The effect of Artemisia annua L. aqueous and methanolic extracts on insulin signaling in liver of HFD/STZ diabetic mice.

OBJECTIVES: Many studies have shown the anti-diabetic effects of medicinal plants. But their molecular mechanism has been less studied. Understanding of these mechanisms can help to better manage the treatment of diabetes by using these plants. So, this research examined the effect of Artemisia annua extract on PI3K (phosphatidylinositol 3-kinase)/AKt (serine/threonine kinase protein B) signaling pathway in liver of high-fat diet (HFD)/Streptozotocin (STZ)-induced type 2 diabetic mice. METHODS: Groups of mice were control, untreated diabetic mice, diabetic mice treated with various doses (400, 200, 100 mg/kg) of methanolic and aqueous extract of A. annua and metformin for four weeks. Type 2 diabetes was produced by feeding high-fat diet following injection of low dose of STZ. After experiment duration all mice were sacrificed and blood glucose, insulin, homeostasis model assessment of insulin resistance index (HOMA-IR), index of insulin sensitivity index (ISI) were detected and liver tissues were isolated for to detect m-RNA expression of PI3K and Akt. RESULTS: Extracts of aqueous and methanolic this plant markedly reduced hyperglycemia, hyperinsulinemia, HOMA-IR and elevated ISI in diabetic group in comparison with un-treated diabetic mice. In addition, they could enhance the expression of AKt and PI3K m-RNA in liver tissues in diabetic mice. CONCLUSIONS: Artemisia annua extract ameliorated insulin resistance and improved insulin action in liver via the high activity of PI3K/AKt signaling pathway. So, it can be a suitable alternative treatment to synthetic antidiabetic drugs to improve insulin action in condition of type 2 diabetes.

Oxidative stress in liver of streptozotocin-induced diabetic mice fed a high-fat diet: A treatment role of Artemisia annua L.

Objective. The aim of this study was the investigation of a treatment role of Artemisia annua L. (AA) on liver dysfunction and oxidative stress in high-fat diet/streptozotocin-induced diabetic (HFD/STZ) mice. Methods. Sixty mice were divided into 12 groups including control, untreated diabetic, and treated diabetic ones with metformin (250 mg/kg), and doses of 100, 200, and 400 mg/kg of water (hot and cold) and alcoholic (methanol) extracts of AA. Type 2 diabetes mellitus (T2DM) was induced in mice by high-fat diet for 8 weeks and STZ injection in experimental animals. After treatment with doses of 100, 200 or 400 mg/kg of AA extracts in HFD/STZ diabetic mice for 4 weeks, oxidative stress markers such as malondialdehyde (MDA), glutathione (GSH), and free radicals (ROS) were determined in the liver tissue in all groups. Results. Diabetic mice treated with metformin and AA extracts showed a significant decrease in ROS and MDA concentrations and a notable increase in GSH level in the liver. Effectiveness of higher doses of AA extracts (200 and 400 mg/kg), especially in hot-water and alcoholic ones, were similar to and/or even more effective than metformin. Conclusion. Therapeutic effects of AA on liver dysfunction showed that antioxidant activity of hot-water and alcoholic AA extracts were similar or higher than of metformin.

Artemisia annua L. Extracts Improved Insulin Resistance via Changing Adiponectin, Leptin and Resistin Production in HFD/STZ Diabetic Mice.

Objectives: Insulin resistance (IR) is major cause of type 2 diabetes (T2D), and adipokines (e.g., adiponectin, leptin, and resistin) play an important role in insulin sensitivity. Medicinal plants are frequently used for T2D treatment. This study investigates the effect of Artemisia annua L. (AA) extracts on adipokines in mice with high-fat-diet (HFD)/streptozotocin (STZ)-induced T2D. Methods: We divided 60 mice into 12 groups (n = 5 per group) control, untreated T2D, treated T2D, and 9 other groups. T2D was induced in all groups, except controls, by 8 weeks of HFD and STZ injection. The treated T2D group was administered 250 mg/kg of metformin (MTF), while the nine other groups were treated with 100, 200, and 400 mg/kg of hot-water extract (HWE), cold-water extract (CWE), and alcoholic extract (ALE) of AA (daily oral gavage) along with 250 mg/kg of MTF for 4 weeks. The intraperitoneal glucose tolerance test (IPGTT) was performed, and the homeostasis model assessment of adiponectin (HOMA-AD) index and blood glucose and serum insulin, leptin, adiponectin, and resistin levels were measured. Results: Similar to MTF, all three types of AA extracts (HWEs, CWEs, and ALEs) significantly (p < 0.0001) decreased the area under the curve (AUC) of glucose during the IPGTT, the HOMA-AD index, blood glucose levels, and serum insulin, leptin, and resistin levels and increased serum adiponectin levels in the MTF group compared to the T2D group (p < 0.0001). The HWEs affected adipokine release, while the CWEs and ALEs decreased leptin and resistin production. Conclusion: Water and alcoholic AA extracts have an antihyperglycemic and antihyperinsulinemic effect on HFD/STZ diabetic mice. In addition, they decrease IR by reducing leptin and resistin production and increasing adiponectin secretion from adipocytes.

Aqueous and alcoholic extracts of Artemisia annua L. improved insulin resistance via decreasing TNF-alpha, IL-6 and free fatty acids in high-fat diet/streptozotocin-induced diabetic mice.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) is a metabolic disease that influences many people worldwide. Management of insulin resistance in T2DM without side effects of chemical drugs, is the ultimate goal of the medical community. Artemisia annua L. is used for the treatment of diabetes in folkloric medicine. The present study investigated the effects of aqueous and alcoholic extracts of A. annua (AA) on insulin resistance in high-fat diet/STZ-induced diabetic mice. MATERIAL AND METHODS: Mice were divided into groups including control with a normal diet, un-treated high-fat diet/streptozotocin-induced diabetic mice, and diabetic mice treated by oral administration of 100, 200, and 400 mg/kg body weight of water (hot and cold) and alcoholic extracts of AA. After four weeks of treatment with AA, blood sampling was carried out to measure factors involved in insulin resistance such as low-density lipoprotein/ High-density lipoprotein (LDL/HDL) ratio, free fatty acids, Tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and homeostasis model assessment of insulin resistance (HOMA-IR) as an index of insulin resistance. RESULTS: The results showed that all AA extracts (100, 200, and 400 mg/kg) and metformin (250 mg/kg) significantly reduced the serum levels of free fatty acids, TNF-alpha, IL-6, LDL/HDL ratio, and HOMA-IR in diabetic mice compared to untreated diabetic mice (p<0.0001). Notably, the 400 mg/kg dose of cold-water extract was more effective than metformin in reduction of TNF-alpha and IL-6 (p<0.01 and p<0.05, respectively). CONCLUSION: These data illustrated that AA extracts attenuated insulin resistance by reducing the lipid profile and adipocytokines.

Pancreatic HB9 protein level is affected by early life stress in young adult rats: possible involvement of TNF-α and corticosterone.

This study examined foot shock stress effects, during weaning, on pancreatic HB9 protein expression in young adult male rats in the presence or absence of adulthood stress. The pups were divided into Control, Early life stress, Young adult stress, and Early + young adult stress groups. Plasma corticosterone, insulin, glucose, and TNF-α concentrations, and pancreatic HB9 protein expression were assessed. At 2 weeks of age, stress increased plasma corticosterone level. During young adulthood, plasma TNF-α and glucose concentrations increased, whereas plasma insulin and pancreatic HB9 protein levels decreased in Early life stress group. Whereas, Early + young adulthood stress group showed no change in the study parameters, except for plasma corticosterone and insulin concentrations. Overall, early life stress reduced pancreatic HB9 protein expression possibly by elevating plasma corticosterone and TNF-α levels in early life and adulthood, respectively. However, combined with adulthood stress, HB9 protein expression increased to the level of Control.

Early-life stress altered pancreatic Krebs cycle-related enzyme activities in response to young adulthood physical and psychological stress in male rat offspring.

OBJECTIVES: Early-life stress (ELS) increases the risk of metabolic disorders in later life. The present study investigated the ELS effect on pancreatic pyruvate dehydrogenase (PDH) protein level, α-ketoglutarate dehydrogenase (α-KGDH), and aconitase activities as metabolic enzymes in response to young adulthood stress in male rat offspring. METHODS: Male Wistar rats were divided into six groups: Control, early life stress (Early STR), young adult foot-shock stress (Y. adult F-SH STR), early + young adult foot-shock stress (Early + Y. adult F-SH STR), young adult psychological stress (Y. adult Psy STR) and early + young adult psychological stress (Early + Y. adult Psy STR). Stress was induced by a communication box at 2 weeks of age and young adulthood for five consecutive days. The blood samples were collected in young adult rats, then pancreases were removed to measure its PDH protein level and aconitase and α-KGDH activities. RESULTS: In ELS animals, applying foot-shock stress in young adulthood increased PDH protein level, decreased α-KGDH and aconitase activities, and increased plasma glucose, insulin, and corticosterone concentrations. However, exposure to young adulthood psychological stress only decreased α-KGDH and aconitase activities. CONCLUSIONS: It seems that ELS altered metabolic response to young adulthood stress through changes of Krebs cycle-related enzymes activities, though the type of adulthood stress was determinant.

Insulin within the Arcuate Nucleus Has Paradoxical Effects on Nociception in Healthy and Diabetic Rats.

INTRODUCTION: Broad neural circuits originate from the hypothalamic arcuate nucleus and project to many parts of the brain which are related to pain perception. Insulin receptors are found in the arcuate nucleus. Since nociception may be affected in type 1 diabetes, the present study aimed to investigate the intra-arcuate nucleus insulin role in pain perception in streptozotocin (STZ)-induced diabetic and healthy rats. METHODS: Regular insulin was microinjected within the arcuate nucleus and the pain tolerance was measured using the hot plate and the tail-flick apparatus in diabetic rats. RESULTS: The results showed that the arcuate nucleus suppression with lidocaine could increase thermal nociception in non-diabetic animals. Also, insulin within the arcuate nucleus decreased the acute thermal pain perception in these animals. STZ-induced diabetes produced hypoalgesia which the latency of these tests, progressively increased over time after induction of diabetes. Also, in the same animal group, intra-arcuate injection of insulin reduced the latency of nociception. CONCLUSION: Intra-arcuate insulin has paradoxical and controversial effects in healthy and diabetic rats' nociception. These effects seem to be due to the insulin effect on releasing proopiomelanocortin and its derivatives.

Early postnatal hypothalamic-pituitary-adrenal axis activity and reduced insulin sensitivity in adult rats.

OBJECTIVE: Early life stress influences the development of metabolic disorders, including functional changes in the developing of pancreas mediated hypothalamic-pituitary-adrenal (HPA) axis. In the present study, the role of an early postnatal stress on corticosterone, glucose, and insulin levels was investigated during young adulthood. METHODS: Two groups of pups were studied, including control group (pups not receiving foot shock by communication box), and early stress group (pups receiving foot shock by communication box 2 times/day for 5 consecutive days). In rats, concentration of plasma corticosterone, glucose, and insulin was detected before and after placing them into the communication box at 2 weeks of age. At 8-10 weeks of age, concentrations of plasma corticosterone, glucose, and insulin and glucose tolerance were measured in young adult rats. RESULTS: Our results showed that early postnatal foot shock stress increased the corticosterone, insulin, and glucose levels in the postnatal age (p<0.01) that did not last until young adult age, but it caused a significant increase in plasma glucose and insulin levels (p<0.05) following the intraperitoneal glucose tolerance test (IPGTT) in young adult rats. CONCLUSIONS: These results suggest that impaired IPGTT in young adult rats who experienced early postnatal stress can indicate insulin resistance or reduced insulin sensitivity that make it at risk of the type 2 diabetes later in life.

Maternal high-fat diet inversely affects insulin sensitivity in dams and young adult male rat offspring.

This study attempts to further clarify the potential effects of maternal high-fat (HF) diet on glucose homeostasis in dams and young adult male rat offspring. Female rats were divided into control (CON dams) and HF (HF dams) diet groups, which received the diet 4 weeks prior to and through pregnancy and lactation periods. Blood samples were taken to determine metabolic parameters, then an intraperitoneal glucose tolerance test (IPGTT) was performed. Maternal HF diet increased intra-abdominal fat mass and plasma corticosterone level, but decreased leptin concentration in dams. In HF offspring intra-abdominal fat mass, plasma leptin, and corticosterone levels decreased. Following IPGTT, the plasma insulin level of HF dams was higher than the controls. In HF offspring plasma insulin level was not significantly different from the controls, but a steeper decrease of their plasma glucose concentration was observed.

Effect of early life stress on pancreatic isolated islets' insulin secretion in young adult male rats subjected to chronic stress.

Early stressful experiences may predispose organisms to certain disorders, including those of metabolic defects. This study aimed to explore the effects of early life stress on pancreatic insulin secretion and glucose transporter 2 (GLUT2) protein levels in stressed young adult male rats. Foot shock stress was induced in early life (at 2 weeks of age) and/or in young adulthood (at 8-10 weeks of age) for five consecutive days. Blood samples were taken before and after stress exposure in young adult rats. At the end of the experiment, glucose tolerance, isolated islets' insulin secretion, and pancreatic amounts of GLUT2 protein were measured. Our results show that early life stress has no effect on basal plasma corticosterone levels and adrenal weight, either alone or combined with young adulthood stress, but that early life + young adulthood stress could prevent weight gain, and cause an increase in basal plasma glucose and insulin. The homeostasis model assessment of insulin resistance index did not increase, when the rats were subjected to early life stress alone, but increased when combined with young adulthood stress. Moreover, glucose tolerance was impaired by the combination of early life + young adult stress. There was a decrease in islet's insulin secretion in rats subjected to early life stress in response to 5.6 mM glucose concentration, but an increase with a concentration of 16.7 mM glucose. However, in rats subjected to early life + young adulthood stress, islet's insulin secretion increased in response to both the levels of glucose concentrations. GLUT2 protein levels decreased in response to early life stress and early life + young adulthood stress, but there was a greater decrease in the early life stress group. In conclusion, perhaps early life stress sensitizes the body to stressors later in life, making it more susceptible to metabolic syndrome only when the two are in combination.