PMID- 17508912
OWN - NLM
STAT- MEDLINE
DCOM- 20070911
LR  - 20210208
IS  - 1523-0864 (Print)
IS  - 1523-0864 (Linking)
VI  - 9
IP  - 7
DP  - 2007 Jul
TI  - Angiotensin II Type 1 receptor antagonism mediates uncoupling protein 2-driven 
      oxidative stress and ameliorates pancreatic islet beta-cell function in young 
      Type 2 diabetic mice.
PG  - 869-78
AB  - We recently identified a local pancreatic islet renin-angiotensin system (RAS), 
      and demonstrated that it is upregulated in an animal model of obesity-induced 
      type 2 diabetes mellitus (T2DM). Moreover, angiotensin II type 1 receptor (AT1R) 
      antagonism improves beta-cell function and glucose tolerance in young T2DM mice 
      and delays the onset of diabetes. Meanwhile, obesity-induced T2DM results in 
      oxidative stress-mediated activation of uncoupling protein 2 (UCP2), a negative 
      regulator of islet function. In the present study, we postulated that some of the 
      protective effects of AT1R antagonism might be mediated through interference with 
      this pathway and tested this hypothesis in a T2DM animal model. Losartan, an AT1R 
      antagonist, was given to 4-week-old obese db/db mice for a period of 8 weeks. 
      UCP2-driven oxidative damage and apoptosis were then analyzed in isolated islets. 
      Losartan selectively inhibited oxidative stress via downregulation of NADPH 
      oxidase; this in turn suppressed UCP2 expression, thus improving beta-cell 
      insulin secretion and decreasing apoptosis-induced beta-cell mass loss in db/db 
      mouse islets. These data indicate that islet AT1R activation in young diabetic 
      mice can generate progressive islet beta-cell failure through UCP-driven 
      oxidative damage.
FAU - Chu, Kwan Yi
AU  - Chu KY
AD  - Department of Physiology, Faculty of Medicine, The Chinese University of Hong 
      Kong, Shatin, Hong Kong, China.
FAU - Leung, Po Sing
AU  - Leung PS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Antioxid Redox Signal
JT  - Antioxidants & redox signaling
JID - 100888899
RN  - 0 (Angiotensin II Type 1 Receptor Blockers)
RN  - 0 (Insulin)
RN  - 0 (Ion Channels)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Ucp2 protein, mouse)
RN  - 0 (Uncoupling Protein 2)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 3.4.22.- (Caspase 3)
RN  - JMS50MPO89 (Losartan)
SB  - IM
MH  - Angiotensin II Type 1 Receptor Blockers/*pharmacology
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Blotting, Western
MH  - Caspase 3/metabolism
MH  - Diabetes Mellitus, Type 2/*drug therapy/genetics/metabolism
MH  - Gene Expression/drug effects
MH  - Immunohistochemistry
MH  - Insulin/metabolism
MH  - Insulin Secretion
MH  - Ion Channels/*metabolism
MH  - Islets of Langerhans/cytology/*drug effects/metabolism
MH  - Losartan/pharmacology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Obese
MH  - Mitochondrial Proteins/*metabolism
MH  - Models, Biological
MH  - NADPH Oxidases/genetics/metabolism
MH  - Obesity/drug therapy/genetics/metabolism
MH  - Oxidative Stress/*drug effects
MH  - Random Allocation
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Uncoupling Protein 2
EDAT- 2007/05/19 09:00
MHDA- 2007/09/12 09:00
CRDT- 2007/05/19 09:00
PHST- 2007/05/19 09:00 [pubmed]
PHST- 2007/09/12 09:00 [medline]
PHST- 2007/05/19 09:00 [entrez]
AID - 10.1089/ars.2007.1590 [doi]
PST - ppublish
SO  - Antioxid Redox Signal. 2007 Jul;9(7):869-78. doi: 10.1089/ars.2007.1590.