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[Sar1, Ile4, Ile8]-angiotensin II Potentiates Insulin Receptor Signalling and Glycogen Synthesis in Hepatocytes

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@article{2041f94448ae4aabaf71c57b4e12ced3,
title = "[Sar1, Ile4, Ile8]-angiotensin II Potentiates Insulin Receptor Signalling and Glycogen Synthesis in Hepatocytes",
abstract = "The angiotensin II type I receptor (AT1R) is involved in the regulation of cardiovascular function. Excessive activation of AT1R by angiotensin II (Ang II) leads to cardiovascular disease and may be involved in the development of insulin resistance and diabetes. Functionally selective Ang II analogues, such as the [Sar1, Ile4, Ile8]-angiotensin II (SII Ang II) analogue, that only activate a subset of signalling networks have been demonstrated to have beneficial effects on cardiovascular function in certain settings, including lowering blood pressure and increasing cardiac performance. Here, we studied the effect of SII Ang II on insulin receptor (IR) signalling and glucose metabolism in primary rat hepatocytes. We show that long-term pre-treatment of hepatocytes with SII Ang II increased insulin-stimulated glycogen synthesis, while Ang II and the AT1R antagonist losartan had no effect. Insulin-stimulated suppression of hepatic glucose output was not affected by Ang II or SII Ang II. It is well known that insulin regulates glycogen synthesis and glucose output through Akt-mediated phosphorylation of glycogen synthase kinase α/β (GSK3α/β) and forkhead box protein O1 (FOXO1), respectively. In line with this, we show that SII Ang II potentiated insulin-stimulated phosphorylation of Akt and GSK3α/β, but not FOXO1. Furthermore, we demonstrate that the effect of SII Ang II on insulin-stimulated signalling and glycogen synthesis was dependent on Src and Gαq, as inhibitors of these proteins abolished the potentiating effect of SII Ang II. Thus, our results demonstrate that SII Ang II may have a positive effect on IR signalling and glucose metabolism in hepatocytes.",
keywords = "Angiotensin II/analogs & derivatives, Animals, Cells, Cultured, Dose-Response Relationship, Drug, Energy Metabolism/drug effects, Glucose/metabolism, Glycogen/biosynthesis, Glycogen Synthase Kinase 3/metabolism, Glycogen Synthase Kinase 3 beta/metabolism, Hepatocytes/drug effects, Insulin/pharmacology, Male, Phosphorylation, Primary Cell Culture, Proto-Oncogene Proteins c-akt/metabolism, Rats, Sprague-Dawley, Receptor, Angiotensin, Type 1/agonists, Receptor, Insulin/agonists, Signal Transduction/drug effects, Time Factors",
author = "Sanni, {Samra Joke} and Christina Lyngs{\o} and Steen Gammeltoft and Hansen, {Jakob Lerche}",
note = "{\textcopyright} 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).",
year = "2018",
month = may,
doi = "10.1111/bcpt.12937",
language = "English",
volume = "122",
pages = "460--469",
journal = "Basic & Clinical Pharmacology & Toxicology Online",
issn = "1742-7843",
publisher = "Wiley-Blackwell Publishing Ltd",
number = "5",

}

RIS

TY - JOUR

T1 - [Sar1, Ile4, Ile8]-angiotensin II Potentiates Insulin Receptor Signalling and Glycogen Synthesis in Hepatocytes

AU - Sanni, Samra Joke

AU - Lyngsø, Christina

AU - Gammeltoft, Steen

AU - Hansen, Jakob Lerche

N1 - © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

PY - 2018/5

Y1 - 2018/5

N2 - The angiotensin II type I receptor (AT1R) is involved in the regulation of cardiovascular function. Excessive activation of AT1R by angiotensin II (Ang II) leads to cardiovascular disease and may be involved in the development of insulin resistance and diabetes. Functionally selective Ang II analogues, such as the [Sar1, Ile4, Ile8]-angiotensin II (SII Ang II) analogue, that only activate a subset of signalling networks have been demonstrated to have beneficial effects on cardiovascular function in certain settings, including lowering blood pressure and increasing cardiac performance. Here, we studied the effect of SII Ang II on insulin receptor (IR) signalling and glucose metabolism in primary rat hepatocytes. We show that long-term pre-treatment of hepatocytes with SII Ang II increased insulin-stimulated glycogen synthesis, while Ang II and the AT1R antagonist losartan had no effect. Insulin-stimulated suppression of hepatic glucose output was not affected by Ang II or SII Ang II. It is well known that insulin regulates glycogen synthesis and glucose output through Akt-mediated phosphorylation of glycogen synthase kinase α/β (GSK3α/β) and forkhead box protein O1 (FOXO1), respectively. In line with this, we show that SII Ang II potentiated insulin-stimulated phosphorylation of Akt and GSK3α/β, but not FOXO1. Furthermore, we demonstrate that the effect of SII Ang II on insulin-stimulated signalling and glycogen synthesis was dependent on Src and Gαq, as inhibitors of these proteins abolished the potentiating effect of SII Ang II. Thus, our results demonstrate that SII Ang II may have a positive effect on IR signalling and glucose metabolism in hepatocytes.

AB - The angiotensin II type I receptor (AT1R) is involved in the regulation of cardiovascular function. Excessive activation of AT1R by angiotensin II (Ang II) leads to cardiovascular disease and may be involved in the development of insulin resistance and diabetes. Functionally selective Ang II analogues, such as the [Sar1, Ile4, Ile8]-angiotensin II (SII Ang II) analogue, that only activate a subset of signalling networks have been demonstrated to have beneficial effects on cardiovascular function in certain settings, including lowering blood pressure and increasing cardiac performance. Here, we studied the effect of SII Ang II on insulin receptor (IR) signalling and glucose metabolism in primary rat hepatocytes. We show that long-term pre-treatment of hepatocytes with SII Ang II increased insulin-stimulated glycogen synthesis, while Ang II and the AT1R antagonist losartan had no effect. Insulin-stimulated suppression of hepatic glucose output was not affected by Ang II or SII Ang II. It is well known that insulin regulates glycogen synthesis and glucose output through Akt-mediated phosphorylation of glycogen synthase kinase α/β (GSK3α/β) and forkhead box protein O1 (FOXO1), respectively. In line with this, we show that SII Ang II potentiated insulin-stimulated phosphorylation of Akt and GSK3α/β, but not FOXO1. Furthermore, we demonstrate that the effect of SII Ang II on insulin-stimulated signalling and glycogen synthesis was dependent on Src and Gαq, as inhibitors of these proteins abolished the potentiating effect of SII Ang II. Thus, our results demonstrate that SII Ang II may have a positive effect on IR signalling and glucose metabolism in hepatocytes.

KW - Angiotensin II/analogs & derivatives

KW - Animals

KW - Cells, Cultured

KW - Dose-Response Relationship, Drug

KW - Energy Metabolism/drug effects

KW - Glucose/metabolism

KW - Glycogen/biosynthesis

KW - Glycogen Synthase Kinase 3/metabolism

KW - Glycogen Synthase Kinase 3 beta/metabolism

KW - Hepatocytes/drug effects

KW - Insulin/pharmacology

KW - Male

KW - Phosphorylation

KW - Primary Cell Culture

KW - Proto-Oncogene Proteins c-akt/metabolism

KW - Rats, Sprague-Dawley

KW - Receptor, Angiotensin, Type 1/agonists

KW - Receptor, Insulin/agonists

KW - Signal Transduction/drug effects

KW - Time Factors

U2 - 10.1111/bcpt.12937

DO - 10.1111/bcpt.12937

M3 - Journal article

C2 - 29136335

VL - 122

SP - 460

EP - 469

JO - Basic & Clinical Pharmacology & Toxicology Online

JF - Basic & Clinical Pharmacology & Toxicology Online

SN - 1742-7843

IS - 5

ER -

ID: 55709079