Class II phosphoinositide 3-kinase regulates exocytosis of insulin granules in pancreatic beta cells.
Phosphoinositide 3-kinases (PI3Ks) are critical regulators of pancreatic β cell mass and survival, whereas their involvement in insulin secretion is more controversial. Furthermore, of the different PI3Ks, the class II isoforms were detected in β cells, although their role is still not well understood. Here we show that down-regulation of the class II PI3K isoform PI3K-C2α specifically impairs insulin granule exocytosis in rat insulinoma cells without affecting insulin content, the number of insulin granules at the plasma membrane, or the expression levels of key proteins involved in insulin secretion. Proteolysis of synaptosomal-associated protein of 25 kDa, a process involved in insulin granule exocytosis, is impaired in cells lacking PI3K-C2α. Finally, our data suggest that the mRNA for PI3K-C2α may be down-regulated in islets of Langerhans from type 2 diabetic compared with non-diabetic individuals. Our results reveal a critical role for PI3K-C2α in β cells and suggest that down-regulation of PI3K-C2α may be a feature of type 2 diabetes.
From the Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute of Cell and Molecular Science, Centre for Diabetes, London E1 2AT, United Kingdom.
Veronica
V
Dominguez
Claudio
C
Raimondi
Sangeeta
S
Somanath
Marco
M
Bugliani
Merewyn K
MK
Loder
Charlotte E
CE
Edling
Nullin
N
Divecha
Gabriela
G
da Silva-Xavier
Lorella
L
Marselli
Shanta J
SJ
Persaud
Mark D
MD
Turner
Guy A
GA
Rutter
Piero
P
Marchetti
Marco
M
Falasca
Tania
T
Maffucci
D000818:Animals; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005089:Exocytosis; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D022142:Secretory Vesicles / Q000378:metabolism*; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism
D007328:Insulin; D007527:Isoenzymes; D012333:RNA, Messenger; D050825:Synaptosomal-Associated Protein 25; D019869:Phosphatidylinositol 3-Kinases; C546621:PIK3C2A protein, human