PMID- 24018562
OWN - NLM
STAT- MEDLINE
DCOM- 20131126
LR  - 20230708
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 123
IP  - 10
DP  - 2013 Oct
TI  - Lipotoxicity disrupts incretin-regulated human beta cell connectivity.
PG  - 4182-94
LID - 68459 [pii]
LID - 10.1172/JCI68459 [doi]
AB  - Pancreatic beta cell dysfunction is pathognomonic of type 2 diabetes mellitus (T2DM) 
      and is driven by environmental and genetic factors. beta cell responses to glucose 
      and to incretins such as glucagon-like peptide-1 (GLP-1) and glucose-dependent 
      insulinotropic polypeptide (GIP) are altered in the disease state. While rodent beta 
      cells act as a coordinated syncytium to drive insulin release, this property is 
      unexplored in human islets. In situ imaging approaches were therefore used to 
      monitor in real time the islet dynamics underlying hormone release. We found that 
      GLP-1 and GIP recruit a highly coordinated subnetwork of beta cells that are 
      targeted by lipotoxicity to suppress insulin secretion. Donor BMI was negatively 
      correlated with subpopulation responses to GLP-1, suggesting that this action of 
      incretin contributes to functional beta cell mass in vivo. Conversely, exposure of 
      mice to a high-fat diet unveiled a role for incretin in maintaining coordinated 
      islet activity, supporting the existence of species-specific strategies to 
      maintain normoglycemia. These findings demonstrate that beta cell connectedness is 
      an inherent property of human islets that is likely to influence 
      incretin-potentiated insulin secretion and may be perturbed by diabetogenic 
      insults to disrupt glucose homeostasis in humans.
FAU - Hodson, David J
AU  - Hodson DJ
FAU - Mitchell, Ryan K
AU  - Mitchell RK
FAU - Bellomo, Elisa A
AU  - Bellomo EA
FAU - Sun, Gao
AU  - Sun G
FAU - Vinet, Laurent
AU  - Vinet L
FAU - Meda, Paolo
AU  - Meda P
FAU - Li, Daliang
AU  - Li D
FAU - Li, Wen-Hong
AU  - Li WH
FAU - Bugliani, Marco
AU  - Bugliani M
FAU - Marchetti, Piero
AU  - Marchetti P
FAU - Bosco, Domenico
AU  - Bosco D
FAU - Piemonti, Lorenzo
AU  - Piemonti L
FAU - Johnson, Paul
AU  - Johnson P
FAU - Hughes, Stephen J
AU  - Hughes SJ
FAU - Rutter, Guy A
AU  - Rutter GA
LA  - eng
GR  - 12/0004431/DUK_/Diabetes UK/United Kingdom
GR  - 11/0004210/DUK_/Diabetes UK/United Kingdom
GR  - MR/J0003042/1/MRC_/Medical Research Council/United Kingdom
GR  - R01 GM077593/GM/NIGMS NIH HHS/United States
GR  - WT_/Wellcome Trust/United Kingdom
GR  - R01-GM077593/GM/NIGMS NIH HHS/United States
GR  - 098424/WT_/Wellcome Trust/United Kingdom
GR  - WT098424AIA/WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130909
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Blood Glucose)
RN  - 0 (Fatty Acids, Nonesterified)
RN  - 0 (Incretins)
RN  - 0 (Insulin)
RN  - 89750-14-1 (Glucagon-Like Peptide 1)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Blood Glucose
MH  - Body Mass Index
MH  - Calcium Signaling
MH  - Cell Communication
MH  - Cells, Cultured
MH  - Diabetes Mellitus, Type 2/metabolism
MH  - Diet, High-Fat
MH  - Fatty Acids, Nonesterified/metabolism/pharmacology
MH  - Gap Junctions/metabolism
MH  - Glucagon-Like Peptide 1/physiology
MH  - Glucose/physiology
MH  - Homeostasis
MH  - Humans
MH  - Incretins/*physiology
MH  - Insulin/metabolism
MH  - Insulin Secretion
MH  - Insulin-Secreting Cells/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Species Specificity
PMC - PMC4382273
EDAT- 2013/09/11 06:00
MHDA- 2013/12/16 06:00
PMCR- 2013/09/09
CRDT- 2013/09/11 06:00
PHST- 2012/12/21 00:00 [received]
PHST- 2013/07/11 00:00 [accepted]
PHST- 2013/09/11 06:00 [entrez]
PHST- 2013/09/11 06:00 [pubmed]
PHST- 2013/12/16 06:00 [medline]
PHST- 2013/09/09 00:00 [pmc-release]
AID - 68459 [pii]
AID - 10.1172/JCI68459 [doi]
PST - ppublish
SO  - J Clin Invest. 2013 Oct;123(10):4182-94. doi: 10.1172/JCI68459. Epub 2013 Sep 9.