Downregulation of diacylglycerol kinase delta contributes to hyperglycemia-induced insulin resistance (Cell, 2008, 132:375-386)

報告日期: 2008/10/28
報告時間: 17:05/17:55
報告學生: 陳立仁
講評老師: 蔡少正

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



Speaker: 陳立仁

Commentator: Dr. 蔡少正 

Date: 2008.10.28 17:00 pm

Room: 602


    Obesity is due to a chronic positive energy balance, which increases the amount of triglycerides (TG) in adipose tissue. However, the TG can also be stored in non-adipose tissue, such as muscle, liver, pancreas and heart. Obese individuals are at much greater risk of developing type 2 diabetes and cardiovascular disease (CVD), it has been suggested that ectopic fat is a link between obesity and these diseases. For DAG it has been shown that the insulin resistance observed in human muscle when plasma FFA levels were elevated during euglycemic–hyperinsulinemic clamping was associated with increases in DAG (diacylglycerol). In vitro was found that this metabolite can activate Protein Kinase C (PKC), thereby triggering a serine/threonine kinase cascade, leading to phosphorylation of serine/threonine sites on insulin receptor substrates. This reduces the ability of the insulin receptor substrates to activate phosphatidylinositol 3- kinase, which ultimately results in a reduced GLUT4 translocation to the cell membrane. In this way, increased DAG concentrations may decrease insulin-stimulated muscle glucose uptake.

    DGKs (diacylglycerol kinases) are members of a unique and conserved family of intracellular lipid kinases that phosphorylate DAG, catalysing its conversion into PA (phosphatidic acid). This reaction leads to attenuation of DAG levels in the cell membrane, providing a link between lipid metabolism and signalling.

     Current study has showed that DGKδ protein expression and total DGK activity are reduced in skeletal muscle from type 2 diabetic patients with hyperglycemia. Reduced DGKδ activity, either by chemical inhibition or by genetic ablation, causes aberrant insulin signaling, glucose uptake defects in skeletal muscle and adipose tissue, impaired whole-body insulin sensitivity, and obesity. this findings suggest that Reduce DGKδ may exacerbate the severity of type 2 diabetes.



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