PMID- 19073772
OWN - NLM
STAT- MEDLINE
DCOM- 20090324
LR  - 20211203
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 58
IP  - 3
DP  - 2009 Mar
TI  - Glycogen synthase kinase-3 and mammalian target of rapamycin pathways contribute 
      to DNA synthesis, cell cycle progression, and proliferation in human islets.
PG  - 663-72
LID - 10.2337/db07-1208 [doi]
AB  - OBJECTIVE: Our previous studies demonstrated that nutrient regulation of 
      mammalian target of rapamycin (mTOR) signaling promotes regenerative processes in 
      rodent islets but rarely in human islets. Our objective was to extend these 
      findings by using therapeutic agents to determine whether the regulation of 
      glycogen synthase kinase-3 (GSK-3)/beta-catenin and mTOR signaling represent key 
      components necessary for effecting a positive impact on human beta-cell mass 
      relevant to type 1 and 2 diabetes. RESEARCH DESIGN AND METHODS: Primary adult 
      human and rat islets were treated with the GSK-3 inhibitors, LiCl and the highly 
      potent 1-azakenpaullone (1-Akp), and with nutrients. DNA synthesis, cell cycle 
      progression, and proliferation of beta-cells were assessed. Measurement of 
      insulin secretion and content and Western blot analysis of GSK-3 and mTOR 
      signaling components were performed. RESULTS: Human islets treated for 4 days 
      with LiCl or 1-Akp exhibited significant increases in DNA synthesis, cell cycle 
      progression, and proliferation of beta-cells that displayed varying degrees of 
      sensitivity to rapamycin. Intermediate glucose (8 mmol/l) produced a striking 
      degree of synergism in combination with GSK-3 inhibition to enhance 
      bromodeoxyuridine (BrdU) incorporation and Ki-67 expression in human beta-cells. 
      Nuclear translocation of beta-catenin responsible for cell proliferation was 
      found to be particularly sensitive to rapamycin. CONCLUSIONS: A combination of 
      GSK-3 inhibition and nutrient activation of mTOR contributes to enhanced DNA 
      synthesis, cell cycle progression, and proliferation of human beta-cells. 
      Identification of therapeutic agents that appropriately regulate GSK-3 and mTOR 
      signaling may provide a feasible and available approach to enhance human islet 
      growth and proliferation.
FAU - Liu, Hui
AU  - Liu H
AD  - Department of Pathology and Immunology, Washington University, St. Louis, 
      Missouri, USA.
FAU - Remedi, Maria S
AU  - Remedi MS
FAU - Pappan, Kirk L
AU  - Pappan KL
FAU - Kwon, Guim
AU  - Kwon G
FAU - Rohatgi, Nidhi
AU  - Rohatgi N
FAU - Marshall, Connie A
AU  - Marshall CA
FAU - McDaniel, Michael L
AU  - McDaniel ML
LA  - eng
GR  - R56 DK006181/DK/NIDDK NIH HHS/United States
GR  - DK-07296/DK/NIDDK NIH HHS/United States
GR  - T32 DK007296/DK/NIDDK NIH HHS/United States
GR  - DK-56341/DK/NIDDK NIH HHS/United States
GR  - R01 DK006181/DK/NIDDK NIH HHS/United States
GR  - DK-006181/DK/NIDDK NIH HHS/United States
GR  - P30 DK056341-08/DK/NIDDK NIH HHS/United States
GR  - P30 DK056341/DK/NIDDK NIH HHS/United States
GR  - P30 DK056341-07/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20081210
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Insulin)
RN  - 0 (Ki-67 Antigen)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Animals
MH  - Cell Cycle/*physiology
MH  - Cell Division/*physiology
MH  - *DNA Replication/drug effects
MH  - Diabetes Mellitus, Type 1/enzymology/*physiopathology
MH  - Diabetes Mellitus, Type 2/enzymology/*physiopathology
MH  - Female
MH  - Glycogen Synthase Kinase 3/antagonists & inhibitors/*metabolism
MH  - Humans
MH  - Insulin/pharmacology
MH  - Islets of Langerhans/*cytology/enzymology/*physiology
MH  - Ki-67 Antigen/genetics
MH  - Male
MH  - Middle Aged
MH  - Protein Kinases/genetics/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases
MH  - Young Adult
PMC - PMC2646065
EDAT- 2008/12/17 09:00
MHDA- 2009/03/25 09:00
PMCR- 2010/03/01
CRDT- 2008/12/17 09:00
PHST- 2008/12/17 09:00 [entrez]
PHST- 2008/12/17 09:00 [pubmed]
PHST- 2009/03/25 09:00 [medline]
PHST- 2010/03/01 00:00 [pmc-release]
AID - db07-1208 [pii]
AID - 583663 [pii]
AID - 10.2337/db07-1208 [doi]
PST - ppublish
SO  - Diabetes. 2009 Mar;58(3):663-72. doi: 10.2337/db07-1208. Epub 2008 Dec 10.