title: Cell type-specific activation of metabolism reveals that beta-cell secretion suppresses glucagon release from alpha-cells in rat pancreatic islets.
abstract: Abnormal glucagon secretion is often associated with diabetes mellitus. However, the mechanisms by which nutrients modulate glucagon secretion remain poorly understood. Paracrine modulation by beta- or delta-cells is among the postulated mechanisms. Herein we present further evidence of the paracrine mechanism. First, to activate cellular metabolism and thus hormone secretion in response to specific secretagogues, we engineered insulinoma INS-1E cells using an adenovirus-mediated expression system. Expression of the Na+-dependent dicarboxylate transporter (NaDC)-1 resulted in 2.5- to 4.6-fold (P < 0.01) increases in insulin secretion in response to various tricarboxylic acid cycle intermediates. Similarly, expression of glycerol kinase (GlyK) increased insulin secretion 3.8- or 4.2-fold (P < 0.01) in response to glycerol or dihydroxyacetone, respectively. This cell engineering method was then modified, using the Cre-loxP switching system, to activate beta-cells and non-beta-cells separately in rat islets. NaDC-1 expression only in non-beta-cells, among which alpha-cells are predominant, caused an increase (by 1.8-fold, P < 0.05) in glucagon secretion in response to malate or succinate. However, the increase in glucagon release was prevented when NaDC-1 was expressed in whole islets, i.e., both beta-cells and non-beta-cells. Similarly, an increase in glucagon release with glycerol was observed when GlyK was expressed only in non-beta-cells but not when it was expressed in whole islets. Furthermore, dicarboxylates suppressed basal glucagon secretion by 30% (P < 0.05) when NaDC-1 was expressed only in beta-cells. These data demonstrate that glucagon secretion from rat alpha-cells depends on beta-cell activation and provide insights into the coordinated mechanisms underlying hormone secretion from pancreatic islets.
authors.affiliation: Div. of Molecular Metabolism and Diabetes, Tohoku Univ. Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Rui
authors.initials: R
authors.lastname: Takahashi
authors.forename: Hisamitsu
authors.initials: H
authors.lastname: Ishihara
authors.forename: Akira
authors.initials: A
authors.lastname: Tamura
authors.forename: Suguru
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamada
authors.forename: Daisuke
authors.initials: D
authors.lastname: Takei
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Endou
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Oka
mesh_terms: D000818:Animals; D002460:Cell Line; D029382:Dicarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D005991:Glycerol Kinase / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism; D019899:Paracrine Communication / Q000502:physiology*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D027981:Symporters / Q000235:genetics / Q000378:metabolism
chemical_list: D029382:Dicarboxylic Acid Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D011994:Recombinant Proteins; C092524:SLC13A2 protein, human; D027981:Symporters; D005934:Glucagon; D005991:Glycerol Kinase