PMID- 34685781
OWN - NLM
STAT- MEDLINE
DCOM- 20211203
LR  - 20220315
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 10
IP  - 10
DP  - 2021 Oct 19
TI  - Pancreatic beta-Cell O-GlcNAc Transferase Overexpression Increases Susceptibility to 
      Metabolic Stressors in Female Mice.
LID - 10.3390/cells10102801 [doi]
LID - 2801
AB  - The nutrient-sensor O-GlcNAc transferase (Ogt), the sole enzyme that adds an 
      O-GlcNAc-modification onto proteins, plays a critical role for pancreatic beta-cell 
      survival and insulin secretion. We hypothesized that beta-cell Ogt overexpression 
      would confer protection from beta-cell failure in response to metabolic stressors, 
      such as high-fat diet (HFD) and streptozocin (STZ). Here, we generated a 
      beta-cell-specific Ogt in overexpressing (betaOgtOE) mice, where a significant increase 
      in Ogt protein level and O-GlcNAc-modification of proteins were observed in 
      islets under a normal chow diet. We uncovered that betaOgtOE mice show normal 
      peripheral insulin sensitivity and glucose tolerance with a regular chow diet. 
      However, when challenged with an HFD, only female betaOgtOE (homozygous) Hz mice 
      developed a mild glucose intolerance, despite increased insulin secretion and 
      normal beta-cell mass. While female mice are normally resistant to low-dose STZ 
      treatments, the betaOgtOE Hz mice developed hyperglycemia and glucose intolerance 
      post-STZ treatment. Transcriptome analysis between islets with loss or gain of 
      Ogt by RNA sequencing shows common altered pathways involving pro-survival Erk 
      and Akt and inflammatory regulators IL1beta and NFkbeta. Together, these data show a 
      possible gene dosage effect of Ogt and the importance O-GlcNAc cycling in beta-cell 
      survival and function to regulate glucose homeostasis.
FAU - Mohan, Ramkumar
AU  - Mohan R
AD  - Department of Integrative Biology and Physiology, University of Minnesota, 
      Minneapolis, MN 55455, USA.
FAU - Jo, Seokwon
AU  - Jo S
AD  - Department of Integrative Biology and Physiology, University of Minnesota, 
      Minneapolis, MN 55455, USA.
FAU - Da Sol Chung, Elina
AU  - Da Sol Chung E
AUID- ORCID: 0000-0001-8031-9481
AD  - Department of Integrative Biology and Physiology, University of Minnesota, 
      Minneapolis, MN 55455, USA.
FAU - Oribamise, Eunice
AU  - Oribamise E
AD  - Department of Integrative Biology and Physiology, University of Minnesota, 
      Minneapolis, MN 55455, USA.
FAU - Lockridge, Amber
AU  - Lockridge A
AUID- ORCID: 0000-0003-1122-6286
AD  - Department of Integrative Biology and Physiology, University of Minnesota, 
      Minneapolis, MN 55455, USA.
FAU - Abrahante-Llorens, Juan E
AU  - Abrahante-Llorens JE
AD  - Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455, USA.
FAU - Ruan, Hai-Bin
AU  - Ruan HB
AD  - Department of Integrative Biology and Physiology, University of Minnesota, 
      Minneapolis, MN 55455, USA.
FAU - Yang, Xiao-Yong
AU  - Yang XY
AD  - Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale 
      University, New Haven, CT 06520, USA.
FAU - Alejandro, Emilyn U
AU  - Alejandro EU
AUID- ORCID: 0000-0002-7941-8439
AD  - Department of Integrative Biology and Physiology, University of Minnesota, 
      Minneapolis, MN 55455, USA.
LA  - eng
GR  - R01 DK115720/DK/NIDDK NIH HHS/United States
GR  - R21 DK112144/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 - 20211019
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Insulin)
RN  - EC 2.4.1.- (N-Acetylglucosaminyltransferases)
RN  - EC 2.4.1.- (O-GlcNAc transferase)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Diet, High-Fat
MH  - Female
MH  - Gene Expression Regulation
MH  - Glucose/metabolism
MH  - Glucose Intolerance/blood/complications/pathology
MH  - Homeostasis
MH  - Hyperglycemia/blood/complications
MH  - Insulin/blood
MH  - Insulin-Secreting Cells/*enzymology
MH  - Male
MH  - Mice, Transgenic
MH  - N-Acetylglucosaminyltransferases/*metabolism
MH  - Reproducibility of Results
MH  - *Stress, Physiological
MH  - Transcriptome/genetics
MH  - Up-Regulation
PMC - PMC8534823
OTO - NOTNLM
OT  - O-GlcNAc transferase
OT  - islet
OT  - streptozocin
COIS- The authors declare no conflict of interest.
EDAT- 2021/10/24 06:00
MHDA- 2021/12/15 06:00
PMCR- 2021/10/19
CRDT- 2021/10/23 01:23
PHST- 2021/09/18 00:00 [received]
PHST- 2021/10/14 00:00 [revised]
PHST- 2021/10/14 00:00 [accepted]
PHST- 2021/10/23 01:23 [entrez]
PHST- 2021/10/24 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2021/10/19 00:00 [pmc-release]
AID - cells10102801 [pii]
AID - cells-10-02801 [pii]
AID - 10.3390/cells10102801 [doi]
PST - epublish
SO  - Cells. 2021 Oct 19;10(10):2801. doi: 10.3390/cells10102801.