title: Diacylglycerol Signaling Pathway in Pancreatic β-Cells: An Essential Role of Diacylglycerol Kinase in the Regulation of Insulin Secretion.
abstract: Diacylglycerol (DAG) is a lipid signal messenger and plays a physiological role in β-cells. Since defective glucose homeostasis increases de novo DAG synthesis, DAG may also contribute to β-cell dysfunction in type 2 diabetes. Although the primary function of DAG is to activate protein kinase C (PKC), the role of PKC in insulin secretion is controversial: PKC has been reported to act as both a positive and negative regulator of insulin secretion. In addition to the PKC pathway, DAG has also been shown to mediate other pathways such as the Munc-13-dependent pathway in β-cells. The intracellular levels of DAG are strictly regulated by diacylglycerol kinase (DGK); however, the role of DGK in β-cells and their involvement in β-cell failure in type 2 diabetes remain to be fully elucidated. We have recently reported the roles of type I DGK, DGKα and γ, in insulin secretion from β-cells. DGKα and γ were activated by glucose or high K(+) stimulation in β-cells, and the inhibition of the DGKs by a type I DGK inhibitor or by knockdown with small interfering RNA (siRNA) decreased insulin secretion. Thus, DGKα and γ are suggested to be activated in response to elevated [Ca(2+)]i in β-cells and to act as positive regulators of insulin secretion. In this article, we review the current understanding of the roles of DAG and DGK in β-cell function and their involvement in the development of β-cell dysfunction in type 2 diabetes.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, University of Shizuoka.
authors.forename: Yukiko K
authors.initials: YK
authors.lastname: Kaneko
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Ishikawa
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D019852:Diacylglycerol Kinase / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*
chemical_list: D004075:Diglycerides; D007328:Insulin; D019852:Diacylglycerol Kinase; D011493:Protein Kinase C; D005947:Glucose; D002118:Calcium