Obesity and insulin resistance

Kahn, Barbara B.; Flier, Jeffrey S.

doi:10.1172/jci10842

Cited by 2,792 publications

(2,161 citation statements)

References 63 publications

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“…3 Furthermore, it has become apparent that excess bodyweight is a root cause in the development of this syndrome, owing to its known link with insulin resistance. 26 Adipose tissue is also an important endocrinological component expressing adipocytokines, including adiponectin, interleukin-6, angiotensinogen/angiotensin II, plasminogen activator inhibitor type 1 and tumor necrosis factor-alpha, all of which contribute to the development of coronary heart disease. 3 In line with these findings, the prevalence of metabolic syndrome in this population increased directly from normal to overweight and to obese children, confirming a recent report in the United States.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal preventive-screening cutoffs for metabolic syndrome in adolescents

et al. 2008

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Objective: To detect metabolic risk factor cutoff points in adolescence for the diagnosis of metabolic syndrome that develops at the age of 17 years (MS 17 ). Design: This study adopted a 6-year design incorporating four data collection time points (TPs). Volunteers were assessed prospectively at the ages of 12, 13, 14 and 17. Participants: A total of 210, 204, 198 and 187 schoolchildren volunteered at the first (TP 1 ¼ 12 years old), second (TP 2 ¼ 13 years old), third (TP 3 ¼ 14 years old) and fourth (TP 4 ¼ 17 years old) data collection TP, respectively. Measurements: At each data collection TP, anthropometrical, biological and lifestyle data were obtained. Identical protocols were used for each assessment conducted by the same trained investigators. Results: A total of 12% of the participants were diagnosed with MS 17 , the majority of them being boys (Po0.05). The prevalence of the syndrome increased directly with the degree of obesity. Using body mass index (BMI), adiposity and/or aerobic fitness levels in both genders, MS 17 could be correctly diagnosed as early as TP 1 . No such cutoff points were found for high-density lipoprotein cholesterol, triglycerides, blood pressure and fasting plasma glucose levels. Conclusion: With respect to the data presented, it has been established that the calculated longitudinal preventive-screening cutoffs allow successful diagnosis of metabolic syndrome in adolescents using BMI, adiposity or aerobic fitness levels in both sexes. Adoption of such pediatric guidelines may help mitigate future increase in the prevalence of metabolic syndrome.

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Section: Discussionmentioning

confidence: 99%

Longitudinal preventive-screening cutoffs for metabolic syndrome in adolescents

et al. 2008

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“…[5][6][7][8] Since adipocyte function is an important factor for systemic insulin sensitivity, 9 ATMs appear to contribute critically to the pathogenesis of type 2 diabetes mellitus and the metabolic syndrome. However, molecular details underlying the insulin desensitizing effects of ATMs are unresolved yet, 10 since the nature of ATMs has remained largely unknown so far.…”

Section: Introductionmentioning

confidence: 99%

Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production

et al. 2007

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Objective: Obesity is associated with a chronic low-grade inflammation and an increased abundance of macrophages in adipose tissue. Adipose tissue macrophages (ATMs) are assumed to interfere with adipocyte function leading to insulin resistance, thereby contributing to the pathogenesis of type 2 diabetes mellitus. Macrophages exist in separate types of differentiation, but the nature of ATMs is largely unknown. Design and measurements: Stromal vascular cells (SVCs) and ATMs were isolated from human adipose tissues from different locations. We characterized ATMs phenotypically and functionally by flow cytometry, endocytosis assay and determination of secreted cytokines. For comparison, we used macrophages of the 'classical' (M1) and the 'alternative', anti-inflammatory (M2) type differentiated in vitro from peripheral blood monocytes. Results: Like prototypic M2 macrophages, ATMs expressed considerable amounts of mannose receptor, haemoglobin scavenger receptor CD163 and integrin avb5. The number of cells expressing these molecules correlated significantly with the donors' body mass indices (BMIs). Notably, SVCs positive for the common monocyte/macrophage marker CD14 contained a considerable fraction of blood monocytes, the abundance of which did not correlate with the BMIs, pointing to the requirement of the surface markers identified here for the identification of ATMs. ATMs showed endocytic activities similar to M2 macrophages and accordingly secreted high amounts of IL-10 and IL-1 receptor antagonist. However, basal and induced secretion of pro-inflammatory mediators TNF-a, IL-6, IL-1, MCP-1 and MIP-1a was even higher in ATMs than in proinflammatory M1 macrophages. Conclusion: ATMs comprise a particular macrophage type that is M2-like by surface marker expression, but they are competent to produce extensive amounts of inflammatory cytokines, which could considerably contribute to the development of insulin resistance.

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“…Normal metabolic and endocrine function of adipose tissue is increasingly recognised as playing a major role in systemic insulin resistance accompanying common conditions such as Type 2 diabetes and obesity (for review see [1]). However, defining the function of adipose tissue in relation to whole-body fuel metabolism, as well as the molecular mechanisms underlying adipocyte insulin resistance, has proven to be a complex task: systemic insulin resistance accompanies both over-abundance of adipose tissue (obesity) [1], as well as conditions in which adipose tissue mass is lacking (lipodystrophy) [2].…”

Section: Introductionmentioning

confidence: 99%

Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-?

et al. 2004

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Aims/hypothesis. Chronic exposure of 3T3-L1 adipocytes to the HIV protease inhibitor nelfinavir induces insulin resistance, recapitulating key metabolic alterations of adipose tissue in the lipodystrophy syndrome induced by these agents. Our goal was to identify the defect in the insulin signal transduction cascade leading to nelfinavir-induced insulin resistance. Methods. Fully differentiated 3T3-L1 adipocytes were exposed to 30 µmol/l nelfinavir for 18 h, after which the amount, the phosphorylation and the localisation of key proteins in the insulin signalling cascade were evaluated.Results. Insulin-induced interaction of phosphatidylinositol 3′-kinase (PI 3-kinase) with IRS proteins was normal in cells treated with nelfinavir, as was IRS-1-associated PI 3-kinase activity. Yet insulin-induced phosphorylation of Akt/protein kinase B (PKB), p70S6 kinase and extracellular signal-regulated kinase 1/2 was significantly impaired. This could not be attributed to increased protein phosphatase 2A activity or to increased expression of phosphoinositide phosphatases (SHIP2 or PTEN). However, insulin failed to induce translocation of the PI 3-kinase effectors Akt/PKB and protein kinase C-ζ (PKC-ζ) to plasma membrane fractions of nelfinavir-treated adipocytes. Conclusions/interpretation. We therefore conclude that nelfinavir induces a defect in the insulin signalling cascade downstream of the activation of PI 3-kinase. This defect manifests itself by impaired insulin-mediated recruitment of Akt/PKB and PKC-ζ to the plasma membrane.

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Obesity and insulin resistance

Cited by 2,792 publications

References 63 publications

Longitudinal preventive-screening cutoffs for metabolic syndrome in adolescents

Longitudinal preventive-screening cutoffs for metabolic syndrome in adolescents

Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production

Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-?

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