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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Transforming growth factor beta-like stimulated clone 22 D4 promotes diabetic hyperglycemia and insulin resistance.
Diabetol. Stoffwechs. 10:FV12 (2015)
Aim: 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. 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. The goal of this study is to characterize the role of Transforming Growth Factor beta-like Stimulated Clone (TSC) 22 D4 protein in insulin resistance and diabetes. Materials and methods: In order to investigate the metabolic function of TSC22D4 in vivo, we employed liver-specific TSC22D4 knockdown and overexpression approaches both in wild type and diabetic mouse models (db/db and NZO mice). Results: We identified TSC22D4 as a critical molecular determinant of insulin signaling and glucose handling. Hepatic TSC22D4 knockdown enhanced insulin signaling in liver, while hepatic TSC22D4 overexpression blunted insulin signaling. Consequently, hepatic TSC22D4 inhibition both prevented and reversed hyperglycemia, glucose intolerance, and insulin resistance in diabetic mouse models (db/db and NZO mice). In addition, we found that TSC22D4 exerts its effects on systemic glucose homeostasis -in large parts- through the transcriptional regulation of the small secretory protein lipocalin (LCN) 13 as demonstrated by in vivo chromatin recruitment and genetic rescue experiments. Conclusion: In support of our hypothesis and findings, diabetic human patients have elevated hepatic TSC22D4 levels correlating with decreased insulin sensitivity and hyperglycemia. Thus, our results establish TSC22D4 as a promising and attractive target for the treatment of diabetes mellitus.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Meeting abstract
ISSN (print) / ISBN
1861-9002
e-ISSN
1861-9010
Zeitschrift
Diabetologie und Stoffwechsel
Quellenangaben
Band: 10,
Artikelnummer: FV12
Verlag
Thieme
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Diabetes and Cancer (IDC)