Increased basal level of Akt-dependent insulin signaling may be responsible for the development of insulin resistance

Liu, Hui Yu; Hong, Tao; Wen, Ge; Han, Jing; Zuo, Degen; Liu, Zhenqi; Cao, Wenhong

doi:10.1152/ajpendo.00374.2009

Cited by 107 publications

(101 citation statements)

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“…It is important to note that our findings are consistent with previous studies showing that basal Akt phosphorylation at threonine 308 and serine 473 is increased in skeletal muscle and liver of high fat diet-induced diabetic rodents (36,37) and Zucker (fa/fa) rats (38), although insulin-stimulated Akt phosphorylation is attenuated in these animals. The authors argued that increased basal Akt phosphorylation in insulin-resistant rodents might result from hyperinsulinemia (37,38), although tyrosine phosphorylation of IR, IRS-1, or IRS-2 was not examined in their studies. However, our data do not exclude the possibility that as yet unclarified factors other than hyperinsulinemia may also contribute in concert to the increased basal phosphorylation of IRS-1 and Akt in both liver and muscle of L-iNOS-Tg mice, based on the following observations.…”

Section: Volume 286 • Number 40 • October 7 2011supporting

confidence: 92%

Liver-specific Inducible Nitric-oxide Synthase Expression Is Sufficient to Cause Hepatic Insulin Resistance and Mild Hyperglycemia in Mice

Shinozaki

Choi

Shimizu

et al. 2011

Journal of Biological Chemistry

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Inducible nitric-oxide synthase (iNOS), a major mediator of inflammation, plays an important role in obesity-induced insulin resistance. Inhibition of iNOS by gene disruption or pharmacological inhibitors reverses or ameliorates obesity-induced insulin resistance in skeletal muscle and liver in mice. It is unknown, however, whether increased expression of iNOS is sufficient to cause insulin resistance in vivo. To address this issue, we generated liver-specific iNOS transgenic (L-iNOS-Tg) mice, where expression of the transgene, iNOS, is regulated under mouse albumin promoter. L-iNOS-Tg mice exhibited mild hyperglycemia, hyperinsulinemia, insulin resistance, and impaired insulin-induced suppression of hepatic glucose output, as compared with wild type (WT) littermates. Insulin-stimulated phosphorylation of insulin receptor substrate-1 (IRS-1) and -2, and Akt was significantly attenuated in liver, but not in skeletal muscle, of L-iNOS-Tg mice relative to WT mice without changes in insulin receptor phosphorylation. Moreover, liverspecific iNOS expression abrogated insulin-stimulated phosphorylation of glycogen synthase kinase-3␤, forkhead box O1, and mTOR (mammalian target of rapamycin), endogenous substrates of Akt, along with increased S-nitrosylation of Akt relative to WT mice. However, the expression of insulin receptor, IRS-1, IRS-2, Akt, glycogen synthase kinase-3␤, forkhead box O1, protein-tyrosine phosphatase-1B, PTEN (phosphatase and tensin homolog), and p85 phosphatidylinositol 3-kinase was not altered by iNOS transgene. Hyperglycemia was associated with elevated glycogen phosphorylase activity and decreased glycogen synthase activity in the liver of L-iNOS-Tg mice, whereas phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and proliferator-activated receptor ␥ coactivator-1␣ expression were not altered. These results clearly indicate that selective expression of iNOS in liver causes hepatic insulin resistance along with deranged insulin signaling, leading to hyperglycemia and hyperinsulinemia. Our data highlight a critical role for iNOS in the development of hepatic insulin resistance and hyperglycemia.The incidence of obesity and type 2 diabetes has been increasing in the United States and worldwide. Hepatic insulin resistance has a critical role in the progression of hyperglycemia in type 2 diabetes. Activation of inflammatory/stress signaling pathways have been recognized as a major culprit of hepatic insulin resistance (1, 2). These inflammatory/stress signaling pathways include the inhibitor of nuclear factor-B (IB) nuclear factor-B (NF-B), 2 c-Jun N-terminal kinase (JNK), and endoplasmic reticulum stress signaling cascades (3-7). Liver-specific activation of nuclear factor-B kinase causes hepatic insulin resistance in mice (8). Nonetheless, it remains to be determined how activation of inflammatory/stress signaling pathways induces hepatic insulin resistance.We and others have shown that the inhibition of inducible nitric-oxide synthase (iNOS, also known as NOS2) by gene disruption or pharma...

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Section: Volume 286 • Number 40 • October 7 2011supporting

confidence: 92%

Liver-specific Inducible Nitric-oxide Synthase Expression Is Sufficient to Cause Hepatic Insulin Resistance and Mild Hyperglycemia in Mice

Shinozaki

Choi

Shimizu

et al. 2011

Journal of Biological Chemistry

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“…Autophagy markers were detected as detailed above. Results showed that the basal level of Akt phosphorylation was increased by the HFD as we previously described (28) but reversed by the treatment with LY294002 (supplemental Fig. 1, A and B).…”

Section: Hepatic Expression Of Key Genes Involved In Activation Of Ausupporting

confidence: 77%

“…To explore whether or not insulin signaling was responsible for the suppressed autophagy in the presence of insulin resistance/hyperinsulinemia, insulin resistance in mice was induced by the HFD (4 weeks) as we previously described (28). Some mice were administered the phosphatidylinositol 3-kinase inhibitor LY294002 during day time (once a day for the last week), when mice normally sleep and do not eat.…”

Section: Hepatic Expression Of Key Genes Involved In Activation Of Aumentioning

confidence: 99%

“…Suppression of mitochondrial biogenesis by antiretroviral nucleoside analogues is associated with the development of insulin resistance in patients with AIDS (26). We have recently shown that mitochondrial production is decreased by prolonged exposure to insulin, which resembles insulin resistance and hyperinsulinemia (10,27,28). However, little attention has been paid to the removal of aged/dysfunctional mitochondria in the presence of insulin resistance and hyperinsulinemia, probably due to the current perception that insulin is not functional in the presence of insulin resistance.…”

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confidence: 99%

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Hepatic Autophagy Is Suppressed in the Presence of Insulin Resistance and Hyperinsulinemia

Liu

Han

Cao

et al. 2009

Journal of Biological Chemistry

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Autophagy is essential for maintaining both survival and health of cells. Autophagy is normally suppressed by amino acids and insulin. It is unclear what happens to the autophagy activity in the presence of insulin resistance and hyperinsulinemia. In this study, we examined the autophagy activity in the presence of insulin resistance and hyperinsulinemia and the associated mechanism. Insulin resistance and hyperinsulinemia were induced in mice by a high fat diet, followed by measurements of autophagy markers. Our results show that autophagy was suppressed in the livers of mice with insulin resistance and hyperinsulinemia. Transcript levels of some key autophagy genes were also suppressed in the presence of insulin resistance and hyperinsulinemia. Conversely, autophagy activity was increased in the livers of mice with streptozotocin-induced insulin deficiency. Levels of vps34, atg12, and gabarapl1 transcripts were elevated in the livers of mice with insulin deficiency. To study the mechanism, autophagy was induced by nutrient deprivation or glucagon in cultured hepatocytes in the presence or absence of insulin. Autophagy activity and transcript levels of vps34, atg12, and gabarapl1 genes were reduced by insulin. The effect of insulin was largely prevented by overexpression of the constitutive nuclear form of FoxO1. Importantly, autophagy of mitochondria (mitophagy) in cultured cells was suppressed by insulin in the presence of insulin resistance. Together, our results show that autophagy activity and expression of some key autophagy genes were suppressed in the presence of insulin resistance and hyperinsulinemia. Insulin suppression of autophagy involves FoxO1-mediated transcription of key autophagy genes.Macroautophagy (autophagy) is a catabolic process whereby long lived large molecules and cellular organelles, such as mitochondria and endoplasmic reticulum (ER), 3 are degraded by lysosomes for an alternative energy source during starvation (1, 2). Autophagy is normally activated by glucagon or deprivation of amino acids during starvation (1) but inhibited by amino acids and/or insulin through the mTOR-or/and Akt-dependent pathways after food intake (3, 4). Thus, autophagy activity fluctuates with food intakes and fasts. Importantly, autophagy is also essential for maintaining cellular health by removing misfolded large molecules and aged/dysfunctional cellular organelles, such as mitochondria and ER (1, 5). In other words, decreased autophagy will inevitably slow the removal of misfolded large molecules and aged/dysfunctional cellular organelles. Accumulation of these molecules and dysfunctional cellular organelles may not only contribute to the development of cancers (1) but also contribute to the development of metabolic diseases, such as insulin resistance. For example, the accumulation of dysfunctional mitochondria will most likely cause increased mitochondrion-derived oxidative stress, which is known to contribute to the development of insulin resistance (6 -10).Insulin resistance is either a precursor or...

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“…Interestingly, hCRP was associated with a significant increase in basal Akt Ser 473 phosphorylation. Previous studies have implicated high-level basal Akt Ser 473 phosphorylation in insulin resistance in the liver and muscle in mice 37 and in low glucose uptake in the heart in diabetic rats. 38 The difference observed between insulin-induced phosphorylation of Akt Ser 473 and Thr 308 is in part due to the significantly different basal phosphorylation levels of the two sites, as suggested previously.…”

Section: Discussionmentioning

confidence: 97%

C-reactive protein impairs hepatic insulin sensitivity and insulin signaling in rats: Role of mitogen-activated protein kinases

et al. 2011

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Plasma C-reactive protein (CRP) concentration is increased in the metabolic syndrome, which consists of a cluster of cardiovascular disease risk factors, including insulin resistance. It is not known, however, whether CRP is merely a marker of accompanying inflammation or whether it contributes causally to insulin resistance. The objective of this study is to investigate the role that CRP may play in the development of insulin resistance. We examined the effect of single-dose intravenous administration of purified human (h)CRP on insulin sensitivity in Sprague-Dawley rats using the euglycemic, hyperinsulinemic clamp technique. hCRP was associated with impaired insulin suppression of endogenous glucose production with no reduction in peripheral tissue glucose uptake, suggesting that hCRP mediated insulin resistance in the liver but not extrahepatic tissues. We further assessed components of the insulin signaling pathway and mitogen-activated protein kinases (MAPKs) in the liver. Liver tissues derived from hCRP-treated rats showed reduced insulin-stimulated insulin receptor substrate (IRS) tyrosine phosphorylation, IRS/phosphatidylinositol 3-kinase (PI3K) association, and Akt phosphorylation, consistent with hCRP-induced impairment of hepatic insulin signaling. Furthermore, hCRP enhanced phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p38 MAPK as well as IRS-1 Ser 612. Finally, we observed in primary cultured rat hepatocytes that U0126 (a selective inhibitor of MAPK/ERK kinase1/2) corrected hCRP-induced impairment of insulin signaling. Conclusions: hCRP plays an active role in inducing hepatic insulin resistance in the rat, at least in part by activating ERK1/2, with downstream impairment in the insulin signaling pathway. (HEPATOLOGY 2011;53:127-135)

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Increased basal level of Akt-dependent insulin signaling may be responsible for the development of insulin resistance

Cited by 107 publications

References 50 publications

Liver-specific Inducible Nitric-oxide Synthase Expression Is Sufficient to Cause Hepatic Insulin Resistance and Mild Hyperglycemia in Mice

Liver-specific Inducible Nitric-oxide Synthase Expression Is Sufficient to Cause Hepatic Insulin Resistance and Mild Hyperglycemia in Mice

Hepatic Autophagy Is Suppressed in the Presence of Insulin Resistance and Hyperinsulinemia

C-reactive protein impairs hepatic insulin sensitivity and insulin signaling in rats: Role of mitogen-activated protein kinases

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