O-linked N-acetylglucosamine transferase (OGT) regulates pancreatic α-cell function in mice

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 (αOGTKO) and an inducible glucagon-Cre (i-αOGTKO), 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. αOGTKO mice demonstrated normal glucose tolerance and insulin sensitivity but displayed significantly lower glucagon levels during both fed and fasted states. αOGTKO mice exhibited significantly lower α-cell glucagon content and α-cell mass at 6 months of age. In fasting, αOGTKO mice showed impaired pyruvate stimulated gluconeogenesis in vivo and reduced glucagon secretion in vitro. i-αOGTKO mice showed similarly reduced blood glucagon levels, defective in vitro glucagon secretion, and normal α-cell mass. Interestingly, both αOGTKO and i-αOGTKO 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. 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 (αOGTKO) and an inducible glucagon-Cre (i-αOGTKO), 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. αOGTKO mice demonstrated normal glucose tolerance and insulin sensitivity but displayed significantly lower glucagon levels during both fed and fasted states. αOGTKO mice exhibited significantly lower α-cell glucagon content and α-cell mass at 6 months of age. In fasting, αOGTKO mice showed impaired pyruvate stimulated gluconeogenesis in vivo and reduced glucagon secretion in vitro. i-αOGTKO mice showed similarly reduced blood glucagon levels, defective in vitro glucagon secretion, and normal α-cell mass. Interestingly, both αOGTKO and i-αOGTKO 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 the pancreas, glucose homeostasis is mainly regulated by the islets of Langerhans, which consist of different endocrine cells including the β-cells and α-cells (1Da Silva Xavier G. The cells of the islets of Langerhans.J. Clin. Med. 2018; 7: 54Crossref Google Scholar). β-cells secrete insulin in response to high blood glucose. In contrast, α-cells secrete glucagon in response to low blood glucose levels. Together, these endocrine cells, secreting their counter regulatory hormones, work together to maintain blood glucose at a physiological level (2Folli F. La Rosa S. Finzi G. Davalli A.M. Galli A. Dick Jr., E.J. Perego C. Mendoza R.G. Pancreatic islet of Langerhans' cytoarchitecture and ultrastructure in normal glucose tolerance and in type 2 diabetes mellitus.Diabetes Obes. Metab. 2018; 20 Suppl 2: 137-144Crossref PubMed Scopus (22) Google Scholar). For both type 1 (T1D) and type 2 (T2D) diabetes, a clear role for absolute deficiency or insufficiency in insulin has been established (3Donath M.Y. Halban P.A. Decreased beta-cell mass in diabetes: Significance, mechanisms and therapeutic implications.Diabetologia. 2004; 47: 581-589Crossref PubMed Scopus (307) Google Scholar). In addition to altered insulin levels, dysregulation of glucagon levels in T1D and T2D contributes to the pathology of these diseases (4D'Alessio D. The role of dysregulated glucagon secretion in type 2 diabetes.Diabetes Obes. Metab. 2011; 13 Suppl 1: 126-132Crossref PubMed Scopus (156) Google Scholar, 5Wewer Albrechtsen N.J. Kuhre R.E. Pedersen J. Knop F.K. Holst J.J. The biology of glucagon and the consequences of hyperglucagonemia.Biomark. Med. 2016; 10: 1141-1151Crossref PubMed Scopus (44) Google Scholar). High glucagon levels in both T1D and T2D exacerbate hyperglycemia due to enhanced hepatic glucose output (6Lund A. Bagger J.I. Christensen M. Knop F.K. Vilsboll T. Glucagon and type 2 diabetes: The return of the alpha cell.Curr. Diab. Rep. 2014; 14: 555Crossref PubMed Scopus (65) Google Scholar). While the cause and result of functional β-cell deficiency have been studied heavily in the field, the mechanisms and impact of α-cell failure are less known. Thus, a greater understanding of processes that regulate α-cell function may present new avenues for optimal glucose control in T1D or advanced therapy for T2D patients. The hexosamine biosynthetic pathway (HBP) is a minor branch of glycolysis responsible for the production of the key substrate for protein glycosylation, UDP-GlcNAc (7Love D.C. Hanover J.A. The hexosamine signaling pathway: Deciphering the “O-GlcNAc code”.Sci. STKE. 2005; 2005re13PubMed Google Scholar). Posttranslational addition of UDP-GlcNAc (known as O-GlcNAcylation) is a dynamic and reversible process analogous to phosphorylation and has been shown to affect the function, stability, and subcellular localization of many proteins (8Hanover J.A. Krause M.W. Love D.C. The hexosamine signaling pathway: O-GlcNAc cycling in feast or famine.Biochim. Biophys. Acta. 2010; 1800: 80-95Crossref PubMed Scopus (231) Google Scholar). O-GlcNAcylation is catalyzed solely by the enzyme O-linked GlcNAc transferase (OGT), by means of the addition of UDP-GlcNAc to the serine or threonine residues on nuclear and cytosolic proteins (9Hart G.W. Akimoto Y. The O-GlcNAc modification.in: Varki A. Cummings R.D. Esko J.D. Freeze H.H. Stanley P. Bertozzi C.R. Hart G.W. Etzler M.E. Essentials of Glycobiology Chapter 18. Cold Spring Harbor, NY2009Google Scholar). Conversely, the O-GlcNAc is removed by the enzyme O-linked β-N-acetyl hexosaminidase (O-GlcNAcase or OGA) (10Gloster T.M. Vocadlo D.J. Mechanism, structure, and inhibition of O-GlcNAc processing enzymes.Curr. Signal Transduct. Ther. 2010; 5: 74-91Crossref PubMed Scopus (42) Google Scholar). Approximately 3 to 5% of glucose entering the is by the and the of O-GlcNAcylation present in the is on the of present in the cellular A. in for of 5: PubMed Scopus Google Scholar). OGT is expressed in the Y. Hart G.W. of the O-linked transferase in PubMed Scopus Google Scholar, Krause M. Hanover J.A. GlcNAc transferase is a protein PubMed Scopus Google Scholar). the protein OGT to expressed in islets the D. S. S. P. of O-linked signaling and Rep. PubMed Scopus Google Scholar). the high OGT has been in both the and β-cells Y. Hart G.W. of the O-linked transferase in PubMed Scopus Google Scholar, J.A. G. O-linked in pancreatic Biophys. PubMed Scopus Google Scholar). that O-GlcNAcylation is for and function. We that of O-GlcNAcylation in the β-cell to failure and diabetes in mice due to and D. S. S. P. of O-linked signaling and Rep. PubMed Scopus Google Scholar). of OGT in pancreatic to an D. A. S. S. G. Y. of in pancreatic and endocrine islet PubMed Scopus Google Scholar). of its role in OGT insulin secretion at D. S. S. P. of O-linked signaling and Rep. PubMed Scopus Google and in in M. J. O-GlcNAcylation is for of insulin secretion Rep. PubMed Scopus Google Scholar). OGT insulin processing target a S. A. and dysregulation in O-GlcNAc pancreatic cells contributes to in PubMed Scopus Google Scholar). as a nutrient sensor protein that is highly expressed in glucagon-secreting cells, the role of OGT in α-cells has been We that OGT a key role in the of α-cell mass and function of secreting glucagon in response to hypoglycemia. is posttranslational O-GlcNAcylation of proteins α-cell mass and function. In the the of mice α-cell the enzyme of O-GlcNAc onto proteins, we that O-GlcNAcylation is necessary for the of α-cell mass and regulation of glucagon High of OGT has been in the Y. Hart G.W. of the O-linked transferase in PubMed Scopus Google Scholar). the is whether α-cells or β-cells OGT Y. Hart G.W. of the O-linked transferase in PubMed Scopus Google Scholar, J.A. G. O-linked in pancreatic Biophys. PubMed Scopus Google Scholar). we first to protein levels of OGT and α-cells and β-cells due to the and of α-cells in levels of OGT and protein in and OGT levels in both in and was a significantly lower level of protein present in the the and Interestingly, the level of by the was both is a specific O-GlcNAc that has been in S. A. and dysregulation in O-GlcNAc pancreatic cells contributes to in PubMed Scopus Google and Y. Stanley P. that O-linked on the of 2014; PubMed Scopus Google Scholar, A. a of nuclear PubMed Scopus Google Scholar). Together, these that OGT and are expressed in and the role of O-GlcNAcylation in α-cell in vivo. we the that OGT is for the of α-cell mass and for α-cell function in vivo. We utilized genetic manipulation to a α-cell specific OGT in vivo. αOGTKO mice by mice αOGTKO mice a or to cells the The was at to of was in a of β-cells C. P. J. mice as a for genetic manipulation in pancreatic alpha PubMed Scopus Google Scholar). In we by immunofluorescent cells of the islet in mice We the in mice in αOGTKO In we to whether genetic of OGT in the α-cells had an effect on 1 of αOGTKO mice showed reduced in cells in the control the cells reduced for of the in these that in a in α-cell that OGT reduced O-GlcNAcylation in we to the metabolic of the αOGTKO mice in fed and fasted in to determine effect this has on islet function. 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