Insulin resistance (IR), defined as an attenuated biological response to circulating insulin, is a fundamental defect in obesity and type 2 diabetes (T2D), and is also linked to a wide spectrum of pathological conditions, such as non-alcoholic fatty liver disease (NAFLD), cognitive impairment, endothelial dysfunction, chronic kidney disease (CKD), polycystic ovary syndrome (PCOS), and some endocrine tumors, including breast cancer. In obesity, the unbalanced production of pro- and anti-inflammatory adipocytokines can lead to the development of IR and its related metabolic complications, which are potentially reversible through weight-loss programs. The Mediterranean diet (MedDiet), characterized by high consumption of extra-virgin olive oil (EVOO), nuts, red wine, vegetables and other polyphenol-rich elements, has proved to be associated with greater improvement of IR in obese individuals, when compared to other nutritional interventions. Also, recent studies in either experimental animal models or in humans, have shown encouraging results for insulin-sensitizing nutritional supplements derived from MedDiet food sources in the modulation of pathognomonic traits of certain IR-related conditions, including polyunsaturated fatty acids from olive oil and seeds, anthocyanins from purple vegetables and fruits, resveratrol from grapes, and the EVOO-derived, oleacein. Although the pharmacological properties and clinical uses of these functional nutrients are still under investigation, the molecular mechanism(s) underlying the metabolic benefits appear to be compound-specific and, in some cases, point to a role in gene expression through an involvement of the nuclear high-mobility group A1 (HMGA1) protein.

Calcific Aortic Valve Disease (CAVD) is the most common valvular heart disease in developed countries and in the ageing population. It is strongly correlated to median age, affecting up to 13% of the population over the age of 65. Pathophysiological analysis indicates CAVD as a result of an active and degenerative disease, starting with sclerosis and chronic inflammation and then leaflet calcification, which ultimately can account for aortic stenosis. Although CAVD has been firstly recognized as a passive event mostly resulting from a degenerative aging process, much evidences suggests that calcification arises from different active processes, involving both aortic valve-resident cells (valve endothelial cells, valve interstitial cells, mesenchymal stem cells, innate immunity cells) and circulating cells (circulating mesenchymal cells, immunity cells). Moreover, a role for the cell-derived “matrix vesicles” and extracellular matrix (ECM) components has also been recognized. The aim of this work is to review the cellular and molecular alterations occurring in aortic valve during CAVD pathogenesis, focusing on the role of ECM in the natural course of the disease.

Insulin resistance (IR), marked by reduced cellular responsiveness to insulin, and obesity, defined by the excessive accumulation of adipose tissue, are two intertwined conditions that significantly contribute to the global burden of cardiometabolic diseases. Adipose tissue, beyond merely storing triglycerides, acts as an active producer of biomolecules. In obesity, as adipose tissue undergoes hypertrophy, it becomes dysfunctional, altering the release of adipocyte-derived factors, known as adipokines. This dysfunction promotes low-grade chronic inflammation, exacerbates IR, and creates a hyperglycemic, proatherogenic, and prothrombotic environment. However, the fundamental cause of these phenomena remains unclear. This narrative review points to hypoxia as a critical trigger for the molecular changes associated with fat accumulation, particularly within visceral adipose tissue (VAT). The activation of hypoxia-inducible factor-1 (HIF-1), a transcription factor that regulates homeostatic responses to low oxygen levels, initiates a series of molecular events in VAT, leading to the aberrant release of adipokines, many of which are still unexplored, and potentially affecting peripheral insulin sensitivity. Recent discoveries have highlighted the role of hypoxia and miRNA-128 in regulating the insulin receptor in visceral adipocytes, contributing to their dysfunctional behavior, including impaired glucose uptake. Understanding the complex interplay between adipose tissue hypoxia, dysfunction, inflammation, and IR in obesity is essential for developing innovative, targeted therapeutic strategies.

Background: Liraglutide is the first glucagon-like peptide-1 receptor agonist (GLP-1 RA) based on the human GLP-1 sequence, with potential weight loss benefits, approved for the treatment of type 2 diabetes (T2D) mellitus. Herein, we aimed to assess the 5-year effectiveness of Liraglutide in the management of weight and glycometabolic control in a Southern Italian cohort of overweight/obese T2D patients, who were naïve to GLP-1 RAs. Patients and Methods: Forty overweight or obese patients treated with Liraglutide at doses up to 1.8 mg/day, in combination with one or more oral antidiabetic agents, were retrospectively assessed at baseline, during, and after 60 months of continuous therapy. Results: After 5 years of Liraglutide treatment, body weight decreased from 92.1 ± 20.5 kg to 87.3 ± 20.0 Kg (p < 0.001), with a mean reduction of 5.0 ± 7.0 Kg and a body mass index (BMI) decrement of −2.0 ± 3.1 Kg/m². On Spearman’s univariate analysis, change in body weight was correlated with female gender and baseline BMI. Hemoglobin A1c (HbA1c) decreased from 7.9 ± 0.9% at baseline to 7.0 ± 0.7% at the end of the study period (p < 0.001), followed by a significant reduction in fasting plasma glucose. No significant differences emerged in other biochemical parameters, despite a trend toward improvement in lipid profile. Notwithstanding encouraging effects on several markers of cardiovascular disease (CVD), increments in the 5- and 10-year risk for the first atherosclerotic cardiovascular event were documented, as four incident cases of myocardial infarction. Conclusions: Prolonging treatment with Liraglutide can lead to durable benefits in relation to weight and glycemic control, with a greater impact on women. These results extend and corroborate previous observations, suggesting that gender per se may modulate the response to Liraglutide. Despite favorable effects on some established CVD risks factors, the long-term role of Liraglutide in primary prevention of CVD in patients with T2D remains controversial.

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.

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.