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Cells ; 10(10)2021 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-34685781

RESUMO

The nutrient-sensor O-GlcNAc transferase (Ogt), the sole enzyme that adds an O-GlcNAc-modification onto proteins, plays a critical role for pancreatic ß-cell survival and insulin secretion. We hypothesized that ß-cell Ogt overexpression would confer protection from ß-cell failure in response to metabolic stressors, such as high-fat diet (HFD) and streptozocin (STZ). Here, we generated a ß-cell-specific Ogt in overexpressing (ßOgtOE) 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 ßOgtOE mice show normal peripheral insulin sensitivity and glucose tolerance with a regular chow diet. However, when challenged with an HFD, only female ßOgtOE (homozygous) Hz mice developed a mild glucose intolerance, despite increased insulin secretion and normal ß-cell mass. While female mice are normally resistant to low-dose STZ treatments, the ßOgtOE 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 IL1ß and NFkß. Together, these data show a possible gene dosage effect of Ogt and the importance O-GlcNAc cycling in ß-cell survival and function to regulate glucose homeostasis.


Assuntos
Células Secretoras de Insulina/enzimologia , N-Acetilglucosaminiltransferases/metabolismo , Estresse Fisiológico , Animais , Dieta Hiperlipídica , Feminino , Regulação da Expressão Gênica , Glucose/metabolismo , Intolerância à Glucose/sangue , Intolerância à Glucose/complicações , Intolerância à Glucose/patologia , Homeostase , Hiperglicemia/sangue , Hiperglicemia/complicações , Insulina/sangue , Masculino , Camundongos Transgênicos , Reprodutibilidade dos Testes , Transcriptoma/genética , Regulação para Cima
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