Fetal insulin and IGF-II contribute to gestational diabetes mellitus (GDM) - associated up-regolation of membrane-type matrix metalloproteinase 1 (MT1-MMP) in the human feto placental endothelium

CONTEXT: Gestational diabetes mellitus (GDM)-associated hormonal and metabolic derangements in mother and fetus affect placental development and function. Indeed, in GDM, placentas are characterized by hypervascularization and vascular dysfunction. The membrane-type matrix metalloproteinase 1 (MT1-MMP) is a key player in angiogenesis and vascular expansion. OBJECTIVE: Here, we hypothesized elevated placental MT1-MMP levels in GDM induced by components of the diabetic environment. Therefore, we measured placental MT1-MMP in normal vs. GDM pregnancies, identified potential functional consequences, and investigated the contribution of hyperglycemia and the insulin/IGF axis. DESIGN: Immunohistochemistry identified placental cell types expressing MT1-MMP. MT1-MMP was compared between normal and GDM placentas by immunoblotting. Quantitative PCR of MT1-MMP in primary feto-placental endothelial cells (fpEC) and trophoblasts isolated from both normal and GDM placentas identified the cells contributing to the GDM-associated changes. A putative MT1-MMP role in angiogenesis was determined using blocking antibodies for in vitro angiogenesis assays. Potential GDM-associated factors and signaling pathways inducing MT1-MMP up-regulation in fpEC were identified using kinase inhibitors. RESULTS: Total and active MT1-MMP was increased in GDM placentas (+51 and 54%, respectively, P<0.05) as a result of up-regulated expression in fpEC (2.1-fold, P=0.02). MT1-MMP blocking antibodies reduced in vitro angiogenesis up to 25% (P=0.03). Pathophysiological levels of insulin and IGF-II, but not IGF-I and glucose, stimulated MT1-MMP expression in fpEC by phosphatidylinositol 3-kinase signals relayed through the insulin, but not IGF-I, receptor. CONCLUSIONS: GDM up-regulates MT1-MMP in the feto-placental endothelium, and insulin and IGF-II contribute. This may account for GDM-associated changes in the feto-placental vasculature

Intrauterine growth restriction is associated with alterations in placental lipoprotein receptors and maternal lipoprotein composition

Among other factors, fetal growth requires maternal supply of cholesterol. Cellular cholesterol uptake is mainly mediated by the LDL receptor (LDL-R) and the scavenger receptor family. We hypothesized that expression levels of key receptors of these families were regulated differently in placentas from IUGR pregnancies with varying degrees of severity. Third-trimester placentas from IUGR pregnancies with (IUGR-S) and without (IUGR-M) fetal hemodynamic changes and from control (AGA) pregnancies were studied. LDL-R, LDL-Rrelated protein (LRP-1), and scavenger receptor class B type I (SR-BI) mRNA and protein levels were measured. Cholesterol concentration and composition of lipoproteins were analyzed enzymatically and by lipid electrophoresis, respectively, in maternal and umbilical cord blood. LDL-R mRNA levels in IUGR-M were similar to AGA but lower (P ! 0.05) in IUGR-S. In contrast, LDL-R protein was twofold (IUGR-M) and 1.8-fold (IUGR-S) higher (P ! 0.05) than in the AGA group. LRP-1 mRNA and protein levels were not altered in the IUGR cases. SR-BI mRNA was unchanged in IUGR, but protein levels were lower (P ! 0.05) in IUGR-S than in the other groups. Maternal plasma concentrations of LDL cholesterol were higher (P ! 0.05) in the AGA group (188.5 " 23.6 mg/dl) than in the IUGR-S group (154.2 " 26.1). Electrophoretic mobility of the LDL fraction in maternal plasma demonstrated significant changes in migration toward higher values (AGA 0.95 " 0.06, IUGR-M 1.12 " 0.11, P ! 0.001; IUGR-S 1.28 " 0.20, P # 0.002). We conclude that LDL-R and SR-BI levels are altered in IUGR pregnancies. These differences were associated with changes in LDL, but not HDL, mobility and cholesterol concentration in maternal circulation

Correction to: Assessing real-world gait with digital technology? Validation, insights and recommendations from the Mobilise-D consortium (<em>Journal of NeuroEngineering and Rehabilitation</em>, (2023), 20, 1, (78), 10.1186/s12984-023-01198-5)

\ua9 The Author(s) 2024.Following publication of the original article [1], the author noticed the errors in Table 1, and in Discussion section. In Table 1 under Metric (Gait sequence detection) column, the algorithms GSDB was updated with wrong description, input, output, language and citation and GSDc with wrong description has been corrected as shown below: (Table presented.) Description of algorithms for each metric: gait sequence detection (GSD), initial contact event detection (ICD), cadence estimation (CAD) and stride length estimation (SL) Metric Name Description Input Output Language References GSDA Based on a frequency-based approach, this algorithm is implemented on the vertical and anterior–posterior acceleration signals. First, these are band pass filtered to keep frequencies between 0.5 and 3 Hz. Next, a convolution of a 2 Hz sinewave (representing a template for a gait cycle) is performed, from which local maxima will be detected to define the regions of gait acc_v: vertical acceleration acc_ap: anterior–posterior acceleration WinS = 3 s; window size for convolution OL = 1.5 s; overlap of windows Activity_thresh = 0.01; Motion threshold Fs: sampling frequency Start: beginning of N gait sequences [s] relative to the start of a recording or a test/trial. Format: 1 7 N vector End: termination of N gait sequences [s] relative to the start of a recording or a test/trial. Format: 1 7 N vector Matlab\uae Iluz, Gazit [40] GSDB This algorithm, based on a time domain-approach, detects the gait periods based on identified steps. First, the norm of triaxial acceleration signal is low-pass filtered (FIR, fc = 3.2 Hz), then a peak detection procedure using a threshold of 0.1 [g] is applied to identify steps. Consecutive steps, detected using an adaptive step duration threshold are associated to gait sequences acc_norm: norm of the 3D-accelerometer signal Fs: sampling frequency th: peak detection threshold: 0.1 (g) Start: beginning of N gait sequences [s] relative to the start of a recording or a test/trial. Format: 1 7 N vector End: termination of N gait sequences [s] relative to the start of a recording or a test/trial. Format: 1 7 N vector Matlab\uae Paraschiv-Ionescu, Newman [41] GSDc This algorithm utilizes the same approach as GSDBthe only difference being a different threshold for peak detection of 0.15 [g] acc_norm: norm of the 3D-accelerometer signal Fs: sampling frequency th: peak detection threshold: 0.15 (g) Start: beginning of N gait sequences [s] relative to the start of a recording or a test/trial. Format: 1 7 N vector End: termination of N gait sequences [s] relative to the start of a recording or a test/trial. Format: 1 7 N vector Matlab\uae Paraschiv-Ionescu, Newman [41] In Discussion section, the paragraph should read as "Based on our findings collectively, we recommend using GSDB on cohorts with slower gait speeds and substantial gait impairments (e.g., proximal femoral fracture). This may be because this algorithm is based on the acceleration norm (overall accelerometry signal rather than a specific axis/direction (e.g., vertical), hence it is more robust to sensor misalignments that are common in unsupervised real-life settings. Moreover, the use of adaptive threshold, that are derived from the features of a subject’s data and applied to step duration for detection of steps belonging to gait sequences, allows increased robustness of the algorithm to irregular and unstable gait patterns" instead of “Based on our findings collectively, we recommend using GSDB on cohorts with slower gait speeds and substantial gait impairments (e.g., proximal femoral fracture). This may be because this algorithm is based on the acceleration norm (overall accelerometry signal rather than a specific axis/direction (e.g., vertical), hence it is more robust to sensor misalignments that are common in unsupervised real-life settings [41]. Moreover, the use of adaptive thresholds, that are derived from the features of a subject’s data and applied to the amplitude of acceleration norm and to step duration for detection of steps belonging to gait sequences, allows increased robustness of the algorithm to irregular and unstable gait patterns”

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

IGF2 stimulates fetal growth in a sex- and organ-dependent manner

BackgroundInsulin-like growth factor 2 (IGF2) is a key determinant of fetal growth, and the altered expression of IGF2 is implicated in fetal growth disorders and maternal metabolic derangements including gestational diabetes. Here we studied how increased levels of IGF2 in late pregnancy affect fetal growth.MethodsWe employed a rat model of repeated intrafetal IGF2 administration in late pregnancy, i.e., during GD19-GD21, and measured the consequences on fetal organ weight and expression of insulin/IGF-axis components.ResultsIGF2 treatment tended to increase fetal weight, but only weight increase of the fetal stomach reached significance (+33±9%; P<0.01). Sex-dependent data analysis revealed a sexual dimorphism of IGF2 action. In male fetuses, IGF2 administration significantly increased fetal weight (+13±3%; P<0.05) and weight of fetal stomach (+42±10%; P<0.01), intestine (+26±5%; P<0.05), liver (+13±4%; P<0.05), and pancreas (+25±8%; P<0.05). Weights of heart, lungs, and kidneys were unchanged. In female fetuses, IGF2 increased only stomach weight (+26±9%; P<0.05). Furthermore, gene expression of insulin/IGF axis in the heart, lungs, liver, and stomach was more sensitive toward IGF2 treatment in male than in female fetuses.ConclusionData suggest that elevated circulating IGF2 in late pregnancy predominantly stimulates organ growth of the digestive system, and male fetuses are more susceptible toward the IGF2 effects than female fetuses.Fil: White, Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Jawerbaum, Alicia Sandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Mazzucco, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Gauster, Martin. Medizinische Universität Graz; AustriaFil: Desoye, Gernot. Medizinische Universität Graz; AustriaFil: Hiden, Ursula. Medizinische Universität Graz; Austri

The Transcriptional Response in Human Umbilical Vein Endothelial Cells Exposed to Insulin: A Dynamic Gene Expression Approach

BACKGROUND: In diabetes chronic hyperinsulinemia contributes to the instability of the atherosclerotic plaque and stimulates cellular proliferation through the activation of the MAP kinases, which in turn regulate cellular proliferation. However, it is not known whether insulin itself could increase the transcription of specific genes for cellular proliferation in the endothelium. Hence, the characterization of transcriptional modifications in endothelium is an important step for a better understanding of the mechanism of insulin action and the relationship between endothelial cell dysfunction and insulin resistance. METHODOLOGY AND PRINCIPAL FINDINGS: The transcriptional response of endothelial cells in the 440 minutes following insulin stimulation was monitored using microarrays and compared to a control condition. About 1700 genes were selected as differentially expressed based on their treated minus control profile, thus allowing the detection of even small but systematic changes in gene expression. Genes were clustered in 7 groups according to their time expression profile and classified into 15 functional categories that can support the biological effects of insulin, based on Gene Ontology enrichment analysis. In terms of endothelial function, the most prominent processes affected were NADH dehydrogenase activity, N-terminal myristoylation domain binding, nitric-oxide synthase regulator activity and growth factor binding. Pathway-based enrichment analysis revealed "Electron Transport Chain" significantly enriched. Results were validated on genes belonging to "Electron Transport Chain" pathway, using quantitative RT-PCR. CONCLUSIONS: As far as we know, this is the first systematic study in the literature monitoring transcriptional response to insulin in endothelial cells, in a time series microarray experiment. Since chronic hyperinsulinemia contributes to the instability of the atherosclerotic plaque and stimulates cellular proliferation, some of the genes identified in the present work are potential novel candidates in diabetes complications related to endothelial dysfunction

Histopathological placental lesions in mild gestational hyperglycemic and diabetic women

Objective: To investigate and compare the incidence of histopathological placental lesions in mild gestational hyperglycemia, gestational diabetes and overt diabetes at term and preterm gestation.Research design and methods: One-hundred-and-thirty-one placental samples were collected from Diabetes mellitus (DM) positive screened patients. Two diagnostic tests, glycemic profile and 100 g oral glucose tolerance test (OGTT) in parallel identified 4 groups normoglycemic, mild gestational hyperglycemia (MGH), gestational DM (GDM) or overt DM (DM). Placental tissue specimens and sections from 4 groups were obtained by uniform random sampling and stained with hematoxylin-eosin.Results: Placentas from MGH group presented 17 types of histopathological change and higher rates of syncytial nodes and endarteritis. GDM placentas presented only nine types of histopathological change, high rates of dysmaturity, low rates of calcification and no syncytial nodes. Overt DM placentas showed 22 types of histopathological change, 21 of which were present in the preterm period. There were histopathological similarities between MGH and DM placentas, but the former exhibited a higher incidence of endarteritis, which has been described as a post-mortem phenomenon.Conclusion: Our results confirmed that the distinct placental changes associated with DM and MGH depend on gestational period during which the diabetic insult occurs. It may reasonably be inferred that subclinical maternal hyperglycemia during pregnancy, as showed in MGH group, is responsible for increased placental endarteritis, a postmortem lesion in the live fetus