Nuovi approcci molecolari nello studio della fisiopatologia del diabete gestazionale

Abstract research study 1 Cross-talk between foetal membranes and visceral adipose tissue involves HMGB1-RAGE and VIP-VPAC2 pathways in human gestational diabetes mellitus Introduction: Gestational diabetes mellitus (GDM) is defined as glucose intolerance that is first diagnosed during pregnancy. Foetal membranes (FMs) and maternal visceral adipose tissue (VAT) secrete various molecules that are relevant players in the pathogenesis of GDM. Aim: This pilot study aimed to comparatively evaluate the expression of high mobility group box 1 protein (HMGB1) and its receptor for advanced glycation end products (RAGE), and vasoactive intestinal peptide (VIP) and its receptors (VPAC1, VPAC2) in FMs and VAT in GDM and in healthy pregnant women. Patients and Methods: FMs, omental VAT explants, and serum samples were obtained from twelve patients with GDM and twelve pregnant women with normal glucose tolerance (NGT) at delivery. The expression of HMGB1, RAGE and VIP, VPAC1 and VPAC2 was detected by Western Blotting in explants; circulating levels and in vitro release of HMGB1 and VIP were measured by ELISA tests. Results: HMGB1 tissue expression was higher in FMs obtained from GDM patients (p=0.02) than in FMs from NGT women. VPAC2 (p=0.03) and RAGE (p=0.03) tissue expressions were significantly increased in VAT from GDM patients compared to NGT. Only FMs of NGT released detectable levels of HMGB1, which was not observed in samples obtained from GDM. VAT of GDM released lower levels of VIP (p=0.05) than NGT samples. Conclusions: This study suggests that a fine tuned regulation exists between FMs and VAT throughout pregnancy to maintain immune metabolic homeostasis. In GDM a balance between pro-inflammatory and anti-inflammatory mediators has been observed. Further studies are needed to establish their exact role on foetal and maternal outcomes in GDM. Abstract research study 2 MicroRNA expression profile in circulating exosomes and plasma of patients with GDM and healthy pregnant women Introduction: MicroRNAs are small non-coding RNAs, playing critical roles in modulating gene expression. The deregulation of microRNAs has been observed in GDM, highlighting their crucial involvement both in the pathogenic mechanisms of this condition and in the development of its complications. Circulating microRNAs can be packaged into exosomes, and exosome signalling has emerged as a novel mechanism of cell-to-cell communication. Through exosomes, microRNAs are delivered in distant target cells and are able to affect gene expression. Aim: The aim of this study was to explore microRNA expression in circulating exosomes and in plasma obtained from patients with GDM and healthy control subjects in the third trimester of gestation, to potentially elucidate some relevant aspects of GDM pathophysiology and individuate novel potential candidate biomarkers for GDM. Patients and Methods: A profiling cohort of plasma samples collected from GDM (n=3, age: 34.7 ± 4.9 years; BMI 27.0 ± 3.7 Kg/m2) and NGT women (n=3, age: 34.3 ± 3.1 years; BMI 26.4 ± 1.1 Kg/m2) was recruited. In addition, a profiling cohort of healthy non-pregnant age- and BMI-matched women (NP, n=5) was used as negative control. The microRNA patterns of expression in exosomes and plasma have been assessed with the innovative technology NanoString nCounter microRNA expression (NanoString Technologies inc., Seattle, WA, USA). Target gene identification and bioinformatics analysis of the differentially expressed microRNAs have been performed with Ingenuity Pathway Analysis (IPA, QIAGEN Redwood City, USA). Results: A specific set of microRNAs resulted to be differentially expressed in exosomes and plasma from GDM patients compared to NGT. Specifically, five exosomal microRNAs were significantly upregulated, while 23 were downregulated in GDM compared to NGT. As for plasma, 4 microRNA were upregulated, while 9 were downregulated in GDM compared to NGT. In addition, two microRNAs, miR-196a-5p and miR-652, resulted to be significantly downregulated in GDM compared both to NGT and NP in exosomes and plasma, respectively, suggesting that their deregulation might hallmark GDM pregnancy. In bioinformatics analysis the major predicted target genes and biological processes of the deregulated microRNAs were associated with insulin resistance, abnormal glucose and lipid metabolism, consistently linked to GDM pathophysiology. Conclusions: GDM might markedly alter microRNA profile in exosomes and plasma, conceivably mirroring the metabolic alterations described in GDM pregnancy. In light of this, exploring circulating microRNA expression might help unravel the molecular events leading to the metabolic alterations observed in GDM

Linking type 2 diabetes and gynecological cancer: An introductory overview

Type 2 diabetes (T2D) is a chronic disease with a growing prevalence and a leading cause of death in many countries. Several epidemiological studies observed an association between T2D and increased risk of many types of cancer, such as gynecologic neoplasms (endometrial, cervical, ovarian and vulvar cancer). Insulin resistance, chronic inflammation and high free ovarian steroid hormones are considered the possible mechanisms behind this complex relationship. A higher risk of endometrial cancer was observed in T2D, even though this association largely attenuated after adjusting for obesity. A clear relationship between the incidence of cervical cancer (CC) and T2D has still not be determined; however T2D might have an impact on prognosis in patients with CC. To date, studies on the association between T2D and ovarian cancer (OC) are limited. The effect of pre-existing diabetes on cancer-specific mortality has been evaluated in several studies, with less clear results. Other epidemiological and experimental studies focused on the potential role of diabetes medications, mainly metformin, in cancer development in women. The correct understanding of the link between T2D and gynecologic cancer risk and mortality is currently imperative to possibly modify screening and diagnostic-therapeutic protocols in the future

Two-hour postload glycemia is associated to an increased risk of NAFLD in healthy subjects with family history of type 2 diabetes: a case control study

Nonalcoholic fatty liver disease (NAFLD) includes steatosis and nonalcoholic steatohepatitis (NASH), which can be complicated by cirrhosis and hepatocellular carcinoma [1]. NAFLD affects over 30 % of the general population and is associated with type 2 diabetes mellitus (T2DM), obesity and metabolic syndrome. NAFLD prevalence in T2DM patients is about 70 % using ultrasonography (US). NAFLD and T2DM share insulinresistance, which in the liver increases gluconeogenesis and glycogenolysis, resulting in hyperglycemia. The pancreatic beta islet cells adapt to hyperglycemia by increasing insulin secretion. Hyperinsulinemia upregulates several lipogenic transcription factors, promoting hepatic lipid synthesis. The association between NAFLD and T2DM seems to be the result of a “common soil”. Several studies showed that NAFLD predicts T2DM and vice versa, and that each condition may act as a progression factor for the other. There is evidence of a high risk of NASH and its progression to hepatocellular carcinoma in T2DM patients [6]. Conversely, recent studies showed that NAFLD not only predicts diabetes, but also contributes to poor glycemic control and chronic complications [8]. Despite its clear link with T2DM, the association of NAFLD with family history of diabetes has been poorly investigated. A recent cross-sectional study in nondiabetic individuals with NAFLD demonstrated that family history of diabetes increased the risk of NASH and fibrosis. The aim of this study was to evaluate the prevalence of NAFLD in healthy first degree relatives of T2DM patients (T2DM-rel) and in healthy subjects without family history of T2DM and to assess the risk factors associated with NAFLD development

Metabolic and cardiovascular response to exercise in patients with type 1 diabetes

Physical activity is an effective therapeutic tool for cardiovascular risk prevention. However, exercise aerobic capacity of patients with type 1 diabetes (T1DM) has not been thoroughly investigated. Aim of the present study is to evaluate exercise aerobic capacity in patients with T1DM compared to a normal control population

High serum osteopontin levels are associated with prevalent fractures and worse lipid profile in post-menopausal women with type 2 diabetes

Purpose: Patients with type 2 diabetes (T2DM) have increased fracture risk. Osteopontin (OPN) is a protein involved in bone remodeling and inflammation. The aim of this study was to evaluate the association of OPN with fracture prevalence and with metabolic parameters in post-menopausal women with T2DM. Methods: Sixty-four post-menopausal women with T2DM (age 67.0 ± 7.8 years, diabetes duration 8.9 ± 6.7 years), enrolled in a previous study, were followed up (3.6 ± 0.9 years). Previous fragility fractures were recorded. The FRAX score (without BMD) was calculated and biochemical parameters (plasma glucose, HbA1c, lipid profile and renal function) were assessed. Serum 25OH-vitamin D, calcium, PTH and OPN were evaluated at baseline. The association between OPN and fracture prevalence at baseline was evaluated by a logistic model. Results: OPN levels were higher in patients with previous fractures (n.25) than in patients without previous fractures at baseline (n.39) (p = 0.006). The odds of having fractures at baseline increased by 6.7 (1.9–31.4, 95% CI, p = 0.007) for each increase of 1 ng/ml in OPN levels, after adjustment for vitamin D and HbA1c levels. Fracture incidence was 4.7%. Higher OPN associated with a decrease in HDL-cholesterol (p = 0.048), after adjustment for age, basal HDL-cholesterol, basal and follow-up HbA1c and follow-up duration. 25OH-vitamin D associated with an increase in FRAX-estimated probability of hip fracture at follow-up (p = 0.029), after adjustment for age, 25OH-vitamin D and time. Conclusions: In post-menopausal women with T2DM, OPN might be a useful marker of fracture and worse lipid profile

Curcumin: could this compound be useful in pregnancy and pregnancy-related complications?

Curcumin, the main polyphenol contained in turmeric root (Curcuma longa), has played a significant role in medicine for centuries. The growing interest in plant-derived substances has led to increased consumption of them also in pregnancy. The pleiotropic and multi-targeting actions of curcumin have made it very attractive as a health-promoting compound. In spite of the beneficial effects observed in various chronic diseases in humans, limited and fragmentary information is currently available about curcumin's effects on pregnancy and pregnancy-related complications. It is known that immune-metabolic alterations occurring during pregnancy have consequences on both maternal and fetal tissues, leading to short- and long-term complications. The reported anti-inflammatory, antioxidant, antitoxicant, neuroprotective, immunomodulatory, antiapoptotic, antiangiogenic, anti-hypertensive, and antidiabetic properties of curcumin appear to be encouraging, not only for the management of pregnancy-related disorders, including gestational diabetes mellitus (GDM), preeclampsia (PE), depression, preterm birth, and fetal growth disorders but also to contrast damage induced by natural and chemical toxic agents. The current review summarizes the latest data, mostly obtained from animal models and in vitro studies, on the impact of curcumin on the molecular mechanisms involved in pregnancy pathophysiology, with the aim to shed light on the possible beneficial and/or adverse effects of curcumin on pregnancy outcomes

Short-term effects of glucagon-like peptide 1 (GLP-1) receptor agonists on fat distribution in patients with type 2 diabetes mellitus: an ultrasonography study

AIMS:Glucagon-like peptide 1 receptor agonists (GLP-1 RA) induce weight loss and reduction in adipose tissue, but the effects of GLP-1 RA on the distribution of fat deposits have been poorly investigated. METHODS: In 25 patients with type 2 diabetes (16 females and 9 males, mean age 63.5 ± 8.8 years), treated with GLP-1 RA (exenatide, n. 12; liraglutide, n.13), both before and 3 months after starting treatment, an abdominal ultrasonographic scan, with Doppler of renal arteries, and echocardiography were performed. Subcutaneous fat width (peri-umbilical and sub-xiphoid), deep fat deposits (pre-aortic, peri-renal, and epicardial), and renal resistive index (RI) were evaluated. RESULTS: GLP-1 RA induced highly significant (p < 0.001) decrease in BMI and in fat thickness at all the assessed sites, without differences between exenatide and liraglutide treatment. A slight decrease in RI (p = 0.055) was also found. The percent changes of fat thickness was different between sites (p < 0.025), and the changes in subcutaneous deposits showed no significant correlation (p = 0.064) with those of deep fat deposits. CONCLUSIONS: A short course of treatment with GLP-1 RA, besides weight loss, induces a redistribution of adipose tissue deposits, possibly contributing to a better cardiovascular risk profile in patients with type 2 diabetes mellitus

Endothelial dysfunction markers as a therapeutic target for Sildenafil treatment and effects on metabolic control in type 2 diabetes

Endothelial dysfunction (ED) plays a role in diabetic cardiovascular complications. Hyperglycemia increases cytockines involved in vascular inflammation. Inhibition of phosphodiesterase type 5 (PDE5) exerts a relaxation on corpora cavernosa and has cardioprotective properties. The effect of chronic sildenafil treatment, on ED markers and metabolic parameters in a non-randomized study on men with type 2 diabetes (T2DM), was investigated