Abstract:Although the developing pancreas is exquisitely sensitive to nutrient supply in utero, it is not entirely clear how nutrient-driven posttranslational modification of proteins impacts the pancreas during development. We hypothesized that the nutrient-sensing enzyme O-GlcNAc transferase (Ogt), which catalyzes an O-GlcNAc-modification onto key target proteins, integrates nutrient-signaling networks to regulate cell survival and development. In this study, we investigated the heretofore unknown role of Ogt in exoc… Show more
“…4 , H and I ). These data suggest that increased ER stress may contribute to cell death in αTC-1 cells when O-GlcNAcylation is blocked, consistent with the reported effects of OGT inhibition in other pancreatic cells ( 14 , 16 ) in vivo . Figure 4 αOGT KO mice show significant reduction in α-cell mass at 6 months .…”
Section: Resultssupporting
confidence: 88%
“…We reported that loss of O-GlcNAcylation in the β-cell leads to cell failure and diabetes in mice due to increased endoplasmic reticulum (ER) stress and apoptosis ( 14 ). Ablation of OGT in pancreatic progenitors also leads to an increased apoptosis ( 16 ). Independent of its role in cell survival, OGT also regulates insulin secretion at basal ( 14 ) and in obesity conditions in part through SERCA2 ( 17 ).…”
The nutrient sensor O-GlcNAc transferase (OGT) catalyzes posttranslational addition of O-GlcNAc onto target proteins, influencing signaling pathways in response to cellular nutrient levels. OGT is highly expressed in pancreatic glucagon-secreting cells (α-cells), which secrete glucagon in response to hypoglycemia. The objective of this study was to determine whether OGT is necessary for the regulation of α-cell mass and function
in vivo
. We utilized genetic manipulation to produce two α-cell specific OGT-knockout models: a constitutive glucagon-Cre (αOGT
KO
) and an inducible glucagon-Cre (i-αOGT
KO
), which effectively delete OGT in α-cells. Using approaches including immunoblotting, immunofluorescent imaging, and metabolic phenotyping
in vivo
, we provide the first insight on the role of O-GlcNAcylation in α-cell mass and function. αOGT
KO
mice demonstrated normal glucose tolerance and insulin sensitivity but displayed significantly lower glucagon levels during both fed and fasted states. αOGT
KO
mice exhibited significantly lower α-cell glucagon content and α-cell mass at 6 months of age. In fasting, αOGT
KO
mice showed impaired pyruvate stimulated gluconeogenesis
in vivo
and reduced glucagon secretion
in vitro
. i-αOGT
KO
mice showed similarly reduced blood glucagon levels, defective
in vitro
glucagon secretion, and normal α-cell mass. Interestingly, both αOGT
KO
and i-αOGT
KO
mice had no deficiency in maintaining blood glucose homeostasis under fed or fasting conditions, despite impairment in α-cell mass and function, and glucagon content. In conclusion, these studies provide a first look at the role of OGT signaling in the α-cell, its effect on α-cell mass, and its importance in regulating glucagon secretion in hypoglycemic conditions.
“…4 , H and I ). These data suggest that increased ER stress may contribute to cell death in αTC-1 cells when O-GlcNAcylation is blocked, consistent with the reported effects of OGT inhibition in other pancreatic cells ( 14 , 16 ) in vivo . Figure 4 αOGT KO mice show significant reduction in α-cell mass at 6 months .…”
Section: Resultssupporting
confidence: 88%
“…We reported that loss of O-GlcNAcylation in the β-cell leads to cell failure and diabetes in mice due to increased endoplasmic reticulum (ER) stress and apoptosis ( 14 ). Ablation of OGT in pancreatic progenitors also leads to an increased apoptosis ( 16 ). Independent of its role in cell survival, OGT also regulates insulin secretion at basal ( 14 ) and in obesity conditions in part through SERCA2 ( 17 ).…”
The nutrient sensor O-GlcNAc transferase (OGT) catalyzes posttranslational addition of O-GlcNAc onto target proteins, influencing signaling pathways in response to cellular nutrient levels. OGT is highly expressed in pancreatic glucagon-secreting cells (α-cells), which secrete glucagon in response to hypoglycemia. The objective of this study was to determine whether OGT is necessary for the regulation of α-cell mass and function
in vivo
. We utilized genetic manipulation to produce two α-cell specific OGT-knockout models: a constitutive glucagon-Cre (αOGT
KO
) and an inducible glucagon-Cre (i-αOGT
KO
), which effectively delete OGT in α-cells. Using approaches including immunoblotting, immunofluorescent imaging, and metabolic phenotyping
in vivo
, we provide the first insight on the role of O-GlcNAcylation in α-cell mass and function. αOGT
KO
mice demonstrated normal glucose tolerance and insulin sensitivity but displayed significantly lower glucagon levels during both fed and fasted states. αOGT
KO
mice exhibited significantly lower α-cell glucagon content and α-cell mass at 6 months of age. In fasting, αOGT
KO
mice showed impaired pyruvate stimulated gluconeogenesis
in vivo
and reduced glucagon secretion
in vitro
. i-αOGT
KO
mice showed similarly reduced blood glucagon levels, defective
in vitro
glucagon secretion, and normal α-cell mass. Interestingly, both αOGT
KO
and i-αOGT
KO
mice had no deficiency in maintaining blood glucose homeostasis under fed or fasting conditions, despite impairment in α-cell mass and function, and glucagon content. In conclusion, these studies provide a first look at the role of OGT signaling in the α-cell, its effect on α-cell mass, and its importance in regulating glucagon secretion in hypoglycemic conditions.
“…In parallel, a high level of O‐GlcNAcylation occurs in the nuclei of β‐cells 18 , which is consistent with the high expression of Ogt in the pancreas (Figure 2) 19,20 . During islet development, Ogt – expressed in pancreatic epithelial progenitor cells – plays an important role in cell survival, and thus pancreatogenesis, which is mediated through pancreatic and duodenal homeobox 1 and p53 21 . In adult mice, greater O‐GlcNAcylation, induced by glutamine:fructose‐6‐aminotransferase overexpression, causes hyperinsulinemia 22 .…”
Section: Pancreatic β‐Cells: a Primary Target In Diabetes Mellitussupporting
Recent studies using genetically manipulated mouse models have shown the pivotal role of O‐linked N‐acetylglucosamine modification (O‐GlcNAcylation) in the metabolism of multiple organs. The molecular mechanism involves the sensing of glucose flux by the hexosamine biosynthesis pathway, which leads to the adjustment of cellular metabolism to protect against changes in the environment of each organ through O‐GlcNAcylation. More recently, not only glucose, but also fluxes of amino acids and fatty acids have been reported to induce O‐GlcNAcylation, affecting multiple cellular processes. In this review, we discuss how O‐GlcNAcylation maintains homeostasis in organs that are affected by diabetes mellitus: skeletal muscle, adipose tissue, liver and pancreatic β‐cells. Furthermore, we discuss the importance of O‐GlcNAcylation in the pathogenesis of diabetic complications. By elucidating the molecular mechanisms whereby cellular homeostasis is maintained, despite changes in metabolic flux, these studies might provide new targets for the treatment and prevention of diabetes and its complications.
“…A most recent study showed that Ogt null mutation in the pancreatic epithelium impacts the development of endocrine and exocrine pancreases. RNA-seq revealed that OGT targets, such as Pdx1, Ptf1a, and p53, are downregulated to induce apoptosis of pancreatic progenitors [138]. Besides, the translocation of β-cell-specific transcription factor NeuroD1 from the cytosol to the nucleus under high glucose conditions is catalyzed by OGN to induce insulin expression in MIN6 cells [139].…”
Section: O-glcnac Is Critical For the Pancreatic Developmentmentioning
The primary cilium, an antenna-like structure on most eukaryotic cells, functions in transducing extracellular signals into intracellular responses via the receptors and ion channels distributed along it membrane. Dysfunction of this organelle causes an array of human diseases, known as ciliopathies, that often feature obesity and diabetes; this indicates the primary cilia’s active role in energy metabolism, which it controls mainly through hypothalamic neurons, preadipocytes, and pancreatic β-cells. The nutrient sensor, O-GlcNAc, is widely involved in the regulation of energy homeostasis. Not only does O-GlcNAc regulate ciliary length, but it also modifies many components of cilia-mediated metabolic signaling pathways. Therefore, it is likely that O-GlcNAcylation (OGN) plays an important role in regulating energy homeostasis in primary cilia. Abnormal OGN, as seen in cases of obesity and diabetes, may play an important role in primary cilia dysfunction mediated by these pathologies.
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