Pancreatic β-cell hyper-O-GlcNAcylation leads to impaired glucose homeostasis in vivo

Jo, Seokwon; Pritchard, Samantha; Wong, Alicia; Avula, Nandini; Essawy, Ahmad; Hanover, John A.; Alejandro, Emilyn U.

doi:10.3389/fendo.2022.1040014

Cited by 6 publications

(3 citation statements)

References 30 publications

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“…6D). Due to the particular importance of these pathways in nutrient sensing and metabolism of pancreatic islets (49), we further investigated O -GlcNAc protein modification in pancreatic islets. Using an antibody against O -GlcNAc, we found enhanced levels of O -GlcNAc protein modification by immunohistochemistry (Fig.…”

Section: Resultsmentioning

confidence: 99%

Pancreatic islets undergo functional and morphological adaptation during development of Barth Syndrome

Carlein,

Hoffmann,

Amaral

et al. 2024

Preprint

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Barth syndrome is a multisystem genetic disorder caused by mutation inTAFAZZIN, a gene that encodes a phospholipid:lysophospholipid transacylase important for cardiolipin remodeling. Barth Syndrome patients suffer from a number of symptoms including early heart failure, fatigue, and systemic metabolic alterations, including hypoglycemia. The endocrine pancreas is central to glucose homeostasis, however, the impact of defective cardiolipin remodeling on pancreatic islet function and the consequences for systemic metabolism is unclear. Surprisingly, in a mouse model with globalTAFAZZINknockdown, we observed improved glucose tolerance compared to wildtype littermates. We show that pancreatic islet metabolism and secretory function are robustly maintained through various compensatory mechanisms including increased glucose uptake and increased mitochondrial volume. Transcriptomics analyses revealed increased expression of genes encoding proteins involved in N-acetylglucosamine synthesis and proteinO-linked N-acetylglucosaminylation. These pathways might provide a molecular mechanism for coupling metabolic changes to mitochondrial volume regulation.

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Section: Resultsmentioning

confidence: 99%

Pancreatic islets undergo functional and morphological adaptation during development of Barth Syndrome

Carlein,

Hoffmann,

Amaral

et al. 2024

Preprint

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“…This also evidences that OGA is restrictedly increased in ECs but not in other cell types. It has been reported that reduction of protein O -GlcNAcylation in skeletal muscles 59,60 in HFD-fed mice improves glucose tolerance, and OGA deletion in β-cells 61 or oocytes 62 leads to impaired glucose tolerance.…”

Section: Discussionmentioning

confidence: 99%

Restoration of coronary microvascular function by OGA overexpression in a high-fat diet with low-dose streptozotocin-induced type 2 diabetic mice

Cabrera

Tsuji‐Hosokawa

et al. 2023

Diabetes and Vascular Disease Research

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Sustained hyperglycemia results in excess protein O-GlcNAcylation, leading to vascular complications in diabetes. This study aims to investigate the role of O-GlcNAcylation in the progression of coronary microvascular disease (CMD) in inducible type 2 diabetic (T2D) mice generated by a high-fat diet with a single injection of low-dose streptozotocin. Inducible T2D mice exhibited an increase in protein O-GlcNAcylation in cardiac endothelial cells (CECs) and decreases in coronary flow velocity reserve (CFVR, an indicator of coronary microvascular function) and capillary density accompanied by increased endothelial apoptosis in the heart. Endothelial-specific O-GlcNAcase (OGA) overexpression significantly lowered protein O-GlcNAcylation in CECs, increased CFVR and capillary density, and decreased endothelial apoptosis in T2D mice. OGA overexpression also improved cardiac contractility in T2D mice. OGA gene transduction augmented angiogenic capacity in high-glucose treated CECs. PCR array analysis revealed that seven out of 92 genes show significant differences among control, T2D, and T2D + OGA mice, and Sp1 might be a great target for future study, the level of which was significantly increased by OGA in T2D mice. Our data suggest that reducing protein O-GlcNAcylation in CECs has a beneficial effect on coronary microvascular function, and OGA is a promising therapeutic target for CMD in diabetic patients.

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“…Reconstituting Akt signaling and alleviating ER stress in β-cells rescues the phenotype associated with the loss of OGT. Furthermore, abrogating OGA in pancreatic β-cells also leads to impaired glucose homeostasis in vivo [ 217 ]. Thus, balanced expression of OGT and OGA in β-cells is necessary for the proper levels of O -GlcNAcylation.…”

Section: Hbp In Health and Diseasementioning

confidence: 99%

The Hexosamine Biosynthesis Pathway: Regulation and Function

Paneque

Fortus

Zheng

et al. 2023

Genes

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The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate-N-acetyl glucosamine, UDP-GlcNAc, which is a key metabolite that is used for N- or O-linked glycosylation, a co- or post-translational modification, respectively, that modulates protein activity and expression. The production of hexosamines can occur via de novo or salvage mechanisms that are catalyzed by metabolic enzymes. Nutrients including glutamine, glucose, acetyl-CoA, and UTP are utilized by the HBP. Together with availability of these nutrients, signaling molecules that respond to environmental signals, such as mTOR, AMPK, and stress-regulated transcription factors, modulate the HBP. This review discusses the regulation of GFAT, the key enzyme of the de novo HBP, as well as other metabolic enzymes that catalyze the reactions to produce UDP-GlcNAc. We also examine the contribution of the salvage mechanisms in the HBP and how dietary supplementation of the salvage metabolites glucosamine and N-acetylglucosamine could reprogram metabolism and have therapeutic potential. We elaborate on how UDP-GlcNAc is utilized for N-glycosylation of membrane and secretory proteins and how the HBP is reprogrammed during nutrient fluctuations to maintain proteostasis. We also consider how O-GlcNAcylation is coupled to nutrient availability and how this modification modulates cell signaling. We summarize how deregulation of protein N-glycosylation and O-GlcNAcylation can lead to diseases including cancer, diabetes, immunodeficiencies, and congenital disorders of glycosylation. We review the current pharmacological strategies to inhibit GFAT and other enzymes involved in the HBP or glycosylation and how engineered prodrugs could have better therapeutic efficacy for the treatment of diseases related to HBP deregulation.

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Pancreatic β-cell hyper-O-GlcNAcylation leads to impaired glucose homeostasis in vivo

Cited by 6 publications

References 30 publications

Pancreatic islets undergo functional and morphological adaptation during development of Barth Syndrome

Pancreatic islets undergo functional and morphological adaptation during development of Barth Syndrome

Restoration of coronary microvascular function by OGA overexpression in a high-fat diet with low-dose streptozotocin-induced type 2 diabetic mice

The Hexosamine Biosynthesis Pathway: Regulation and Function

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