Expression Profiling Identifies Genes That Continue to Respond to Insulin in Adipocytes Made Insulin-resistant by Treatment with Tumor Necrosis Factor-α

Sartipy, Peter; Loskutoff, David J.

doi:10.1074/jbc.m306922200

Cited by 63 publications

(54 citation statements)

References 53 publications

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“…ABCA1 is expressed in pancreatic ␤-cells and is regulated by a transcriptional regulatory network including several proteins and drugs involved in lipid and glucose metabolism (6,7). Moreover, insulin downregulates ABCA1 expression in vitro, while glucose upregulates ABCA1 expression in leukocytes in vivo (8,9). Very recently, mice with specific inactivation of ABCA1 in ␤-cells showed accumulation of cellular cholesterol, marked insulin secretion reduction in vivo, and progressive glucose tolerance impairment, establishing a pivotal role for ABCA1 in pancreatic ␤-cell function (10).…”

Section: T He Identification Of Atp-binding Cassette Transporter A1 (mentioning

confidence: 99%

Association of the ATP-Binding Cassette Transporter A1 R230C Variant With Early-Onset Type 2 Diabetes in a Mexican Population

et al. 2008

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OBJECTIVE—The ATP-binding cassette transporter A1 (ABCA1) R230C variant is associated with low HDL cholesterol levels, obesity, and the metabolic syndrome in Mexican-Mestizos. Because a pivotal role for ABCA1 in pancreatic β-cell function was recently observed in the mouse model, we assessed the association of this variant with type 2 diabetes in this population. RESEARCH DESIGN AND METHODS—The initial group included 446 unrelated Mexican individuals: 244 with type 2 diabetes aged 20–69 years (121 with onset ≤45 years), and 202 nondiabetic control subjects aged >50 years. An independent study group included 242 type 2 diabetic case subjects and 225 control subjects with similar characteristics. RESULTS—R230C/C230C genotypes were significantly more frequent in type 2 diabetic individuals (24.6%) than in control subjects (11.4%) in the initial study group (OR 2.501; P = 0.001). After stratifying by age at diagnosis, the association was significant only in the early-onset group (age at diagnosis ≤45 years) (OR 3.776, P = 3.3 × 10−6). Both associations remained significant after adjusting for admixture (P = 0.0008 and P = 8.1 × 10−6, respectively). Similar trends were observed in the independent study group, and the combined analysis of both populations showed a highly significant association of the R230C variant with type 2 diabetes, particularly with that of early onset (P = 7.6 × 10−6 and 9.4 × 10−8, respectively). CONCLUSIONS—The R230C ABCA1 variant is associated with type 2 diabetes, particularly of early onset, in the Mexican-Mestizo population.

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Section: T He Identification Of Atp-binding Cassette Transporter A1 (mentioning

confidence: 99%

Association of the ATP-Binding Cassette Transporter A1 R230C Variant With Early-Onset Type 2 Diabetes in a Mexican Population

et al. 2008

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“…Collectively, these observations raise the possibility that in the situation of metabolic insulin resistance accompanied by hyperinsulinemia, the expression of certain insulin-responding genes may dramatically increase in insulin target tissues. Expression profiling studies in adipocytes have identified a number of genes that continue to respond normally or are hyperresponsive to insulin even though the adipocytes themselves were metabolically insulin resistant; i.e., they displayed a significantly decreased rate of insulin-mediated glucose uptake (42). Identification of genes that continue to respond to insulin in an insulinresistant state such as obesity, in concert with studies of the properties of these genes and the signaling pathways that regulate them, may provide novel insights into the molecular mechanisms that control abnormal gene expression in obesity and provide novel opportunities for rational drug development.…”

Section: Diabetes Vol 55 September 2006mentioning

confidence: 99%

Altered Adipose and Plasma Sphingolipid Metabolism in Obesity

et al. 2006

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The adipose tissue has become a central focus in the pathogenesis of obesity-mediated cardiovascular and metabolic disease. Here we demonstrate that adipose sphingolipid metabolism is altered in genetically obese (ob/ob) mice. Expression of enzymes involved in ceramide generation (neutral sphingomyelinase [NSMase], acid sphingomyelinase [ASMase], and serine-palmitoyl-transferase [SPT]) and ceramide hydrolysis (ceramidase) are elevated in obese adipose tissues. Our data also suggest that hyperinsulinemia and elevated tumor necrosis factor (TNF)-␣ associated with obesity may contribute to the observed increase in adipose NSMase, ASMase, and SPT mRNA in this murine model of obesity. Liquid chromatography/mass spectroscopy revealed a decrease in total adipose sphingomyelin and ceramide levels but an increase in sphingosine in ob/ob mice compared with lean mice. In contrast to the adipose tissue, plasma levels of total sphingomyelin, ceramide, sphingosine, and sphingosine 1-phosphate (S1P) were elevated in ob/ob mice. In cultured adipocytes, ceramide, sphingosine, and S1P induced gene expression of plasminogen activator inhibitor-1, TNF-␣, monocyte chemoattractant protein-1, interleukin-6, and keratinocytederived chemokine. Collectively, our results identify a novel role for sphingolipids in contributing to the prothrombotic and proinflammatory phenotype of the obese adipose tissue currently believed to play a major role in the pathogenesis of obesity-mediated cardiovascular and metabolic disease. Diabetes

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“…Insulin induces the production and secretion of substantial amounts of MCP-1 in insulin-resistant adipocytes and insulin-resistant obese mice [10]. MCP-1 is similar to other genes such as PAI-1 and SREBP-1c in that it continues to respond to exogenous insulin in insulin-resistant states [10,21]. Moreover, MCP-1 inhibits (by approximately 30%) insulin-stimulated glucose uptake into mouse adipocytes [10].…”

Section: Introductionmentioning

confidence: 99%

Association between the A?2518G polymorphism in the monocyte chemoattractant protein-1 gene and insulin resistance and Type 2 diabetes mellitus

et al. 2004

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Aims/hypothesis. The molecular mechanisms of obesity-related insulin resistance are incompletely understood. Macrophages accumulate in adipose tissue of obese individuals. In obesity, monocyte chemoattractant protein-1 (MCP-1), a key chemokine in the process of macrophage accumulation, is overexpressed in adipose tissue. MCP-1 is an insulin-responsive gene that continues to respond to exogenous insulin in insulin-resistant adipocytes and mice. MCP-1 decreases insulin-stimulated glucose uptake into adipocytes. The A-2518G polymorphism in the distal regulatory region of MCP-1 may regulate gene expression. The aim of this study was to investigate the impact of this gene polymorphism on insulin resistance. Methods. We genotyped the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort (n=3307). Insulin resistance, estimated by homeostasis model assessment, and Type 2 diabetes were diagnosed in 803 and 635 patients respectively. Results. Univariate analysis revealed that plasma MCP-1 levels were significantly and positively correlated with WHR (p=0.011), insulin resistance (p=0.0097) and diabetes (p<0.0001). Presence of the MCP-1 G-2518 allele was associated with decreased plasma MCP-1 (p=0.017), a decreased prevalence of insulin resistance (odds ratio [OR]=0.82, 95% CI: 0.70-0.97, p=0.021) and a decreased prevalence of diabetes (OR=0.80, 95% CI: 0.67-0.96, p=0.014). In multivariate analysis, the G allele retained statistical significance as a negative predictor of insulin resistance (OR=0.78, p=0.0060) and diabetes (OR=0.80, p=0.018). Conclusions/interpretation. In a large cohort of Caucasians, the MCP-1 G-2518 gene variant was significantly and negatively correlated with plasma MCP-1 levels and the prevalence of insulin resistance and Type 2 diabetes. These results add to recent evidence supporting a role for MCP-1 in pathologies associated with hyperinsulinaemia.

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Expression Profiling Identifies Genes That Continue to Respond to Insulin in Adipocytes Made Insulin-resistant by Treatment with Tumor Necrosis Factor-α

Cited by 63 publications

References 53 publications

Association of the ATP-Binding Cassette Transporter A1 R230C Variant With Early-Onset Type 2 Diabetes in a Mexican Population

Association of the ATP-Binding Cassette Transporter A1 R230C Variant With Early-Onset Type 2 Diabetes in a Mexican Population

Altered Adipose and Plasma Sphingolipid Metabolism in Obesity

Association between the A?2518G polymorphism in the monocyte chemoattractant protein-1 gene and insulin resistance and Type 2 diabetes mellitus

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