1. Protein kinase C-δ signaling regulates glucagon secretion from pancreatic islets
- Author
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Natsumi Tokashiki, Motoyuki Tamaki, Kiyotake Yamamoto, Hiroyuki Mizuguchi, Youichi Sato, Hiroyuki Fukui, Aiko Yamauchi, and Makoto Kobayashi
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,endocrine system ,030209 endocrinology & metabolism ,In Vitro Techniques ,Glucagon ,General Biochemistry, Genetics and Molecular Biology ,Diabetes Mellitus, Experimental ,03 medical and health sciences ,chemistry.chemical_compound ,Islets of Langerhans ,Mice ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Humans ,Phosphorylation ,Protein kinase C ,streptozotocin-induced diabetic mice ,PKCδ ,Pancreatic islets ,pancreatic α-cells ,Glucagon secretion ,General Medicine ,Mice, Inbred C57BL ,Protein Kinase C-delta ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Phorbol ,Disease Progression ,glucagon secretion ,Tetradecanoylphorbol Acetate ,Quercetin ,Signal transduction ,Rottlerin ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction - 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 Tyr311 of 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.
- Published
- 2017