Lack of Insulin Receptor Substrate-2 Causes Progressive Neointima Formation in Response to Vessel Injury

Kubota, Tetsuya; Kubota, Naoto; Moroi, Masao; Terauchi, Yasuo; Kobayashi, Tsuneo; Kamata, Katsuo; Suzuki, Ryo; Tobe, Kazuyuki; Namiki, Atsushi; Aizawa, Shinichi; Nagai, Ryozo; Kadowaki, Takashi; Yamaguchi, Tetsu

doi:10.1161/01.cir.0000070937.52035.25

Cited by 111 publications

(62 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Abe and coworkers (Abe et al, 1998) previously showed that IRS-1-deficient mice exhibit insulin resistance, hypertension, and impaired endothelium-derived relaxation. Furthermore, a comparison of endotheliumdependent relaxation responses among IRS-1-deficient, IRS-2-deficient, and wild-type mice (Kubota et al, 2003) revealed that relaxation was impaired in the IRS-2-deficient mice at 20 weeks, but not at 8 weeks. In addition, in the IRS-1-deficient mice there was a mild impairment of endothelium-dependent vascular relaxation at 20 weeks.…”

Section: Pi3-k/akt Pathway and Endothelial Dysfunction In Type II Diamentioning

confidence: 99%

The PI3-K/Akt pathway: roles related to alterations in vasomotor responses in diabetic models

Kobayashi

Matsumoto

Kamata

2005

J Smooth Muscle Res

Self Cite

View full text Add to dashboard Cite

Macro-and microvascular disease states currently represent the principal causes of morbidity and mortality in patients with type I or type II diabetes mellitus. Abnormal vasomotor responses and impaired endothelium-dependent vasodilation have been demonstrated in various beds in different animal models of diabetes and in humans with type I or type II diabetes. Several mechanisms leading to endothelial dysfunction have been reported, including changes in substrate avail ability, impaired release of NO, and increased destruction of NO. The principal mediators of diabetes-associated endothelial dysfunction are (a) increases in oxidized low density lipoprotein, endothelin-1, angiotensin II, oxidative stress, and (b) decreases in the actions of insulin or growth factors in endothelial cells. An accumulating body of evidence indicates that abnormal regulation of the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway may be one of several factors contributing to vascular dysfunction in diabetes. The PI3-K pathway, which activates serine/threonine protein kinase Akt, enhances NO synthase phosphorylation and NO production. Several studies suggest that in diabetes the relative ineffectiveness of insulin and the hyperglycemia act together to reduce activity in the insulin-receptor substrates (IRS)/PI3-K/Akt pathway, resulting in impairments of both IRS/PI3-K/Akt-mediated endothelial function and NO production. This article summarizes the PI3-K/Akt pathway-mediated contraction and relaxation responses induced by various agents in the blood vessels of diabetic animals.

show abstract

Section: Pi3-k/akt Pathway and Endothelial Dysfunction In Type II Diamentioning

confidence: 99%

The PI3-K/Akt pathway: roles related to alterations in vasomotor responses in diabetic models

Kobayashi

Matsumoto

Kamata

2005

J Smooth Muscle Res

Self Cite

View full text Add to dashboard Cite

show abstract

“…Insulin receptor substrate-2 (Irs2) is the major insulin receptor substrate isoform expressed in endothelial cells (13). We previously reported that mice with the Irs2 deletion (knockout [KO]) in endothelial cells (ETIrs2KO mice) exhibited an attenuation of the insulin-induced capillary blood flow in skeletal muscle (14).…”

mentioning

confidence: 99%

Insulin Receptor Substrate-2 (Irs2) in Endothelial Cells Plays a Crucial Role in Insulin Secretion

et al. 2014

Self Cite

View full text Add to dashboard Cite

Endothelial cells are considered to be essential for normal pancreatic β-cell function. The current study attempted to demonstrate the role of insulin receptor substrate-2 (Irs2) in endothelial cells with regard to insulin secretion. Endothelial cell–specific Irs2 knockout (ETIrs2KO) mice exhibited impaired glucose-induced, arginine-induced, and glucagon-induced insulin secretion and showed glucose intolerance. In batch incubation and perifusion experiments using isolated islets, glucose-induced insulin secretion was not significantly different between the control and the ETIrs2KO mice. In contrast, in perfusion experiments, glucose-induced insulin secretion was significantly impaired in the ETIrs2KO mice. The islet blood flow was significantly impaired in the ETIrs2KO mice. After the treatment of these knockout mice with enalapril maleate, which improved the islet blood flow, glucose-stimulated insulin secretion was almost completely restored to levels equal to those in the control mice. These data suggest that Irs2 deletion in endothelial cells leads to a decreased islet blood flow, which may cause impaired glucose-induced insulin secretion. Thus, Irs2 in endothelial cells may serve as a novel therapeutic target for preventing and ameliorating type 2 diabetes and metabolic syndrome.

show abstract

“…Although IRS-1 is most important to insulin action in skeletal muscle, IRS-2 appears to be required for insulin/IGF-I and, importantly, cytokine signaling in liver, muscle, fat, pancreatic ␤ cells, B cells, T cells, and macrophages (9,(23)(24)(25). IRS-2 knock-out studies in mice have shown that IRS-2 is important for neuroendocrine function, and a lack of IRS-2 leads to enhanced neointima formation (26,27). Furthermore, IRS-2 is necessary for IL-4-induced proliferation and differentiation of T cells (28).…”

mentioning

confidence: 99%

Insulin Receptor Substrate-2-dependent Interleukin-4 Signaling in Macrophages Is Impaired in Two Models of Type 2 Diabetes Mellitus

Hartman

O’Connor

Godbout

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

We have shown previously that hyperinsulinemia inhibits interferon-␣-dependent activation of phosphatidylinositol 3-kinase (PI3-kinase) through mammalian target of rapamycin (mTOR)-induced serine phosphorylation of insulin receptor substrate (IRS)-1. Here we report that chronic insulin and high glucose synergistically inhibit interleukin (IL)-4-dependent activation of PI3-kinase in macrophages via the mTOR pathway. Resident peritoneal macrophages (PerM⌽s) from diabetic (db/db) mice showed a 44% reduction in IRS-2-associated PI3-kinase activity stimulated by IL-4 compared with PerM⌽s from heterozygote (db/؉) control mice. IRS-2 from db/db mouse PerM⌽s also showed a 78% increase in Ser/Thr-Pro motif phosphorylation without a difference in IRS-2 mass. To investigate the mechanism of this PI3-kinase inhibition, 12-O-tetradecanoylphorbol-13-acetate-matured U937 cells were treated chronically with insulin (1 nM, 18 h) and high glucose (4.5 g/liter, 48 h). In these cells, IL-4-stimulated IRS-2-associated PI3-kinase activity was reduced by 37.5%. Importantly, chronic insulin or high glucose alone did not impact IL-4-activated IRS-2-associated PI3-kinase. Chronic insulin ؉ high glucose did reduce IL-4-dependent IRS-2 tyrosine phosphorylation and p85 association by 54 and 37%, respectively, but did not effect IL-4-activated JAK/STAT signaling. When IRS-2 Ser/Thr-Pro motif phosphorylation was examined, chronic insulin ؉ high glucose resulted in a 92% increase in IRS-2 Ser/Thr-Pro motif phosphorylation without a change in IRS-2 mass. Pretreatment of matured U937 cells with rapamycin blocked chronic insulin ؉ high glucose-dependent IRS-2 Ser/Thr-Pro motif phosphorylation and restored IL-4-dependent IRS-2-associated PI3-kinase activity. Taken together these results indicate that IRS-2-dependent IL-4 signaling in macrophages is impaired in models of type 2 diabetes mellitus through a mechanism that relies on insulin/ glucose-dependent Ser/Thr-Pro motif serine phosphorylation mediated by the mTOR pathway.The first member of the insulin receptor substrate (IRS) 1 family, IRS-1, was initially discovered in Fao hepatoma cells as a tyrosine-phosphorylated substrate of the insulin receptor (1). In addition to insulin signaling, IRS proteins are integrally linked to intracellular signaling pathways initiated by IGF-I and the cytokines IL-2, 3, 4, 7, 9, 10, 13, 15 and IFN-␣ and IFN-␥ (2-10). Importantly, serine phosphorylation of IRS-1 blocks insulin, IGF-I, and cytokine signaling through IRS-1 (11-15) and appears critical to the initiation of proteasomedependent IRS-1 degradation (16,17). We have shown that chronic insulin in the presence of high glucose leads to serine phosphorylation of IRS-1 through an mTOR-dependent mechanism and that this renders IRS-1 a poorer substrate for JAK1 (18). In addition, we have shown that serine phosphorylation targets IRS-1 for proteasome-dependent degradation in L6 muscle cells (19). However, these same mechanisms have not been investigated in relation to IRS-2-dependent cytokine signaling.IRS-2 is...

show abstract

Lack of Insulin Receptor Substrate-2 Causes Progressive Neointima Formation in Response to Vessel Injury

Cited by 111 publications

References 22 publications

The PI3-K/Akt pathway: roles related to alterations in vasomotor responses in diabetic models

The PI3-K/Akt pathway: roles related to alterations in vasomotor responses in diabetic models

Insulin Receptor Substrate-2 (Irs2) in Endothelial Cells Plays a Crucial Role in Insulin Secretion

Insulin Receptor Substrate-2-dependent Interleukin-4 Signaling in Macrophages Is Impaired in Two Models of Type 2 Diabetes Mellitus

Contact Info

Product

Resources

About