scholarly journals Hepatic Insulin Resistance and Altered Gluconeogenic Pathway in Premature Baboons

Endocrinology ◽  
2017 ◽  
Vol 158 (5) ◽  
pp. 1140-1151 ◽  
Author(s):  
Lisa McGill-Vargas ◽  
Amalia Gastaldelli ◽  
Hanyu Liang ◽  
Diana Anzueto Guerra ◽  
Teresa Johnson-Pais ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Insulin Signaling ◽  
Glycogen Synthase ◽  
Adult Life ◽  
Hepatic Insulin Resistance ◽  
Glucose Regulation ◽  
Postnatal Life ◽  
Hepatic Insulin Signaling ◽  
Altered Glucose ◽  
Increased Risk

Abstract Premature infants have altered glucose regulation early in life and increased risk for diabetes in adulthood. Although prematurity leads to an increased risk of diabetes and metabolic syndrome in adult life, the role of hepatic glucose regulation and adaptation to an early extrauterine environment in preterm infants remain unknown. The purpose of this study was to investigate developmental differences in glucose metabolism, hepatic protein content, and gene expression of key insulin-signaling/gluconeogenic molecules. Fetal baboons were delivered at 67%, 75%, and term gestational age and euthanized at birth. Neonatal baboons were delivered prematurely (67% gestation), survived for two weeks, and compared with similar postnatal term animals and underwent serial hyperinsulinemic-euglycemic clamp studies. Premature baboons had decreased endogenous glucose production (EGP) compared with term animals. Consistent with these results, the gluconeogenic molecule, phosphoenolpyruvate carboxykinase messenger RNA, was decreased in preterm baboons compared with terms. Hepatic insulin signaling was altered by preterm birth as evidenced by decreased insulin receptor–β, p85 subunit of phosphoinositide 3-kinase, phosphorylated insulin receptor substrate 1, and Akt-1 under insulin-stimulated conditions. Furthermore, preterm baboons failed to have the normal increase in glycogen synthase kinase-α from fetal to postnatal life. The blunted responses in hepatic insulin signaling may contribute to the hyperglycemia of prematurity, while impaired EGP leads to hypoglycemia of prematurity.

Sequential phosphorylation of insulin receptor substrate-2 by glycogen synthase kinase-3 and c-Jun NH2-terminal kinase plays a role in hepatic insulin signaling

2008 ◽  
Vol 294 (2) ◽  
pp. E307-E315 ◽  
Author(s):  
Hadar Sharfi ◽  
Hagit Eldar-Finkelman
Keyword(s):  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Insulin Signaling ◽  
Glycogen Synthase ◽  
Serine Phosphorylation ◽  
Glycogen Synthase Kinase ◽  
Regulatory Subunit ◽  
Insulin Receptor Substrate ◽  
Phosphorylation Sites ◽  
Hepatic Insulin Signaling

Serine phosphorylation of insulin receptor substrate (IRS) proteins is a potential inhibitory mechanism in insulin signaling. Here we show that IRS-2 is phosphorylated by glycogen synthase kinase (GSK)-3. Phosphorylation by GSK-3 requires prior phosphorylation of its substrates, prompting us to identify the “priming kinase.” It was found that the stress activator anisomycin enhanced the ability of GSK-3 to phosphorylate IRS-2. Use of a selective c-Jun NH2-terminal kinase (JNK) inhibitor and cells overexpressing JNK implicated JNK as the priming kinase. This allowed us to narrow down the number of potential GSK-3 phosphorylation sites within IRS-2 to four regions that follow the motif SXXXSP. IRS-2 deletion mutants enabled us to localize the GSK-3 and JNK phosphorylation sites to serines 484 and 488, respectively. Mutation at serine 488 reduced JNK phosphorylation of IRS-2, and mutation of each site separately abolished GSK-3 phosphorylation of IRS-2. Treatment of H4IIE liver cells with anisomycin inhibited insulin-induced tyrosine phosphorylation of IRS-2; inhibition was reversed by pretreatment with the JNK and GSK-3 inhibitors. Moreover, overexpression of JNK and GSK-3 in H4IIE cells reduced insulin-induced tyrosine phosphorylation of IRS-2 and its association with the p85 regulatory subunit of phosphatidylinositol 3-kinase. Finally, both GSK-3 and JNK are abnormally upregulated in the diabetic livers of ob/obmice. Together, our data indicate that IRS-2 is sequentially phosphorylated by JNK and GSK-3 at serines 484/488 and provide evidence for their inhibitory role in hepatic insulin signaling.

scholarly journals Dynamic Functional Relay between Insulin Receptor Substrate 1 and 2 in Hepatic Insulin Signaling during Fasting and Feeding

2008 ◽  
Vol 8 (1) ◽  
pp. 49-64 ◽  
Author(s):  
Naoto Kubota ◽  
Tetsuya Kubota ◽  
Shinsuke Itoh ◽  
Hiroki Kumagai ◽  
Hideki Kozono ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Insulin Signaling ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1 ◽  
Hepatic Insulin Signaling

scholarly journals EET Analog Treatment Improves Insulin Signaling in a Genetic Mouse Model of Insulin Resistance

2021 ◽  
Author(s):  
Kakali Ghoshal ◽  
Xiyue Li ◽  
Dungeng Peng ◽  
John R. Falck ◽  
Raghunath Reddy Anugu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Signaling ◽  
Genetic Model ◽  
Water Soluble ◽  
Hepatic Insulin Resistance ◽  
Epoxyeicosatrienoic Acid ◽  
Genetic Mouse Model ◽  
Hepatic Insulin Signaling ◽  
Underlying Mechanisms

We previously showed that global deletion of the cytochrome P450 epoxygenase <i>Cyp2c44</i>, a major epoxyeicosatrienoic acid (EET) producing enzyme in mice, leads to impaired hepatic insulin signaling resulting in insulin resistance. This finding led us to investigate whether administration of a water soluble EET analog restores insulin signaling <i>in vivo</i> in <i>Cyp2c44(-/-)</i> mice and investigated the underlying mechanisms by which this effect is exerted. <i>Cyp2c44(-/-)</i> mice treated with the analog EET-A for 4 weeks improved fasting glucose and glucose tolerance compared to <i>Cyp2c44(-/-)</i> mice treated with vehicle alone. This beneficial effect was accompanied by enhanced hepatic insulin signaling, decreased expression of gluconeogenic genes and increased expression of glycogenic genes. Mechanistically, we show that insulin-stimulated phosphorylation of insulin receptor β (IRβ) is impaired in primary <i>Cyp2c44(-/-) </i>hepatocytes and this can be restored by cotreatment with EET-A and insulin. Plasma membrane fractionations of livers indicated that EET-A enhances the retention of IRβ in membrane rich fractions, thus potentiating its activation. Altogether, EET analogs ameliorate insulin signaling in a genetic model of hepatic insulin resistance by stabilizing membrane-associated IRβ and potentiating insulin signaling.

scholarly journals Postreceptoral Adipocyte Insulin Resistance Induced by Nelfinavir Is Caused by Insensitivity of PKB/Akt to Phosphatidylinositol-3,4,5-Trisphosphate

Endocrinology ◽  
2009 ◽  
Vol 150 (6) ◽  
pp. 2618-2626 ◽  
Author(s):  
Ilana Kachko ◽  
Adva Maissel ◽  
Livnat Mazor ◽  
Ronit Ben-Romano ◽  
Robert T. Watson ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Membrane Fusion ◽  
Insulin Signaling ◽  
Glycogen Synthase ◽  
Signal Propagation ◽  
Kinase Assay ◽  
Pleckstrin Homology Domain ◽  
Akt Activation ◽  
Rate Limiting

Adipocyte insulin resistance can be caused by proximal insulin signaling defects but also from postreceptor mechanisms, which in large are poorly characterized. Adipocytes exposed for 18 h to the HIV protease inhibitor nelfinavir manifest insulin resistance characterized by normal insulin-stimulated tyrosine phosphorylation of the insulin receptor and insulin receptor substrate proteins, preserved in vitro phosphatidylinositol 3-kinase (PI 3-kinase) assay activity but impaired activation of PKB/Akt and stimulation of glucose uptake. Here we aimed to assess whether impaired PKB/Akt activation is indeed rate limiting for insulin signaling propagation in response to nelfinavir and the mechanism for defective PKB/Akt activation. Nelfinavir treatment of 3T3-L1 adipocytes impaired the insulin-stimulated translocation and membrane fusion of myc-glucose transporter (GLUT)-4-green fluorescent protein (GFP) reporter. Phosphorylation of PKB/Akt substrates including glycogen synthase kinase-3 and AS160 decreased in response to nelfinavir, and this remained true, even in cells with forced generation of phosphatidylinositol-3,4,5-trisphohphate (PIP3) by a membrane-targeted active PI 3-kinase, confirming that impaired PKB/Akt activation was rate limiting for insulin signal propagation. Cells expressing a GFP-tagged pleckstrin homology domain of general receptors for phosphoinositides 1, which binds PIP3, revealed intact PIP3-mediated plasma membrane translocation of this reporter in nelfinavir-treated cells. However, expression of a membrane-targeted catalytic subunit of PI 3-kinase failed to induce myc-GLUT4-GFP translocation in the absence of insulin, as it did in control cells. Conversely, a membrane-targeted and constitutively active PKB/Akt mutant was normally phosphorylated on S473 and T308, confirming intact PKB/Akt kinases activity, and induced myc-GLUT4-GFP translocation. Collectively, nelfinavir uncovers a postreceptor mechanism for insulin resistance, caused by interference with the sensing of PIP3 by PKB/Akt, leading to impaired GLUT4 translocation and membrane fusion.

scholarly journals Linagliptin Ameliorates Hepatic Steatosis via Non-Canonical Mechanisms in Mice Treated with a Dual Inhibitor of Insulin Receptor and IGF-1 Receptor

2020 ◽  
Vol 21 (21) ◽  
pp. 7815
Author(s):  
Tomoko Okuyama ◽  
Jun Shirakawa ◽  
Kazuki Tajima ◽  
Yoko Ino ◽  
Heidrun Vethe ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Hepatic Steatosis ◽  
Insulin Signaling ◽  
Inflammatory Responses ◽  
Gene Expressions ◽  
Dual Inhibitor ◽  
Insulin Resistant ◽  
Glucose Levels ◽  
Hepatic Insulin Signaling ◽  
Igf1r Inhibitor

Abnormal hepatic insulin signaling is a cause or consequence of hepatic steatosis. DPP-4 inhibitors might be protective against fatty liver. We previously reported that the systemic inhibition of insulin receptor (IR) and IGF-1 receptor (IGF1R) by the administration of OSI-906 (linsitinib), a dual IR/IGF1R inhibitor, induced glucose intolerance, hepatic steatosis, and lipoatrophy in mice. In the present study, we investigated the effects of a DPP-4 inhibitor, linagliptin, on hepatic steatosis in OSI-906-treated mice. Unlike high-fat diet-induced hepatic steatosis, OSI-906-induced hepatic steatosis is not characterized by elevations in inflammatory responses or oxidative stress levels. Linagliptin improved OSI-906-induced hepatic steatosis via an insulin-signaling-independent pathway, without altering glucose levels, free fatty acid levels, gluconeogenic gene expressions in the liver, or visceral fat atrophy. Hepatic quantitative proteomic and phosphoproteomic analyses revealed that perilipin-2 (PLIN2), major urinary protein 20 (MUP20), cytochrome P450 2b10 (CYP2B10), and nicotinamide N-methyltransferase (NNMT) are possibly involved in the process of the amelioration of hepatic steatosis by linagliptin. Thus, linagliptin improved hepatic steatosis induced by IR and IGF1R inhibition via a previously unknown mechanism that did not involve gluconeogenesis, lipogenesis, or inflammation, suggesting the non-canonical actions of DPP-4 inhibitors in the treatment of hepatic steatosis under insulin-resistant conditions.

Hemorrhage induces the rapid development of hepatic insulin resistance

2003 ◽  
Vol 284 (1) ◽  
pp. G107-G115 ◽  
Author(s):  
Yuchen Ma ◽  
Ping Wang ◽  
Joachim F. Kuebler ◽  
Irshad H. Chaudry ◽  
Joseph L. Messina
Keyword(s):  
Insulin Resistance ◽  
Insulin Signaling ◽  
Metabolic Response ◽  
Rapid Development ◽  
Convincing Evidence ◽  
Pi3 Kinase ◽  
Hepatic Insulin Resistance ◽  
Adult Rats ◽  
Male Adult ◽  
Hepatic Insulin Signaling

Hyperglycemia is an early metabolic response to trauma and hemorrhage. The role of hepatic insulin resistance to the development of this hyperglycemia is not well understood. The aim of this study was to determine whether the liver becomes insulin resistant and to identify the particular hepatic insulin signaling pathways that may be compromised following trauma and hemorrhage. Male adult rats were bled to a mean arterial pressure of 40 mmHg and maintained at that pressure for 90 min followed by resuscitation with Ringer lactate. Data showed that trauma and hemorrhage rapidly induced profound hyperinsulinemia in combination with significant hyperglycemia, suggesting the development of insulin resistance. After trauma and hemorrhage, hepatic insulin signaling via the insulin-induced phosphatidylinositol 3 (PI3)-kinase-Akt pathway was abolished, whereas ERK1/2 signaling was relatively normal. The regulation (inhibition) of a hepatic-, insulin-, and the PI3-kinase-dependent gene, IGF binding protein-1, was also lost. The present study provides convincing evidence of a rapid onset hepatic insulin resistance following a combination of trauma and hemorrhage.

scholarly journals Role of inhibitory κB kinase and c-Jun NH2-terminal kinase in the development of hepatic insulin resistance in critical illness diabetes

2011 ◽  
Vol 301 (3) ◽  
pp. G454-G463 ◽  
Author(s):  
Shaoning Jiang ◽  
Joseph L. Messina
Keyword(s):  
Insulin Resistance ◽  
Critical Illness ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Adenovirus Vector ◽  
Dominant Negative ◽  
Serine Phosphorylation ◽  
Hepatic Insulin Resistance ◽  
Mortality And Morbidity ◽  
Hepatic Insulin Signaling

Hyperglycemia and insulin resistance induced by acute injuries or critical illness are associated with increased mortality and morbidity, as well as later development of type 2 diabetes. The molecular mechanisms underlying the acute onset of insulin resistance following critical illness remain poorly understood. In the present studies, the roles of serine kinases, inhibitory κB kinase (IKK) and c-Jun NH2-terminal kinase (JNK), in the acute development of hepatic insulin resistance were investigated. In our animal model of critical illness diabetes, activation of hepatic IKK and JNK was observed as early as 15 min, concomitant with the rapid impairment of hepatic insulin signaling and increased serine phosphorylation of insulin receptor substrate 1. Inhibition of IKKα or IKKβ, or both, by adenovirus vector-mediated expression of dominant-negative IKKα or IKKβ in liver partially restored insulin signaling. Similarly, inhibition of JNK1 kinase by expression of dominant-negative JNK1 also resulted in improved hepatic insulin signaling, indicating that IKK and JNK1 kinases contribute to critical illness-induced insulin resistance in liver.

scholarly journals Elevated basal PI 3-kinase activity and reduced insulin signaling in sucrose-induced hepatic insulin resistance

2002 ◽  
Vol 282 (1) ◽  
pp. E170-E176 ◽  
Author(s):  
Michael J. Pagliassotti ◽  
Jione Kang ◽  
Jeffrey S. Thresher ◽  
Chin K. Sung ◽  
Michael E. Bizeau
Keyword(s):  
Portal Vein ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Kinase Activity ◽  
Control Diet ◽  
Diet Group ◽  
Hepatic Insulin Resistance ◽  
Sucrose Diet ◽  
High Sucrose Diet ◽  
High Sucrose

Sucrose feeding reduces the ability of insulin to suppress glucose production and hepatic gluconeogenesis. The present study examined the effect of a high-sucrose diet on early insulin-signaling steps in the liver. Rats were provided a high-starch (STD, control diet) or high-sucrose diet (HSD) for 3 wk. On the day of study, overnight-fasted rats were anesthetized and injected with either saline ( n = 5/diet group) or insulin (2 mU/kg, n = 5/diet group) via the portal vein. Portal venous blood and liver tissue were harvested 2 min after injections. Portal vein plasma glucose levels were not significantly different among groups, pooled average 147 ± 12 mg/dl. Western blot analysis revealed no significant differences in the amount of insulin receptor (IR), insulin receptor substrates-1 and -2 (IRS-1, IRS-2), and the p85 subunit of phosphatidylinositol (PI) 3-kinase. In contrast, the amount of the p110β subunit of PI 3-kinase was increased ∼2-fold in HSD vs. STD ( P < 0.05). After saline injection, tyrosine phosphorylation (pY) of IR, IRS-1, and IRS-2 was not significantly different between groups. However, PI 3-kinase activity associated with phosphorylated proteins was increased ∼40% in HSD vs. STD ( P < 0.05). After insulin injection, pY of the IR was not different between groups, whereas pY of IRS-1 and IRS-2 was reduced ( P < 0.05) in HSD vs. STD. In addition, association of IRS-1 and IRS-2 with p85 was significantly reduced in HSD vs. STD. These data demonstrate that an HSD impairs insulin-stimulated early postreceptor signaling (pY of IRS proteins, IRS interaction with p85). Furthermore, the increased amount of p110β and increased basal PI 3-kinase activity suggest a diet-induced compensatory response.

scholarly journals Caffeine modulates phosphorylation of insulin receptor substrate-1 and impairs insulin signal transduction in rat skeletal muscle

2011 ◽  
Vol 111 (6) ◽  
pp. 1629-1636 ◽  
Author(s):  
Tatsuro Egawa ◽  
Satoshi Tsuda ◽  
Xiao Ma ◽  
Taku Hamada ◽  
Tatsuya Hayashi
Keyword(s):  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Kinase Inhibitor ◽  
Glycogen Synthase ◽  
Mammalian Target Of Rapamycin ◽  
Insulin Receptor Substrate ◽  
Dependent Manner ◽  
Insulin Signal Transduction ◽  
Physiological Dose

Caffeine decreases insulin sensitivity and insulin-stimulated glucose transport in skeletal muscle; however, the precise mechanism responsible for this deleterious effect is not understood fully. We investigated the effects of incubation with caffeine on insulin signaling in rat epitrochlearis muscle. Caffeine (≥1 mM, ≥15 min) suppressed insulin-stimulated insulin receptor substrate (IRS)-1 Tyr612 phosphorylation in a dose- and time-dependent manner. These responses were associated with inhibition of the insulin-stimulated phosphorylation of phosphatidylinositol 3-kinase (PI3K) Tyr458, Akt Ser473, and glycogen synthase kinase-3β Ser9 and with inhibition of insulin-stimulated 3- O-methyl-d-glucose (3MG) transport but not with inhibition of the phosphorylation of insulin receptor-β Tyr1158/62/63. Furthermore, caffeine enhanced phosphorylation of IRS-1 Ser307 and an IRS-1 Ser307 kinase, inhibitor-κB kinase (IKK)-α/β Ser176/180. Blockade of IKK/IRS-1 Ser307 by caffeic acid ameliorated the caffeine-induced downregulation of IRS-1 Tyr612 phosphorylation and 3MG transport. Caffeine also increased the phosphorylation of IRS-1 Ser789 and an IRS-1 Ser789 kinase, 5′-AMP-activated protein kinase (AMPK). However, inhibition of IRS-1 Ser789 and AMPK phosphorylation by dantrolene did not rescue the caffeine-induced downregulation of IRS-1 Tyr612 phosphorylation or 3MG transport. In addition, caffeine suppressed the phosphorylation of insulin-stimulated IRS-1 Ser636/639 and upstream kinases, including the mammalian target of rapamycin and p70S6 kinase. Intravenous injection of caffeine at a physiological dose (5 mg/kg) in rats inhibited the phosphorylation of insulin-stimulated IRS-1 Tyr612 and Akt Ser473 in epitrochlearis muscle. Our results indicate that caffeine inhibits insulin signaling partly through the IKK/IRS-1 Ser307 pathway, via a Ca2+- and AMPK-independent mechanism in skeletal muscle.

scholarly journals Akt signaling as a mediator of cardiac adaptation to low birth weight

2017 ◽  
Vol 233 (2) ◽  
pp. R81-R94 ◽  
Author(s):  
Kimberley C W Wang ◽  
Kimberley J Botting ◽  
Song Zhang ◽  
I Caroline McMillen ◽  
Doug A Brooks ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Birth Weight ◽  
Low Birth Weight ◽  
Adult Life ◽  
Epidemiological Studies ◽  
Left Ventricular ◽  
Postnatal Life ◽  
Risk Of Death ◽  
Expression Of Genes ◽  
Increased Risk

Intrauterine insults, such as poor nutrition and placental insufficiency, can alter cardiomyocyte development, and this can have significant long-term implications for heart health. Consequently, epidemiological studies have shown that low-birth-weight babies have an increased risk of death from cardiovascular disease in adult life. In addition, intrauterine growth restriction can result in increased left ventricular hypertrophy, which is the strongest predictor for poor health outcomes in cardiac patients. The mechanisms responsible for these associations are not clear, but a suboptimal intrauterine environment can program alternative expression of genes such as cardiac IGF-2/H19, IGF-2R and AT1R through either an increase or decrease in DNA methylation or histone acetylation at specific loci. Furthermore, hypoxia and other intrauterine insults can also activate the IGF-1 receptor via IGF-1 and IGF-2, and the AT1 receptor via angiotensin signaling pathways; both of which can result in the phosphorylation of Akt and the activation of a range of downstream pathways. In turn, Akt activation can increase cardiac angiogenesis and cardiomyocyte apoptosis and promote a reversion of metabolism in postnatal life to a fetal phenotype, which involves increased reliance on glucose. Cardiac Akt can also be indirectly regulated by microRNAs and conversely can target microRNAs that will eventually affect other specific cardiac genes and proteins. This review aims to discuss our understanding of this complex network of interactions, which may help explain the link between low birth weight and the increased risk of cardiovascular disease in adult life.

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