Amino acids and leucine allow insulin activation of the PKB/mTOR pathway in normal adipocytes treated with wortmannin and in adipocytes from<i>db/db</i>mice

Hinault, Charlotte; Mothe-Satney, Isabelle; Gautier, Nadine; Lawrence, John C.; Obberghen, Emmanuel Van

doi:10.1096/fj.03-1409fje

Cited by 72 publications

(74 citation statements)

References 41 publications

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“…In response to insulin and amino acids, mTOR, which is a serine/threonine kinase, phosphorylates and modulates activities of p70 S6 kinase (S6K1 kinase) and an inhibitor of translational initiation, eIF-4E binding protein (46 -48). While insulin activates mTOR and S6K1 kinase via the IRS-1/PI 3-kinase/Akt pathway (49,50), amino acids seem to exert their effect through a direct influence of mTOR (44,51,52). In any event, activation of mTOR and S6K1 kinase causes serine phosphorylation of IRS-1, with a subsequent decline in the IRS-1-associated PI 3-kinase activity (Fig.…”

Section: Serine Phosphorylation Of Irs-1mentioning

confidence: 98%

Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85α

2006

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Initial attempts to unravel the molecular mechanism of insulin resistance have strongly suggested that a defect responsible for insulin resistance in the majority of patients lies at the postreceptor level of insulin signaling. Subsequent studies in insulin-resistant animal models and humans have consistently demonstrated a reduced strength of insulin signaling via the insulin receptor substrate (IRS)-1/phosphatidylinositol (PI) 3-kinase pathway, resulting in diminished glucose uptake and utilization in insulin target tissues. However, the nature of the triggering event(s) remains largely enigmatic. Two separate, but likely, complementary mechanisms have recently emerged as a potential explanation. First, it became apparent that serine phosphorylation of IRS proteins can reduce their ability to attract PI 3-kinase, thereby minimizing its activation. A number of serine kinases that phosphorylate serine residues of IRS-1 and weaken insulin signal transduction have been identified. Additionally, mitochondrial dysfunction has been suggested to trigger activation of several serine kinases, leading to a serine phosphorylation of IRS-1. Second, a distinct mechanism involving increased expression of p85␣ has also been found to play an important role in the pathogenesis of insulin resistance. Conceivably, a combination of both increased expression of p85␣ and increased serine phosphorylation of IRS-1 is needed to induce clinically apparent insulin resistance. Diabetes 55: 2392-2397, 2006 E ven though insulin resistance has emerged as an enormous health care problem, trespassing the fields of obesity, diabetes, hypertension, and cardiovascular diseases (1,2), its molecular mechanism remains incompletely understood. Clinically, the term insulin resistance implies that higher-than-normal concentrations of insulin are required to maintain normoglycemia. On a cellular level, this term defines an inadequate strength of insulin signaling from the insulin receptor downstream to the final substrates of insulin action involved in multiple metabolic and mitogenic aspects of cellular function (3).Insulin action is initiated by an interaction of insulin with its cell surface receptor (4). The insulin receptor is a heterotetrameric protein that consists of two extracellular ␣ subunits and two transmembrane ␤ subunits connected by disulfide bridges (5-7). Insulin binding to the extracellular ␣ subunit induces conformational changes of the insulin receptor that activate the tyrosine kinase domain of the intracellular portion of the ␤ subunit (8 -11). Once the tyrosine kinase of insulin receptors is activated, it promotes autophosphorylation of the ␤ subunit itself, where phosphorylation of three tyrosine residues (Tyr-1158, Tyr-1162, and Tyr-1163) is required for amplification of the kinase activity (12,13). Activation of the tyrosine kinase of the insulin receptor also leads to a rapid phosphorylation of the so-called "docking proteins," such as insulin receptor substrate (IRS)-1, -2, -3, and -4, and several Shc proteins (52-, 46-, and...

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Section: Serine Phosphorylation Of Irs-1mentioning

confidence: 98%

Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85α

2006

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“…The metabolic effects of insulin are mediated through IRS-1/IRS-2-mediated activation of the phosphatidylinositol-3 kinase pathway [12]. Several post-insulin-receptor molecules have been indicated to play significant roles in insulin signalling, including the serine/threonine protein kinase Akt, protein-tyrosine phosphatase 1B (PTP1B), peroxisome proliferator-activated receptor γ (PPARγ), and mammalian target of rapamycin and S6 kinase [13][14][15]. It has been speculated that malfunction of these signalling molecules (either dampened or hyperactivated) may contribute to development of insulin resistance [3,16].…”

Section: Introductionmentioning

confidence: 99%

Cardiac overexpression of catalase rescues cardiac contractile dysfunction induced by insulin resistance: role of oxidative stress, protein carbonyl formation and insulin sensitivity

et al. 2006

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Aims/hypothesis: Insulin resistance leads to oxidative stress and cardiac dysfunction. This study examined the impact of catalase on insulin-resistanceinduced cardiac dysfunction, oxidative damage and insulin sensitivity. Methods: Insulin resistance was initiated in FVB and catalase-transgenic mice by 12 weeks of sucrose feeding. Contractile and intracellular Ca 2+ properties were evaluated in cardiomyocytes including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR 90 ), half-width duration (HWD), maximal velocity of shortening/relengthening (±dL/dt), fura-fluorescence intensity change (ΔFFI) and intracellular Ca 2+ clearance rate (τ). Reactive oxygen species (ROS) and protein damage were evaluated with dichlorodihydrofluorescein and protein carbonyl formation. Results: Sucrose-fed mice displayed hyperinsulinaemia, impaired glucose tolerance and normal body weight. Myocytes from FVB sucrose-fed mice exhibited depressed PS and ±dL/dt, prolonged TR 90 and τ, and reduced ΔFFI associated with normal TPS and HWD compared with those from starch-fed control mice. ROS and protein carbonyl formation were elevated in FVB sucrose-fed mice. Insulin sensitivity was reduced, evidenced by impaired insulin-stimulated 2-deoxy-D-[ 3 H] glucose uptake. Western blot analysis indicated that sucrose feeding: (1) inhibited insulin-stimulated phosphorylation of insulin receptor and Akt; (2) enhanced proteintyrosine phosphatase 1B (PTP1B) expression; and (3) suppressed endothelial nitric oxide synthase (eNOS) and Na + -Ca 2+ exchanger expression without affecting peroxisome proliferator-activated receptor γ (PPARγ), sarco(endo)plasmic reticulum Ca 2+ -ATPase isozyme 2a and phospholamban. Catalase ablated insulin-resistanceinduced mechanical dysfunction, ROS production and protein damage, and reduced eNOS, but not insulin insensitivity. Catalase itself decreased resting FFI and enhanced expression of PTP1B and PPARγ. Conclusions/ interpretation: These data indicate that catalase rescues insulin-resistance-induced cardiac dysfunction related to ROS production and protein oxidation but probably does not improve insulin sensitivity.

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“…In response to insulin and amino acids, mTOR phosphorylates and modulates the activities of p70 S6 kinase and an inhibitor of translational initiation, eIF-4E-binding protein [24][25][26]. Whereas insulin activates mTOR and p70S6 kinase via the IRS-1-PI 3-kinase-Akt pathway [27,28], amino acids seem to exert their effect through a direct influence of Akt [29]. In any event, activation of mTOR and p70S6 kinase causes increased serine phosphorylation of IRS-1 with a subsequent decline in IRS-1-associated PI 3-kinase activity.…”

Section: Discussionmentioning

confidence: 99%

Nutritional upregulation of p85α expression is an early molecular manifestation of insulin resistance

et al. 2006

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Aims/hypothesis: We sought to define early molecular alterations associated with nutritionally induced insulin resistance in humans. Methods: Insulin sensitivity was assessed using a hyperinsulinaemic-euglycaemic clamp in eight healthy women while on an isocaloric diet and after 3 days of overfeeding (50% above eucaloric diet). Expression of phosphatidylinositol (PI) 3-kinase subunits p85α and p110 was assessed and measurements were made of IRS-1-associated PI 3-kinase activity, tyrosine and serine phosphorylation of IRS-1, and serine and threonine phosphorylation of p70S6 kinase. Measurements were made in skeletal muscle biopsies obtained before and after overfeeding. Results: Three days of overfeeding resulted in a reduction of insulin sensitivity accompanied by: (1) increased expression of skeletal muscle p85α; (2) an alteration in the ratio of p85α to p110; (3) a decrease in the amount of IRS-1-associated p110; and (4) a decrease in PI 3-kinase activity. Increases in expression of p85α and in the p85α:p110 ratio demonstrated a highly significant inverse correlation with insulin sensitivity, and changes in PI 3-kinase activity correlated with changes in insulin sensitivity. Tyrosine and serine phosphorylation of IRS-1 and serine and threonine phosphorylation of p70S6 kinase were unaffected by 3 days of overfeeding. Conclusions/interpretation: We identified a novel mechanism of nutritionally induced insulin resistance in healthy women of normal weight. We conclude that increased expression of p85α may be one of the earliest molecular alterations in the mechanism of the insulin resistance associated with overfeeding.

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Amino acids and leucine allow insulin activation of the PKB/mTOR pathway in normal adipocytes treated with wortmannin and in adipocytes fromdb/dbmice

Cited by 72 publications

References 41 publications

Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85α

Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85α

Cardiac overexpression of catalase rescues cardiac contractile dysfunction induced by insulin resistance: role of oxidative stress, protein carbonyl formation and insulin sensitivity

Nutritional upregulation of p85α expression is an early molecular manifestation of insulin resistance

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