Impaired Insulin Signaling in Skeletal Muscles from Transgenic Mice Expressing Kinase-deficient Insulin Receptors

Impaired insulin signaling has been thought of as important step in both Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM). Posttranslational modifications (PTMs) regulate functions and interaction of insulin with insulin receptors substrates (IRSs) and activate insulin signaling downstream pathways via autophosphorylation on several tyrosine (TYR) residues on IRSs. Two important insulin receptor substrates 1 and 2 are widely expressed in human, and alternative phosphorylation on their serine (Ser) and threonine (Thr) residues has been known to block the Tyr phosphorylation of IRSs, thus inhibiting insulin signaling and promoting insulin resistance. Like phosphorylation, O-glycosylation modification is important PTM and inhibits phosphorylation on same or neighboring Ser/Thr residues, often called Yin Yang sites. Both IRS-1 and IRS-2 have been shown to be O-glycosylated; however exact sites are not determined yet. In this study, by using neuronal network based prediction methods, we found more than 50 Ser/Thr residues that have potential to be O-glycosylated and may act as possible sites as well. Moreover, alternative phosphorylation and O-glycosylation on IRS-1 Ser-312, 984, 1037, and 1101 may act as possible therapeutic targets to minimize the risk of AD and T2DM.

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Differential interaction of Apolipoprotein-E isoforms with insulin receptors modulates brain insulin signaling in mutant human amyloid precursor protein transgenic mice

Scientific Reports ◽

10.1038/srep13842 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 20

Author(s):

Elizabeth S Chan ◽

Christopher Chen ◽

Gregory M Cole ◽

Boon-Seng Wong

Keyword(s):

Transgenic Mice ◽

Amyloid Precursor Protein ◽

Apolipoprotein E ◽

Insulin Signaling ◽

Insulin Receptors ◽

Precursor Protein ◽

Differential Interaction ◽

Brain Insulin

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Impaired Insulin Signaling Affects Renal Organic Anion Transporter 3 (Oat3) Function in Streptozotocin-Induced Diabetic Rats

PLoS ONE ◽

10.1371/journal.pone.0096236 ◽

2014 ◽

Vol 9 (5) ◽

pp. e96236 ◽

Cited By ~ 15

Author(s):

Anusorn Lungkaphin ◽

Phatchawan Arjinajarn ◽

Anchalee Pongchaidecha ◽

Chutima Srimaroeng ◽

Lisa Chatsudthipong ◽

...

Keyword(s):

Insulin Signaling ◽

Organic Anion ◽

Diabetic Rats ◽

Organic Anion Transporter ◽

Anion Transporter ◽

Impaired Insulin ◽

Organic Anion Transporter 3

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Endothelial insulin receptors differentially control insulin signaling kinetics in peripheral tissues and brain of mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1710625114 ◽

2017 ◽

Vol 114 (40) ◽

pp. E8478-E8487 ◽

Cited By ~ 37

Author(s):

Masahiro Konishi ◽

Masaji Sakaguchi ◽

Samuel M. Lockhart ◽

Weikang Cai ◽

Mengyao Ella Li ◽

...

Keyword(s):

Insulin Resistance ◽

Endothelial Cells ◽

Food Intake ◽

Insulin Signaling ◽

Insulin Action ◽

Insulin Receptors ◽

Brain Regions ◽

Peripheral Tissues ◽

Systemic Insulin Resistance

Insulin receptors (IRs) on endothelial cells may have a role in the regulation of transport of circulating insulin to its target tissues; however, how this impacts on insulin action in vivo is unclear. Using mice with endothelial-specific inactivation of the IR gene (EndoIRKO), we find that in response to systemic insulin stimulation, loss of endothelial IRs caused delayed onset of insulin signaling in skeletal muscle, brown fat, hypothalamus, hippocampus, and prefrontal cortex but not in liver or olfactory bulb. At the level of the brain, the delay of insulin signaling was associated with decreased levels of hypothalamic proopiomelanocortin, leading to increased food intake and obesity accompanied with hyperinsulinemia and hyperleptinemia. The loss of endothelial IRs also resulted in a delay in the acute hypoglycemic effect of systemic insulin administration and impaired glucose tolerance. In high-fat diet-treated mice, knockout of the endothelial IRs accelerated development of systemic insulin resistance but not food intake and obesity. Thus, IRs on endothelial cells have an important role in transendothelial insulin delivery in vivo which differentially regulates the kinetics of insulin signaling and insulin action in peripheral target tissues and different brain regions. Loss of this function predisposes animals to systemic insulin resistance, overeating, and obesity.

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Mechanisms of impaired insulin signaling in calcineruin A‐alpha knockout mice

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.597.10 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Jennifer L Gooch ◽

Tiffany K Roberts ◽

Russ Price ◽

Ramesh N Reddy

Keyword(s):

Insulin Signaling ◽

Knockout Mice ◽

Impaired Insulin

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Effect of Subtoxic DDT Exposure on Glucose Uptake and Insulin Signaling in Rat L6 Myoblast-Derived Myotubes

International Journal of Toxicology ◽

10.1177/1091581819850577 ◽

2019 ◽

Vol 38 (4) ◽

pp. 303-311 ◽

Cited By ~ 2

Author(s):

Vijay Kumar Singh ◽

Sajib Kumar Sarkar ◽

Alpana Saxena ◽

Bidhan Chandra Koner

Keyword(s):

Insulin Resistance ◽

Glucose Uptake ◽

Tyrosine Phosphorylation ◽

Insulin Signaling ◽

Messenger Rna ◽

Insulin Receptors ◽

Serine Phosphorylation ◽

Enzyme Linked Immunosorbent Assay ◽

Antioxidant Content ◽

L6 Myoblast

Exposure to persistent organic pollutants including dichlorodiphenyltrichloroethane (DDT) induces insulin resistance. But the mechanism is not clearly known. The present study was designed to explore the effect of subtoxic DDT exposure on (1) insulin-stimulated glucose uptake, (2) malondialdehyde (MDA) level and total antioxidant content, (3) activation of redox sensitive kinases (RSKs), and (4) insulin signaling in rat L6 myoblast-derived myotubes. Exposure to 30 mg/L and 60 mg/L of DDT for 18 hours dose dependently decreased glucose uptake and antioxidant content in myotubes and increased MDA levels. The exposures did not alter tumor necrosis factor α (TNF-α) level as determined by enzyme-linked immunosorbent assay, despite decreased messenger RNA expression following DDT exposures. Phosphorylation of c-Jun N-terminal kinases and IκBα, an inhibitory component of nuclear factor κB (NFκB), was increased, suggesting activation of RSKs. The level of tyrosine phosphorylation of insulin receptor substrate 1 and serine phosphorylation of protein kinase B (Akt) on insulin stimulation decreased in myotubes with exposure to subtoxic concentrations of DDT, but there was no change in tyrosine phosphorylation level of insulin receptors. We conclude that subtoxic DDT exposure impairs insulin signaling and thereby induces insulin resistance in muscle cells. Data show that oxidative stress-induced activation of RSKs is responsible for impairment of insulin signaling on DDT exposure.

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Overexpression of Galgt2 in skeletal muscle prevents injury resulting from eccentric contractions in both mdx and wild-type mice

AJP Cell Physiology ◽

10.1152/ajpcell.00456.2008 ◽

2009 ◽

Vol 296 (3) ◽

pp. C476-C488 ◽

Cited By ~ 53

Author(s):

Paul T. Martin ◽

Rui Xu ◽

Louise R. Rodino-Klapac ◽

Elaine Oglesbay ◽

Marybeth Camboni ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscular Dystrophy ◽

Transgenic Mice ◽

Skeletal Muscles ◽

Eccentric Contractions ◽

Cytotoxic T Cell ◽

Muscle Pathology ◽

Mdx Mice ◽

Specific Force ◽

Wild Type

The cytotoxic T cell (CT) GalNAc transferase, or Galgt2, is a UDP-GalNAc:β1,4- N-acetylgalactosaminyltransferase that is localized to the neuromuscular synapse in adult skeletal muscle, where it creates the synaptic CT carbohydrate antigen {GalNAcβ1,4[NeuAc(orGc)α2, 3]Galβ1,4GlcNAcβ-}. Overexpression of Galgt2 in the skeletal muscles of transgenic mice inhibits the development of muscular dystrophy in mdx mice, a model for Duchenne muscular dystrophy. Here, we provide physiological evidence as to how Galgt2 may inhibit the development of muscle pathology in mdx animals. Both Galgt2 transgenic wild-type and mdx skeletal muscles showed a marked improvement in normalized isometric force during repetitive eccentric contractions relative to nontransgenic littermates, even using a paradigm where nontransgenic muscles had force reductions of 95% or more. Muscles from Galgt2 transgenic mice, however, showed a significant decrement in normalized specific force and in hindlimb and forelimb grip strength at some ages. Overexpression of Galgt2 in muscles of young adult mdx mice, where Galgt2 has no effect on muscle size, also caused a significant decrease in force drop during eccentric contractions and increased normalized specific force. A comparison of Galgt2 and microdystrophin overexpression using a therapeutically relevant intravascular gene delivery protocol showed Galgt2 was as effective as microdystrophin at preventing loss of force during eccentric contractions. These experiments provide a mechanism to explain why Galgt2 overexpression inhibits muscular dystrophy in mdx muscles. That overexpression also prevents loss of force in nondystrophic muscles suggests that Galgt2 is a therapeutic target with broad potential applications.

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PGRN Induces Impaired Insulin Sensitivity and Defective Autophagy in Hepatic Insulin Resistance

Molecular Endocrinology ◽

10.1210/me.2014-1266 ◽

2015 ◽

Vol 29 (4) ◽

pp. 528-541 ◽

Cited By ~ 21

Author(s):

Jiali Liu ◽

Huixia Li ◽

Bo Zhou ◽

Lin Xu ◽

Xiaomin Kang ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Insulin Signaling ◽

Nuclear Factor Κb ◽

Hepatic Insulin Resistance ◽

Causative Role ◽

Dependent Manner ◽

Nuclear Factor ◽

Impaired Insulin

Abstract Progranulin (PGRN) has recently emerged as an important regulator for glucose metabolism and insulin sensitivity. However, the underlying mechanisms of PGRN in the regulation of insulin sensitivity and autophagy remain elusive. In this study, we aimed to address the direct effects of PGRN in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. We found that mice treated with PGRN for 21 days exhibited the impaired glucose tolerance and insulin tolerance and hepatic autophagy imbalance as well as defective insulin signaling. Furthermore, treatment of mice with TNF receptor (TNFR)-1 blocking peptide-Fc, a TNFR1 blocking peptide-Fc fusion protein to competitively block the interaction of PGRN and TNFR1, resulted in the restoration of systemic insulin sensitivity and the recovery of autophagy and insulin signaling in liver. Consistent with these findings in vivo, we also observed that PGRN treatment induced defective autophagy and impaired insulin signaling in hepatocytes, with such effects being drastically nullified by the addition of TNFR1 blocking peptide -Fc or TNFR1-small interference RNA via the TNFR1-nuclear factor-κB-dependent manner, indicating the causative role of PGRN in hepatic insulin resistance. In conclusion, our findings supported the notion that PGRN is a key regulator of hepatic insulin resistance and that PGRN may mediate its effects, at least in part, by inducing defective autophagy via TNFR1/nuclear factor-κB.

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