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Functional dissection of metabolic trait-associated variants in steady state and stimulated human skeletal muscle cells [II]

ABSTRACT: Type 2 diabetes (T2D) is a common metabolic disorder characterized by dysregulation of glucose metabolism. Genome-wide association studies have defined hundreds of signals associated with T2D and related metabolic traits, most of which are found in noncoding regions. Given their central role in insulin production and glucose homeostasis, much focus has been devoted to investigating T2D-associated genetic variation in pancreatic islets; however, metabolic disease pathogenesis and risk is distributed across other important metabolic tissues, including the liver, adipose, and skeletal muscle. Here, we used a massively parallel reporter assay (MPRA) to characterize the regulatory activity of T2D-associated variants in human skeletal muscle cells at basal and multiple stimulatory states. We constructed a library of 1,255 oligos spanning 333 metabolic trait-associated variants, half of which were previously characterized using luciferase reporters or in MPRA libraries in any metabolic tissue, and therefore serve as positive controls. We delivered this library to LHCN-M2 human skeletal muscle myocytes in one of four conditions: (1) undifferentiated or differentiated with (2) basal media, (3) media supplemented with the AMP analog 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to mimic physiological effects of exercise or (4) media containing sodium palmitate which is known to induce insulin resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282190 | GEO | 2025/01/02

REPOSITORIES: GEO

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Project description:Physical inactivity and western diet are the main factors leading to skeletal muscle (and whole-body) insulin resistance – a defect in insulin-mediated glucose uptake and metabolism – and associated metabolic diseases, such as obesity and type 2 diabetes mellitus (T2D). The study of the response to a mixed meal (normalized for body mass and/or basal metabolic rate) is of particular interest, as it simulates the physiological response to a typical (daily) single meal that depends on both the secretory function of the beta cells (insulin response) and the sensitivity of skeletal muscle signaling to insulin – variables, which markedly changing during development of insulin resistance and T2D. We aimed to compare the early transcriptomic response to a mixed meal normalized to body mass in skeletal muscle of healthy subjects and obese patients without (Ob) and with T2D (Ob+T2D). To investigate the early transcriptomic response we took biopsy samples from the vastus lateralis muscle prior to and 1 h after a meal. In the Ob+T2D group the average level and increase in C-peptide and insulin in the blood were comparable with healthy subjects that, apparently, is explained by dysfunction of the beta-cells induced by chronic T2D. At the same time, the Ob+T2D group demonstrated dysregulation of mixed meal-induced gene expression in skeletal muscle: morу than two times lower number of DEGs and a small overlapping with the gene response in the control group. On the contrary, the postprandial level of C-peptide and insulin in the Ob group was significantly greater than in healthy control that is related to insulin oversecretion associated with insulin resistance. Despite this, the gene response in skeletal muscle was also significantly dysregulated; moreover, it differed from the response in the Ob+T2D group. It means that defect in regulation of insulin-induced gene expression (insulin resistance in terms of gene expression) appears at the first stage of the development of metabolic disorders.

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Functional dissection of metabolic trait-associated variants in steady state and stimulated human skeletal muscle cells [II]

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