Protein kinase Cdelta plays a non-redundant role in insulin secretion in pancreatic beta cells.
Protein kinase C (PKC) is considered to modulate glucose-stimulated insulin secretion. Pancreatic beta cells express multiple isoforms of PKCs; however, the role of each isoform in glucose-stimulated insulin secretion remains controversial. In this study we investigated the role of PKCdelta, a major isoform expressed in pancreatic beta cells on beta cell function. Here, we showed that PKCdelta null mice manifested glucose intolerance with impaired insulin secretion. Insulin tolerance test showed no decrease in insulin sensitivity in PKCdelta null mice. Studies using islets isolated from these mice demonstrated decreased glucose- and KCl-stimulated insulin secretion. Perifusion studies indicated that mainly the second phase of insulin secretion was decreased. On the other hand, glucose-induced influx of Ca2+ into beta cells was not altered. Immunohistochemistry using total internal reflection fluorescence microscopy and electron microscopic analysis showed an increased number of insulin granules close to the plasma membrane in beta cells of PKCdelta null mice. Although PKC is thought to phosphorylate Munc18-1 and facilitate soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors complex formation, the phosphorylation of Munc18-1 by glucose stimulation was decreased in islets of PKCdelta null mice. We conclude that PKCdelta plays a non-redundant role in glucose-stimulated insulin secretion. The impaired insulin secretion in PKCdelta null mice is associated with reduced phosphorylation of Munc18-1.
Uchida
Toyoyoshi
T
Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, 2-1-1, Tokyo 113-8421, Japan.
Iwashita
Noseki
N
Ohara-Imaizumi
Mica
M
Ogihara
Takeshi
T
Nagai
Shintaro
S
Choi
Jong Bock
JB
Tamura
Yoshifumi
Y
Tada
Norihiro
N
Kawamori
Ryuzo
R
Nakayama
Keiichi I
KI
Nagamatsu
Shinya
S
Watada
Hirotaka
H
D000818:Animals; D002118:Calcium / Q000378:metabolism; D005089:Exocytosis; D005947:Glucose / Q000378:metabolism; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D051938:Munc18 Proteins / Q000378:metabolism; D010477:Perfusion; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000378:metabolism*; D015398:Signal Transduction
D007328:Insulin; D051938:Munc18 Proteins; D051745:Protein Kinase C-delta; D005947:Glucose; D002118:Calcium