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Increasing circulating IGFBP1 levels improves insulin sensitivity, promotes nitric oxide production, lowers blood pressure, and protects against atherosclerosis.

ABSTRACT: Low concentrations of insulin-like growth factor (IGF) binding protein-1 (IGFBP1) are associated with insulin resistance, diabetes, and cardiovascular disease. We investigated whether increasing IGFBP1 levels can prevent the development of these disorders. Metabolic and vascular phenotype were examined in response to human IGFBP1 overexpression in mice with diet-induced obesity, mice heterozygous for deletion of insulin receptors (IR(+/-)), and ApoE(-/-) mice. Direct effects of human (h)IGFBP1 on nitric oxide (NO) generation and cellular signaling were studied in isolated vessels and in human endothelial cells. IGFBP1 circulating levels were markedly suppressed in dietary-induced obese mice. Overexpression of hIGFBP1 in obese mice reduced blood pressure, improved insulin sensitivity, and increased insulin-stimulated NO generation. In nonobese IR(+/-) mice, overexpression of hIGFBP1 reduced blood pressure and improved insulin-stimulated NO generation. hIGFBP1 induced vasodilatation independently of IGF and increased endothelial NO synthase (eNOS) activity in arterial segments ex vivo, while in endothelial cells, hIGFBP1 increased eNOS Ser(1177) phosphorylation via phosphatidylinositol 3-kinase signaling. Finally, in ApoE(-/-) mice, overexpression of hIGFBP1 reduced atherosclerosis. These favorable effects of hIGFBP1 on insulin sensitivity, blood pressure, NO production, and atherosclerosis suggest that increasing IGFBP1 concentration may be a novel approach to prevent cardiovascular disease in the setting of insulin resistance and diabetes.

SUBMITTER: Rajwani A

PROVIDER: S-EPMC3314358 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Increasing circulating IGFBP1 levels improves insulin sensitivity, promotes nitric oxide production, lowers blood pressure, and protects against atherosclerosis.

Rajwani Adil A Rajwani Adil A Ezzat Vivienne V Smith Jessica J Yuldasheva Nadira Y NY Duncan Edward R ER Gage Matthew M Cubbon Richard M RM Kahn Matthew B MB Imrie Helen H Abbas Afroze A Viswambharan Hema H Aziz Amir A Sukumar Piruthivi P Vidal-Puig Antonio A Sethi Jaswinder K JK Xuan Shouhong S Shah Ajay M AM Grant Peter J PJ Porter Karen E KE Kearney Mark T MT Wheatcroft Stephen B SB

Diabetes 20120222 4

Low concentrations of insulin-like growth factor (IGF) binding protein-1 (IGFBP1) are associated with insulin resistance, diabetes, and cardiovascular disease. We investigated whether increasing IGFBP1 levels can prevent the development of these disorders. Metabolic and vascular phenotype were examined in response to human IGFBP1 overexpression in mice with diet-induced obesity, mice heterozygous for deletion of insulin receptors (IR(+/-)), and ApoE(-/-) mice. Direct effects of human (h)IGFBP1 o ...[more]

PMID: 22357965

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Project description:Nitric oxide (NO) is involved in all major environmental stresses. However, most of these understandings were mainly based on pharmacological study using NO modulator compounds. Recently, our studies together with others provided a new class of plant experimental system with specific in vivo NO release through constitutively overexpressing rat neuronal NO synthase (nNOS) in plants. In this study, we found that the nNOS transgenic Arabidopsis plants displayed lower level of H2O2 content, but higher levels of antioxidant enzyme activities and osmolytes under drought stress conditions. Transcriptomic analysis identified 490 and 20 genes that were differentially expressed in wild type (WT) and nNOS transgenic plants under control and drought stress conditions, respectively. Pathway analysis revealed that many genes involved in photosynthesis, cell, misc, co-factor and vitamin metabolism, major CHO metabolism, OPP and secondary metabolism were largely changed in nNOS vs. WT under control or drought stress conditions. Interestingly, CBF1/2 and 13 zinc finger family proteins, known as important family of transcription regulators in modulating several stress-responsive genes, were differentially expressed by nNOS transgenic effect. Additionally, some genes were commonly regulated by nNOS transgenic and abscisic acid (ABA) effects, indicating new insights to cross-talk between ABA and NO. Taken together, in vivo NO modulated antioxidant enzyme activities, osmolyte level, and the expression of genes involved in several pathways, thereby resulting in enhanced stress tolerance in nNOS transgenic plants. These observations might provide some insights to understand the physiological and molecular mechanisms of NO in response to drought stress in Arabidopsis. Two transgenic Arabidopsis lines (nNOS-2 and nNOS-25) with the nNOS gene under the control of the cauliflower mosaic virus (CaMV) 35S promoter, as well as Col-0 (WT), were used in this research. RNA samples from two nNOS transgenic lines were pooled for cRNA labelling and chip hybridization.

Project description:Vascular endothelial dysfunction develops with aging, as indicated by impaired endothelium-dependent dilation, and is related to increased cardiovascular disease risk. We hypothesized that short-term treatment with fenofibrate, a lipid-lowering agent with potential pleiotropic effects, would improve endothelium-dependent dilation in middle-aged and older normolipidemic adults by reducing oxidative stress. Brachial artery flow-mediated dilation, a measure of endothelium-dependent dilation, was assessed in 22 healthy adults aged 50 to 77 years before and after 7 days of fenofibrate (145 mg/d; n=12) or placebo (n=10). Brachial flow-mediated dilation was unchanged with placebo, but improved after 2 and 7 days of fenofibrate (5.1 ± 0.7 versus 2 days: 6.0 ± 0.7 and 7 days: 6.4 ± 0.6%δ; both P<0.005). The improvements in flow-mediated dilation after 7 days remained significant (P<0.05) after accounting for modest changes in plasma total and low-density lipoprotein cholesterol. Endothelium-independent dilation was not affected by fenofibrate or placebo (P>0.05). Intravenous infusion of the antioxidant vitamin C improved brachial flow-mediated dilation at baseline in both groups and during placebo treatment (P<0.05), but not after 2 and 7 days of fenofibrate (P>0.05). Fenofibrate treatment also reduced plasma-oxidized low-density lipoprotein, a systemic marker of oxidative stress, compared with placebo (P<0.05). In vascular endothelial cells sampled from peripheral veins of the subjects, endothelial nitric oxide synthase protein expression was unchanged with placebo and after 2 days of fenofibrate, but was increased after 7 days of fenofibrate (0.54 ± 0.03 versus 2 days: 0.52 ± 0.04 and 7 days: 0.76 ± 0.11 intensity/human umbilical vein endothelial cell control; P<0.05, 7 days). Short-term treatment with fenofibrate improves vascular endothelial function in healthy normolipidemic middle-aged and older adults by reducing oxidative stress and induces an increase in endothelial nitric oxide synthase.

Dataset Information

Increasing circulating IGFBP1 levels improves insulin sensitivity, promotes nitric oxide production, lowers blood pressure, and protects against atherosclerosis.

Publications

Increasing circulating IGFBP1 levels improves insulin sensitivity, promotes nitric oxide production, lowers blood pressure, and protects against atherosclerosis.

Similar Datasets

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