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Inhibition of Grb14, a negative modulator of insulin signaling, improves glucose homeostasis without causing cardiac dysfunction

ABSTRACT: Insulin resistance increases patient’s risk of developing type 2 diabetes (T2D), nonalcoholic steatohepatitis (NASH) and a host of other comorbidities including cardiovascular disease and cancer. At the molecular level, insulin exerts its function through the insulin receptor (IR), a transmembrane receptor tyrosine kinase. Data from human genetic studies have shown that Grb14 functions as a negative modulator of IR activity, and germline Grb14-knockout (KO) mice have improved insulin signaling in liver and muscle tissues. Here, we show that Grb14 knockdown in the liver and the heart with an AAV-shRNA (Grb14-shRNA) improves glucose homeostasis in diet-induced obese (DIO) mice. A previous report has shown that germline deletion of Grb14 in mice results in cardiac hypertrophy and decreased systolic function, effects that could severely limit the therapeutic potential of targeting Grb14. In this report, we demonstrate that there are no significant changes in hemodynamic function as measured by echocardiography in DIO Grb14 and DIO sham mice for a period of four months. While additional studies are needed to further establish efficacy and to de-risk potential negative cardiac effects in pre-clinical heart failure models, our data support inhibiting Grb14 to treat diabetes and related conditions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE143319 | GEO | 2020/04/14

REPOSITORIES: GEO

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Transcription profiling of mouse liver from JNK knocked down animals

Project description:Liver-specific Knockdown of JNK1 Up-regulates Proliferator-activated Receptor Coactivator 1 and Increases Plasma Triglyceride despite Reduced Glucose and Insulin Levels in Diet-induced Obese Mice. The c-Jun N-terminal kinases (JNKs) have been implicated in the development of insulin resistance, diabetes, and obesity. Genetic disruption of JNK1, but not JNK2, improves insulin sensitivity in diet-induced obese (DIO) mice. We applied RNA interference to investigate the specific role of hepatic JNK1 in contributing to insulin resistance in DIO mice. Adenovirus-mediated delivery of JNK1 short-hairpin RNA (Ad-shJNK1) resulted in almost complete knockdown of hepatic JNK1 protein without affecting JNK1 protein in other tissues. Liver-specific knockdown of JNK1 resulted in significant reductions in circulating insulin and glucose levels, by 57 and 16%, respectively. At the molecular level, JNK1 knockdown mice had sustained and significant increase of hepatic Akt phosphorylation. Furthermore, knockdown of JNK1 enhanced insulin signaling in vitro. Unexpectedly, plasma triglyceride levels were robustly elevated upon hepatic JNK1 knockdown. Concomitantly, expression of proliferator-activated receptor coactivator 1, glucokinase, and microsomal triacylglycerol transfer protein was increased. Further gene expression analysis demonstrated that knockdown of JNK1 up-regulates the hepatic expression of clusters of genes in glycolysis and several genes in triglyceride synthesis pathways. Our results demonstrate that liver-specific knockdown of JNK1 lowers circulating glucose and insulin levels but increases triglyceride levels in DIO mice. Experiment Overall Design: Liver sample from vehicle, GFP Adv-shRNA, or Jnk1 Adv-shRNA treated DIO mice with 5, 4, and 5 replicates, respectively

2008-06-15 | E-GEOD-7648 | biostudies-arrayexpress

Expression data in mouse liver expressing or not the adapter Grb14

Project description:Grb14 is an endogenous inhibitor of insulin signaling We used microarrays to investigate gene expression patterns after Grb14 silencing in mouse liver Ten week old mice were injected intraveinously with recombinant adenovirus expressing a control sh RNA (sh scramble) or a sh targetting Grb14 (shGrb14), and liver were studied in the fed state 7 days after the infection

2016-07-03 | E-GEOD-53521 | biostudies-arrayexpress

Insulin and IGF-1 Receptors Regulate Complex-I Dependent Mitochondrial Bioenergetics and Supercomplexes via FoxOs in Muscle

Project description:Decreased skeletal muscle strength and mitochondrial dysfunction are characteristic of diabetes. Action of insulin through insulin receptor (IR) and IGF-1 receptor (IGF1R) maintain muscle mass via suppression of FoxOs, but whether FoxO activation coordinates atrophy in concert with mitochondrial dysfunction is unknown. In the absence of systemic glucose or lipid abnormalities, muscle-specific IR knockout (MIRKO) or combined IR/IGF1R knockout (MIGIRKO) impaired mitochondrial respiration, decreased ATP production, and increased ROS. These mitochondrial abnormalities were not present in muscle-specific IR/IGF1R and FoxO1/3/4 quintuple knockout mice (QKO). Although autophagy was increased when IR/IGF1R were deleted in muscle, mitophagy was not increased. Mechanistically, RNA-seq revealed that complex-I core subunits were decreased in MIGIRKO muscle, and these were reversed with FoxO knockout. Thus, insulin-deficient diabetes or loss of insulin/IGF-1 action in muscle decreases complex-I driven mitochondrial respiration and supercomplex assembly, in part by FoxO-mediated repression of Complex-I subunit expression.

2021-07-21 | GSE178356 | GEO

Expression data in mouse liver expressing or not the adapter Grb14

Project description:Grb14 is an endogenous inhibitor of insulin signaling We used microarrays to investigate gene expression patterns after Grb14 silencing in mouse liver

2016-01-01 | GSE53521 | GEO

Expression data in mouse liver expressing or not the adapter Grb14

Project description:Grb14 is an endogenous inhibitor of insulin signaling We used microarrays to investigate gene expression patterns after Grb14 silencing in mouse liver

2016-10-28 | GSE81387 | GEO

Transcriptomic profile in lymphomonocytes of healthy subjects identifies an early signature of insulin resistance and related diseases

Project description:Insulin resistance is considered to be a pathogenetic mechanism in several and diverse diseases (e.g. type 2 diabetes, atherosclerosis) often antedating them in apparently healthy subjects. The aim of this study was to investigate whether IR per se is characterized by a specific pattern of gene expression. We analyzed the transcriptomic profile of peripheral blood mononuclear cells in two groups (10 subjects each) of healthy individuals, with extreme insulin resistance or sensitivity, matched for BMI, age and gender, selected within the MultiKnowledge Study cohort (n=148). Data were analyzed with an ad-hoc rank-based classification method. 321 genes composed the gene set distinguishing the insulin resistant and sensitive groups, within which the “Adrenergic signaling in cardiomyocytes” Kegg pathway was significantly represented, suggesting a pattern of increased intracellular cAMP and Ca2+, and apoptosis in the IR group. The same pathway allow to discriminate between insulin resistance and insulin sensitive subjects with BMI >25, supporting his role as a biomarker of IR. Moreover, ASCM pathway harbored biomarkers able to distinguish healthy and diseased subjects (from publicly available data sets) in IR-related diseases involving excitable cells: type 2 diabetes, chronic heart failure, and Alzheimer’s disease. Altered gene expression profile of the ASCM pathway is an early molecular signature of IR and could provide a common molecular pathogenetic platform for IR-related disorders, possibly representing an important aid in the efforts aiming at preventing, early detecting and optimally treating IR-related diseases.

2017-08-18 | GSE87005 | GEO

Title Page Cardiac Gene Therapy Rescues Diabetic Cardiomyopathy and Lowers Blood Glucose

Project description:Diabetic cardiomyopathy, an increasingly global epidemic and a major cause of heart failure with preserved ejection fraction (HFpEF), is associated with hyperglycemia, insulin resistance, and intra-cardiomyocyte calcium mishandling. Here we identify that, in db/db mice with type 2 diabetes induced HFpEF, abnormal remodeling of cardiomyocyte transverse-tubule microdomains occurs with downregulation of the membrane scaffolding protein cardiac bridging integrator 1 (cBIN1). Transduction of cBIN1 by AAV9 gene therapy can restore transverse-tubule microdomains to normalize intracellular distribution of calcium handling proteins and, surprisingly, glucose transporter 4 (GLUT4). Cardiac proteomics revealed that AAV9-cBIN1 normalizes components of calcium handling and GLUT4 translocation machineries. Functional studies further identified that AAV9-cBIN1 normalizes insulin-dependent glucose uptake in diabetic cardiomyocytes. Phenotypically, AAV9-cBIN1 rescues cardiac lusitropy, improves exercise intolerance, and ameliorates hyperglycemia in diabetic mice. Restoration of transverse-tubule microdomains can improve cardiac function in the setting of diabetic cardiomyopathy, and also improve systemic glycemic control.

2023-10-24 | PXD044236 | Pride

IGF1-receptor signalling attenuates the age-related decline of diastolic cardiac function

Project description:Insulin-like growth factor (IGF1R) signalling has been implicated to play an important role in regulation of cardiac growth, hypertrophy and contractile function, and has been linked to the development of age related congestive heart failure. Here we address the question to what extent cardiomyocyte specific IGF1 signalling is essential for maintenance of the structural and functional integrity of the adult murine heart. To investigate the effects of IGF1 signalling in the adult heart without confounding effects due to IGF1 over-expression or adaptation during embryonic and early post-natal development, we inactivated the IGF1R by a 4-hydroxy tamoxifen inducible Cre recombinase in adult cardiac myocytes. Efficient inactivation of the IGF1R (iCMIGF1RKO) as assessed by Western analysis and real-time PCR went along with reduced IGF1-dependent AKT and GSK3Î²-phosphorylation. Functional analysis by conductance manometry and magnetic resonance imaging (MRI) revealed no functional alterations in young adult iCMIGF1RKO mice (age 3 month). However, when induced in aged mice (11 month) diastolic cardiac function was depressed. To address the question if insulin signalling might compensate for the defective IGF1R signalling we inactivated Î²-cells by streptozotocin. However, the diabetes associated functional depression was similar in controls and iCMIGF1RKO mice. Similarly, analysis of the cardiac gene expression profile on 44K microarrays did not reveal activation of overt adaptive processes. Endogenous IGF1 receptor signalling is required for conservation of cardiac function of the aging heart, but not for the integrity of cardiac structure and function of young hearts. Four samples of each group: the control group, positive for Cre recombinase, but negative for the floxed IGF-1R and the experimental group with double transgenic mice (merCremer/+ IGFloxP/IGFloxP).

2012-07-31 | E-GEOD-32936 | biostudies-arrayexpress

Genome-wide analysis of gene expression changes in miR-214 KO mouse hearts and skeletal muscle

Project description:Early reperfusion of ischemic cardiac tissue remains the most effective intervention for improving clinical outcome following myocardial infarction. However, abrupt increases in intracellular Ca2+ during myocardial reperfusion cause cardiomyocyte death and consequent loss of cardiac function, referred to as ischemia/reperfusion (IR) injury. Cardiac IR is accompanied by dynamic changes in expression of microRNAs (miRNAs), which inhibit specific mRNA targets. miR-214 is up-regulated during ischemic injury and heart failure in mice and humans, but its potential role in these processes is unknown. We show that genetic deletion of miR-214 in mice causes loss of cardiac contractility, increased apoptosis, and excessive fibrosis in response to IR injury.

2012-01-31 | GSE35421 | GEO

ATF3 coordinates the survival/proliferation of cardiac macrophages to protect against ischemia-reperfusion injury

Project description:Cardiac resident MerTK+ macrophages exert multiple protective roles post-ischemic injury, however, the mechanisms regulating their fate are not fully understood. Here we show that GAS6-inducible transcription factor ATF3 prevents apoptosis of MerTK+ macrophages after ischemia-reperfusion (IR) injury, by repressing the transcription of multiple genes involved in type I interferon expression (Ifih1 and Infb1) and apoptosis (Apaf1). Mice lacking ATF3 in cardiac macrophages or myeloid cells showed excessive loss of MerTK+ cardiac macrophages, poor angiogenesis, and worse heart dysfunction post-IR, which were rescued by the transfer of MerTK+ cardiac macrophages. GAS6 administration improved cardiac repair in an ATF3-dependent manner. Finally, we showed a negative association of GAS6 and ATF3 expression with the risk of major adverse cardiac events in patients with ischemic heart disease. These results indicate that the GAS6-ATF3 axis has a protective role against IR injury by regulating MerTK+ cardiac macrophage survival/proliferation.

2023-11-07 | GSE247139 | GEO

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