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Diabetes mellitus is a heterogeneous, multifactorial, chronic disease characterized by hyperglycemia owing to insulin insufficiency and insulin resistance (IR). Recent epidemiological studies showed that the diabetes epidemic affects 382 million people worldwide in 2013, and this figure is expected to be 600 million people by 2035. Diabetes is associated with microvascular and macrovascular complications resulting in accelerated endothelial dysfunction (ED), atherosclerosis, and cardiovascular disease (CVD). Unfortunately, the complex pathophysiology of diabetic cardiovascular damage is not fully understood. Therefore, there is a clear need to better understand the molecular pathophysiology of ED in diabetes, and consequently, better treatment options and novel efficacious therapies could be identified. In the light of recent extensive research, we re-investigate the association between diabetes-associated metabolic disturbances (IR, subclinical inflammation, dyslipidemia, hyperglycemia, dysregulated production of adipokines, defective incretin and gut hormones production/action, and oxidative stress) and ED, focusing on oxidative stress and endothelial progenitor cells (EPCs). In addition, we re-emphasize that oxidative stress is the final common pathway that transduces signals from other conditions-either directly or indirectly-leading to ED and CVD.

The cholinergic anti-inflammatory pathway is one of the putative biochemical pathways that link diabetes with Alzheimer disease. Hence, we aimed to verify the potential antidiabetic effect of galantamine, unveil the possible mechanisms and evaluate its interaction with vildagliptin. The n5-STZ rat model was adopted and the diabetic animals were treated with galantamine and/or vildagliptin for 4 weeks. Galantamine lowered the n5-STZ-induced elevation in body weight, food/water intake, serum levels of glucose, fructosamine, and ALT/AST, as well as AChE in the tested organs. Moreover, it modulated successfully the lipid profile assessed in serum, liver, and muscle, and increased serum insulin level, as well as % β-cell function, in a pattern similar to that of vildagliptin. Additionally, galantamine confirmed its antioxidant (Nrf2, TAC, MDA), anti-inflammatory (NF-κB, TNF-α, visfatin, adiponectin) and anti-apoptotic (caspase-3, cytochrome c) capabilities by altering the n5-STZ effect on all the aforementioned parameters. On the molecular level, galantamine/vildagliptin have improved the insulin (p-insulin receptor, p-Akt, GLUT4/GLUT2) and Wnt/β-catenin (p-GSK-3β, β-catenin) signaling pathways. On almost all parameters, the galantamine effects surpassed that of vildagliptin, while the combination regimen showed the best effects. The present results clearly proved that galantamine modulated glucose/lipid profile possibly through its anti-oxidant, -apoptotic, -inflammatory and -cholinesterase properties. These effects could be attributed partly to the enhancement of insulin and Wnt/β-catenin signaling pathways. Galantamine can be strongly considered as a potential antidiabetic agent and as an add-on therapy with other oral antidiabetics.

Transgenerational inheritance of various diseases and phenotypes has been demonstrated in diverse species and involves various epigenetic markers. Obesity and malnourishment are nutritional stresses that have effects on offspring through increasing their risk of diabetes and/or obesity. Obesity and malnourishment both affect glucose metabolism and alter oxidative stress parameters in key organs. We induced obesity and malnutrition in F0 female rats by the use of obesogenic diet and protein-deficient diet, respectively. F0 obese and malnourished females were mated with control males and their offspring (F1 generation) were maintained on control diets. The male and female F1 offspring were mated with controls and the resultant offspring (F2 generation) were maintained on control diet. Glucose-sensing markers, glucose metabolism, indicators of insulin resistance and oxidative stress parameters were assessed during fetal development and till the adulthood of the offspring. Glucose-sensing genes were significantly over-expressed in distinct fetal tissues of F2 offspring of malnourished F1 females (F2-MF1F), specifically in fetal pancreas, liver, and adipose tissue. Nuclear and mitochondrial 8-oxo-dG DNA content was significantly elevated in F2-MF1F fetal pancreas. Maternal FBG was significantly elevated in F2-MF1F and F2 offspring of obese F1 females (F2-OF1F) during pregnancy. Males and females offspring of F2-OF1 exhibited significantly elevated FBG and impaired OGTT. Offspring of F2-MF1F showed similar results, while that of F2-MF1M did not significantly deviate from controls. F2-OF1F and F2-MF1F offspring exhibited significant deviation in insulin levels and HOMA-IR levels from controls. Malnourishment has a stronger transgenerational effect through maternal line compared to obesity and malnourishment through paternal line in increasing risk of diabetes in F2 generation.

Type 2 diabetes mellitus (T2DM) is a group of metabolic disorders characterized by hyperglycemia owing to insulin resistance and/or insulin deficiency. Current theories of T2DM pathophysiology include a decline in β-cells function, a defect in insulin signaling pathways, and a dysregulation of secretory function of adipocytes. This study aimed to investigate the effect of different antidiabetic drugs on serum levels of certain adipocytokines and nonesterified fatty acids (NEFA) in high-fat diet (HFD)/streptozotocin- (STZ-) induced diabetic rats. All treatments significantly decreased serum NEFA level. Metformin and sitagliptin increased serum adiponectin level, whereas they decreased serum leptin level. Glimepiride showed significant decline in serum levels of both adiponectin and leptin. All treatments remarkably ameliorated insulin resistance, suggested by an improvement of glycemic control, a significant reduction in homeostasis model assessment of insulin resistance (HOMA-IR), and a correction in lipid profile. Modulation of adipocytokines production (i.e., increased serum adiponectin and decreased serum leptin) may also underlie the improvement of insulin resistance and could be a possible mechanism for the beneficial cardiovascular effects of metformin and sitagliptin.

The maintenance of genome integrity is essential for organism survival. Therefore, eukaryotic cells possess many DNA repair mechanisms in response to DNA damage. Acetyltransferase, Tip60, plays a central role in ATM and p53 activation which are involved in DNA repair. Recent works uncovered the roles of Tip60 in ATM and p53 activation and how Tip60 is recruited to double-strand break sites. Moreover, recent works have demonstrated the role of Tip60 in cancer progression. Here, we review the current understanding of how Tip60 activates both ATM and p53 in response to DNA damage and his new roles in tumorigenesis.

Type 2 diabetes mellitus (T2DM) is among the leading causes of death in postmenopausal women. The disruption of ovarian function may contribute to the incidence of T2DM. The purpose of this study was to investigate the effects of ovariectomy and T2DM on glucose and lipid homeostasis, perilipin levels in adipose tissues, as a lipolytic regulator, and levels of certain adipokines. Ovariectomized (OVX) rats were used as a model for postmenopausal women. The study was performed on sham, OVX, sham diabetic, and OVX diabetic female rats. The results indicated that ovariectomy alters adipose tissue metabolism through reducing perilipin content in white adipose tissue (WAT); however it has no effect on perilipin level in brown adipose tissue (BAT). OVX diabetic females suffer from serious metabolic disturbances, suggested by exacerbation of insulin resistance in terms of disrupted lipid profile, higher HOMA-IR, hyperinsulinemia, higher leptin, and lower adiponectin concentrations. These metabolic derangements may underlie the predisposition for cardiovascular disease in women after menopause. Therefore, for efficient treatment, the menopausal status of diabetic female should be addressed, and the order of events is of great importance because ovariectomy following development of diabetes has more serious complications compared to development of diabetes as result of menopause.