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Downregulation of Diacylglycerol Kinase Delta Contributes to Hyperglycemia-Induced Insulin Resistance
Open accessAbstract
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 delta (DGKdelta) expression and DGK activity in skeletal muscle from type 2 diabetic patients. In diabetic animals, reduced DGKdelta protein and DGK kinase activity were restored upon correction of glycemia. DGKdelta 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 DGKdelta haploinsufficient mice. We reveal a previously unrecognized role for DGKdelta in contributing to hyperglycemia-induced peripheral insulin resistance and thereby exacerbating the severity of type 2 diabetes. DGKdelta 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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“Increased tissue lipid load, as with obesity, and/or sustained inactivity, may lead to the accumulation of fatty acyl coenzyme A (CoA), diacylglycerols, ceramides, products of incomplete oxidation, and ROS, all of which have been linked experimentally to reduced insulin signaling and action (96 -102).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [101]
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Metadata
- Authors
- Chibalin, A. V., Leng, Y., Vieira, E., Krook, A., Björnholm, M., Long, Y. C., Kotova, O., Zhong, Z., Sakane, F., Steiler, T., Nylén, C., Wang, J., Laakso, M., Topham, M. K., Gilbert, M., Wallberg-Henriksson, H., & Zierath, J. R.
- Affiliations
- Karolinska Institutet (SE)
- University of Eastern Finland (FI)
- Corresponding author
- Zierath, Juleen R.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2008-02
- Volume
- 132
- Issue
- 3
- Pages
- 375-386
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2066159172
- Cited by
- 232
- References
- 53
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 10 · 2023: 9 · 2022: 6 · 2021: 9 · 2020: 11 · 2019: 11 · 2018: 14 · 2017: 12 · 2016: 17 · 2015: 12 · 2014: 18 · 2013: 18 · 2012: 23
- FWCI
- 7.14
- Type
- journal article
- Language
- en
- Update notices
- erratum (2022-01-20)
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1993 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- type 2 diabetes, hyperglycemia, insulin resistance, skeletal muscle, diacylglycerol, insulin signaling, glucose transport, metabolic inflexibility, obesity, energy homeostasis, glucose metabolism
- MeSH terms
- Adult, Aging, Animals, Diabetes Mellitus, Type 2, Diglycerides, Energy Metabolism, Glucose, Humans, Hyperglycemia, Insulin Resistance, Male, Obesity, Protein Kinase C, Signal Transduction, Down-Regulation, Rats, Wistar, Muscle, Skeletal, Diacylglycerol Kinase, Gene Expression Profiling, Lipid Metabolism, Mice, Rats
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