Effect of Various Radical Generators on Insulin-Dependent Regulation of Hepatic Gene Expression

Kimura, Kumi; Tawara, Satoshi; Igarashi, Kiharu; Takenaka, Asako

doi:10.1271/bbb.60016

Cited by 10 publications

(11 citation statements)

References 23 publications

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“…Further, prolonged exposure to reactive oxygen species has been shown to down-regulate IRS-2 and Akt phosphorylation in vitro (29,33,35,53).…”

Section: Discussionmentioning

confidence: 99%

“…It is possible that a chronic elevation in cAMP levels (as mediated by chronic Ex-4 administration) may not induce PEPCK expression. The mechanisms responsible for the reduction in PEPCK levels in Ex-4 IUGR animals are more likely to be secondary to prevention of oxidative stress, which has been shown to lead to elevated PEPCK expression (29).…”

Section: Discussionmentioning

confidence: 99%

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Neonatal exendin-4 treatment reduces oxidative stress and prevents hepatic insulin resistance in intrauterine growth-retarded rats

Raab

Vuguin

Stoffers

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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(IUGR) has been linked to the development of Type 2 diabetes in adulthood. We have developed an IUGR model in the rat whereby the animals develop diabetes later in life. Previous studies demonstrate that administration of the long-acting glucagonlike-peptide-1 agonist, Exendin-4, during the neonatal period prevents the development of diabetes in IUGR rats. IUGR animals exhibit hepatic insulin resistance early in life (prior to the onset of hyperglycemia), characterized by blunted suppression of hepatic glucose production (HGP) in response to insulin. Basal HGP is also significantly higher in IUGR rats. We hypothesized that neonatal administration of Exendin-4 would prevent the development of hepatic insulin resistance. IUGR and control rats were given Exendin-4 on days 1-6 of life. Hyperinsulinemic-euglycemic clamp studies showed that Ex-4 significantly reduced basal HGP by 20% and normalized insulin suppression of HGP in IUGR rats. While Ex-4 decreased body weight and fat content in both Control and IUGR animals, these differences were only statistically significant in Controls. Exendin-4 prevented development of oxidative stress in liver and reversed insulin-signaling defects in vivo, thereby preventing the development of hepatic insulin resistance. Defects in glucose disposal and suppression of hepatic glucose production in response to insulin were reversed. Similar results were obtained in isolated Ex-4-treated neonatal hepatocytes. These results indicate that exposure to Exendin-4 in the newborn period reverses the adverse consequences of fetal programming and prevents the development of hepatic insulin resistance. intrauterine growth retardation; diabetes; liver; insulin resistance UTEROPLACENTAL INSUFFICIENCY limits availability of substrates to the fetus and retards growth during gestation (40, 47). We have previously shown in a rat model of uteroplacental insufficiency and intrauterine growth retardation (IUGR) that this abnormal metabolic intrauterine milieu affects the development of the fetus by inducing mitochondrial dysfunction and oxidative stress which, in turn, modifies gene expression and function of susceptible cells in the pancreas, muscle, and liver (43,46,48). The end result is the later development of diabetes in adulthood with the salient features of most forms of Type 2 diabetes (T2DM) in the human: defects in insulin action and insulin secretion (49). IUGR animals exhibit hepatic insulin resistance early in life (prior to the onset of hyperglycemia), characterized by blunted suppression of hepatic glucose production (HGP) in response to insulin (62). Basal HGP is also mildly elevated in IUGR rats (62). These defects in hepatic glucose metabolism are secondary to oxidative stress, which impairs insulin signaling (43,62).We have also demonstrated that short-term administration of the long-acting incretin hormone glucagon-like peptide-1 (GLP-1) receptor agonist, Exendin-4 (Ex-4), during the neonatal period, improves glucose tolerance, prevents the progressive reduction in ␤-cell mass tha...

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“…Further, prolonged exposure to reactive oxygen species has been shown to down-regulate IRS-2 and Akt phosphorylation in vitro (29,33,35,53).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Neonatal exendin-4 treatment reduces oxidative stress and prevents hepatic insulin resistance in intrauterine growth-retarded rats

Raab

Vuguin

Stoffers

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Paraquat is not itself an ROS but is capable of generating oxygen radicals through the redox cycling mechanism (20,21). Paraquat has been used experimentally to research the effects of oxidative stress on intracellular signaling and also on various bioactivities, including cell apoptosis (17,(22)(23)(24)(25)(26). Here, we report that paraquat-induced oxidative stress impairs PI 3-kinase activity, resulting in repression of insulindependent glucose uptake in 3T3-L1 adipocytes.…”

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confidence: 81%

“…Previous studies have demonstrated that oxidative stress induced by hydrogen peroxide disrupts subcellular localization of IRSs, and PI 3-kinase causes insulin resistance in cultured adipocytes (15). Although hydrogen peroxide is often utilized to induce oxidative stress, oxidative stress induced by other agents through varying mechanisms results in different oxidative damage to proteins or gene expression compared with changes caused by hydrogen peroxide (16,17). A series of results suggests that the specific effects of ROS generators on insulin signaling are dependent on the quantity, duration, and location of ROS generation (16,17).…”

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confidence: 99%

Paraquat-induced Oxidative Stress Represses Phosphatidylinositol 3-Kinase Activities Leading to Impaired Glucose Uptake in 3T3-L1 Adipocytes

Shibata

Hakuno

Yamanaka

et al. 2010

Journal of Biological Chemistry

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Accumulated evidence indicates that oxidative stress causes and/or promotes insulin resistance; however, the mechanism by which this occurs is not fully understood. This study was undertaken to elucidate the molecular mechanism by which oxidative stress induced by paraquat impairs insulin-dependent glucose uptake in 3T3-L1 adipocytes. We confirmed that paraquatinduced oxidative stress decreased glucose transporter 4 (GLUT4) translocation to the cell surface, resulting in repression of insulin-dependent 2-deoxyglucose uptake. Under these conditions, oxidative stress did not affect insulin-dependent tyrosine phosphorylation of insulin receptor, insulin receptor substrate (IRS)-1 and -2, or binding of the phosphatidylinositol 3-OH kinase (PI 3-kinase) p85 regulatory subunit or p110␣ catalytic subunit to each IRS. In contrast, we found that oxidative stress induced by paraquat inhibited activities of PI 3-kinase bound to IRSs and also inhibited phosphorylation of Akt, the downstream serine/threonine kinase that has been shown to play an essential role in insulindependent translocation of GLUT4 to the plasma membrane. Overexpression of active form Akt (myr-Akt) restored inhibition of insulin-dependent glucose uptake by paraquat, indicating that paraquat-induced oxidative stress inhibits insulin signals upstream of Akt. Paraquat treatment with and without insulin treatment decreased the activity of class Ia PI 3-kinases p110␣ and p110␤ that are mainly expressed in 3T3-L1 adipocytes. However, paraquat treatment did not repress the activity of the PI 3-kinase p110␣ mutated at Cys 90 in the p85 binding region. These results indicate that the PI 3-kinase p110 is a possible primary target of paraquat-induced oxidative stress to reduce the PI 3-kinase activity and impaired glucose uptake in 3T3-L1 adipocytes. Reactive oxygen species (ROS)2 are generated in organisms during metabolic reactions that use oxygen. Increased ROS production causes oxidative stress, which is frequently associated with various disorders such as hypertension, inflammation, and diabetes (1, 2). For example, it is well known that in many diabetic patients and animal models of diabetes, increased generation of ROS and the onset of diabetes are closely associated with oxidative stress (2). Antioxidants such as ␣-lipoic acid and vitamins C and E have been shown to improve insulin sensitivity in diabetic models, further evidence that oxidative stress is associated with insulin resistance (3-5).In general, the intracellular insulin signal is initiated by insulin binding to its receptor (IR), resulting in activation of the intrinsic tyrosine kinase of the receptor. This leads to the recruitment and tyrosine phosphorylation of intracellular insulin receptor substrates (IRS) 1-4 (6). Phosphorylated IRS proteins bind signaling molecules possessing the Src homology 2 domain such as the class Ia PI 3-kinases that are heterodimers of a p85 regulatory subunit and a p110 catalytic subunit. Three isoforms of p110 catalytic subunit, ␣, ␤, and ␦, have been identified. ...

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“…These compounds are non-selective herbicides that enter into a cycling reaction with, among others, nicotinamide adenine dinucleotide (NAD + /NADH) and oxygen molecules that are broken into singlet oxygen (Koch and Hill, 2017). However, while we were interested in the potential effects of OS on sperm traits, it is worth noting that both paraquat-and diquat-induced ROS can also pleiotropically affect several physiological traits (Adachi et al, 2003;Kimura et al, 2007;Shibata et al, 2010). Paraquat and diquat are broadly used under the brand names Gramoxone ® (Paraquat, Syngenta AG, Basel, Switzerland) and Reglone ® (Diquat 20%, Syngenta AG), respectively.…”

Section: Materials and Methods Pilot Studymentioning

confidence: 99%

Oxidative stress affects sperm performance and ejaculate redox status in subordinate House Sparrows

Mora

Firth

Blareau

et al. 2017

Journal of Experimental Biology

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Oxidative stress is the result of random cellular damage caused by reactive oxygen species that leads to cell death, ageing or illness. Most physiological processes can result in oxidative stress, which in turn has been identified as a major cause of infertility. In promiscuous species, the fertilizing ability of the ejaculate partly determines the male reproductive success. When dominance determines access to fertile females, theory predicts that lower ranking males should increase resource investment into enhancing ejaculate quality. We hypothesized that subordinate males should thus prioritize antioxidant protection of their ejaculates to protect them from oxidative stress. We put this hypothesis to the test by chronically dosing wild house sparrows with diquat (∼1 mg kg), a herbicide that increases pro-oxidant generation. We found that, although they increased their antioxidant levels in the ejaculate, diquat-treated males produced sperm with reduced velocity. Importantly, and contrary to our hypothesis, males at the bottom of the hierarchy suffered the largest reduction in sperm velocity. We suggest that resource access hinders individuals' ability to cope with environmental hazards. Our results point at oxidative stress as a likely physiological mechanism mediating ejaculate quality, while individual ability to access resources may play a role in constraining the extent to which such resources can be allocated into the ejaculate.

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Effect of Various Radical Generators on Insulin-Dependent Regulation of Hepatic Gene Expression

Cited by 10 publications

References 23 publications

Neonatal exendin-4 treatment reduces oxidative stress and prevents hepatic insulin resistance in intrauterine growth-retarded rats

Neonatal exendin-4 treatment reduces oxidative stress and prevents hepatic insulin resistance in intrauterine growth-retarded rats

Paraquat-induced Oxidative Stress Represses Phosphatidylinositol 3-Kinase Activities Leading to Impaired Glucose Uptake in 3T3-L1 Adipocytes

Oxidative stress affects sperm performance and ejaculate redox status in subordinate House Sparrows

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