Abstract
BackgroundMetabolic alterations relevant to postprandial dyslipidemia were previously identified in the intestine of obese insulin-resistant subjects. The aim of the study was to identify the genes deregulated by systemic insulin resistance in the intestine of severely obese subjects.MethodsTranscripts from duodenal samples of insulin-sensitive (HOMA-IR < 3, n = 9) and insulin-resistant (HOMA-IR > 7, n = 9) obese subjects were assayed by microarray (Illumina HumanHT-12).ResultsA total of 195 annotated genes were identified as differentially expressed between these two groups (Fold change > 1.2). Of these genes, 36 were found to be directly involved in known intestinal functions, including digestion, extracellular matrix, endocrine system, immunity and cholesterol metabolism. Interestingly, all differentially expressed genes (n = 8) implicated in inflammation and oxidative stress were found to be upregulated in the intestine of insulin-resistant compared to insulin-sensitive subjects. Metabolic pathway analysis revealed that several signaling pathways involved in immunity and inflammation were significantly enriched in differently expressed genes and were predicted to be activated in the intestine of insulin-resistant subjects. Using stringent criteria (Fold change > 1.5; FDR < 0.05), three genes were found to be significantly and differently expressed in the intestine of insulin-resistant compared to insulin-sensitive subjects: the transcripts of the insulinotropic glucose-dependant peptide (GIP) and of the β-microseminoprotein (MSMB) were significantly reduced, but that of the humanin like-1 (MTRNR2L1) was significantly increased.ConclusionThese results underline that systemic insulin resistance is associated with remodeling of key intestinal functions. Moreover, these data indicate that small intestine metabolic dysfunction is accompanied with a local amplification of low-grade inflammatory process implicating several pathways. Genes identified in this study are potentially triggered throughout the development of intestinal metabolic abnormalities, which could contribute to dyslipidemia, a component of metabolic syndrome and diabetes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12876-015-0342-y) contains supplementary material, which is available to authorized users.
Highlights
Metabolic alterations relevant to postprandial dyslipidemia were previously identified in the intestine of obese insulin-resistant subjects
The study sample was selected from a larger pool to establish two groups paired for sex, age and body mass index (BMI) but with divergent homeostatic model assessment of insulin resistance (HOMA-IR) index values, namely the insulin-sensitive (HOMA-IR < 3, n = 9) and the insulin-resistant (HOMA-IR > 7, n = 9) obese subjects [10]
Animal and human studies have recently allowed to display a similar behavior in the intestine of obese and insulin-resistant subjects [3,4,5,6,7,8,9,10, 25, 26]. Since these defects were accompanied with an intestinal triglyceride-rich lipoprotein (TRL) overproduction, we have argued that postprandial dyslipidemia associated to insulin resistance and type 2 diabetes (T2D) is at least partially driven by an adverse intestinal lipid metabolism [11, 27]
Summary
Metabolic alterations relevant to postprandial dyslipidemia were previously identified in the intestine of obese insulin-resistant subjects. Various animal models have been employed to examine the impact of systemic insulin resistance on intestinal lipid metabolism [3,4,5,6,7,8,9]. The low grade inflammatory state was highlighted by enhanced p38 MAPK and NF-κB pathway activation and by increased expression levels of TNF-α, IL-6, ICAM and PTGS-2 in the intestine of insulin-resistant subjects [10]. Adverse changes in the expression of key proteins involved in lipid/lipoprotein metabolism [i.e., liver and intestinal specific fatty acid binding proteins (FABP), microsomal triglyceride transfer protein (MTP)] and cholesterol metabolism [i.e., adenosine triphosphatase-binding cassette A1 (ABCA1) and proprotein convertase subtilisin/kexin type 9 (PCSK9)] were observed in insulin-resistant subjects [10]
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