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.

Insulin resistance (IR) is a condition which refers to individuals whose cells and tissues become insensitive to the peptide hormone, insulin. Over the recent years, a wealth of data has made it clear that a synergistic relationship exists between IR, type 2 diabetes mellitus, and cancer. Although the underlying mechanism(s) for this association remain unclear, it is well established that hyperinsulinemia, a hallmark of IR, may play a role in tumorigenesis. On the other hand, IR is strongly associated with visceral adiposity dysfunction and systemic inflammation, two conditions which favor the establishment of a pro-tumorigenic environment. Similarly, epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNA, in IR states, have been often associated with tumorigenesis in numerous types of human cancer. In addition to these observations, it is also broadly accepted that gut microbiota may play an intriguing role in the development of IR-related diseases, including type 2 diabetes and cancer, whereas potential chemopreventive properties have been attributed to some of the most commonly used antidiabetic medications. Herein we provide a concise overview of the most recent literature in this field and discuss how different but interrelated molecular pathways may impact on tumor development.

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. 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. 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. 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. 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).

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.

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.