PMID- 22403300
OWN - NLM
STAT- MEDLINE
DCOM- 20120725
LR  - 20211021
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 61
IP  - 6
DP  - 2012 Jun
TI  - The novel therapeutic effect of phosphoinositide 3-kinase-gamma inhibitor AS605240 in 
      autoimmune diabetes.
PG  - 1509-18
LID - 10.2337/db11-0134 [doi]
AB  - Type 1 diabetes (T1D) remains a major health problem worldwide, with a steadily 
      rising incidence yet no cure. Phosphoinositide 3-kinase-gamma (PI3Kgamma), a member of a 
      family of lipid kinases expressed primarily in leukocytes, has been the subject 
      of substantial research for its role in inflammatory diseases. However, the role 
      of PI3Kgamma inhibition in suppressing autoimmune T1D remains to be explored. We 
      tested the role of the PI3Kgamma inhibitor AS605240 in preventing and reversing 
      diabetes in NOD mice and assessed the mechanisms by which this inhibition 
      abrogates T1D. Our data indicate that the PI3Kgamma pathway is highly activated in 
      T1D. In NOD mice, we found upregulated expression of phosphorylated Akt (PAkt) in 
      splenocytes. Notably, T regulatory cells (Tregs) showed significantly lower 
      expression of PAkt compared with effector T cells. Inhibition of the PI3Kgamma 
      pathway by AS605240 efficiently suppressed effector T cells and induced Treg 
      expansion through the cAMP response element-binding pathway. AS605240 effectively 
      prevented and reversed autoimmune diabetes in NOD mice and suppressed T-cell 
      activation and the production of inflammatory cytokines by autoreactive T cells 
      in vitro and in vivo. These studies demonstrate the key role of the PI3Kgamma pathway 
      in determining the balance of Tregs and autoreactive cells regulating autoimmune 
      diabetes.
FAU - Azzi, Jamil
AU  - Azzi J
AD  - Transplantation Research Center, Renal Division, Brigham and Women's Hospital and 
      Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
FAU - Moore, Robert F
AU  - Moore RF
FAU - Elyaman, Wassim
AU  - Elyaman W
FAU - Mounayar, Marwan
AU  - Mounayar M
FAU - El Haddad, Najib
AU  - El Haddad N
FAU - Yang, Sunmi
AU  - Yang S
FAU - Jurewicz, Mollie
AU  - Jurewicz M
FAU - Takakura, Ayumi
AU  - Takakura A
FAU - Petrelli, Alessandra
AU  - Petrelli A
FAU - Fiorina, Paolo
AU  - Fiorina P
FAU - Ruckle, Thomas
AU  - Ruckle T
FAU - Abdi, Reza
AU  - Abdi R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120308
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Quinoxalines)
RN  - 0 (Thiazolidinediones)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Animals
MH  - Diabetes Mellitus, Type 1/*drug therapy/metabolism
MH  - Female
MH  - Hyperglycemia/drug therapy/metabolism
MH  - Mice
MH  - Mice, Inbred NOD
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation/drug effects
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Quinoxalines/pharmacology/*therapeutic use
MH  - Spleen/drug effects/metabolism
MH  - T-Lymphocytes, Regulatory/*drug effects/metabolism
MH  - Thiazolidinediones/pharmacology/*therapeutic use
PMC - PMC3357271
EDAT- 2012/03/10 06:00
MHDA- 2012/07/26 06:00
PMCR- 2013/06/01
CRDT- 2012/03/10 06:00
PHST- 2012/03/10 06:00 [entrez]
PHST- 2012/03/10 06:00 [pubmed]
PHST- 2012/07/26 06:00 [medline]
PHST- 2013/06/01 00:00 [pmc-release]
AID - db11-0134 [pii]
AID - 0134 [pii]
AID - 10.2337/db11-0134 [doi]
PST - ppublish
SO  - Diabetes. 2012 Jun;61(6):1509-18. doi: 10.2337/db11-0134. Epub 2012 Mar 8.