Abstract
Although insulin resistance (IR) is a key pathophysiologic condition underlying various metabolic disorders, impaired cellular glucose uptake is one of many manifestations of metabolic derangements in the human body. To study the systems-wide molecular changes associated with obesity-dependent IR, we integrated information on plasma proteins and microRNAs in eight obese insulin-resistant (OIR, HOMA-IR > 2.5) and nine lean insulin-sensitive (LIS, HOMA-IR < 1.0) normoglycemic males. Of 374 circulating miRNAs we profiled, 65 species increased and 73 species decreased in the OIR compared to the LIS subjects, suggesting that the overall balance of the miRNA secretome is shifted in the OIR subjects. We also observed that 40 plasma proteins increased and 4 plasma proteins decreased in the OIR subjects compared to the LIS subjects, and most proteins are involved in metabolic and endocytic functions. We used an integrative -omics analysis framework called iOmicsPASS to link differentially regulated miRNAs with their target genes on the TargetScan map and the human protein interactome. Combined with tissue of origin information, the integrative analysis allowed us to nominate obesity-dependent and obesity-independent protein markers, along with potential sites of post-transcriptional regulation by some of the miRNAs. We also observed the changes in each -omics platform that are not linked by the TargetScan map, suggesting that proteins and microRNAs provide orthogonal information for the progression of OIR. In summary, our integrative analysis provides a network of elevated plasma markers of OIR and a global shift of microRNA secretome composition in the blood plasma.
Highlights
Insulin resistance (IR) is a state where a high concentration of insulin is needed to exert its normal biological functions, in particular in regulating glucose metabolism and maintaining the balance with lipid and protein metabolism
In a large-scale genome-wide association study of 188,577 individuals, Lotta et al (2017) identified 53 genetic loci that are associated with a human IR phenotype, and hypothesized that these genetic loci might have influence on the capacity of peripheral adipose tissue to store fat in the pathogenesis of IR-related cardiometabolic disease
Further adjustment for age did not alter the significant differences between the two groups
Summary
Insulin resistance (IR) is a state where a high concentration of insulin is needed to exert its normal biological functions, in particular in regulating glucose metabolism and maintaining the balance with lipid and protein metabolism. It is described as an adaptive physiological response that accompanies many metabolic disorders such as T2D, hypertension, cardiovascular disease, dyslipidemia, and polycystic ovarian disease. A growing number of studies have already provided first snapshots of the molecular landscape of IR at the genome, transcriptome, proteome and metabolome level, dissecting the difference between obesity-dependent and obesity-independent pathways leading to IR. Frankie and Abbas showed that the transcriptome and proteome of the insulin signaling, gluconeogenic and inflammatory pathways in skeletal muscle and T-lymphocytes are significantly different between healthy subjects and patients with T2D (Stentz and Kitabchi, 2007)
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