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.

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-3ß (p-GSK-3ß)], 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.

Intrauterine diabetic milieu instigates dysregulated adipocytokines production in F1 offspring.

BACKGROUND: Intrauterine environment plays a pivotal role in the origin of fatal diseases such as the metabolic syndrome. Diabetes is associated with low-grade inflammatory state and dysregulated adipokines production. The aim of this study is to investigate the effect of maternal diabetes on adipocytokines (adiponectin, leptin and TNF-α) production in F1 offspring in rats. METHODS: The offspring groups were as follows: F1 offspring of control mothers under control diet (CD) (CF1-CD), F1 offspring of control mothers under high caloric diet (HCD) (CF1-HCD), F1 offspring of diabetic mothers under CD (DF1-CD), and F1 offspring of diabetic mothers under HCD (DF1-HCD). Every 5 weeks post-natal, 10 pups of each subgroup were culled to obtain blood samples for biochemical analysis. RESULTS: The results indicate that DF1-CD and DF1-HCD groups exhibited hyperinsulinemia, dyslipidemia, insulin resistance and impaired glucose homeostasis compared to CF1-CD (p > 0.05). DF1-CD and DF1-HCD groups had high hepatic and muscular depositions of TGs. The significant elevated NEFA level only appeared in offspring of diabetic mothers that was fed HCD. DF1-CD and DF1-HCD groups demonstrated low serum levels of adiponectin, high levels of leptin, and elevated levels of TNF-α compared to CF1-CD (p > 0.05). These results reveal the disturbed metabolic lipid profile of offspring of diabetic mothers and could guide further characterization of the mechanisms involved. CONCLUSION: Dysregulated adipocytokines production could be a possible mechanism for the transgenerational transmittance of diabetes, especially following a postnatal diabetogenic environment. Moreover, the exacerbating effects of postnatal HCD on NEFA in rats might be prone to adipcytokine dysregulation. Furthermore, dysregulation of serum adipokines is a prevalent consequence of maternal diabetes and could guide further investigations to predict the development of metabolic disturbances.

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 (AU)

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In Utero Nutritional Manipulation Provokes Dysregulated Adipocytokines Production in F1 Offspring in Rats.

Background. Intrauterine environment plays a pivotal role in the origin of fatal diseases such as diabetes. Diabetes and obesity are associated with low-grade inflammatory state and dysregulated adipokines production. This study aims to investigate the effect of maternal obesity and malnutrition on adipokines production (adiponectin, leptin, and TNF-α) in F1 offspring in rats. Materials and Methods. Wistar rats were allocated in groups: F1 offspring of control mothers under control diet (CF1-CD) and under high-fat diet (CF1-HCD), F1 offspring of obese mothers under CD (OF1-CD) and under HCD (OF1-HCD), and F1 offspring of malnourished mothers under CD (MF1-CD) and under HCD (MF1-HCD). Every 5 weeks postnatally, blood samples were obtained for biochemical analysis. Results. At the end of the 30-week follow-up, OF1-HCD and MF1-HCD exhibited hyperinsulinemia, moderate dyslipidemia, insulin resistance, and impaired glucose homeostasis compared to CF1-CD and CF1-HCD. OF1-HCD and MF1-HCD demonstrated low serum levels of adiponectin and high levels of leptin compared to CF1-CD and CF1-HCD. OF1-CD, OF1-HCD, and MF1-HCD had elevated serum levels of TNF-α compared to CF1-CD and CF1-HCD (p < 0.05). Conclusion. Maternal nutritional manipulation predisposes the offspring to development of insulin resistance in their adult life, probably via instigating dysregulated adipokines production.

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.

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.

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 ß-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.

Impaired peripheral glucose sensing in F1 offspring of diabetic pregnancy

Maternal diabetes can induce permanent changes in glucose homeostasis that can occur pre- and post-natal and leads to type 2 diabetes in adulthood. This study aimed to investigate the effect of maternal diabetes on the F1 offspring peripheral glucose sensing and mitochondrial biogenesis in an attempt to clarify the mechanism of diabetogenic programming. Two groups of female Wistar rats were used (diabetic and control); diabetes was neonatally induced by STZ injection to 5-day old rats. After the pregnancy and delivery, the offspring were weaned to control diet or high-caloric (HCD) diet and followed up for 30 weeks. Every 5 weeks, OGTT was constructed, and serum and tissues were obtained for the assessment of mTFA, mtDNA, UCP2, insulin receptor (IR), phospho-insulin receptor (phospho-IR), and GLUT4. The result indicated impaired glucose tolerance (IGT) and insulin resistance in the offspring under control diet at the 15th week of age and thereafter while those offspring under HCD showed IGT at 10th week, and diabetes was evidenced at the 25th week of age. This defect in glucose metabolism was preceded by impairment in the phosphorylation of IR and decreased IR and Glut4 that cause impaired glucose sensing together with inhibited mitochondrial biogenesis in muscle and adipose tissues. This study indicated that maternal diabetes caused impaired glucose sensing and insulin resistance in the peripheral tissues and caused change in the expression of genes involved in mitochondrial biogenesis and function. Post-natal feeding with HCD may accelerate these changes. Male F1 offspring appears to be more sensitive than females for fetal programming of T2D (AU)

Impaired peripheral glucose sensing in F1 offspring of diabetic pregnancy.

Maternal diabetes can induce permanent changes in glucose homeostasis that can occur pre- and post-natal and leads to type 2 diabetes in adulthood. This study aimed to investigate the effect of maternal diabetes on the F1 offspring peripheral glucose sensing and mitochondrial biogenesis in an attempt to clarify the mechanism of diabetogenic programming. Two groups of female Wistar rats were used (diabetic and control); diabetes was neonatally induced by STZ injection to 5-day old rats. After the pregnancy and delivery, the offspring were weaned to control diet or high-caloric (HCD) diet and followed up for 30 weeks. Every 5 weeks, OGTT was constructed, and serum and tissues were obtained for the assessment of mTFA, mtDNA, UCP2, insulin receptor (IR), phospho-insulin receptor (phospho-IR), and GLUT4. The result indicated impaired glucose tolerance (IGT) and insulin resistance in the offspring under control diet at the 15th week of age and thereafter while those offspring under HCD showed IGT at 10th week, and diabetes was evidenced at the 25th week of age. This defect in glucose metabolism was preceded by impairment in the phosphorylation of IR and decreased IR and Glut4 that cause impaired glucose sensing together with inhibited mitochondrial biogenesis in muscle and adipose tissues. This study indicated that maternal diabetes caused impaired glucose sensing and insulin resistance in the peripheral tissues and caused change in the expression of genes involved in mitochondrial biogenesis and function. Post-natal feeding with HCD may accelerate these changes. Male F1 offspring appears to be more sensitive than females for fetal programming of T2D.