Low Grade Inflammation in Juvenile Obesity and Type 1 Diabetes Associated with Early Signs of Atherosclerosis

Mangge, Harald; Schauenstein, Konrad; Stroedter, L.; Griesl, A.; Maerz, Winfried; Borkenstein, Martin

doi:10.1055/s-2004-821023

Cited by 106 publications

(84 citation statements)

References 25 publications

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“…In this study, the association of CSWA with leptin remained significant even after adjusting for BMI as well as body surface area and waist-to-hip ratio in sensitivity analysis. 35,36 This suggests that the increase in CSWA was not due to functional changes to normalize tensile stress, which occur with volume loading due to an increase in fat mass, 37 but rather that elevated leptin levels contribute to thickening of the arterial wall via mechanisms that are independent of obesity per se. The association between CSWA and leptin may be explained by multiple mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Carotid cross-sectional wall area is significantly associated with serum leptin levels, independent of body mass index: the SABPA study

et al. 2012

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Hypertension and obesity are serious health burdens in sub-Saharan Africa. Urbanized Africans seem to be more susceptible to the development of these diseases than Caucasians. Current research suggests that leptin may be an important contributor to the development of hypertension and atherosclerosis. The aim of this study was to investigate leptin levels and their associations with cardiovascular function in urbanized Africans and Caucasians. Serum leptin, ambulatory blood pressure and carotid intima-media thickness were measured, and the cross-sectional wall area (CSWA) was calculated. The results showed that Africans had higher leptin levels (Po0.001), ambulatory blood pressure (Po0.001), carotid intima-media thickness (Po0.01) and CSWA (Po0.01) than Caucasians. As we found no interaction between ethnicity and gender for the association between leptin and the cardiovascular variables, we focused mainly on the total group of Africans and Caucasians. In single, partial and multiple regression analyses, positive associations of ambulatory systolic blood pressure (b ¼ 0.256; Po0.001), diastolic blood pressure (b ¼ 0.143; P ¼ 0.012), pulse pressure (b ¼ 0.327; Po0.001) and CSWA (b ¼ 0.107; P ¼ 0.038) with leptin were observed. Even after adjusting for body mass index (BMI), the association between CSWA (b ¼ 0.107; P ¼ 0.038) and leptin remained. Our findings therefore suggest that leptin may contribute to the development of atherosclerosis, independent of BMI.

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Section: Discussionmentioning

confidence: 99%

Carotid cross-sectional wall area is significantly associated with serum leptin levels, independent of body mass index: the SABPA study

et al. 2012

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“…Increased BMI in youth with T1D has been reported in clinic based and national cohorts (7)(8)(9)(10)(11)(12)(13)(14) and is associated with a more atherogenic cardiovascular disease risk profile (11,13,15).…”

Section: Introductionmentioning

confidence: 90%

Obesity in Youth with Type 1 Diabetes in Germany, Austria, and the United States

DuBose

Hermann²,

Tamborlane

et al. 2015

The Journal of Pediatrics

156

129

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“…inflammation | cell adhesion | cell migration | metabolic diseases M etabolic disorders such as obesity and diabetes are associated with a state of chronic, low-grade inflammation (1,2), which appears to contribute to the development of micro-and macrovascular complications such as atherosclerosis, nephropathy, and retinopathy (3)(4)(5). The cellular and molecular mechanisms involved in chronic inflammation associated with metabolic disorders are not yet fully understood, but the recruitment of blood monocytes to sites of vascular injury appears to play a central and rate-limiting role in all these complications.…”

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confidence: 99%

Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage recruitment

Kim¹,

Ullevig

Zamora³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

104

125

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Monocytic adhesion and chemotaxis are regulated by MAPK pathways, which in turn are controlled by redox-sensitive MAPK phosphatases (MKPs). We recently reported that metabolic disorders prime monocytes for enhanced recruitment into vascular lesions by increasing monocytes' responsiveness to chemoattractants. However, the molecular details of this proatherogenic mechanism were not known. Here we show that monocyte priming results in the S-glutathionylation and subsequent inactivation and degradation of MKP-1. Chronic exposure of human THP-1 monocytes to diabetic conditions resulted in the loss of MKP-1 protein levels, the hyperactivation of ERK and p38 in response to monocyte chemoattractant protein-1 (MCP-1), and increased monocyte adhesion and chemotaxis. Knockdown of MKP-1 mimicked the priming effects of metabolic stress, whereas MKP-1 overexpression blunted both MAPK activation and monocyte adhesion and migration induced by MCP-1. Metabolic stress promoted the Sglutathionylation of MKP-1, targeting MKP-1 for proteasomal degradation. Preventing MKP-1 S-glutathionylation in metabolically stressed monocytes by overexpressing glutaredoxin 1 protected MKP-1 from degradation and normalized monocyte adhesion and chemotaxis in response to MCP-1. Blood monocytes isolated from diabetic mice showed a 55% reduction in MKP-1 activity compared with nondiabetic mice. Hematopoietic MKP-1 deficiency in atherosclerosis-prone mice mimicked monocyte priming and dysfunction associated with metabolic disorders, increased monocyte chemotaxis in vivo, and accelerated atherosclerotic lesion formation. In conclusion, we identified MKP-1 as a central redox-sensitive regulator of monocyte adhesion and migration and showed that the loss of MKP-1 activity is a critical step in monocyte priming and the metabolic stress-induced conversion of blood monocytes into a proatherogenic phenotype.M etabolic disorders such as obesity and diabetes are associated with a state of chronic, low-grade inflammation (1, 2), which appears to contribute to the development of micro-and macrovascular complications such as atherosclerosis, nephropathy, and retinopathy (3-5). The cellular and molecular mechanisms involved in chronic inflammation associated with metabolic disorders are not yet fully understood, but the recruitment of blood monocytes to sites of vascular injury appears to play a central and rate-limiting role in all these complications. Metabolic disorders impact blood vessels at multiple levels, including lipid depositions, endothelial injury, and smooth muscle cell proliferation and migration, which individually or in concert initiate monocyte recruitment and promote vascular inflammation (6, 7). However, metabolic disorders also appear to affect blood monocytes directly. A number of studies reported that monocytes both in patients with metabolic disorders and in dyslipidemic or diabetic mice undergo phenotypical and functional changes that may contribute directly to the development and progression of chronic inflammatory vascular diseases (8-13)...

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Low Grade Inflammation in Juvenile Obesity and Type 1 Diabetes Associated with Early Signs of Atherosclerosis

Cited by 106 publications

References 25 publications

Carotid cross-sectional wall area is significantly associated with serum leptin levels, independent of body mass index: the SABPA study

Carotid cross-sectional wall area is significantly associated with serum leptin levels, independent of body mass index: the SABPA study

Obesity in Youth with Type 1 Diabetes in Germany, Austria, and the United States

Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage recruitment

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