Cargando…

TRIB3 Mediates Glucose-Induced Insulin Resistance via a Mechanism That Requires the Hexosamine Biosynthetic Pathway

In the current study, we investigated the role of tribbles homolog 3 (TRIB3) in glucose-induced insulin resistance and whether the induction of TRIB3 by glucose is dependent on the nutrient-sensing hexosamine biosynthetic pathway (HBP) known to mediate glucose toxicity in diabetes. In diabetic rats,...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhang, Wei, Liu, Jiarong, Tian, Ling, Liu, Qinglan, Fu, Yuchang, Garvey, W. Timothy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837074/
https://www.ncbi.nlm.nih.gov/pubmed/23990361
http://dx.doi.org/10.2337/db13-0312
_version_ 1782292401309614080
author Zhang, Wei
Liu, Jiarong
Tian, Ling
Liu, Qinglan
Fu, Yuchang
Garvey, W. Timothy
author_facet Zhang, Wei
Liu, Jiarong
Tian, Ling
Liu, Qinglan
Fu, Yuchang
Garvey, W. Timothy
author_sort Zhang, Wei
collection PubMed
description In the current study, we investigated the role of tribbles homolog 3 (TRIB3) in glucose-induced insulin resistance and whether the induction of TRIB3 by glucose is dependent on the nutrient-sensing hexosamine biosynthetic pathway (HBP) known to mediate glucose toxicity in diabetes. In diabetic rats, TRIB3 expression in skeletal muscle was increased after 10 days of hyperglycemia, and glycemia and muscle TRIB3 were both restored toward normal by insulin therapy. In L6 myocytes, the induction of TRIB3 by high glucose or glucosamine was reversible upon removal of these substrates. To assess the role of HBP in the induction of TRIB3, we demonstrated that the ability of high glucose to augment TRIB3 expression was prevented by azaserine, an inhibitor of glutamine: fructose-6-phosphate amidotransferase (GFAT), which is the rate-limiting enzyme in the HBP pathway. TRIB3 expression was also substantially stimulated by glucosamine, which bypasses GFAT, accompanied by a decrease in the insulin-stimulated glucose transport rate, and neither response was affected by azaserine. Further, knockdown of TRIB3 inhibited, and TRIB3 overexpression enhanced, the ability of both high glucose and glucosamine to induce insulin resistance. These data provide the mechanistic link between the HBP flux and insulin resistance and point to TRIB3 as a novel target for treatment of glucose-induced insulin resistance.
format Online
Article
Text
id pubmed-3837074
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher American Diabetes Association
record_format MEDLINE/PubMed
spelling pubmed-38370742014-12-01 TRIB3 Mediates Glucose-Induced Insulin Resistance via a Mechanism That Requires the Hexosamine Biosynthetic Pathway Zhang, Wei Liu, Jiarong Tian, Ling Liu, Qinglan Fu, Yuchang Garvey, W. Timothy Diabetes Original Research In the current study, we investigated the role of tribbles homolog 3 (TRIB3) in glucose-induced insulin resistance and whether the induction of TRIB3 by glucose is dependent on the nutrient-sensing hexosamine biosynthetic pathway (HBP) known to mediate glucose toxicity in diabetes. In diabetic rats, TRIB3 expression in skeletal muscle was increased after 10 days of hyperglycemia, and glycemia and muscle TRIB3 were both restored toward normal by insulin therapy. In L6 myocytes, the induction of TRIB3 by high glucose or glucosamine was reversible upon removal of these substrates. To assess the role of HBP in the induction of TRIB3, we demonstrated that the ability of high glucose to augment TRIB3 expression was prevented by azaserine, an inhibitor of glutamine: fructose-6-phosphate amidotransferase (GFAT), which is the rate-limiting enzyme in the HBP pathway. TRIB3 expression was also substantially stimulated by glucosamine, which bypasses GFAT, accompanied by a decrease in the insulin-stimulated glucose transport rate, and neither response was affected by azaserine. Further, knockdown of TRIB3 inhibited, and TRIB3 overexpression enhanced, the ability of both high glucose and glucosamine to induce insulin resistance. These data provide the mechanistic link between the HBP flux and insulin resistance and point to TRIB3 as a novel target for treatment of glucose-induced insulin resistance. American Diabetes Association 2013-12 2013-11-16 /pmc/articles/PMC3837074/ /pubmed/23990361 http://dx.doi.org/10.2337/db13-0312 Text en © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Original Research
Zhang, Wei
Liu, Jiarong
Tian, Ling
Liu, Qinglan
Fu, Yuchang
Garvey, W. Timothy
TRIB3 Mediates Glucose-Induced Insulin Resistance via a Mechanism That Requires the Hexosamine Biosynthetic Pathway
title TRIB3 Mediates Glucose-Induced Insulin Resistance via a Mechanism That Requires the Hexosamine Biosynthetic Pathway
title_full TRIB3 Mediates Glucose-Induced Insulin Resistance via a Mechanism That Requires the Hexosamine Biosynthetic Pathway
title_fullStr TRIB3 Mediates Glucose-Induced Insulin Resistance via a Mechanism That Requires the Hexosamine Biosynthetic Pathway
title_full_unstemmed TRIB3 Mediates Glucose-Induced Insulin Resistance via a Mechanism That Requires the Hexosamine Biosynthetic Pathway
title_short TRIB3 Mediates Glucose-Induced Insulin Resistance via a Mechanism That Requires the Hexosamine Biosynthetic Pathway
title_sort trib3 mediates glucose-induced insulin resistance via a mechanism that requires the hexosamine biosynthetic pathway
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837074/
https://www.ncbi.nlm.nih.gov/pubmed/23990361
http://dx.doi.org/10.2337/db13-0312
work_keys_str_mv AT zhangwei trib3mediatesglucoseinducedinsulinresistanceviaamechanismthatrequiresthehexosaminebiosyntheticpathway
AT liujiarong trib3mediatesglucoseinducedinsulinresistanceviaamechanismthatrequiresthehexosaminebiosyntheticpathway
AT tianling trib3mediatesglucoseinducedinsulinresistanceviaamechanismthatrequiresthehexosaminebiosyntheticpathway
AT liuqinglan trib3mediatesglucoseinducedinsulinresistanceviaamechanismthatrequiresthehexosaminebiosyntheticpathway
AT fuyuchang trib3mediatesglucoseinducedinsulinresistanceviaamechanismthatrequiresthehexosaminebiosyntheticpathway
AT garveywtimothy trib3mediatesglucoseinducedinsulinresistanceviaamechanismthatrequiresthehexosaminebiosyntheticpathway