nodal activity inhibition in theca cells

ObjectiveSusceptibility to obesity in humans is driven by the intricate interplay of genetic, environmental and behavioural factors. Moreover, the mechanisms linking maternal obesity to infertility remain largely understudied. In this study, we investigated how variable susceptibility to obesity in mice affects ovarian steroidogenesis, with a particular focus on the leptin-mediated dysregulation of Nodal signalling pathway in theca cells (TC). MethodsC56BL/6J (B6) and 129S1/SvlmJ (129) mice, models of maternal obesity (MO), were fed a chow diet (CD) and a high fat diet (HFD) for 16 weeks. To investigate the contrasting effects of leptin on ovarian steroidogenesis, B6 mice pharmacologically treated with leptin for 16 days on CD were used to model hyperleptinemia, while homozygous ob/ob (-/-) mice with genetic leptin deficiency, also on a CD, were used to examine the effects of obesity in the absence of leptin. Following the characterisation of the mouse phenotype, gonadal fat (GON), whole ovaries (WO), ovarian TC and granulosa cell (GC) fractions were collected for mRNA transcription and protein expression analysis. Finally, in vitro treated ovarian explants obtained from B6 mice were used to further elucidate the effects of Nodal on steroidogenesis. ResultsThe significant gain in body weight (BW) and fat mass (FM) in HFD-fed B6 mice (p<0.05), was associated with increased mRNA transcription of the adipose tissue expansion genes Polymerase I and transcript release factor (Cavin), Secreted frizzled- related protein 5 (Sfrp5) and Mesoderm specific transcript (Mest) in GON (p<0.05). Furthermore, the HFD-fed B6 mice presented also impaired glucose metabolism and insulin sensitivity (p<0.05). In contrast, the HFD-fed 129 mice exhibited no changes in BW and FM, maintaining glucose and insulin metabolism. At the ovarian level, decreased protein expression of Steroidogenic Acute Regulatory Protein (StAR) in WO obtained from HFD-fed B6 mice (p=0.05), was followed by reduced transcription of key steroidogenic genes like Star and Cytochrome P450 17a1 (Cyp17a) in TC (p<0.05). Furthermore, the transcription of Nodal and its receptors was downregulated (p<0.05), whereas mRNA levels of Suppressor of cytokine signalling 3 (Socs3) and SMAD family member 7 (Smad7) were upregulated in TC obtained from HFD-fed B6 mice (p<0.05). No changes were seen in the genes regulating steroidogenesis, Nodal signalling, or Socs3 and Smad7 activity in the ovaries of HFD-fed 129 mice. Importantly, the pharmacological treatment of lean mice with leptin, upregulated the ovarian transcription of Socs3 and Smad7, while downregulating Nodal and its receptors (p<0.05). Finally, in vitro pharmacological inhibition of Nodal signalling pathway in ovarian explants isolated from CD-fed B6 mice decreased the transcription of Star and Cyp17a in TC (p<0.05), whereas Nodal treatment of explants obtained from HFD-fed B6 mice restored the transcription of both genes (p<0.05). ConclusionsIncreased susceptibility to obesity in MO is associated with systemic hyperleptinemia and hypoestrogenism due to compromised ovarian steroidogenesis, largely driven by the inhibitory effects of leptin-Smad7 pathway on Nodal signalling activity in the TC compartment of ovarian follicles.

Single-Cell Analysis Reveals the Cellular and Molecular Changes of Liver Injury and Fibrosis in Mice During the Progression of Schistosoma japonicum Infection

Schistosomiasis is a parasitic disease that poses a serious threat to human health. However, the pathogenic mechanism during the progression of Schistosoma japonicum infection remains unclear. In order to elucidate this mechanism, we used single-cell RNA sequencing (scRNA-seq) to investigate the transcriptome characteristics of the cellular (single-cell) landscape in the livers of mice infected with Schistosoma japonicum, which were divided into three groups: uninfected mice (0 week (w)), infected mice at 6 w post-infection (the acute phase), and infected mice at 10 w post-infection (the chronic phase). A total of 31,847 liver cells were included and clustered into 21 groups. The cells and T-cells had high heterogeneity in the liver during the progression of schistosome infection. The number and intensity of the intercellular interactions significantly increased at 6 w after infection but decreased at 10 w. The inflammatory signaling pathways chemoattractant cytokine ligand (CCL)5-chemokine C-C-motif receptor (CCR)5 between macrophages and T-cells were predominant at 6 w post-infection; the CCL6-CCR2 signaling pathway between macrophages was predominant at 10 w. The CD80 signaling pathway related to T-cell activation was increased at 6 w after infection, and increased expression of its receptor CD28 on the surfaces of CD4+ and CD8+ T-cells was confirmed by flow cytometry, suggesting an increase in their activation. In addition, scRNA-seq and quantitative reverse transcription polymerase chain reaction (qRT-PCR) confirmed that the intercellular communication between secretory phosphoprotein 1 (SPP1)-cluster of differentiation (CD44), insulin-like growth factor (IGF)-1-IGF1r and visfatin-insulin receptor (Insr) associated with bone metabolism and insulin metabolism was increased and enhanced in the liver at 6 w post-infection. Overall, we provide the comprehensive single-cell transcriptome landscape of the liver in mice during the progression of schistosome infection and delineate the key cellular and molecular events involved in schistosome infection-induced liver injury and fibrosis. The elevated CCL5-CCR5 and CCL6-CCR2 signaling pathways in the liver may be a drug target for liver injury and fibrosis caused by schistosome infection, respectively.

Vitamin B12 is correlated with insulin resistance and metabolism disorder markers in women with recurrent pregnancy loss

ObjectivesRecurrent pregnancy loss (RPL) seriously affects women's reproductive and mental health, and the incidence has increased in recent years. Insulin resistance (IR) acts as a significant contributing factor to RPL. Studies suggest that vitamin B12, folate intake, and homocysteine are correlated with IR, but the exact nature remains controversial and requires further investigation. In this study, we aimed to assess the levels and correlations between vitamin B12-folate-homocysteine and insulin resistance in RPL patients. Study design73 control subjects and 256 RPL patients (144 RPL patients without IR and 112 RPL patients with IR) were included in this observational retrospective cross-sectional study. The differences in vitamin B12, folate, and homocysteine levels between RPL patients with and without IR were analyzed using a Student's t-test. Pearson correlations were utilized to examine the correlation between vitamin B12-folate-homocysteine and glucose and lipid metabolism parameters. Multivariable linear regressions were used to assess the independent correlation of each factor with HOMA-IR. ResultsCompared to the control subjects, RPL patients exhibited lower vitamin B12 (p < 0.001) and folate (p < 0.001), and higher homocysteine (p = 0.001). RPL patients with IR described decreases in vitamin B12 (p = 0.003) and folate (p = 0.028), and increases in homocysteine (p = 0.033) as RPL patients without IR. Vitamin B12 in RPL patients was significantly negatively correlated with homocysteine (r = −0.348, p < 0.001), HOMA-IR (r = −0.214, p < 0.001), BMI (r = −0.160, p = 0.017), TG (r = −0.148, p = 0.039) and CHO (r = −0.149, p = 0.038) and positively correlated with folate (r = 0.217, p < 0.001). In multivariable linear regressions, after adjusting for age, strong correlations were observed between vitamin B12 (β = −0.197, p = 0.010), BMI (β = 0.466, p < 0.001), and HOMA-IR in RPL patients. ConclusionVitamin B12 is significantly correlated with IR in RPL patients. Circulating vitamin B12-folate-homocysteine metabolism could be a window of the pathological process of IR, obesity, and lipid metabolism disorders in RPL patients.

One-Year Effect of Elexacaftor/Tezacaftor/Ivacaftor Therapy on HbA1c Levels and Insulin Requirement in Patients with Insulin-Dependent Cystic Fibrosis-Related Diabetes: A Retrospective Observational Study.

The impact of ETI therapy on pulmonary function and nutritional status has been widely studied; the literature on the possible outcomes on glycemic control and insulin requirement in patients affected by CFRD is controversial. The main objective of our study was to evaluate HbA1c levels in patients with cystic fibrosis-related diabetes (CFRD) after one year of therapy with elexacaftor/tezacaftor/ivacaftor (ETI). The secondary objective was to study the changes in the total daily insulin dose (TDD), pulmonary function and metabolism in this population. A retrospective single-center observational study was conducted at the Regional Cystic Fibrosis Centre and Diabetology Centre of IRCCS Istituto Giannina Gaslini. The observation period was divided into four different time points: initiation (T0), 3 months (T3mo), 6 months (T6mo) and 12 months (T12mo) of ETI therapy. Demographic and clinical data were collected. The results were then stratified by genotype (homozygous or heterozygous F508del). Twenty-eight patients with CFRD undergoing insulin therapy were included. TDD (IU) significantly decreased at T3mo and T6mo, but not at T12mo, whereas HbA1c decreased significantly at all three times. The number of hospitalizations and pulmonary exacerbations decreased significantly. We demonstrated both improvement in glycemic control (by means of HbA1c) and insulin requirement in insulin-dependent CFRD patients after one year of ETI treatment.

Characterization of human placental fetal vessels in gestational diabetes mellitus.

Gestational diabetes mellitus is one of the most common complications during pregnancy. Its prevalence is rapidly increasing worldwide. Gestational diabetes mellitus is leading to an elevated risk for the development of endothelial dysfunction and cardiovascular diseases both in the mother and the child in later life. The underlying pathophysiological mechanisms are not well-understood. Therefore, we aimed to characterize the endothelial function in fetal placental vessels from mothers with gestational diabetes mellitus. In this study, we distinguished between insulin-treated and diet-controlled gestational diabetes mothers and compared them to a normoglycemic control group. The clinical data confirmed pre-conceptional overweight as a risk factor in women with insulin-treated gestational diabetes mellitus. The insulin-treated gestational diabetes group was also characterized by a recent family history of diabetes compared to mothers of the control or diet-controlled gestational diabetes group. Analyses of blood serum from umbilical cords suggested a reduced fetal insulin metabolism in the insulin-treated gestational diabetes group. Vascular function analysis in fetal placental vessels revealed an altered substance P-induced vasorelaxation in vessels from patients with insulin-dependent gestational diabetes. Inhibition of nitric oxide synthase affected only fetal vessel segments from the control group or diet-controlled gestational diabetes group, but not from insulin-dependent gestational diabetes. Finally, we found a significantly decreased substance P receptor (TACR1) mRNA expression in fetal vessel segments from patients with insulin-treated gestational diabetes. In conclusion, we provide evidence that different pathophysiological mechanisms might be responsible for the development of insulin-treated versus diet-controlled gestational diabetes. Only in fetal vessels from patients with insulin-treated gestational diabetes were we able to detect an endothelial dysfunction and a reduced fetal insulin conversion. This provides novel insights into the pathophysiology of the subtypes of gestational diabetes.

Linking the reversal of gestational insulin resistance to postpartum depression.

Postpartum depression (PPD) constitutes a significant mental health disorder affecting almost one fifth of pregnancies globally. Despite extensive research, the precise etiological mechanisms underlying PPD remain elusive. However, several risk factors like genetic predisposition, hormonal fluctuations, and stress-related environmental and psychosocial triggers have been found to be implicated in its development. MAIN: Recently, an increased risk of PPD has been reported to be associated with gestational diabetes mellitus (GDM), which is characterized by the disruption of glucose metabolism, primarily attributed to the emergence of insulin resistance (IR). While IR during pregnancy seems to be an evolutionary adaptative mechanism to handle the profound metabolic alterations during pregnancy, its subsequent resolution following delivery necessitates a reconfiguration of the metabolic landscape in both peripheral tissues and the central nervous system (CNS). Considering the pivotal roles of energy metabolism, particularly glucose metabolism, in CNS functions, we propose a novel model that such pronounced changes in IR and the associated glucose metabolism seen postpartum might account for PPD development. This concept is based on the profound influences from insulin and glucose metabolism on brain functions, potentially via modulating neurotransmitter actions of dopamine and serotonin. Their sudden postpartum disruption is likely to be linked to mood changes, as observed in PPD. The detailed pathogenesis of PPD might be multifactorial and still remains to be fully elucidated. Nevertheless, our hypothesis might account in part for an additional etiological factor to PPD development. If our concept is validated, it can provide guidance for future PPD prevention, diagnosis, and intervention.

Network pharmacology analysis revealed the mechanism and active compounds of jiao tai wan in the treatment of type 2 diabetes mellitus via SRC/PI3K/AKT signaling

Ethnopharmacological relevanceJiao-tai-wan (JTW) is a traditional Chinese herbal prescription, exerts its therapeutic effects on type 2 diabetes mellitus (T2DM). However, its mechanisms and active components remain unclear. Aim of the studyTo investigate the therapeutic mechanisms of JTW in treating type 2 diabetes mellitus (T2DM), focusing on identifying active components, their targets, and validating efficacy through SRC/PI3K/AKT signaling pathway modulation in vitro and in vivo. Materials and methodsActive ingredients were retrieved from the Traditional Chinese Medicine System Pharmacology (TCMSP) and Comprehensive Traditional Chinese Medicine Database (TCMID). Targets for these components were identified using the ChemMapper database based on 3D structural similarity. T2DM-related genes were sourced from the DisGeNET and Gene Expression Omnibus (GEO) databases. Protein-protein interaction (PPI) analysis and functional enrichment analysis were conducted to construct a pathway network of “herbs-active ingredients-candidate targets”, identifying core molecular mechanisms and key active ingredients. SwissDock was used for molecular docking to predict ligands for candidate targets. The diabetic models were established using C57BL/6 mice and human liver HepG2 cell lines. Their Effectiveness and key molecules were verified through biochemical detection and immunoblotting. ResultsTotal 30 active compounds, 597 active ingredient targets, 9631 T2DM-related genes, and 521 overlapping candidate targets were found for JTW on T2DM. Go enrichment indicated the core pathways enriched on insulin and glucose metabolism. The auto-docking demonstrated SRC has potential binds to ingredients of JTW. In vivo, JTW can reduce blood glucose, and blood lipid levels, and HOMA-IR, and increase HOMA-ISI levels in T2DM mice with reduced ALT, AST, MDA levels and increased SOD levels. Meanwhile, decreased phosphorylation of SRC, along with increased levels of phosphorylated PI3K, PI3K, and phosphorylated AKT, were observed. HE staining of liver tissues further confirmed that JTW administration improved liver morphology, reducing inflammation and necrosis. In vitro, JTW significantly ameliorates upstream dysregulation by reducing SRC phosphorylation while enhancing phosphorylated PI3K, PI3K, and AKT phosphorylation levels. ConclusionJTW may alleviate glucose, insulin resistance, and lipid metabolism disorders by the SRC/PI3K/AKT signaling pathway, that provide a novel view of potential active compounds and essential targets in treating T2DM.

Unraveling the genetic and singaling landscapes of pediatric cancer

Pediatric cancer (PAEC) arises from gene mutations and their disrupted pathways, often driven by genetic instability affecting cell signaling. These pathways can help identify cancer triggers. Genomic studies have examined PAEC gene etiologies and disorders, but further analysis is needed to understand tumor progression mechanisms. We systematically analyzed PAEC datasets from cBioPortal, encompassing thirteen studies with 6568 samples. We identified 827 PAEC genes with mutation frequencies over fifteen across four tiers (I-IV). Tier I (mutation frequency ≥1 %) includes 40 genes, while Tier II(0.90–0.70 %), Tier III(0.60–0.50 %), and Tier IV(0.40–0.10 %) comprise 126, 336, and 325 genes, respectively. Key Tier I genes include TP53(5 %), NRAS(2.2 %), KRAS(1.8 %), CTNNB1(1.4 %), ATM(1.3 %), CREBBP(1.2 %), JAK2 (1.1 %), PIK3CA(1 %), PTEN(1 %), BRAF(0.9 %), EGFR(0.9 %), PIK3R1(0.8 %), and PTPN11(0.8 %). These genes participate in various signaling pathways (PI3K/AKT/mTOR, RAS/RAF/MAPK, JAK/STAT, and WNT/β-catenin), which are interconnected. We compared several PAEC panels with Tier I genes, and we found that the most shared across PAEC panels were TP53 (8), PTEN (7), and ATM (4). We further examined roles of TP53 in normal cells versus PEAC tumors using digital cellular and pathological imaging data supported by Human Protein Atlas. TP53 is expressed in cytosol, nucleosol, and vesicles and during cell-cycle TP53 protein in key regulator and it is present during all major cell-cycle events. Balancing of TP53WT and TP53MUT is the hallmark of the TP53 pathophysiology with severe functional implications. Notably, genes linked to insulin metabolism disorders may be PAEC risk factors, suggesting metabolic pathways as key research targets. This study highlights the therapeutic, prognostic, and diagnostic significance of these genes and pathways, emphasizing the need for ongoing PAEC research.

Effects of Cryptorchidism on the Semen Quality of Giant Pandas from the Perspective of Seminal Plasma Proteomics

Giant pandas are an endangered species with low reproductive rates. Cryptorchidism, which can negatively affect reproduction, is also often found in pandas. Seminal plasma plays a crucial role in sperm–environment interactions, and its properties are closely linked to conception potential in both natural and assisted reproduction. The research sought to identify seminal fluid protein content variations between normal and cryptorchid giant pandas. Methods: Using a label-free MS-based method, the semen proteomes of one panda with cryptorchidism and three normal pandas were studied, and the identified proteins were compared and functionally analyzed. Results: Mass spectrometry identified 2059 seminal plasma proteins, with 361 differentially expressed proteins (DEPs). Gene ontology (GO) analysis revealed that these DEPs are mainly involved in the phosphate-containing compound metabolic, hydrolase activity, and kinase activity areas (p ≤ 0.05). The KEGG functional enrichment analysis revealed that the top 20 pathways were notably concentrated in the adipocyte lipolysis and insulin metabolism pathway, with a significance level of p ≤ 0.05. Further analysis through a protein–protein interaction (PPI) network identified nine key proteins that may play crucial roles, including D2GXH8 (hexokinase Fragment), D2HSQ6 (protein tyrosine phosphatase), and G1LHZ6 (Calmodulin 2). Conclusions: We suspect that the high abundance of D2HSQ6 in cryptorchid individuals is associated with metabolic pathways, especially the insulin signal pathway, as a typical proteomic feature related to its pathological features. These findings offer insight into the ex situ breeding conditions of this threatened species.

Genome-Wide Search for Gene Mutations Likely Conferring Insecticide Resistance in the Common Bed Bug, Cimex lectularius.

Insecticide resistance in the bed bug Cimex lectularius is poorly understood due to the lack of genome sequences for resistant strains. In Japan, we identified a resistant strain of C. lectularius that exhibits a higher pyrethroid resistance ratio compared to many previously discovered strains. We sequenced the genomes of the pyrethroid-resistant and susceptible strains using long-read sequencing, resulting in the construction of highly contiguous genomes (N50 of the resistant strain: 2.1 Mb and N50 of the susceptible strain: 1.5 Mb). Gene prediction was performed by BRAKER3, and the functional annotation was performed by the Fanflow4insects workflow. Next, we compared their amino acid sequences to identify gene mutations, identifying 729 mutated transcripts that were specific to the resistant strain. Among them, those defined previously as resistance genes were included. Additionally, enrichment analysis implicated DNA damage response, cell cycle regulation, insulin metabolism, and lysosomes in the development of pyrethroid resistance. Genome editing of these genes can provide insights into the evolution and mechanisms of insecticide resistance. This study expanded the target genes to monitor allele distribution and frequency changes, which will likely contribute to the assessment of resistance levels. These findings highlight the potential of genome-wide approaches to understand insecticide resistance in bed bugs.

Hypoglycaemia in screening oral glucose tolerance test in pregnancy with low birth weight fetus.

Maternal hypoglycemia, a condition characterized by lower than normal blood glucose levels in pregnant women, has been increasingly associated with adverse pregnancy outcomes, including low birth weight (LBW) in neonates. LBW, defined as a birth weight of less than 2500 g, can result from various factors, including maternal nutrition, health status, and metabolic conditions like hypoglycemia. Maternal hypoglycemia may affect fetal growth by altering the supply of essential nutrients and oxygen to the fetus, leading to restricted fetal development and growth. This condition poses significant risks not only during pregnancy but also for the long-term health of the child, increasing the likelihood of developmental delays, health issues, and chronic conditions later in life. Research in this area has focused on understanding the mechanisms through which maternal hypoglycemia influences fetal development, with studies suggesting that alterations in placental blood flow and nutrient transport, as well as direct effects on fetal insulin levels and metabolism, may play a role. Given the potential impact of maternal hypoglycemia on neonatal health outcomes, early detection and management are crucial to minimize risks for LBW and its associated complications. Further investigations are needed to fully elucidate the complex interactions between maternal glucose levels and fetal growth, as well as to develop targeted interventions to support the health of both mother and child. Understanding these relationships is vital for improving prenatal care and outcomes for pregnancies complicated by hypoglycemia.

112 Effects of maternal body condition on colostrum, foal weight, and foal IgG concentration

Abstract Foals are born with little to no immunity and rely on maternal colostrum to develop adequate circulating immunoglobulin G (IgG) concentrations in the periparturient period. Colostrum directly impacts the health of the foal, and there are limited data assessing how maternal metabolism and body condition impacts IgG in colostrum and in the foal postnatally. To determine the influence of maternal body condition score (BCS) and cresty neck score (CNS) on glucose and insulin metabolism in the pregnant mare, colostrum composition, and colostrum and foal IgG concentrations, light breed mares (n = 6) were divided into two groups based on BCS and CNS at 315 ± 0.45 d of gestation. The groups were identified as moderately obese (MO; n = 3, BCS) and lean (LN; n = 3). Mares were fasted overnight and then underwent an intravenous (iv) glucose tolerance test at 315 ± 0.45 d gestation. Blood samples were collected at -30, -15 and 0 min and mares were administered dextrose iv [0.3 g/kg body weight (BW)] over 3.7 ± 0.17 min followed by an intravenous infusion of insulin (0.3 mU/kg BW) 20-min later. Additional blood samples were collected 2, 5, 10, 15, 20, 25, 30, 45, 60, and 120 min after initiation of dextrose infusion. At parturition, a colostrum sample was collected before foals nursed and analyzed for protein and fat, and IgG concentration. A foal blood sample was collected 18 h after birth to determine passive transfer of IgG. Placental, mare, and foal weights were measured at birth. Data were analyzed using a t-test with significance at P ≤ 0.05 and a tendency at 0.05 &amp;lt; P ≤ 0.10. The MO group had greater BCS (P = 0.01) and CNS (P = 0.01) than the LN group. Moderately obese mares tended to have 9% greater glucose area under the curve (AUC) after dextrose (P = 0.10) and a 9% greater glucose AUC after insulin infusion (P = 0.10) than LN mares. Colostrum IgG concentrations, and protein and fat content (P ≥ 0.3) did not differ between groups. Foal serum IgG concentrations, foal BW, and placental weights were similar between groups (P ≥ 0.8). The ratios between foal BW and placenta weight, and between foal BW and mare BW were similar between groups (P ≥ 0.3). Moderately obese maternal BCS and CNS scores may decrease maternal glucose clearance during late gestation but did not impact colostrum quality or foal IgG concentrations within 24 h postpartum. As the equine fetus matures later in gestation than other livestock species and relies heavily on glucose uptake from the placenta, it is critical to increase our understanding of the impacts of maternal obesity and glucose clearance on foal development and pre- and post-natal health.

The influence of lactation on insulin and glucose metabolism, lipid profile, and cytokines in pregnant mares

Glucose metabolism adapts to gestation, resulting in progressive physiological insulin resistance and increased insulin secretion to maintain maternal euglycemia and glucose availability for the developing fetus. These changes can impact mare fertility and maternal and neonatal health. This is the first comparison of body condition, regional adiposity, insulin and glucose dynamics, lipid metabolism, and cytokine production between lactating and non-lactating mares before, during pregnancy, and early postpartum. Twelve pregnancies from 9 broodmares, five nonlactating (NL) and seven lactating (L), were used. Evaluations were performed on the day of ovulation, at 55, 110, 165, 220, 275, and 330 days of gestation (D55, D110, D165, D220, D275, D330) and 21 days postpartum (21pp). Mares in the L group had lower basal insulin and glucose at the beginning of pregnancy, smaller area under the curve of insulin and glucose, and greater insulin sensitivity and glucose tolerance. Resistin was higher in D110 and D165 than in D0, D275, 330 and 21pp, while leptin was higher in D55, and in D110, at D110 it was equal to D0, D220, and D275, but higher than at D330 and D21pp. As for the groups, L presented lower body condition score (BCS), crest neck score (CNS), rump fat thickness (RUM), basal insulin, glucose area under the curve (AUCg), MIRG and higher RISQI, adiponectin and tumor necrosis factor (TNFα). There was no effect over time in non-esterified fatty acids (NEFA) concentrations between the L mares; in the NL, D275 presented higher concentrations than those of D0, D55, and D110, which in turn were equal to the other time points; there were higher concentrations in NL mares than L in samples D165 and D275. In conclusion, a different metabolic profile during pregnancy was detected, and NL mares were closer to the metabolic threshold for the occurrence of metabolic syndrome during pregnancy. Understanding the impacts of these differences on mare's health and their offspring's future is fundamental as most of our recipient mares for embryo transfer are non-lactating. Therefore, we suggest that further studies be performed to evaluate lactation's influence on mares' metabolic parameters.

Polyphenols in foods: a potential strategy for preventing and managing the postprandial hyperglycemic response.

Type 2 diabetes mellitus (T2DM) is a significant health risk worldwide, and effective management strategies are needed. Polyphenols exhibit diverse biological functions, are abundant in various plants, and influence carbohydrate digestion and absorption. This review provides a comprehensive overview of clinical evidence regarding the relationship between dietary polyphenols and the postprandial hyperglycemic response. Human intervention studies have demonstrated the benefits of polyphenol-rich foods in improving glucose and insulin metabolism, underscoring their role in preventing T2DM. These findings highlight the potential of polyphenol-rich foods for managing hyperglycemia and mitigating T2DM risk and provide insight into effective dietary strategies for glycemic control and overall health.

Follicle-stimulating hormone receptor gene polymorphisms influence Body Mass Index, metabolism, and bone mineral density in postmenopausal women.

Covering a significant part of a woman's life, the postmenopausal phase is often associated with the onset of obesity, metabolic dysfunction, osteoporosis, and their most disabling complications. In this context, scant evidence from both preclinical and clinical studies suggests that single nucleotide polymorphisms (SNPs) of the follicle-stimulating hormone receptor (FSHR) gene might be involved in the etiopathogenesis of these conditions, posing them as possible molecular predictors of their development. Therefore, this study aimed to evaluate the role of the FSHR gene SNPs c.2039A>G and c.-29 G>A on Body Mass Index (BMI), metabolic parameters, and bone metabolism in postmenopausal women. To achieve this goal, 49 postmenopausal Caucasian women aged from 45 to 80 years and with no factors known to influence metabolism and/or bone mineral density (BMD) were enrolled and assessed for their medical history, medical family history, anthropometric parameters and hormonal, metabolic and lipid profiles, and BMD. Then, they were genotyped for the FSHR gene SNPs c.2039A>G and c.-29G>A. Finally, the resulting data were classified according to woman's genotypes and subjected to statistical analysis. No significant differences were found between the distributions of most endpoint parameters examined by genotype. However, none of the women with the c.2039A>G FSHR GG gene SNP were affected by obesity and had the highest lumbar BMD z-score within the cohort. Additionally, those with the FSHR c.-29G>A AA genotype had the lowest serum glucose levels. This preliminary study suggests that the FSHR c.2039A>G GG SNP, which is associated with reduced sensitivity of the FSHR, may have a protective role against obesity, offering further evidence for the possible association among FSH, FSHR polymorphisms, and insulin metabolism.