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- Title
Pancreatic β-Cell O-GlcNAc Transferase Overexpression Increases Susceptibility to Metabolic Stressors in Female Mice.
- Authors
Mohan, Ramkumar; Jo, Seokwon; Da Sol Chung, Elina; Oribamise, Eunice; Lockridge, Amber; Abrahante-Lloréns, Juan E.; Ruan, Hai-Bin; Yang, Xiao-Yong; Alejandro, Emilyn U.
- Abstract
The nutrient-sensor O-GlcNAc transferase (Ogt), the sole enzyme that adds an O-GlcNAc-modification onto proteins, plays a critical role for pancreatic β-cell survival and insulin secretion. We hypothesized that β-cell Ogt overexpression would confer protection from β-cell failure in response to metabolic stressors, such as high-fat diet (HFD) and streptozocin (STZ). Here, we generated a β-cell-specific Ogt in overexpressing (βOgtOE) 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 βOgtOE mice show normal peripheral insulin sensitivity and glucose tolerance with a regular chow diet. However, when challenged with an HFD, only female βOgtOE (homozygous) Hz mice developed a mild glucose intolerance, despite increased insulin secretion and normal β-cell mass. While female mice are normally resistant to low-dose STZ treatments, the βOgtOE 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 IL1β and NFkβ. Together, these data show a possible gene dosage effect of Ogt and the importance O-GlcNAc cycling in β-cell survival and function to regulate glucose homeostasis.
- Subjects
INSULIN sensitivity; GLUCOSE intolerance; HIGH-fat diet; MICE; STREPTOZOTOCIN; PANCREATIC beta cells
- Publication
Cells (2073-4409), 2021, Vol 10, Issue 10, p2801
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells10102801