title: Protein kinase C-δ signaling regulates glucagon secretion from pancreatic islets.
abstract: Accumulating evidence supports the "glucagonocentric hypothesis", in which antecedent α-cell failure and inhibition of glucagon secretion are responsible for diabetes progression. Protein kinase C (PKC) is involved in glucagon secretion from α-cells, although which PKC isozyme is involved and the mechanism underlying this PKC-regulated glucagon secretion remains unknown. Here, the involvement of PKCδ in the onset and progression of diabetes was elucidated. Immunofluorescence studies revealed that PKCδ was expressed and activated in α-cells of STZ-induced diabetic model mice. Phorbol 12-myristate 13-acetate (PMA) stimulation significantly augmented glucagon secretion from isolated islets. Pre-treatment with quercetin and rottlerin, PKCδ signaling inhibitors, significantly suppressed the PMA-induced elevation of glucagon secretion. While Go6976, a Ca2+-dependent PKC selective inhibitor did not suppress glucagon secretion. Quercetin suppressed PMA-induced phosphorylation of Tyr311of PKCδ in isolated islets. However, quercetin itself had no effect on either glucagon secretion or glucagon mRNA expression. Our data suggest that PKCδ signaling inhibitors suppressed glucagon secretion. Elucidation of detailed signaling pathways causing PKCδ activation in the onset and progression of diabetes followed by the augmentation of glucagon secretion could lead to the identification of novel therapeutic target molecules and the development of novel therapeutic drugs for diabetes. J. Med. Invest. 64: 122-128, February, 2017.
authors.affiliation: Department of Pharmaceutical Information Science, Institute of Biomedical Sciences, Tokushima University Graduate School.
authors.forename: Kiyotake
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizuguchi
authors.forename: Natsumi
authors.initials: N
authors.lastname: Tokashiki
authors.forename: Makoto
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Tamaki
authors.forename: Youichi
authors.initials: Y
authors.lastname: Sato
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fukui
authors.forename: Aiko
authors.initials: A
authors.lastname: Yamauchi
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000503:physiopathology; D018450:Disease Progression; D005934:Glucagon / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D005934:Glucagon; D011794:Quercetin; C497259:Prkcd protein, mouse; D051745:Protein Kinase C-delta; D013755:Tetradecanoylphorbol Acetate