Transcriptomics

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Transforming growth factor beta-like stimulated clone 22 D4 promotes diabetic hyperglycemia and insulin resistance [skeletal muscle]


ABSTRACT: Obesity-related insulin resistance represents the core component of the so-called Metabolic Syndrome, ultimately promoting glucose intolerance, pancreatic beta cell failure, and overt type 2 diabetes 1 2. Based on substantial side effects of existing pharmacological approaches, efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications. Here, we identify Transforming Growth Factor beta-like Stimulated Clone (TSC) 22 D4 as a critical molecular determinant of insulin signaling and glucose handling. Hepatocyte-specific inactivation of TSC22D4 enhanced insulin signaling in liver and skeletal muscle, while hepatic TSC22D4 overexpression blunted insulin tissue responses. Consequently, hepatic TSC22D4 inhibition both prevented and reversed hyperglycemia, glucose intolerance, and insulin resistance in various diabetes mouse models, respectively. TSC22D4 was found to exert its effects on systemic glucose homeostasis –in large parts- through the transcriptional regulation of the small secretory protein lipocalin (LCN) 13 as demonstrated by chromatin recruitment and genetic rescue experiments in vivo. As hepatic TSC22D4 levels were found to be elevated in human diabetic patients, correlating with decreased insulin sensitivity and hyperglycemia, our results establish the inhibition of TSC22D4 as an attractive insulin sensitizing option in diabetes therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE53754 | GEO | 2014/10/15

SECONDARY ACCESSION(S): PRJNA232813

REPOSITORIES: GEO

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