PMID- 9988280
OWN - NLM
STAT- MEDLINE
DCOM- 19990225
LR  - 20171229
IS  - 1061-4036 (Print)
IS  - 1061-4036 (Linking)
VI  - 21
IP  - 2
DP  - 1999 Feb
TI  - Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha 
      subunit of phosphoinositide 3-kinase.
PG  - 230-5
AB  - The hallmark of type 2 diabetes, the most common metabolic disorder, is a defect 
      in insulin-stimulated glucose transport in peripheral tissues. Although a role 
      for phosphoinositide-3-kinase (PI3K) activity in insulin-stimulated glucose 
      transport and glucose transporter isoform 4 (Glut4) translocation has been 
      suggested in vitro, its role in vivo and the molecular link between activation of 
      PI3K and translocation has not yet been elucidated. To determine the role of PI3K 
      in glucose homeostasis, we generated mice with a targeted disruption of the gene 
      encoding the p85alpha regulatory subunit of PI3K (Pik3r1; refs 3-5). Pik3r1-/- 
      mice showed increased insulin sensitivity and hypoglycaemia due to increased 
      glucose transport in skeletal muscle and adipocytes. Insulin-stimulated PI3K 
      activity associated with insulin receptor substrates (IRSs) was mediated via 
      full-length p85 alpha in wild-type mice, but via the p50 alpha alternative 
      splicing isoform of the same gene in Pik3r1-/- mice. This isoform switch was 
      associated with an increase in insulin-induced generation of 
      phosphatidylinositol(3,4,5)triphosphate (PtdIns(3,4,5)P3) in Pik3r1-/- adipocytes 
      and facilitation of Glut4 translocation from the low-density microsome (LDM) 
      fraction to the plasma membrane (PM). This mechanism seems to be responsible for 
      the phenotype of Pik3r1-/- mice, namely increased glucose transport and 
      hypoglycaemia. Our work provides the first direct evidence that PI3K and its 
      regulatory subunit have a role in glucose homeostasis in vivo.
FAU - Terauchi, Y
AU  - Terauchi Y
AD  - Department of Internal Medicine, Research Center for Advanced Science and 
      Technology, University of Tokyo, Japan.
FAU - Tsuji, Y
AU  - Tsuji Y
FAU - Satoh, S
AU  - Satoh S
FAU - Minoura, H
AU  - Minoura H
FAU - Murakami, K
AU  - Murakami K
FAU - Okuno, A
AU  - Okuno A
FAU - Inukai, K
AU  - Inukai K
FAU - Asano, T
AU  - Asano T
FAU - Kaburagi, Y
AU  - Kaburagi Y
FAU - Ueki, K
AU  - Ueki K
FAU - Nakajima, H
AU  - Nakajima H
FAU - Hanafusa, T
AU  - Hanafusa T
FAU - Matsuzawa, Y
AU  - Matsuzawa Y
FAU - Sekihara, H
AU  - Sekihara H
FAU - Yin, Y
AU  - Yin Y
FAU - Barrett, J C
AU  - Barrett JC
FAU - Oda, H
AU  - Oda H
FAU - Ishikawa, T
AU  - Ishikawa T
FAU - Akanuma, Y
AU  - Akanuma Y
FAU - Komuro, I
AU  - Komuro I
FAU - Suzuki, M
AU  - Suzuki M
FAU - Yamamura, K
AU  - Yamamura K
FAU - Kodama, T
AU  - Kodama T
FAU - Suzuki, H
AU  - Suzuki H
FAU - Yamamura, K
AU  - Yamamura K
FAU - Kodama, T
AU  - Kodama T
FAU - Suzuki, H
AU  - Suzuki H
FAU - Koyasu, S
AU  - Koyasu S
FAU - Aizawa, S
AU  - Aizawa S
FAU - Tobe, K
AU  - Tobe K
FAU - Fukui, Y
AU  - Fukui Y
FAU - Yazaki, Y
AU  - Yazaki Y
FAU - Kadowaki, T
AU  - Kadowaki T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Nat Genet
JT  - Nature genetics
JID - 9216904
RN  - 0 (Insulin)
RN  - 0 (Isoenzymes)
RN  - 9G2MP84A8W (Deoxyglucose)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.137 (Class Ia Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.1.137 (Pik3r1 protein, mouse)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Biological Transport/genetics
MH  - Class Ia Phosphatidylinositol 3-Kinase/*deficiency/*genetics/metabolism
MH  - Crosses, Genetic
MH  - Deoxyglucose/metabolism
MH  - Enzyme Activation/genetics
MH  - Glucose/metabolism
MH  - Hypoglycemia/*genetics
MH  - Insulin/*pharmacology
MH  - Isoenzymes/deficiency/genetics/metabolism
MH  - Kinetics
MH  - Mice
MH  - Mice, Knockout
MH  - Muscle, Skeletal/enzymology
MH  - Phosphatidylinositol 3-Kinases/*deficiency/*genetics/metabolism
MH  - Subcellular Fractions/enzymology
EDAT- 1999/02/13 03:14
MHDA- 2001/03/23 10:01
CRDT- 1999/02/13 03:14
PHST- 1999/02/13 03:14 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 1999/02/13 03:14 [entrez]
AID - 10.1038/6023 [doi]
PST - ppublish
SO  - Nat Genet. 1999 Feb;21(2):230-5. doi: 10.1038/6023.