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Downregulation of Diacylglycerol Kinase Delta Contributes to Hyperglycemia-Induced Insulin Resistance

Chibalin, Alexander V. ; Leng, Ying ; Vieira, Elaine ; Krook, Anna ; Björnholm, Marie ; Long, Yun Chau ; Kotova, Olga LU ; Zhong, Zhihui ; Sakane, Fumio and Steiler, Tatiana , et al. (2008) In Cell 132(3). p.375-386
Abstract

Type 2 (non-insulin-dependent) diabetes mellitus is a progressive metabolic disorder arising from genetic and environmental factors that impair beta cell function and insulin action in peripheral tissues. We identified reduced diacylglycerol kinase δ (DGKδ) expression and DGK activity in skeletal muscle from type 2 diabetic patients. In diabetic animals, reduced DGKδ protein and DGK kinase activity were restored upon correction of glycemia. DGKδ haploinsufficiency increased diacylglycerol content, reduced peripheral insulin sensitivity, insulin signaling, and glucose transport, and led to age-dependent obesity. Metabolic flexibility, evident by the transition between lipid and carbohydrate utilization during fasted and fed conditions,... (More)

Type 2 (non-insulin-dependent) diabetes mellitus is a progressive metabolic disorder arising from genetic and environmental factors that impair beta cell function and insulin action in peripheral tissues. We identified reduced diacylglycerol kinase δ (DGKδ) expression and DGK activity in skeletal muscle from type 2 diabetic patients. In diabetic animals, reduced DGKδ protein and DGK kinase activity were restored upon correction of glycemia. DGKδ haploinsufficiency increased diacylglycerol content, reduced peripheral insulin sensitivity, insulin signaling, and glucose transport, and led to age-dependent obesity. Metabolic flexibility, evident by the transition between lipid and carbohydrate utilization during fasted and fed conditions, was impaired in DGKδ haploinsufficient mice. We reveal a previously unrecognized role for DGKδ in contributing to hyperglycemia-induced peripheral insulin resistance and thereby exacerbating the severity of type 2 diabetes. DGKδ deficiency causes peripheral insulin resistance and metabolic inflexibility. These defects in glucose and energy homeostasis contribute to mild obesity later in life.

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publication status
published
subject
keywords
CELLBIO, HUMDISEASE, SIGNALING
in
Cell
volume
132
issue
3
pages
12 pages
publisher
Cell Press
external identifiers
  • pmid:18267070
  • scopus:38849090672
ISSN
0092-8674
DOI
10.1016/j.cell.2007.12.035
language
English
LU publication?
no
id
ccdf9ccd-10d9-4bcc-80b2-8c5911f5651a
date added to LUP
2019-06-03 13:34:40
date last changed
2020-03-24 06:53:37
@article{ccdf9ccd-10d9-4bcc-80b2-8c5911f5651a,
  abstract     = {<p>Type 2 (non-insulin-dependent) diabetes mellitus is a progressive metabolic disorder arising from genetic and environmental factors that impair beta cell function and insulin action in peripheral tissues. We identified reduced diacylglycerol kinase δ (DGKδ) expression and DGK activity in skeletal muscle from type 2 diabetic patients. In diabetic animals, reduced DGKδ protein and DGK kinase activity were restored upon correction of glycemia. DGKδ haploinsufficiency increased diacylglycerol content, reduced peripheral insulin sensitivity, insulin signaling, and glucose transport, and led to age-dependent obesity. Metabolic flexibility, evident by the transition between lipid and carbohydrate utilization during fasted and fed conditions, was impaired in DGKδ haploinsufficient mice. We reveal a previously unrecognized role for DGKδ in contributing to hyperglycemia-induced peripheral insulin resistance and thereby exacerbating the severity of type 2 diabetes. DGKδ deficiency causes peripheral insulin resistance and metabolic inflexibility. These defects in glucose and energy homeostasis contribute to mild obesity later in life.</p>},
  author       = {Chibalin, Alexander V. and Leng, Ying and Vieira, Elaine and Krook, Anna and Björnholm, Marie and Long, Yun Chau and Kotova, Olga and Zhong, Zhihui and Sakane, Fumio and Steiler, Tatiana and Nylén, Carolina and Wang, Jianjun and Laakso, Markku and Topham, Matthew K. and Gilbert, Marc and Wallberg-Henriksson, Harriet and Zierath, Juleen R.},
  issn         = {0092-8674},
  language     = {eng},
  month        = {02},
  number       = {3},
  pages        = {375--386},
  publisher    = {Cell Press},
  series       = {Cell},
  title        = {Downregulation of Diacylglycerol Kinase Delta Contributes to Hyperglycemia-Induced Insulin Resistance},
  url          = {http://dx.doi.org/10.1016/j.cell.2007.12.035},
  doi          = {10.1016/j.cell.2007.12.035},
  volume       = {132},
  year         = {2008},
}