Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia

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.

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Failure of compensatory beta-cell hyperplasia in response to insulin resistance plays a crucial role in the development of type 2 diabetes

Diabetes Research and Clinical Practice ◽

10.1016/s0168-8227(00)82063-x ◽

2000 ◽

Vol 50 ◽

pp. 177

Author(s):

Yasuo Terauchi ◽

Kajuro Komeda ◽

Naoto Kubota ◽

Kazuhiro Eto ◽

Yoshiharu Tsubamoto ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Beta Cell ◽

Crucial Role ◽

Cell Hyperplasia ◽

Beta Cell Hyperplasia

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

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.19:106-114 ◽

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.

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Attenuation of Insulin-stimulated Insulin Receptor Substrate-1 Serine 307 Phosphorylation in Insulin Resistance of Type 2 Diabetes

Journal of Biological Chemistry ◽

10.1074/jbc.c500230200 ◽

2005 ◽

Vol 280 (41) ◽

pp. 34389-34392 ◽

Cited By ~ 55

Author(s):

Anna Danielsson ◽

Anita Öst ◽

Fredrik H. Nystrom ◽

Peter Strålfors

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Receptor ◽

Insulin Receptor Substrate ◽

Insulin Receptor Substrate 1

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

Diabetes ◽

10.2337/db13-1872 ◽

2014 ◽

Vol 63 (6) ◽

pp. 1933-1947 ◽

Cited By ~ 33

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

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

Biochemical Society Transactions ◽

10.1042/bst0311152 ◽

2003 ◽

Vol 31 (6) ◽

pp. 1152-1156 ◽

Cited By ~ 55

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.

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

Endocrinology ◽

10.1210/en.2011-1278 ◽

2012 ◽

Vol 153 (3) ◽

pp. 1129-1140 ◽

Cited By ~ 13

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.

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Comparison of Sleeve Gastrectomy and Conservatory Treatment Effect on Biochemical and Hormonal Profile of Obese Type 2 Diabetes Subjects: CREDOR Randomized Controlled Study Results

Revista de Chimie ◽

10.37358/rc.17.7.5730 ◽

2017 ◽

Vol 68 (7) ◽

pp. 1622-1627 ◽

Cited By ~ 1

Author(s):

Diana Simona Stefan ◽

Andrada Mihai ◽

Daiana Bajko ◽

Daniela Lixandru ◽

Laura Petcu ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Weight Loss ◽

Sleeve Gastrectomy ◽

Beta Cell ◽

Beta Cell Dysfunction ◽

Control Group ◽

Cell Dysfunction ◽

Randomized Controlled

Metabolic surgery is the most efficacious method for the treatment of morbid obesity and was recently included among the antidiabetes treatments recommended in obese type 2 diabetes (T2D) patients. The aim of this study was to compare in a randomized controlled trial the effect of sleeve gastrectomy (SG) to that of intensive lifestyle intervention plus pharmacologic treatment on some markers of insulin resistance and beta cell function as well as some appetite controlling hormones in a group of male obese T2D subjects. The study groups comprised 20 subjects for SG and 21 control subjects. Fasting blood glucose, insulin, proinsulin, adiponectin, leptin, ghrelin, HOMA-IR, HOMA-%B, proinsulin-to-insulin ratio and proinsulin-to-adiponectin ratio were evaluated at baseline and after one year follow-up. Overall, patients in the SG group lost 78.98% of excess weight loss (%EWL) in comparison with 9.45% in the control group. This was accompanied by a significant improvement of insulin resistance markers, including increase of adiponectin and decrease of HOMA-IR, while no changes were recorded in the control group. Weight loss was also associated with a significant improvement of proinsulin-to-insulin and proinsulin-to-adiponectin ratio, both surrogate markers of beta cell dysfunction. These also improved in the control group, but were only marginally significant. Our findings suggest that improved insulin resistance and decreased beta cell dysfunction after sleeve gastrectomy might explain diabetes remission associated with metabolic surgery.

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