Pericyte insulin receptors modulate retinal vascular remodeling and endothelial angiopoietin signaling

Abstract Pericytes regulate vascular development, stability and quiescence; their dysfunction contributes to diabetic retinopathy. To explore the role of insulin receptors in pericyte biology, we created pericyte insulin receptor knockout mice (PIRKO) by crossing PDGFR β-Cre mice with insulin receptor (Insr) floxed mice. Their neonatal retinal vasculature exhibited peri-venous hypervascularity with venular dilatation, plus increased angiogenic sprouting in superficial and deep layers. Pericyte coverage of capillaries was unaltered in peri-venous and peri-arterial plexi and no differences in vascular regression or endothelial proliferation were apparent. Isolated brain pericytes from PIRKO had decreased angiopoietin-1 mRNA, whereas retinal and lung angiopoietin-2 mRNA was increased. Endothelial phospho-Tie2 staining was diminished and FoxO1 was more frequently nuclear localized in the peri-venous plexus of PIRKO, in keeping with reduced angiopoietin-Tie2 signaling. Silencing of Insr in human brain pericytes led to reduced insulin-stimulated angiopoietin-1 secretion, and conditioned media from these cells was less able to induce Tie2 phosphorylation in human endothelial cells. Hence, insulin signaling in pericytes promotes angiopoietin-1 secretion and endothelial Tie2 signaling and perturbation of this leads to excessive vascular sprouting and venous plexus abnormalities. This phenotype mimics elements of diabetic retinopathy, and future work should evaluate pericyte insulin signaling in this disease.

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Glucose Effects on Beta-Cell Growth and Survival Require Activation of Insulin Receptors and Insulin Receptor Substrate 2

Molecular and Cellular Biology ◽

10.1128/mcb.01489-08 ◽

2009 ◽

Vol 29 (11) ◽

pp. 3219-3228 ◽

Cited By ~ 104

Author(s):

Anke Assmann ◽

Kohjiro Ueki ◽

Jonathon N. Winnay ◽

Takahashi Kadowaki ◽

Rohit N. Kulkarni

Keyword(s):

Insulin Receptor ◽

Signaling Pathway ◽

Cell Lines ◽

Insulin Signaling ◽

Insulin Receptors ◽

Insulin Signaling Pathway ◽

Insulin Receptor Substrate ◽

Β Cells ◽

Β Cell ◽

Growth And Survival

ABSTRACT Insulin and insulin-like growth factor I (IGF-I) are ubiquitous hormones that regulate growth and metabolism of most mammalian cells, including pancreatic β-cells. In addition to being an insulin secretagogue, glucose regulates proliferation and survival of β-cells. However, it is unclear whether the latter effects of glucose occur secondary to autocrine activation of insulin signaling proteins by secreted insulin. To examine this possibility we studied the effects of exogenous glucose or insulin in β-cell lines completely lacking either insulin receptors (βIRKO) or insulin receptor substrate 2 (βIRS2KO). Exogenous addition of either insulin or glucose activated proteins in the insulin signaling pathway in control β-cell lines with the effects of insulin peaking earlier than glucose. Insulin stimulation of βIRKO and βIRS2KO cells led to blunted activation of phosphatidylinositol 3-kinase and Akt kinase, while surprisingly, glucose failed to activate either kinase but phosphorylated extracellular signal-regulated kinase. Control β-cells exhibited low expression of IGF-1 receptors compared to compensatory upregulation in βIRKO cells. The signaling data support the slow growth and reduced DNA and protein synthesis in βIRKO and βIRS2KO cells in response to glucose stimulation. Together, these studies provide compelling evidence that the growth and survival effects of glucose on β-cells require activation of proteins in the insulin signaling pathway.

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Muscle Specific Insulin Receptor Overexpression Protects Mice from Diet-Induced Glucose Intolerance but Leads to Post-Receptor Insulin Resistance

10.2337/figshare.12860798.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Guoxiao Wang ◽

Yingying Yu ◽

Weikang Cai ◽

Thiago M. Batista ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Glucose Tolerance ◽

Insulin Receptor ◽

Insulin Signaling ◽

Insulin Receptors ◽

Akt Phosphorylation ◽

Skeletal Muscle Insulin Resistance ◽

Diet Induced Obesity ◽

Similar Body

Skeletal muscle insulin resistance is a prominent early feature in the pathogenesis of type 2 diabetes (T2D). In attempt to overcome this defect, we generated mice overexpressing insulin receptors (IR) specifically in skeletal muscle (IRMOE). On normal chow, IRMOE mice have similar body weight as controls, but an increase in lean mass and glycolytic muscle fibers and reduced fat mass. IRMOE mice also show higher basal phosphorylation of IR, IRS-1 and Akt in muscle and improved glucose tolerance compared to controls. When challenged with high fat diet (HFD), IRMOE mice are protected from diet-induced obesity. This is associated with reduced inflammation in fat and liver, improved glucose tolerance and improved systemic insulin sensitivity. Surprisingly, however, in both chow and HFD-fed mice, insulin stimulated Akt phosphorylation is significantly reduced in muscle of IRMOE mice, indicating post-receptor insulin resistance. RNA sequencing reveals downregulation of several post-receptor signaling proteins that contribute to this resistance. Thus, enhancing early insulin signaling in muscle by overexpression of the insulin receptor protects mice from diet-induced obesity and its effects on glucose metabolism. However, chronic overstimulation of this pathway leads to post-receptor desensitization, indicating the critical balance between normal signaling and hyperstimulation of the insulin signaling pathway.

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