scholarly journals Differential Insulin Receptor Substrate-1 (IRS1)-Related Modulation of Neuropeptide Y and Proopiomelanocortin Expression in Nondiabetic and Diabetic IRS2−/− Mice

Endocrinology ◽  
2012 ◽  
Vol 153 (3) ◽  
pp. 1129-1140 ◽  
Author(s):  
Emma Burgos-Ramos ◽  
Águeda González-Rodríguez ◽  
Sandra Canelles ◽  
Eva Baquedano ◽  
Laura M. Frago ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Food Intake ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Janus Kinase ◽  
Insulin Receptor Substrate ◽  
Mrna Levels ◽  
Hypothalamic Inflammation

Insulin resistance and type 2 diabetes correlate with impaired leptin and insulin signaling. Insulin receptor substrate-2 deficient (IRS2−/−) mice are an accepted model for the exploration of alterations in these signaling pathways and their relationship with diabetes; however, disturbances in hypothalamic signaling and the effect on neuropeptides controlling food intake remain unclear. Our aim was to analyze how leptin and insulin signaling may differentially affect the expression of hypothalamic neuropeptides regulating food intake and hypothalamic inflammation in diabetic (D) and nondiabetic (ND) IRS2−/− mice. We analyzed the activation of leptin and insulin targets by Western blotting and their association by immunoprecipitation, as well as the mRNA levels of neuropeptide Y (NPY), proopiomelanocortin, and inflammatory markers by real-time PCR and colocalization of forkhead box protein O1 (FOXO1) and NPY by double immunohistochemistry in the hypothalamus. Serum leptin and insulin levels and hypothalamic Janus kinase 2 and signal transducer and activator of transcription factor 3 activation were increased in ND IRS2−/− mice. IRS1 levels and its association with Janus kinase 2 and p85 and protein kinase B activation were increased in ND IRS2−/−. Increased FOXO1 positively correlated with NPY mRNA levels in D IRS2−/− mice, with FOXO1 showing mainly nuclear localization in D IRS2−/− and cytoplasmic in ND IRS2−/− mice. D IRS2−/− mice exhibited higher hypothalamic inflammation markers than ND IRS2−/− mice. In conclusion, differential activation of these pathways and changes in the expression of NPY and inflammation may exert a protective effect against hypothalamic deregulation of appetite, suggesting that manipulation of these targets could be of interest in the treatment of insulin resistance and type 2 diabetes.

Echinops Spp. Polysaccharide B Ameliorates Metabolic Abnormalities in a Rat Model of Type 2 Diabetes Mellitus

2020 ◽  
Vol 19 (1) ◽  
pp. 106-114
Author(s):  
Guang Hao ◽  
Xiaoyu Ma ◽  
Mengru Jiang ◽  
Zhenzhen Gao ◽  
Ying Yang
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Secretion ◽  
Insulin Receptor ◽  
Skeletal Muscles ◽  
Insulin Receptor Substrate ◽  
Sprague Dawley

This study examined the in vivo effects of Echinops spp. polysaccharide B on type 2 diabetes mellitus in Sprague-Dawley rats. We constructed a type 2 diabetes mellitus Sprague-Dawley rat models by feeding a high-fat and high-sugar diet plus intraperitoneal injection of a small dose of streptozotocin. Using this diabetic rat model, different doses of Echinops polysaccharide B were administered orally for seven weeks. Groups receiving Xiaoke pill and metformin served as positive controls. The results showed that Echinops polysaccharide B treatment normalized the weight and blood sugar levels in the type 2 diabetes mellitus rats, increased muscle and liver glycogen content, improved glucose tolerance, increased insulin secretion, and reduced glucagon and insulin resistance indices. More importantly, Echinops polysaccharide B treatment upregulated the expression of insulin receptor in the liver, skeletal muscles, and pancreas, and significantly improved the expression levels of insulin receptor substrate-2 protein in the liver and pancreas, as well as it increased insulin receptor substrate-1 expression in skeletal muscles. These two proteins play crucial roles in increasing insulin secretion and in controlling type 2 diabetes mellitus. The findings of the present study suggest that Echinops polysaccharide B could improve the status of diabetes in type 2 diabetes mellitus rats, which may be achieved by improving insulin resistance. Our study provides a new insight into the development of a natural drug for the control of type 2 diabetes mellitus.

scholarly journals Phenylalanine Impairs Insulin Signaling and Inhibits Glucose Uptake by Modifying IRβ

2021 ◽  
Author(s):  
Qian Zhou ◽  
Wan-Wan Sun ◽  
Jia-Cong Chen ◽  
Huilu Zhang ◽  
Jie Liu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Amino Acids ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Trna Synthetase ◽  
Blood Samples ◽  
Receptor Beta

Abstract Although elevated circulating amino acids are associated with the onset of type 2 diabetes (T2D), how amino acids act on cell insulin signaling and glucose uptake remains unclear. Herein, we report that phenylalanine modifies insulin receptor beta (IRβ) and inactivates insulin signaling and glucose uptake. Mice fed phenylalanine-rich chow or overexpressing human phenylalanyl-tRNA synthetase (hFARS) developed insulin resistance and symptoms of T2D. Mechanistically, FARS phenylalanylated lysine 1057/1079 of IRβ (F-K1057/1079) inactivated IRβ and prevented insulin from generating insulin signaling to promote glucose uptake by cells. SIRT1 reversed F-K1057/1079 and counteracted the insulin-inactivating effects of hFARS and phenylalanine. F-K1057/1079 and SIRT1 levels of white cells of T2D patients’ blood samples were positively and negatively correlated with T2D onset, respectively. Blocking F-K1057/1079 with phenylalaninol sensitized insulin signaling and relieved T2D symptoms in hFARS-transgenic and db/db mice. We revealed mechanisms of how phenylalanylation inactivates insulin signaling that may be employed to control T2D.

scholarly journals MicroRNA 144 Impairs Insulin Signaling by Inhibiting the Expression of Insulin Receptor Substrate 1 in Type 2 Diabetes Mellitus

PLoS ONE ◽  
2011 ◽  
Vol 6 (8) ◽  
pp. e22839 ◽  
Author(s):  
Dwi Setyowati Karolina ◽  
Arunmozhiarasi Armugam ◽  
Subramaniam Tavintharan ◽  
Michael T. K. Wong ◽  
Su Chi Lim ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1

scholarly journals Increased Interaction With Insulin Receptor Substrate 1, a Novel Abnormality in Insulin Resistance and Type 2 Diabetes

Diabetes ◽  
2014 ◽  
Vol 63 (6) ◽  
pp. 1933-1947 ◽  
Author(s):  
Michael Caruso ◽  
Danjun Ma ◽  
Zaher Msallaty ◽  
Monique Lewis ◽  
Berhane Seyoum ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Receptor ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1

Discordant effects of a chronic physiological increase in plasma FFA on insulin signaling in healthy subjects with or without a family history of type 2 diabetes

2004 ◽  
Vol 287 (3) ◽  
pp. E537-E546 ◽  
Author(s):  
Sangeeta R. Kashyap ◽  
Renata Belfort ◽  
Rachele Berria ◽  
Swangjit Suraamornkul ◽  
Thongchai Pratipranawatr ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Family History ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Low Dose ◽  
History Of ◽  
Plasma Ffa

Muscle insulin resistance develops when plasma free fatty acids (FFAs) are acutely increased to supraphysiological levels (∼1,500–4,000 μmol/l). However, plasma FFA levels >1,000 μmol/l are rarely observed in humans under usual living conditions, and it is unknown whether insulin action may be impaired during a sustained but physiological FFA increase to levels seen in obesity and type 2 diabetes mellitus (T2DM) (∼600–800 μmol/l). It is also unclear whether normal glucose-tolerant subjects with a strong family history of T2DM (FH+) would respond to a low-dose lipid infusion as individuals without any family history of T2DM (CON). To examine these questions, we studied 7 FH+ and 10 CON subjects in whom we infused saline (SAL) or low-dose Liposyn (LIP) for 4 days. On day 4, a euglycemic insulin clamp with [3-3H]glucose and indirect calorimetry was performed to assess glucose turnover, combined with vastus lateralis muscle biopsies to examine insulin signaling. LIP increased plasma FFA ∼1.5-fold, to levels seen in T2DM. Compared with CON, FH+ were markedly insulin resistant and had severely impaired insulin signaling in response to insulin stimulation. LIP in CON reduced insulin-stimulated glucose disposal (Rd) by 25%, insulin-stimulated insulin receptor tyrosine phosphorylation by 17%, phosphatidylinositol 3-kinase activity associated with insulin receptor substrate-1 by 20%, and insulin-stimulated glycogen synthase fractional velocity over baseline (44 vs. 15%; all P < 0.05). In contrast to CON, a physiological elevation in plasma FFA in FH+ led to no further deterioration in Rd or to any additional impairment of insulin signaling. In conclusion, a 4-day physiological increase in plasma FFA to levels seen in obesity and T2DM impairs insulin action/insulin signaling in CON but does not worsen insulin resistance in FH+. Whether this lack of additional deterioration in insulin signaling in FH+ is due to already well-established lipotoxicity, or to other molecular mechanisms related to insulin resistance that are nearly maximally expressed early in life, remains to be determined.

Targeting type 2 diabetes: lessons from a knockout model of insulin receptor substrate 2

2014 ◽  
Vol 92 (8) ◽  
pp. 613-620 ◽  
Author(s):  
Joana Moitinho Oliveira ◽  
Sandra A. Rebuffat ◽  
Rosa Gasa ◽  
Ramon Gomis
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Beta Cell ◽  
Insulin Receptor ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Mitogen Activated Protein Kinase ◽  
Insulin Receptor Substrate ◽  
Beta Cell Failure

Insulin receptor substrate 2 (IRS2) is a widely expressed protein that regulates crucial biological processes including glucose metabolism, protein synthesis, and cell survival. IRS2 is part of the insulin – insulin-like growth factor (IGF) signaling pathway and mediates the activation of the phosphotidylinositol 3-kinase (PI3K)–Akt and the Ras–mitogen-activated protein kinase (MAPK) cascades in insulin target tissues and in the pancreas. The best evidence of this is that systemic elimination of the Irs2 in mice (Irs2−/−) recapitulates the pathogenesis of type 2 diabetes (T2D), in that diabetes arises as a consequence of combined insulin resistance and beta-cell failure. Indeed, work using this knockout mouse has confirmed the importance of IRS2 in the control of glucose homeostasis and especially in the survival and function of pancreatic beta-cells. These studies have shown that IRS2 is critically required for beta-cell compensation in conditions of increased insulin demand. Importantly, islets isolated from T2D patients exhibit reduced IRS2 expression, which supports the likely contribution of altered IRS2-dependent signaling to beta-cell failure in human T2D. For all these reasons, the Irs2−/− mouse has been and will be essential for elucidating the inter-relationship between beta-cell function and insulin resistance, as well as to delineate therapeutic strategies to protect beta-cells during T2D progression.

Fatty acid-induced insulin resistance: role of insulin receptor substrate 1 serine phosphorylation in the retroregulation of insulin signalling

2003 ◽  
Vol 31 (6) ◽  
pp. 1152-1156 ◽  
Author(s):  
Y. Le Marchand-Brustel ◽  
P. Gual ◽  
T. Grémeaux ◽  
T. Gonzalez ◽  
R. Barrès ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Glucose Transport ◽  
Insulin Signalling ◽  
Serine Phosphorylation ◽  
Insulin Receptor Substrate

Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterized by a decrease in the insulin effect on glucose transport in muscle and adipose tissue. Tyrosine phosphorylation of IRS-1 (insulin receptor substrate 1) and its binding to PI 3-kinase (phosphoinositide 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Various studies have implicated lipids as a cause of insulin resistance in muscle. Elevated plasma fatty acid concentrations are associated with reduced insulin-stimulated glucose transport activity as a consequence of altered insulin signalling through PI 3-kinase. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine phosphorylation, PI 3-kinase activity and glucose transport. Recent findings demonstrate that non-esterified fatty acids, as well as other factors such as tumour necrosis factor α, hyperinsulinaemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser307 as one of the phosphorylated sites. Moreover, several kinases able to phosphorylate this serine residue have been identified. These exciting results suggest that Ser307 phosphorylation is a possible hallmark of insulin resistance in biologically insulin-responsive cells or tissues. Identification of IRS-1 kinases could enable rational drug design in order to selectively inhibit the activity of the relevant enzymes and generate a novel class of therapeutic agents for type 2 diabetes.

Abstract 506: Hepatic Insulin Signaling Regulates ApoAI Expression Through Type I Deiodinase

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Jing Liu ◽  
Antonio Hernandez-Ono ◽  
Valerie A Galton ◽  
Henry N Ginsberg
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Signaling ◽  
Knockout Mice ◽  
Luciferase Activity ◽  
Hdl Cholesterol ◽  
Mrna Levels ◽  
Cholesterol Levels ◽  
Low Hdl

Low HDL cholesterol is a common feature of insulin resistant states such as type 2 diabetes, but little is known about the regulation of HDL cholesterol and apoAI levels by insulin signaling. In prior studies, we observed that liver insulin receptor (Insr) knockout mice (LIRKO) had very low plasma HDL cholesterol and apoAI levels compared with their controls. HDL cholesterol levels were normalized when we restored insulin signaling by expression of constitutively active (CA) AKT1. Acute knock down of hepatic Insr by adenovirus-mediated expression of albumin-Cre in Insr flox/flox mice resulted in a marked decrease in the levels of ApoAI and Dio1 mRNA in the liver. Dio1 encodes the Type 1 deiodinase (D1), which can convert thyroxine to 3,5,3’-triiodothyronine. Adenovirus mediated overexpression of Dio1 increased HDL cholesterol and apoAI levels in LIRKO mice. D1 knockout mice exhibited a significant reduction in hepatic ApoAI mRNA levels. In McArdle cells, short interfering (si) RNA-mediated knockdown of Insr reduced both Dio1 and ApoAI mRNA levels. Knockdown of Insr by siRNA reduced luciferase activity of both hDio1 and hApoAI promoter constructs in HepG2 cells. Furthermore, siRNA-mediated knockdown of Dio1 expression also decreased hApoAI luciferase activity. These findings indicate that insulin signaling regulates the expression of both Dio1 and ApoAI, and that Dio1 regulates ApoAI expression. Reductions in ApoAI gene expression may play a role in the etiology of low HDL cholesterol levels commonly present in states of insulin resistance. Targeting D1 may be a novel way to increase apoAI and HDL cholesterol levels in people with insulin resistance or type 2 diabetes mellitus.

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