title: Downregulation of diacylglycerol kinase delta contributes to hyperglycemia-induced insulin resistance.
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 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.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, S-171 77, Stockholm, Sweden.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Chibalin
authors.forename: Ying
authors.initials: Y
authors.lastname: Leng
authors.forename: Elaine
authors.initials: E
authors.lastname: Vieira
authors.forename: Anna
authors.initials: A
authors.lastname: Krook
authors.forename: Marie
authors.initials: M
authors.lastname: Björnholm
authors.forename: Yun Chau
authors.initials: YC
authors.lastname: Long
authors.forename: Olga
authors.initials: O
authors.lastname: Kotova
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Zhong
authors.forename: Fumio
authors.initials: F
authors.lastname: Sakane
authors.forename: Tatiana
authors.initials: T
authors.lastname: Steiler
authors.forename: Carolina
authors.initials: C
authors.lastname: Nylén
authors.forename: Jianjun
authors.initials: J
authors.lastname: Wang
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Topham
authors.forename: Marc
authors.initials: M
authors.lastname: Gilbert
authors.forename: Harriet
authors.initials: H
authors.lastname: Wallberg-Henriksson
authors.forename: Juleen R
authors.initials: JR
authors.lastname: Zierath
mesh_terms: D000328:Adult; D000375:Aging; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D019852:Diacylglycerol Kinase / Q000235:genetics / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism; D015536:Down-Regulation; D004734:Energy Metabolism; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
chemical_list: D004075:Diglycerides; C497139:DGKD protein, human; D019852:Diacylglycerol Kinase; D011493:Protein Kinase C; D005947:Glucose