Glucose Sensitivity Research Articles

Cardiovascular Risk Assessment in the Immediate Postoperative Period of Bariatric Surgery

Objectives: Since obesity and overweight are strongly associated with cardiovascular diseases, we investigated cardiovascular events risk in individuals who lost weight through bariatric surgery. Methods: Serum levels of glucose, insulin, triacylglycerol, HDL cholesterol, non-HDLDL cholesterol, and lipoprotein ratios were assessed in patients with obesity before and after bariatric surgery, including a 6-month follow-up period. Results: Bariatric surgery significantly improved BMI, triglyceride levels, glucose, and insulin sensitivity. However, HDL cholesterol levels dropped sharply in the first month (p < 0.0001), coinciding with elevated atherogenic indices, indicating a transient increase in cardiovascular risk. By 6 months, indices improved significantly, HDL recovered, and LDL particle size increased, suggesting reduced atherogenic potential. Conclusions: Individuals undergoing bariatric surgery have a higher cardiovascular events risk in the immediate postoperative period. Health professionals should be aware of and monitor these patients closely.

High fructose rewires gut glucose sensing via glucagon-like peptide 2 to impair metabolic regulation in mice.

Increased fructose consumption contributes to type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), but the mechanisms are ill-defined. Gut nutrient sensing involves enterohormones like Glucagon-like peptide (Glp)2, which regulates the absorptive capacity of luminal nutrients. While glucose is the primary dietary energy source absorbed in the gut, it is unknown whether excess fructose alters gut glucose sensing to impair blood glucose regulation and liver homeostasis. Mice were fed diets where carbohydrates were either entirely glucose (70 %Kcal) or glucose partially replaced with fructose (8.5 %Kcal). Glp2 receptor (Glp2r) was inhibited with Glp2 (3-33) injections. Glucose tolerance, insulin sensitivity, and gut glucose absorption were concomitantly assessed, and enteric sugar transporters and absorptive surface were quantified by RT-qPCR and histological analysis, respectively. High fructose feeding led to impairment of blood glucose disposal, ectopic fat accumulation in the liver, and hepatic (but not muscle or adipose tissue) insulin resistance independent of changes in fat mass. This was accompanied by increased gut glucose absorption, which preceded glucose intolerance and liver steatosis. Fructose upregulated glucose transporters and enlarged the gut surface, but these effects were prevented by Glp2r inhibition. Blocking Glp2r prevented fructose-induced impairments in glucose disposal and hepatic lipid handling. Excess fructose impairs blood glucose and liver homeostasis by rewiring gut glucose sensing and exacerbating gut glucose absorption. Our findings are positioned to inform novel early diagnostic tools and treatments tailored to counter high fructose-induced metabolic derangements predisposing to T2D and MASLD.

A Mechanistic Insight into the Effects of Marine Sources as Functional Foods Against Metabolic Syndrome: A Review Article

Introduction: Marine organisms are a rich source of metabolites that can be considered functional foods and produce new medicines against metabolic syndrome, including hypertension, dyslipidemia, hyperglycemia, obesity, insulin resistance, and hyperinsulinemia. Method: A total of 609 publications were searching results, 283 were screened entirely, and 43 duplications were removed. Results: These compounds, found in marine organisms such as algae, sponges, and mollusks, have vasodilatory properties, inhibit certain enzymes involved in blood pressure regulation, and exhibit anti-oxidant activity, making them promising candidates for developing hypertension treatments. Marine organisms showed an improvement in insulin sensitivity and blood glucose level regulation, suggesting their potential in developing novel therapies for diabetes management. Furthermore, some marine sources inhibit lipid accumulation, regulate metabolism, and suppress appetite, indicating their potential as therapeutic agents in combating obesity. Conclusion: However, further studies on the pharmacological effects of marines should be performed to evaluate the potential of these compounds to produce novel drugs, but they hope this study paves and lights the way.

Current approaches in CRISPR-Cas systems for diabetes.

In the face of advancements in health care and a shift towards healthy lifestyle, diabetes mellitus (DM) still presents as a global health challenge. This chapter explores recent advancements in the areas of genetic and molecular underpinnings of DM, addressing the revolutionary potential of CRISPR-based genome editing technologies. We delve into the multifaceted relationship between genes and molecular pathways contributing to both type1 and type 2 diabetes. We highlight the importance of how improved genetic screening and the identification of susceptibility genes are aiding in early diagnosis and risk stratification. The spotlight then shifts to CRISPR-Cas9, a robust genome editing tool capable of various applications including correcting mutations in type 1 diabetes, enhancing insulin production in T2D, modulating genes associated with metabolism of glucose and insulin sensitivity. Delivery methods for CRISPR to targeted tissues and cells are explored, including viral and non-viral vectors, alongside the exciting possibilities offered by nanocarriers. We conclude by discussing the challenges and ethical considerations surrounding CRISPR-based therapies for DM. These include potential off-target effects, ensuring long-term efficacy and safety, and navigating the ethical implications of human genome modification. This chapter offers a comprehensive perspective on how genetic and molecular insights, coupled with the transformative power of CRISPR, are paving the way for potential cures and novel therapeutic approaches for DM.

Isoleucine Enriched Branched-Chain Amino Acid Supplement Improves Glucose and Insulin Sensitivity in Healthy College-Age Males but Not in Females

Isoleucine Enriched Branched-Chain Amino Acid Supplement Improves Glucose and Insulin Sensitivity in Healthy College-Age Males but Not in Females

An acute bout of 4 × 4-min or 10 × 1-min HIIT improves β cell glucose sensitivity in postmenopausal females with type 2 diabetes: a secondary analysis.

Improvements in glycemic control following acute exercise are typically attributed to improved postexercise insulin sensitivity (IS) with comparatively little known about how acute exercise impacts β cell function, especially in postmenopausal females. We determined how two high-intensity interval training (HIIT) protocols, matched for total estimated energy expenditure, impact β cell function in postmenopausal females with type 2 diabetes. Thirteen postmenopausal females (70 ± 5 yr; 12 ± 7 yr since diagnosis, 80.9 ± 13.8 kg, 32.4 ± 5.6 kg·m2; HbA1c-49.8 ± 10.3 mmol/mol [6.7 ± 1.0]) living with type 2 diabetes were included in this semirandomized crossover trial. The trial involved an initial resting control condition followed by two HIIT conditions [4 × 4-min HIIT (HIIT4) and 10 × 1-min HIIT (HIIT10)] completed in a randomized order 2-4 days apart. β cell function (glucose sensitivity) and insulin sensitivity were determined from a 2-h mixed-meal tolerance test performed 2 h after rest or HIIT. Both HIIT4 and HIIT10 significantly improved β cell glucose sensitivity compared with control (15 pmol/min/m2/[mmol/L], [95% confidence interval (CI) 6, 23]; P = 0.002 and 16 pmol/min/m2/[mmol/L], [95% CI 7, 25]; P = 0.002, respectively), with no difference between HIIT protocols (1 [-8, 10], P = 0.79). There were no significant differences in IS metrics (Matsuda index, OGIS, Stumvoli, and QUICKI) between the conditions. An acute bout of 4 × 4-min or 10 × 1-min HIIT improves β cell glucose sensitivity in postmenopausal females living with type 2 diabetes. ClinicalTrials.gov: NCT04986345.NEW & NOTEWORTHY This is the first study to explore the effects of acute high-intensity interval training (HIIT) on β cell function in postmenopausal women with type 2 diabetes. Our crossover trial compares two HIIT protocols, matched for total estimated energy expenditure, examining their impacts on β cell function and insulin sensitivity. Despite the absence of an insulin-sensitizing effect, we show robust effects of HIIT on β-cell function, including an improvement in β-cell glucose sensitivity.

Dual-Valence Copper Nanostructures with Cu+/Cu2+ Interfaces for High-Sensitivity Glucose Electrochemical Sensing.

Copper-based materials, renowned for their redox versatility and conductivity, have extensive applications in electrochemical sensing. Herein, we construct stable Cu+/Cu2+ interfaces within dual-valence copper nanostructures to achieve enhanced sensitivity in glucose sensing. By employing a hydrolysis method to tune Cu2+/Cu+ ratios precisely, we achieved an optimal electrochemical interface with heightened stability and reactivity. The Cu+/Cu2+ interface-based flexible electrode demonstrated excellent glucose sensitivity (332.4 µA mmol/L-1 cm-2 at +0.65 V), wide linear range (up to 10 mmol), a low detection limit of 1.02 nmol/L, and strong selectivity, including detection in human sweat, making this study significant for advanced electrochemical sensors.

Maternal Supplementation with Lacticaseibacillus rhamnosus GG Improves Glucose Tolerance and Modulates the Intestinal Microbiota of Offspring.

Consuming hypercaloric diets during pregnancy induces metabolic, immune, and maternal intestinal dysbiosis disorders. These conditions are transferred to the offspring through the placenta and breastfeeding, increasing susceptibility to metabolic diseases. We investigated the effect of L. rhamnosus GG supplementation on offspring maternally programmed with a hypercaloric diet. Our study involved sixteen female Wistar rats aged ten weeks, which were divided into four groups based on their diets: control (Ctrl), cafeteria (CAF), control + probiotic (PRO), and cafeteria + probiotic (CPRO). The control + probiotic and cafeteria + probiotic groups received a daily oral administration of 250 μL of L. rhamnosus GG cell suspension (equivalent to 109 UFC) for nine weeks. The body weight of the animals was recorded weekly, and their food intake was monitored every 24 h. An oral glucose tolerance test was conducted on the offspring at seven weeks of age. At the ninth week of age, animals were euthanized, and blood, tissues, and organs were collected. Maternal supplementation with L. rhamnosus GG decreased food intake and the average birth weight, improved glucose sensitivity, and lowered the levels of LDL, cholesterol, triglycerides, and mesenteric adipose tissue in offspring compared with the control and cafeteria groups. Our findings indicate that supplementing with LGG during maternal programming could protect offspring from metabolic disruptions caused by a hypercaloric maternal diet.

Human subjects with impaired beta-cell function and glucose tolerance have higher levels of intra-islet intact GLP-1

AimsA number of studies have suggested that pancreatic α cells produce intact GLP-1, thereby constituting a gut-independent paracrine incretin system. However, the debate on whether human α cells contain intact GLP-1 and whether this relates to the presence of diabetes is still ongoing. This study aimed to determine the presence of proglucagon-derived peptides, including GLP-1 isoforms, in pancreas biopsies obtained during partial pancreatectomy from metabolically profiled human donors, stratified according to pre-surgery glucose tolerance. MethodsWe enrolled 61 individuals with no known history of type 2 diabetes (31F/30M, age 64.6 ± 10.6 yrs., BMI 24.2 ± 3.68 kg/m2) scheduled for partial pancreatectomy for periampullary neoplasm. Differences in glucose tolerance and insulin secretion/sensitivity were assessed using preoperative 2 h OGTT, 4 h-Mixed Meal Test and Hyperinsulinemic Euglycemic Clamp. Subjects were subsequently classified as normal glucose tolerant (NGT, n = 19), impaired glucose tolerant (IGT, n = 20) or newly diagnosed diabetes (DM) (n = 22). We measured total GLP-1, intact GLP-1, glucagon, insulin, and C-peptide in pancreas biopsies and plasma from these subjects and correlated the results with their secretory and metabolic parameters. ResultsExtractable levels of total GLP-1 were 23.9 ± 2.66 pmol/g, while intact GLP-1 levels were 1.15 ± 0.18 pmol/g. When we examined proglucagon derived peptides (adjusted for glucagon levels), in subjects classified according to glucose tolerance, we observed similar levels of total GLP-1, however, intact GLP-1 was significantly increased in IGT and DM groups and inversely associated with beta cell glucose sensitivity and insulin secretion in vivo. ConclusionsOur data show that development of glucose intolerance and beta cell dysfunction are significantly associated with increased levels of intra-islet intact GLP-1, a potentially beneficial adaptation of the paracrine regulation of insulin secretion in type 2 diabetes.

CsWRKY29, a key transcription factor in tea plant for freezing tolerance, ABA sensitivity, and sugar metabolism

Tea plants (Camellia sinensis L.) are prone to spring frosts, leading to substantial economic damage. WRKY transcription factors are key in plant abiotic stress responses, yet the role of CsWRKY29 in freezing tolerance is unclear. In this study, quantitative real-time PCR (qRT-PCR) and transient green fluorescent protein assay revealed that CsWRKY29 localizes to the nucleus and its expression is induced by cold and abscisic acid (ABA). CsWRKY29 overexpression in Arabidopsis enhanced freezing tolerance, reduced electrolyte leakage, increased soluble sugars, and boosted superoxide dismutase activity, with upregulated COR genes. These lines also showed heightened ABA and glucose sensitivity. Cold treatment of CsWRKY29-overexpressing lines upregulated AtABI5, AtHXK1, and AtSUS4 compared to wild type, and yeast one-hybrid assays confirmed CsWRKY29 binding to the W-box in the CsABI5 promoter. Furthermore, the application of virus-induced gene silencing (VIGS) technology to reduce CsWRKY29 expression in tea plants revealed a significant decrease in the transcript levels of CsCBFs, CsABI5, CsHXK1, and CsSUS4 in the silenced plants. In summary, our findings indicate that CsWRKY29 may serve as a critical transcription factor that contributes to freezing tolerance, ABA responsiveness, and sugar metabolism within tea plants.

Association between total, regional and organ fat and type 2 diabetes risk factors among Latino youth: A longitudinal study.

To examine whether within-person changes in total, regional and organ fat were associated with within-person changes in type 2 diabetes (T2D)-related biomarkers following interventions. A secondary analysis from a randomised trial among Latino youth (30 males, 25 females) aged 12-16 years with obesity. The study sample combined participants randomised to either lifestyle intervention (N = 39) or usual care (N = 16). Total body composition was assessed by DEXA. Hepatic and pancreatic fat fractions were assessed using MRI. T2D risk factors included insulin sensitivity, beta-cell function and post-challenge glucose. Significant changes in %body fat, lean mass, insulin sensitivity and 2-h glucose were observed. Changes in fat mass were associated with changes in insulin sensitivity (β = -0.45, p < 0.001), while changes in lean mass were associated with changes in 2-h glucose concentrations (β = -0.50, p = 0.02). No association between changes in total, regional, or organ fat and beta cell function were noted. Our study revealed that within-person changes in fat mass and lean mass were associated with increased insulin sensitivity and reduced 2-h glucose concentrations, respectively, among high-risk Latino youth. The impact of reductions in regional and organ fat deposition on T2D risk factors warrants further examination.

Alpha-glucosidase inhibitory and glucoregulatory potential of soy protein fermented with a bacterium (Bacillus subtilis PM_NEIST_3) isolated from Hawaijar

Soybean-derived proteins are known to exert hypoglycemic effects; however, some soy proteins may cause anti-nutritional effects. Fermentation of soybean promotes hydrolysis of major anti-nutrient proteins and generation of bioactive peptides with antidiabetic potency. The present study aims to screen antidiabetic potential of protein isolates from ethnic fermented soybean (FS) of North-East (NE) India and to develop fermented soy protein isolate (FSPI) under controlled conditions by using the proficient bacteria isolated from the most effective FS with sound antidiabetic activity. Results showed that Hawaijar, a FS of Manipur, NE India, exhibited significant α-glucosidase and α-amylase inhibitory potential among the well-known FS of NE India under investigation. Thereafter, in the laboratory, the fermented soy protein isolate (FSPI-BS) was prepared by fermenting the SPI using a bacterial strain (Bacillus subtilis PM_NEIST_3) isolated from Hawaijar. The FSPI-BS generated by 72h fermentation exhibited significant α-glucosidase inhibitory potential. Further in vitro studies revealed that FSPI-BS promoted muscle glucose uptake and metabolism against high-glucose exposure via stimulating the PI3K/AKT/GLUT4 signaling cascade. In vivo studies using sucrose-induced Wistar rats demonstrated the inhibitory effect of FSPI-BS on postprandial blood glucose elevation. Moreover, studies with high-fat diet-fed model of type 2 diabetes revealed the benefits of FSPI-BS supplementation in improving glycemic parameters, glucose tolerance, insulin sensitivity, and skeletal muscle glucose metabolism. SDS-PAGE and western-blotting data unraveled a modification in protein profile with reduction in allergens and other baneful proteins in FSPI-BS. Therefore, FSPI-BS can be effectively used in managing hyperglycemia with no side effects.

Evaluation of a High Sensitivity Glucose Biosensor Based on Carbon Nanotubes and Gold Nanoparticles

Evaluation of a High Sensitivity Glucose Biosensor Based on Carbon Nanotubes and Gold Nanoparticles

In-situ electrochemical synthesis of Ni/Ni(OH)2/molecularly imprinted polymer nanocomposite for high-performance glucose detection

This study presents a novel non-enzymatic glucose sensor that synergistically combines the high catalytic activity of nickel hydroxide (Ni(OH)2) with the selective recognition of molecularly imprinted polymers (MIPs). The sensors were fabricated through an entirely in-situ synthesis directly on the electrode, comprising electrodeposition and oxidation of Ni/Ni(OH)2 nanoparticles and electropolymerization of a glucose-imprinted MIP layer using pyrrole and 3-aminophenyl boronic acid. The integrated MIP layer significantly enhanced selectivity against common interferents while amplifying glucose sensitivity. The resulting sensor demonstrated a high sensitivity of 1802 μA mM−1 cm−2 with a linear range from 0.04 to 2.6 mM. Notably, the sensor exhibited remarkable stability, retaining 97.2 % of its original sensitivity after 6 months of room-temperature storage. To extend the linear range, Nafion coatings at two concentrations were applied, achieving ranges up to 0.04–11.6 mM with adjusted sensitivities. This innovative approach, leveraging MIPs to provide selectivity to electrocatalytic nanomaterials, offers a promising strategy for developing high-performance non-enzymatic sensors for glucose and other biomolecules in diabetes monitoring and beyond.

Control of sensitivity in metal oxide electrolyte gated field-effect transistor-based glucose sensor by electronegativity modulation

In this study, the sensitivity of electrolyte-gated field-effect transistor-based glucose sensors using oxide semiconductor materials was controlled via electronegativity modulation. By controlling the enzymatic reaction between glucose and glucose oxidase, which is affected by the surface potential, the sensitivity of the glucose sensor can be effectively adjusted. To evaluate the sensitivity characteristics of the glucose sensor according to electronegativity control, devices were fabricated based on InO through Ga and Zn doping. The results confirmed that the specific sensitivity range could be adjusted by increasing the electronegativity. In addition, density functional theory calculations, confirmed that the attachment energy of the surface-functionalized material and the enzyme binding energy in the surface-functionalized thin film can be modulated depending on the electronegativity difference. The dissociation constant was controlled in both directions by doping with metal cations with larger(Ga, 1.81) or smaller(Zn, 1.65) electronegativities in InO(In, 1.78). We expect that this study will provide a simple method for the gradual and bidirectional control of the glucose sensitivity region.

Co-Micronized Palmitoylethanolamide and Rutin Associated With Hydroxytyrosol Recover Diabesity-Induced Hepatic Dysfunction in Mice: InVitro Insights Into the Synergistic Effect.

Metabolic dysfunction-associated fatty liver disease (MAFLD) and diabesity (diabetes related to obesity) are interrelated since glucose and lipid alterations play a vital role in the development of both disorders. Due to their multi-variant metabolic features, more than one drug or natural product may be required to achieve proper therapeutic effects. This study aimed to evaluate the effectiveness of a formulation containing co-micronized palmitoylethanolamide and rutin (PEA-Rut) associated with hydroxytyrosol (HT), namely NORM3, against hepatic damage and metabolic alterations in high-fat diet (HFD)-induced diabesity in mice. NORM3 decreased the body weight and fat mass of obese mice. The formulation improved HFD-altered insulin sensitivity and hepatic glucose production and metabolism, as shown by glucose, insulin, pyruvate tolerance tests, Western blot, and real-time PCR. In the liver, NORM3 limited macro- and micro-vacuolar steatosis, as revealed by morphological analysis, and reduced the associated hepatic inflammation. NORM3 counteracted lipid dysfunctions of HFD animals, activating AMPK, a key cellular energy sensor, and normalizing the expression of carnitine palmitoyl-transferase (CPT)1, a rate-limiting enzyme of fatty acid β-oxidation, and other genes involved in lipid homeostasis. Relevantly, the hepatic antioxidant activity of NORM3 was proved (reduced ROS and increased detoxifying factors and enzymes). Finally, invitro synergistic protective effects of the components (PEA-Rut and HT) on H2O2-induced oxidative challenge in HepG2 were determined (ROS production, inflammation, and antioxidant defense). Our results show the beneficial effect of NORM3 and its potential as an innovative phytotherapeutic combination in limiting hepatic damage progression and counteracting glucose and lipid dysmetabolism associated with diabesity.

Functional study of amine oxidase copper-containing 1 (AOC1) in lipid metabolism

Amine oxidase copper-containing 1 (AOC1) is a key member of copper amine oxidase family, which is responsible for deamination oxidation of histamine and putrescine. In recent years, AOC1 has been reported to be associated with various cancers, with its expression levels significantly elevated in certain cancer cells, suggesting its potential role in cancer progression. However, its function in lipid metabolism still remains unclear. Through genetic analysis, we have discovered a potential relationship between AOC1 and lipid metabolism. To further investigate, we generated Aoc1 -/- mice and characterized their metabolic phenotypes on both chow diet and high-fat diet (HFD) feeding conditions. On HFD feeding conditions, Aoc1 -/- mice exhibited significantly higher fat mass and impaired glucose sensitivity, and lipid accumulation in white adipose tissue and liver was also increased. This study uncovers the potential role of AOC1 in lipid metabolism and its implications in metabolic disorders such as obesity and type 2 diabetes, providing new targets and research directions for treating metabolic diseases.

Effect of short-term dopamine reduction on insulin sensitivity and post-prandial insulin and glucose responses in Standardbred horses

The role of dopamine in the regulation of insulin secretion in horses is poorly understood and requires further investigation. Pituitary pars intermedia dysfunction (PPID) is associated with decreased activity of dopaminergic neurons which normally suppress peptide hormone secretion from the pituitary pars intermedia. A high proportion of horses with PPID also have insulin dysregulation (ID), characterised by post-prandial hyperinsulinaemia and/or tissue insulin resistance, which are risk factors for the development of laminitis. The aim of this study was to investigate the effects of alpha-methyl-para-tyrosine (AMPT), a tyrosine hydroxylase inhibitor that reduces dopamine production, on insulin sensitivity and the post-prandial insulin response to a glucose-containing meal. Six healthy Standardbred horses were enrolled in a placebo-controlled randomised crossover study, in which one dose of AMPT (40 mg/kg BW) or placebo was administered orally, prior to performing an in-feed oral glucose test (OGT) and a frequently sampled intravenous glucose tolerance test (FSIGTT). Dopamine reduction by AMPT was confirmed by an increase in plasma prolactin concentration and the lack of post-prandial increase in plasma dopamine concentration compared to placebo. Post-prandial insulin responses, both peak and AUCi, were increased after AMPT compared to placebo (P=0.048 and P=0.005, respectively), without affecting blood glucose concentrations. However, one dose of AMPT did not appear to affect tissue sensitivity as assessed by the FSIGTT. This study confirmed that dopamine plays a role in the regulation of insulin secretion in horses, as it does in other species, whereby the post-prandial release of dopamine into the circulation may inhibit pancreatic insulin secretion. Further studies are required to evaluate different dosing protocols for AMPT, and to further investigate the links between PPID, ID and laminitis risk in horses.

Female Specific Restrictive Cardiomyopathy and Metabolic Dysregulation in transgenic mice expressing a Peptide of the Amino-Terminus of GRK2.

Cardiovascular disease and heart failure are a major health challenge, with sex differences in pathophysiology and treatment responses critically influencing patient outcomes. G protein-coupled receptor (GPCR) kinase 2 (GRK2) is a pivotal regulator of cellular signaling whose elevation is a hallmark of heart failure progression. Its complex network of protein interactions impact a wide range of physiological and pathophysiological processes including cardiac function. In this study, we examined the effects of cardiac-restricted expression of an amino-terminal peptide of GRK2 (βARKnt) in female mice subjected to acute and chronic pressure overload. Our findings reveal that that βARKnt affects hypertrophy development and cardiac function differently in female mice than in males, leading to a transition to heart failure not observed in control females or βARKnt males. Notably, the βARKnt female mice exhibited baseline hypertrophy with distinct left atrial morphology, increased fibrosis, and immune cell infiltration compared to the controls, which progressed under chronic stress, indicating adverse cardiac remodeling. Furthermore, βARKnt female mice, unlike males, exhibit impaired tissue respiration following acute pressure overload and altered glucose sensitivity and insulin tolerance, highlighting significant remodeling of cardiac and systemic metabolism.

MCM proteins are up-regulated in placentas of women with reduced insulin sensitivity.

In the first trimester of pregnancy the human placenta grows rapidly, making it sensitive to changes in the intrauterine environment. To test whether exposure to an environment in utero often associated with obesity modifies placental proteome and function, we performed untargeted proteomics (LC-MS/MS) in placentas from 19 women (gestational age 35-48 days, i.e. 5+0-6+6 weeks). Maternal clinical traits (body mass index, leptin, glucose, C-peptide and insulin sensitivity) and gestational age were recorded. DNA replication and cell cycle pathways were enriched in the proteome of placentas of women with low maternal insulin sensitivity. Driving these pathways were the minichromosome maintenance (MCM) proteins MCM2, MCM3, MCM4, MCM5, MCM6 and MCM7 (MCM-complex). These proteins are part of the pre-replicative complex and participate in DNA damage repair. Indeed, MCM6 and γH2AX (DNA-damage marker) protein levels correlated in first trimester placental tissue (r = 0.514, P<0.01). MCM6 and γH2AX co-localized to nuclei of villous cytotrophoblast cells, the proliferative cell type of the placenta, suggesting increased DNA damage in this cell type. To mimic key features of the intrauterine obesogenic environment, a first trimester trophoblast cell line, i.e., ACH-3P, was exposed to high insulin (10 nM) or low oxygen tension (2.5% O2). There was a significant correlation between MCM6 and γH2AX protein levels, but these were independent of insulin or oxygen exposure. These findings show that chronic exposure in utero to reduced maternal insulin sensitivity during early pregnancy induces changes in the early first trimester placental proteome. Pathways related to DNA replication, cell cycle and DNA damage repair appear especially sensitive to such an in utero environment.