Coexistence of Hashimoto's Thyroiditis in Differentiated Thyroid Cancer: Post-Operative Monitoring of Anti-Thyroglobulin Antibodies and Assessment of Treatment Response.

INTRODUCTION: Differentiated thyroid carcinoma (DTC) is frequently found in conjunction with autoimmune thyroid disorders, particularly Hashimoto's thyroiditis (HT). This study investigates the impact of coexisting HT on the persistence of an indeterminate response to therapy due to positive anti-thyroglobulin antibodies (AbTg), measured via competitive immunoassay, in a consecutive patient series from Calabria, Southern Italy. METHODS: This retrospective longitudinal study analyzed 259 consecutive DTC patients managed at the Endocrinology Unit of Renato Dulbecco Hospital (Catanzaro, Italy) up to 2023. Patients with medullary and undifferentiated thyroid carcinoma, partial thyroidectomy, less than six months of post-operative monitoring, or missing clinical data were excluded. Demographic information, histological findings, initial tumor stage, and ATA risk category were collected. The response to therapy was assessed based on ATA guidelines. RESULTS: Among the 259 patients, 29% had coexisting HT. Patients with HT exhibited distinct characteristics: a higher proportion of females (87.0% vs. 74.7%), a shorter post-operative monitoring duration (median 3 vs. 5 years), and a higher prevalence of papillary thyroid carcinoma (PTC) (97.4% vs. 86.3%). The tumor size, lymph node involvement, and distant metastasis were similar between the groups, with patients without HT having a higher incidence of extrathyroidal tumor extension. However, the initial TNM stage and ATA risk category did not differ significantly. At the six-month follow-up, HT patients showed a higher rate of indeterminate responses, primarily due to positive AbTg. After 12 months, the response categories aligned, with decreasing AbTg levels in the HT group. After 24 months, most patients with long-term follow-up demonstrated an excellent response to DTC therapy, irrespective of HT coexistence. CONCLUSIONS: While HT does not worsen DTC prognosis, it may result in indeterminate responses. AbTg measurements in the peri-operative period should be encouraged to facilitate post-operative monitoring, emphasizing the importance of using standardized assays. Further research in larger populations with extended follow-up is needed to comprehensively understand the HT-DTC relationship.

Metformin in Gestational Diabetes Mellitus: To Use or Not to Use, That Is the Question.

In recent years, there has been a dramatic increase in the number of pregnancies complicated by gestational diabetes mellitus (GDM). GDM occurs when maternal insulin resistance develops and/or progresses during gestation, and it is not compensated by a rise in maternal insulin secretion. If not properly managed, this condition can cause serious short-term and long-term problems for both mother and child. Lifestyle changes are the first line of treatment for GDM, but if ineffective, insulin injections are the recommended pharmacological treatment choice. Some guidance authorities and scientific societies have proposed the use of metformin as an alternative pharmacological option for treating GDM, but there is not yet a unanimous consensus on this. Although the use of metformin appears to be safe for the mother, concerns remain about its long-term metabolic effects on the child that is exposed in utero to the drug, given that metformin, contrary to insulin, crosses the placenta. This review article describes the existing lines of evidence about the use of metformin in pregnancies complicated by GDM, in order to clarify its potential benefits and limits, and to help clinicians make decisions about who could benefit most from this drug treatment.

From Euglycemia to Recent Onset of Type 2 Diabetes Mellitus: A Proof-of-Concept Study on Circulating microRNA Profiling Reveals Distinct, and Early microRNA Signatures.

Background and aim-Alterations in circulating microRNA (miRNA) expression patterns are thought to be involved in the early stages of prediabetes, as well as in the progression to overt type 2 diabetes mellitus (T2D) and its vascular complications. However, most research findings are conflicting, in part due to differences in miRNA extraction and normalization methods, and in part due to differences in the study populations and their selection. This cross-sectional study seeks to find new potentially useful biomarkers to predict and/or diagnose T2D by investigating the differential expression patterns of circulating miRNAs in the serum of patients with impaired fasting glucose (IFG) and new-onset T2D, with respect to euglycemic controls, using a high-throughput 384-well array and real-time PCR. Methods-Thirty subjects, aged 45-65 years, classified into three matched groups (of 10 participants each) according to their glycometabolic status, namely (1) healthy euglycemic controls, (2) patients with IFG and (3) patients with new-onset, uncomplicated T2D (<2 years since diagnosis) were enrolled. Circulating miRNAs were extracted from blood serum and profiled through real-time PCR on a commercial 384 well-array, containing spotted forward primers for 372 miRNAs. Data analysis was performed by using the online data analysis software GeneGlobe and normalized by the global Ct mean method. Results-Of the 372 analyzed miRNAs, 33 showed a considerably different expression in IFG and new-onset T2D compared to healthy euglycemic controls, with 2 of them down-regulated and 31 up-regulated. Stringent analysis conditions, using a differential fold regulation threshold ≥ 10, revealed that nine miRNAs (hsa-miR-3610, hsa-miR-3200-5p, hsa-miR-4651, hsa-miR-3135b, hsa-miR-1281, hsa-miR-4301, hsa-miR-195-5p, hsa-miR-523-5p and hsa-let-7a-5p) showed a specific increase in new-onset T2D patients compared to IFG patients, suggesting their possible role as early biomarkers of progression from prediabetes to T2D. Moreover, by conventional fold regulation thresholds of ±2, hsa-miR-146a-5p was down-regulated and miR-1225-3p up-regulated in new-onset T2D patients only. Whereas hsa-miR-146a-5p has a well-known role in glucose metabolism, insulin resistance and T2D complications, no association between hsa-miR-1225-3p and T2D has been previously reported. Bioinformatic and computational analysis predict a role of hsa-miR-1225-3p in the pathogenesis of T2D through the interaction with MAP3K1 and HMGA1. Conclusions-The outcomes of this study could aid in the identification and characterization of circulating miRNAs as potential novel biomarkers for the early diagnosis of T2D and may serve as a proof-of-concept for future mechanistic investigations.

The anticancer effects of Metformin in the male germ tumor SEM-1 cell line are mediated by HMGA1.

Introduction: Germ cell tumors (GCTs) are the most common type of cancer in young men. These tumors usually originate from the testis, but they can occasionally develop from extragonadal sites probably due to primordial germ cells (PGCs) migration errors. Cisplatin-based chemotherapy is usually effective for male GCTs, but the risk of toxicity is high and new therapeutic strategies are needed. Although Metformin (Met) has been widely studied as a potential cancer treatment over the past decades, there is limited evidence to support its use in treating male GCTs. Additionally, the mechanism by which it acts on tumor cells is still not entirely understood. Methods: SEM-1 cells, a newly established human cell line of extragonadal origin, were treated with Met. Cell viability was studied by MTT assay, while cell migration and invasion were studied by the wound healing assay and the transwell assay, respectively. The effect of Met on 3D spheroid formation was determined by seeding SEM-1 cells in appropriate cell suspension culture conditions, and cell cycle was characterized by flow cytometry. Factors involved in PGCs migration and GCT invasion, such as IGFBP1, IGF1R, MMP-11 and c-Kit, together with cyclin D1 (a key regulator of cell cycle progression), and the upstream factor, HMGA1, were determined by immunoblots. Results: Treatment of SEM-1 cells with Met resulted in a potent and dose-dependent reduction of cell proliferation, as evidenced by decreased nuclear abundance of cyclin D1 and cell cycle arrest in G1 phase. Also, Met prevented the formation of 3D spheroids, and blocked cell migration and invasion by reducing the expression of IGFBP1, IGF1R and MMP-11. Both, IGFBP1 and MMP-11 are under control of HMGA1, a chromatin-associated protein that is involved in the regulation of important oncogenic, metabolic and embryological processes. Intriguingly, an early reduction in the nuclear abundance of HMGA1 occurred in SEM-1 cells treated with Met. Conclusions: Our results document the antiproliferative and antimigratory effects of Met in SEM-1 cells, providing new insights into the potential treatments for male GCTs. The anticancer properties of Met in SEM-1 cells are likely related to its ability to interfere with HMGA1 and downstream targets, including cyclin D1, the IGFs system, and MMP-11.

Predicting the response to SGLT-2 inhibitors as add-on therapy to multiple day injection insulin with glycated albumin: a pilot study.

BACKGROUND: Achieving optimal glycemic targets is the main therapeutic goal in patients with type 2 diabetes (T2D) mellitus. HbA1c is the reference biomarker for monitoring glycemic control; however, in specific conditions affecting erythrocyte turnover or in patients on multiple daily injection (MDI) insulin regimens, the determination of glycated albumin (GA) may be preferable. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors represent a novel class of antidiabetic drugs that lower plasma glucose concentrations quickly, with insulin-independent mechanisms. Herein, we explored the role of GA in predicting the short-term response to SGLT-2 inhibitors as add-on to MDI insulin. METHODS: Sixteen patients with long-standing, poorly controlled T2D on MDI insulin starting an SGLT-2 inhibitor were subjected to plasma GA and HbA1c measurements at 30 days intervals for up to 3 months in order to examine the temporal changes of these glycemic biomarkers. RESULTS: At the end of the study, grossly coincident with the life span of erythrocytes, a significant decrease in median HbA1c was observed, (from 8.7 [range: 8.2-9.3%] at baseline to 7.2 [range: 7.0-7.9%]), with the advantage of less insulin dose requirements. However, significant, and incremental reductions in median GA determinations could be already evident after 30 days (-3.5 [range: -7.5, -2.5%]) and 60 days (-6.4 [range: -10.5, -4.7%]) from the start of SGLT-2 inhibitor treatment and persisted for up to 3 months (-8.6 [range: -12.1, 6.1%]). The decrements of HbA1c observed at the 3-month visit were highly correlated with the concurrent absolute reductions of plasma GA (ρ=0.550, P=0.027), whereas a borderline significance could be demonstrated with reference to reductions in plasma GA at 30 and 60 days. CONCLUSIONS: Although limited by the small number of participants, these preliminary findings suggest that GA, rather than HbA1c, could represent a useful and reliable biomarker in T2D to monitor the early glucose-lowering effects of antidiabetic drugs with rapid onset of action, such as SGLT-2 inhibitors and MDI insulin.

Obesity-related hypoxia via miR-128 decreases insulin-receptor expression in human and mouse adipose tissue promoting systemic insulin resistance.

BACKGROUND: Insulin resistance in visceral adipose tissue (VAT), skeletal muscle and liver is a prominent feature of most patients with obesity. How this association arises remains poorly understood. The objective of this study was to demonstrate that the decrease in insulin receptor (INSR) expression and insulin signaling in VAT from obese individuals is an early molecular manifestation that might play a crucial role in the cascade of events leading to systemic insulin resistance. METHODS: To clarify the role of INSR and insulin signaling in adipose tissue dysfunction in obesity, we first measured INSR expression in VAT samples from normal-weight subjects and patients with different degrees of obesity. We complemented these studies with experiments on high-fat diet (HFD)-induced obese mice, and in human and murine adipocyte cultures, in both normoxic and hypoxic conditions. FINDINGS: An inverse correlation was observed between increasing body mass index and decreasing INSR expression in VAT of obese humans. Our results indicate that VAT-specific downregulation of INSR is an early event in obesity-related adipose cell dysfunction, which increases systemic insulin resistance in both obese humans and mice. We also provide evidence that obesity-related hypoxia in VAT plays a determinant role in this scenario by decreasing INSR mRNA stability. This decreased stability is through the activation of a miRNA (miR-128) that downregulates INSR expression in adipocytes. INTERPRETATION: We present a novel pathogenic mechanism of reduced INSR expression and insulin signaling in adipocytes. Our data provide a new explanation linking obesity with systemic insulin resistance. FUNDING: This work was partly supported by a grant from Nutramed (PON 03PE000_78_1) and by the European Commission (FESR FSE 2014-2020 and Regione Calabria).

MicroRNA-1281 as a Novel Circulating Biomarker in Patients With Diabetic Retinopathy.

Objective: Recently, the role of circulating miRNAs as non-invasive biomarkers for the identification and monitoring of diabetes microvascular complications has emerged. Herein, we aimed to: identify circulating miRNAs differentially expressed in patients with and without diabetic retinopathy (DR); examine their predictive value; and understand their pathogenic impact. Methods: Pooled serum samples from randomly selected matched patients with type 2 diabetes, either with or without DR, were used for initial serum miRNA profiling. Validation of the most relevant miRNAs was thereafter conducted by RT-qPCR in an extended sample of patients with DR and matched controls. Results: Following miRNA profiling, 43 miRNAs were significantly up- or down-regulated in patients with DR compared with controls. After individual validation, 5 miRNAs were found significantly overexpressed in patients with DR. One of them, miR-1281, was the most up-regulated and appeared to be specifically related to DR. Furthermore, secreted levels of miR-1281 were increased in high glucose-cultured retinal cells, and there was evidence of a potential link between glucose-induced miR-1281 up-regulation and DR. Conclusion: Our findings suggest miR-1281 as a circulating biomarker of DR. Also, they highlight the pathogenic significance of miR-1281, providing insights for a new potential target in treating DR.

Laboratory Parameters of Hemostasis, Adhesion Molecules, and Inflammation in Type 2 Diabetes Mellitus: Correlation with Glycemic Control.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by a prothrombotic state, predisposing to vascular complications. Some related markers, linking thrombophilia to hemostasis and inflammation, however, have been poorly explored in relation to patients' glycemia. We therefore investigated the association of laboratory hemostatic parameters, circulating adhesion molecules (ADMs), white blood cell (WBC) count, and neutrophil/lymphocyte ratio (NLR) with T2DM and glycemic control. RESEARCH DESIGN: In this study, 82 subjects, grouped into T2DM patients (n = 41) and healthy individuals (n = 41) were enrolled. To evaluate glycemic control, the T2DM cohort was expanded to 133 patients and sub-classified according to glycated hemoglobin (HbA1c) <7% and ≥ 7% (n = 58 and n = 75, respectively). We assessed glycemia, HbA1c, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, plasminogen activator inhibitor-1 (PAI-1), platelet and leukocyte parameters, vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and selectins (E-, P-, L-). RESULTS: PT % activity, PAI-1, VCAM-1, WBC, and neutrophil counts were significantly higher in T2DM patients than in healthy subjects. Poor glycemic control (HbA1c ≥ 7%) was correlated with increased PT activity (p = 0.015), and higher levels of E-selectin (p = 0.009), P-selectin (p = 0.012), and NLR (p = 0.019). CONCLUSIONS: Both T2DM and poor glycemic control affect some parameters of hemostasis, inflammation, and adhesion molecules. Further studies are needed to establish their clinical utility as adjuvant markers for cardio-vascular risk in T2DM patients.

First Trimester Combined Test (FTCT) as a Predictor of Gestational Diabetes Mellitus.

Background-The first trimester combined test (FTCT) is an effective screening tool to estimate the risk of fetal aneuploidy. It is obtained by the combination of maternal age, ultrasound fetal nuchal translucency (NT) measurement, and the maternal serum markers free ß-human chorionic gonadotropin (ß-hCG) and pregnancy-associated plasma protein A (PAPP-A). However, conflicting data have been reported about the association of FTCT, ß-hCG, or PAPP-A with the subsequent diagnosis of gestational diabetes mellitus (GDM). Research design and methods-2410 consecutive singleton pregnant women were retrospectively enrolled in Calabria, Southern Italy. All participants underwent examinations for FTCT at 11-13 weeks (plus 6 days) of gestation, and screening for GDM at 16-18 and/or 24-28 weeks of gestation, in accordance with current Italian guidelines and the International Association Diabetes Pregnancy Study Groups (IADPSG) glycemic cut-offs. Data were examined by univariate and logistic regression analyses. Results-1814 (75.3%) pregnant women were normal glucose tolerant, while 596 (24.7%) were diagnosed with GDM. Spearman univariate analysis demonstrated a correlation between FTCT values and subsequent GDM diagnosis (ρ = 0.048, p = 0.018). The logistic regression analysis showed that women with a FTCT <1:10000 had a major GDM risk (p = 0.016), similar to women with a PAPP-A <1 multiple of the expected normal median (MoM, p = 0.014). Conversely, women with ß-hCG ≥2.0 MoM had a reduced risk of GDM (p = 0.014). Conclusions-Our findings indicate that GDM susceptibility increases with fetal aneuploidy risk, and that FTCT and its related maternal serum parameters can be used as early predictors of GDM.

Cell-line characterization by infrared-induced pyroelectric effect.

Evaluation of cellular thermodynamics has recently received a high interest because of its implication in many mechanisms related with function, structure and health of cells. Recent literature reported significant efforts to provide affordable intracellular thermal components of absorption, such as thermal conductivity, to overcome the lack of experimental data. Herein, we provide lines of evidence towards the fabrication of an electronic system, using a rapid thermoelectric technique based on infrared-induced pyroelectric effect for in-vitro cell model characterization. Results demonstrated that the assessment of the average single cell thermal conductivity, sample concentration, and information on cell viability is possible over a wide concentration range. The proposed electronic system establishes a different analysis paradigm if compared to those reported in the literature, with consistent results, demonstrating that the adopted technique can provide cell-specific information and knowledge, closely linked to cell viability and its vital functions.

Barriers to Postpartum Glucose Intolerance Screening in an Italian Population.

Background: Gestational diabetes mellitus (GDM) is a strong risk factor for type 2 diabetes mellitus (T2D) and the postpartum period is crucial for early treatment in at-risk women. However, despite recommendations, only a fraction of women undergo a postpartum screening for glucose intolerance (ppOGTT). The present study aims to verify the reason(s) for poor adherence in our population. Research design and methods: This retrospective study includes 451 women in which GDM was diagnosed between 2015⁻2016. During 2017, we verified by phone interview how many women underwent ppOGTT at 6⁻12 weeks postpartum, as recommended by the Italian guidelines. The non-compliant women were asked about the reason(s) for failing to screen. The non-parametric Mann-Whitney test and the 2-tailed Fisher exact test were used to compare continuous and categorical features, respectively, among women performing or non-performing ppOGTT. Results: Out of 451 women with GDM diagnosis, we recorded information from 327. Only 97 (29.7%) performed ppOGTT. The remaining 230 women (70.3%) provided the following explanation for non-compliance: (1) newborn care (30.4%); (2) misunderstood importance (28.3%); (3) oversight (13.0%); (4) unavailability of test reservation in the nearest centers (10.4%); (5) normal glycemic values at delivery (8.3%); (6) discouragement by primary care physician (5.6%). Conclusions: In our population, most women with recent GDM failed to perform ppOGTT. Our results indicated that the prominent barriers could potentially be overcome.

Transcriptional Regulation of Glucose Metabolism: The Emerging Role of the HMGA1 Chromatin Factor.

HMGA1 (high mobility group A1) is a nonhistone architectural chromosomal protein that functions mainly as a dynamic regulator of chromatin structure and gene transcription. As such, HMGA1 is involved in a variety of fundamental cellular processes, including gene expression, epigenetic regulation, cell differentiation and proliferation, as well as DNA repair. In the last years, many reports have demonstrated a role of HMGA1 in the transcriptional regulation of several genes implicated in glucose homeostasis. Initially, it was proved that HMGA1 is essential for normal expression of the insulin receptor (INSR), a critical link in insulin action and glucose homeostasis. Later, it was demonstrated that HMGA1 is also a downstream nuclear target of the INSR signaling pathway, representing a novel mediator of insulin action and function at this level. Moreover, other observations have indicated the role of HMGA1 as a positive modulator of the Forkhead box protein O1 (FoxO1), a master regulatory factor for gluconeogenesis and glycogenolysis, as well as a positive regulator of the expression of insulin and of a series of circulating proteins that are involved in glucose counterregulation, such as the insulin growth factor binding protein 1 (IGFBP1), and the retinol binding protein 4 (RBP4). Thus, several lines of evidence underscore the importance of HMGA1 in the regulation of glucose production and disposal. Consistently, lack of HMGA1 causes insulin resistance and diabetes in humans and mice, while variations in the HMGA1 gene are associated with the risk of type 2 diabetes and metabolic syndrome, two highly prevalent diseases that share insulin resistance as a common pathogenetic mechanism. This review intends to give an overview about our current knowledge on the role of HMGA1 in glucose metabolism. Although research in this field is ongoing, many aspects still remain elusive. Future directions to improve our insights into the pathophysiology of glucose homeostasis may include epigenetic studies and the use of "omics" strategies. We believe that a more comprehensive understanding of HMGA1 and its networks may reveal interesting molecular links between glucose metabolism and other biological processes, such as cell proliferation and differentiation.

Type 2 Diabetes Mellitus and Cardiovascular Disease: Genetic and Epigenetic Links.

Type 2 diabetes mellitus (DM) is a common metabolic disorder predisposing to diabetic cardiomyopathy and atherosclerotic cardiovascular disease (CVD), which could lead to heart failure through a variety of mechanisms, including myocardial infarction and chronic pressure overload. Pathogenetic mechanisms, mainly linked to hyperglycemia and chronic sustained hyperinsulinemia, include changes in metabolic profiles, intracellular signaling pathways, energy production, redox status, increased susceptibility to ischemia, and extracellular matrix remodeling. The close relationship between type 2 DM and CVD has led to the common soil hypothesis, postulating that both conditions share common genetic and environmental factors influencing this association. However, although the common risk factors of both CVD and type 2 DM, such as obesity, insulin resistance, dyslipidemia, inflammation, and thrombophilia, can be identified in the majority of affected patients, less is known about how these factors influence both conditions, so that efforts are still needed for a more comprehensive understanding of this relationship. The genetic, epigenetic, and environmental backgrounds of both type 2 DM and CVD have been more recently studied and updated. However, the underlying pathogenetic mechanisms have seldom been investigated within the broader shared background, but rather studied in the specific context of type 2 DM or CVD, separately. As the precise pathophysiological links between type 2 DM and CVD are not entirely understood and many aspects still require elucidation, an integrated description of the genetic, epigenetic, and environmental influences involved in the concomitant development of both diseases is of paramount importance to shed new light on the interlinks between type 2 DM and CVD. This review addresses the current knowledge of overlapping genetic and epigenetic aspects in type 2 DM and CVD, including microRNAs and long non-coding RNAs, whose abnormal regulation has been implicated in both disease conditions, either etiologically or as cause for their progression. Understanding the links between these disorders may help to drive future research toward an integrated pathophysiological approach and to provide future directions in the field.

Secretome Analysis of Hypoxia-Induced 3T3-L1 Adipocytes Uncovers Novel Proteins Potentially Involved in Obesity.

In the obese state, as adipose tissue expands, adipocytes become hypoxic and dysfunctional, leading to changes in the pattern of adipocyte-secreted proteins. To better understand the role of hypoxia in the mechanisms linked to obesity, we comparatively analyzed the secretome of murine differentiated 3T3-L1 adipocytes exposed to normoxia or hypoxia for 24 h. Proteins secreted into the culture media were precipitated by trichloroacetic acid and then digested with trypsin. The peptides were labeled with dimethyl labeling and analyzed by reversed phase nanoscale liquid chromatography coupled to a quadrupole Orbitrap mass spectrometer. From a total of 1508 identified proteins, 109 were differentially regulated, of which 108 were genuinely secreted. Factors significantly downregulated in hypoxic conditions included adiponectin, a known adipokine implicated in metabolic processes, as well as thrombospondin-1 and -2, and matrix metalloproteinase-11, all multifunctional proteins involved in extracellular matrix (ECM) homeostasis. Findings were validated by Western blot analysis. Expression studies of the relative genes were performed in parallel experiments in vitro, in differentiated 3T3-L1 adipocytes, and in vivo, in fat tissues from obese versus lean mice. Our observations are compatible with the concept that hypoxia may be an early trigger for both adipose cell dysfunction and ECM remodeling.

Insulin and osteocalcin: further evidence for a mutual cross-talk.

PURPOSE: In the last few years, bone has been recognized as an endocrine organ that modulates glucose metabolism by secretion of osteocalcin, an osteoblast-specific hormone, that influences fat deposition and blood sugar levels. To date, however, very few in vitro models have been developed to investigate, at the molecular levels, the relationship between glucose, insulin and osteocalcin. This study aims at covering this gap. METHODS: We studied osteogenic differentiation, osteocalcin gene expression, and osteblast-mediated insulin secretion, using cultured MG-63 human osteoblast-like cells that underwent glucotoxicity and insulin resistance. In addition, we investigated whether a correlation existed between hyperglycemia and/or insulin resistance and total osteocalcin serum concentrations in patients. RESULTS: While insulin and low glucose increased osteocalcin gene expression, disruption of insulin signaling in MG-63 osteoblasts and high glucose concentration in cell culture medium decreased osteocalcin gene transcription and reduced osteogenic differentiation. Concomitantly, insulin secretion was significantly impaired in rat INS-1 ß-cells treated with conditioned medium from insulin resistant MG-63 cells or cells exposed to high glucose concentrations. Also, chronic hyperglycemia, but not insulin resistance, inversely correlated with circulating osteocalcin levels in patients. CONCLUSION: Our results further support the existence of an endocrine axis between bone, where osteocalcin is produced, and pancreatic ß-cells, and add new insights into the molecular details of this relationship. These findings may contribute to the understanding of osteocalcin regulation and its role in metabolism.

Correction to: Insulin and osteocalcin: further evidence for a mutual cross-talk.

Correction to: Endocrine https://doi.org/10.1007/s12020-017-1396-0 The article Insulin and osteocalcin: further evidence for a mutual cross-talk, written by Francesco L. Bilotta, Biagio Arcidiacono, Sebastiano Messineo, Marta Greco, Eusebio Chiefari, Domenico Britti, Tomoko Nakanishi, Daniela P. Foti, Antonio Brunetti, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 2 September 2017 without open access.

HMGA1 is a novel transcriptional regulator of the FoxO1 gene.

PURPOSE: The forkhead transcription factor (FoxO1) is a master transcriptional regulator of fundamental cellular processes ranging from cell proliferation and differentiation to inflammation and metabolism. However, despite its relevance, the mechanism(s) underlying FoxO1 gene regulation are largely unknown. We have previously shown that the chromatin factor high-mobility group A1 (HMGA1) plays a key role in the transcriptional regulation of glucose-responsive genes, including some that are involved in FoxO1-mediated glucose metabolism. Here we investigated the impact of HMGA1 on FoxO1 gene expression. METHODS: FoxO1 protein and gene expression studies were performed by Western blot analysis combined with qRT-PCR of material from human cultured cells and EBV-transformed lymphoblasts, and from primary cultured hepatocytes from wild-type and Hmga1 -/- mice. Reporter gene assays and chromatin immunoprecipitation for binding of HMGA1 to the endogenous FoxoO1 locus were performed in cells overexpressing HMGA1 and in cells pretreated with siRNA targeting HMGA1. RESULTS: HMGA1 increased FoxO1 mRNA and protein expression in vitro, in cultured HepG2 and HEK-293 cells by binding FoxO1 gene promoter, thereby activating FoxO1 gene transcription. Forced expression of HMGA1 in primary cultured hepatocytes from Hmga1 -/- mice and in EBV-transformed lymphoblasts from subjects with reduced expression of endogenous HMGA1 increased FoxO1 mRNA and protein levels. CONCLUSION: These findings may contribute to the understanding of FoxO1 gene regulation and its role in metabolism.

Impact of Seasonality on Gestational Diabetes Mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) is a major health concern that seems to be influenced by seasonality. OBJECTIVE: To assess the impact of seasonality on the incidence of GDM in an Italian population. METHOD: This is a retrospective cohort study of 5,473 pregnant women attending the Operative Unit of Diabetes, who underwent GDM screening by means of the 75-g oral glucose tolerance test (OGTT), during the period from August 2011 to December 2016. Screening was performed at 16-18 or 24-28 weeks&apos; gestation, following the Health Italian Minister guidelines. All blood samples were undertaken in the Hospital itself, under the same temperature conditions, and analyzed in the nearby biochemical laboratory. Statistical analysis was performed by SPSS software. RESULTS: 1,559 of 5,473 enrolled women (28.5%) were affected by GDM. The incidence of GDM was significantly higher during the summer season (33.7%) (P<0.001), and significantly lower during the winter (23.3%), compared with spring (P=0.035) and fall seasons (P=0.002). When the year was divided on a 24-hr temperature basis into two parts only, the warm half and the cold half, GDM was considerably lower in cold months compared to warm ones (P<0.0001). No difference was observed between the medians of fasting glycemia throughout the four seasons; instead, serum glucose levels at 1-h and 2-h after OGTT were higher in summer than in spring, autumn and winter. Results from multiple linear regression analysis supported the hypothesis that glucose levels at 1-h and 2-h following OGTT could be influenced by ambient temperature. CONCLUSION: Our data indicate that seasonal changes may influence variations in glucose tolerance during pregnancy, with GDM incidence increasing during the summer and declining during cold months.

Effects of acute physical exercise on oxidative stress and inflammatory status in young, sedentary obese subjects.

Circulating oxidative stress and pro-inflammatory markers change after regular physical exercise; however, how a short session of acute physical activity affects the inflammatory status and redox balance in sedentary individuals is still unclear. Aim of this study is to assess antioxidant and inflammatory parameters, both at rest and after acute exercise, in sedentary young men with or without obesity. Thirty sedentary male volunteers, aged 20-45 (mean age 32 ± 7 years), were recruited, divided into 3 groups (normal weight: BMI < 25 kg/m2; overweight to moderate obesity: 25-35 kg/m2; severe obesity: 35-40 kg/m2), and their blood samples collected before and after a 20-min run at ~ 70% of their VO2max for the measurement of Glutathione Reductase, Glutathione Peroxidase, Superoxide Dismutase, Total Antioxidant Status (TAS) and cytokines (IL-2, IL-4, IL-6, IL-8, IL-10, IL-1α, IL-1ß, TNFα, MCP-1, VEGF, IFNγ, EGF). Inter-group comparisons demonstrated significantly higher Glutathione Reductase activity in severely obese subjects in the post-exercise period (P = 0.036), and higher EGF levels in normal weight individuals, either before (P = 0.003) and after exercise (P = 0.05). Intra-group comparisons showed that the acute exercise stress induced a significant increase in Glutathione Reductase activity in severely obese subjects only (P = 0.007), a significant decrease in MCP-1 in the normal weight group (P = 0.02), and a decrease in EGF levels in all groups (normal weight: P = 0.025, overweight/moderate obesity: P = 0.04, severe obesity: P = 0.018). Altogether, these findings suggest that in sedentary individuals with different ranges of BMI, Glutathione Reductase and distinct cytokines are differentially involved into the adaptive metabolic changes and redox responses induced by physical exercise. Therefore, these biomarkers may have the potential to identify individuals at higher risk for developing diseases pathophysiologically linked to oxidative stress.