title: β-cell differentiation status in type 2 diabetes.
abstract: Type 2 diabetes (T2D) affects 415 million people worldwide and is characterized by chronic hyperglycaemia and insulin resistance, progressing to insufficient insulin production, as a result of β-cell failure. Over time, chronic hyperglycaemia can ultimately lead to loss of β-cell function, leaving patients insulin-dependent. Until recently the loss of β-cell mass seen in T2D was considered to be the result of increased rates of apoptosis; however, it has been proposed that apoptosis alone cannot account for the extent of β-cell mass loss seen in the disease, and that a loss of function may also occur as a result of changes in β-cell differentiation status. In the present review, we consider current knowledge of determinants of β-cell fate in the context of understanding its relevance to disease process in T2D, and also the impact of a diabetogenic environment (hyperglycaemia, hypoxia, inflammation and dyslipidaemia) on the expression of genes involved in maintenance of β-cell identity. We describe current knowledge of the impact of the diabetic microenvironment on gene regulatory processes such alternative splicing, the expression of disallowed genes and epigenetic modifications. Elucidating the molecular mechanisms that underpin changes to β-cell differentiation status and the concomitant β-cell failure offers potential treatment targets for the future management of patients with T2D.
authors.affiliation: Department of Molecular Genetics, Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter, Devon, UK.
authors.forename: Nicola
authors.identifier: 0000-0002-4101-2345
authors.initials: N
authors.lastname: Jeffery
authors.affiliation: Department of Molecular Genetics, Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter, Devon, UK.
authors.forename: Lorna W
authors.initials: LW
authors.lastname: Harries
mesh_terms: D000818:Animals; D017209:Apoptosis; D054337:Cell Dedifferentiation; D002454:Cell Differentiation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D014157:Transcription Factors
keywords: alternative splicing; diabetogenic micro-environment; epigenetic regulation; gene expression; glucotoxicity; miRNA regulation; type 2 diabetes; β-cell differentiation