O-linked N-acetylglucosamine transferase (OGT) regulates pancreatic α-cell function in mice
Year: 2021
Type: article
Abstract: 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.
Source: Journal of Biological Chemistry
Institution: University of Minnesota
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,500
Awards: Innate Immune Complement System and Developmental Programming of Functional β Cell Mass, G1594731290, G3908460148, The role of O-linked N-Acetylglucosamine Homeostasis in Pancreatic Beta-cell Development and Function, G9000131229, Training Grant in Diabetes and Endocrinology to Enhance Metabolic Healthspan
OpenAlex ID: W3122739596