Mervat Y. Hanafi

Maternal obesity and malnourishment exacerbate perinatal oxidative stress resulting in diabetogenic programming in F1 offspring

The effect of in-utero environment on fetal health and survival is long-lasting, and this is known as the fetal origin hypothesis. The oxidative stress state during gestation could play a pivotal role in fetal programming and development of diseases such as diabetes. In this study, we investigated the effect of intra-uterine obesity and malnutrition on oxidative stress markers in pancreatic and peripheral tissues of F1 offspring both prenatally and postnatally. Furthermore, the effect of postnatal diet on oxidative stress profile was evaluated. The results indicated that intra-uterine obesity and malnourishment significantly increased oxidative stress in F1 offspring. Moreover, the programming effect of obesity was more pronounced and protracted than malnutrition. The obesity-induced programming of offspring tissues was independent of high-caloric environment that the offspring endured; however, high-caloric diet potentiated its effect. In addition, pancreas and liver were the most affected tissues by fetal reprogramming both prenatally and postnatally. In conclusion, maternal obesity and malnutrition-induced oxidative stress could predispose offspring to insulin resistance and diabetes.

Modulation of Adipocytokines Production and Serum NEFA Level by Metformin, Glimepiride, and Sitagliptin in HFD/STZ Diabetic Rats

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.

Transgenerational effects of obesity and malnourishment on diabetes risk in F2 generation.

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.

Diabetes-induced perturbations are subject to intergenerational transmission through maternal line

The hypothesis of fetal origins of adult disease states that early life events program the occurrence of significant adult diseases, including diabetes and obesity. Maternal diabetes is associated with general stress environment for developing fetus, and gestational diabetes is an independent risk factor for type 2 diabetes and metabolic syndrome in offspring. Intra-uterine fetal programming of fetal tissues exposes the offspring to increased risk of impaired glucose tolerance, type 2 diabetes, and cardiovascular disease. Here, we examined the transmission of maternal diabetes-induced fetal programming in second generation and compared maternal and paternal routes of intergenerational effects. We organized 40 Wistar rats into three groups, male offspring of diabetic mothers, female offspring of diabetic mothers, and offspring of control mothers. These groups were mated with normal healthy rats to assess the effect of grand-maternal diabetes on pregnancy outcome in F2 rats, as well as glucose-sensing parameters, insulin resistance, and glucose tolerance prenatally and postnatally. We found that F2 offspring of diabetic mothers had impaired glucose sensing, increased oxidative stress, insulin resistance, and impaired glucose tolerance, and these effects were more prominent in the F2 offspring of F1 female rats (F2-DF1F). We deduce that fetal programming of maternal diabetes is mostly transmitted through maternal line across two generations.

Vitamin C and E chronic supplementation differentially affect hepatic insulin signaling in rats

Aim: Vitamin C and vitamin E supplementations and their beneficial effects on type 2 diabetes mellitus (T2DM) have been subjected to countless controversial data. Hence, our aim is to investigate the hepatic molecular mechanisms of any diabetic predisposing risk of the chronic administration of different doses of vitamin E or vitamin C in rats. Main methods: The rats were supplemented with different doses of vitamin C or vitamin E for eight months. Key findings: Vitamin C and vitamin E increased fasting blood glucose, insulin, and homeostasis model assessment index for insulin resistance (HOMA). Vitamin C disrupted glucose tolerance by attenuating upstream hepatic insulin action through impairing the phosphorylation and activation of insulin receptor and its subsequent substrates; however, vitamin E showed its effect downstream insulin receptor in the insulin signaling pathway, reducing hepatic glucose transporter‐2 (GLUT2) and phosphorylated protein kinase (p‐Akt). Moreover, both vitamins showed their antioxidant capabilities [nuclear factor‐erythroid‐2‐related factor 2 (Nrf2), total and reduced glutathione] and their negative effect on Wnt pathway [phosphorylated glycogen synthase kinase‐3&bgr; (p‐GSK‐3&bgr;)], by altering the previously mentioned parameters, inevitably leading to severe reduction of reactive oxygen species (ROS) below the physiological levels. Significance: In conclusion, a detrimental effect of chronic antioxidant vitamins supplementation was detected; leading to insulin resistance and impaired glucose tolerance obviously through different mechanisms. Overall, these findings indicate that the conventional view that vitamins promote health benefits and delay chronic illnesses and aging should be modified or applied with caution. Graphical abstract: Figure. No caption available.

The therapeutic effects of bee venom on some metabolic and antioxidant parameters associated with HFD‑induced non‑alcoholic fatty liver in rats

The present study was designed to investigate the therapeutic effects of bee venom (BV) on high-fat diet (HFD)-induced non-alcoholic fatty liver (NAFL) in rats at different levels. Histological manifestations, hepatic lipid content, liver function tests, glucose homeostasis, lipid abnormalities, adipocytokines, lipid peroxidation, disturbed glutathione and antioxidant enzymes systems and dysregulation of Nrf2 transcription factor were assessed. In the present study, the NAFL rats were subcutaneously treated with BV with different doses (0.01, 0.05, 0.1 mg/kg). The results indicated that BV treatment completely normalized the lipid profile values of NAFL rats. Fasting blood sugar, insulin level and homeostatic model assessment of insulin resistance significantly decreased. BV treated rats showed a significantly lower level of all liver enzymes and bilirubin. Moreover, BV treatment significantly increased the levels of active nuclear erythroid factor 2 like 2, glutathione (GSH) (total and reduced), GSH/glutathione disulphide ratio and activities of glutathione reductase, glutathione-S-transferase and glutathione peroxidase (total and Se-dependent). The level of tumor necrosis factor-α was reduced. Treatment showed correction of adiponectin level, and significant downregulation of hepatic triglycerides and cholesterol. At the histological level, BV improved the architecture of liver cells showing normal sinusoids. It may be concluded that BV may represent an interesting therapeutic alternative for the treatment of NAFL disease.