Glucose uptake is regulated by several mechanisms, where insulin plays the most prominent role. This powerful anabolic hormone regulates the transport of glucose into the cell through translocation of glucose transporter from an intracellular pool to the plasma membrane mainly in metabolically active tissues like skeletal muscles, adipose tissue, or liver (GLUT4). This translocation occurs through multiple steps of PI3K/AKT signaling pathway. In this chapter, we will focus on molecular events leading to GLUT4 translocation, starting with activation of insulin receptors through signaling cascade involving phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB) and finally, the action of their effectors. We will present regulatory mechanisms and modulators of insulin-mediated glucose uptake.

Evidence strongly suggest that Sirtuin1 upregulation may serve as a potent therapeutic approach against development and progression of diabetic complications.

Nowadays, it is well-known that the deregulation of epigenetic machinery is a common biological event leading to the development and progression of metabolic disorders. Moreover, the expression level and actions of leptin, a vast adipocytokine regulating energy metabolism, appear to be strongly associated with epigenetics. Therefore, the aim of this review was to summarize the current knowledge of the epigenetic regulation of leptin as well as the leptin-induced epigenetic modifications in metabolic disorders and associated phenomena. The collected data indicated that the deregulation of leptin expression and secretion that occurs during the course of metabolic diseases is underlain by a variation in the level of promoter methylation, the occurrence of histone modifications, along with miRNA interference. Furthermore, leptin was proven to epigenetically regulate several miRNAs and affect the activity of the histone deacetylases. These epigenetic modifications were observed in obesity, gestational diabetes, metabolic syndrome and concerned various molecular processes like glucose metabolism, insulin sensitivity, liver fibrosis, obesity-related carcinogenesis, adipogenesis or fetal/early postnatal programming. Moreover, the circulating miRNA profiles were associated with the plasma leptin level in metabolic syndrome, and miRNAs were found to be involved in hypothalamic leptin sensitivity. In summary, the evidence suggests that leptin is both a target and a mediator of epigenetic changes that develop in numerous tissues during metabolic disorders.

Disturbances in adipose tissue significantly contribute to the development of metabolic disorders, which are connected with hyperglycemia (HG) and underlain by epigenetics-based mechanisms. Therefore, we aimed to evaluate the effect of hyperglycemia on proliferating, differentiating and maturating human visceral pre/adipocytes (HPA-v). Three stages of cell culture were conducted under constant or variable glycemic conditions. Adipogenesis progress was assessed using BODIPY 505/515 staining. Lipid content typical for normal and hyperglycemic conditions of adipocytes was analyzed using Raman spectroscopy and imaging. Expression of adipogenic markers, PPARγ and C/EBPα, was determined at the mRNA and protein levels. We also examined expression of miRNAs proven to target PPARγ (miR-34a-5p) and C/EBPα (miR-137-3p), employing TaqMan Low-Density Arrays (TLDA) cards. Hyperglycemia altered morphology of differentiating HPA-v in relation to normoglycemia by accelerating the formation of lipid droplets and making their numbers and volume increase. Raman results confirmed that the qualitative and quantitative lipid composition under normal and hyperglycemic conditions were different, and that the number of lipid droplets increased in (HG)-treated cells. Expression profiles of both examined genes markedly changed either during adipogenesis under physiological and hyperglycemic conditions, orat particular stages of adipogenesis upon chronic and/or variable glycemia. Expression levels of PPARγ seemed to correspond to some expression changes of miR-34a-5p. miR-137-3p, whose expression was rather stable throughout the culture, did not seem to affect C/EBPα. Our observations revealed that chronic and intermittent hyperglycemia change the morphology of visceral pre/adipocytes during adipogenesis. Moreover, hyperglycemia may utilize miR-34a-5p to induce some expression changes in PPARγ.

Hypertrophic and hypoxic visceral adipose tissue (VAT) secretes proinflammatory cytokines promoting insulin resistance (IR), prediabetes and type 2 diabetes (T2DM) microRNAs (miRNAs) are markers of metabolic disorders regulating genes critical for e.g., inflammation, glucose metabolism, and antioxidant defense, with raising diagnostic value. The aim of the current study was to evaluate whether hyperglycemia is able to affect the expression of selected miRNAs in VAT of prediabetic (IFG) and diabetic (T2DM) patients vs. normoglycemic (NG) subjects using qPCR. Statistical analyses suggested that miRNAs expression could be sex-dependent. Thus, we determined 15 miRNAs as differentially expressed (DE) among NG, T2DM, IFG females (miR-10a-5p, let-7d-5p, miR-532-5p, miR-127-3p, miR-125b-5p, let-7a-5p, let-7e-5p, miR-199a-3p, miR-365a-3p, miR-99a-5p, miR-100-5p, miR-342-3p, miR-146b-5p, miR-204-5p, miR-409-3p). Majority of significantly changed miRNAs was similarly upregulated in VAT of female T2DM and IFG patients in comparison to NG subjects, positively correlated with FPG and HbA1c, yet, uncorrelated with WHR/BMI. Enrichment analyses indicated involvement of 11 top DE miRNAs in oxidative stress, inflammation and insulin signaling. Those miRNAs expression changes could be possibly associated with low-grade chronic inflammation and oxidative stress in VAT of hyperglycemic subjects.