title: Pancreatic β-cell identity, glucose sensing and the control of insulin secretion.
abstract: Insulin release from pancreatic β-cells is required to maintain normal glucose homoeostasis in man and many other animals. Defective insulin secretion underlies all forms of diabetes mellitus, a disease currently reaching epidemic proportions worldwide. Although the destruction of β-cells is responsible for Type 1 diabetes (T1D), both lowered β-cell mass and loss of secretory function are implicated in Type 2 diabetes (T2D). Emerging results suggest that a functional deficiency, involving de-differentiation of the mature β-cell towards a more progenitor-like state, may be an important driver for impaired secretion in T2D. Conversely, at least in rodents, reprogramming of islet non-β to β-cells appears to occur spontaneously in models of T1D, and may occur in man. In the present paper, we summarize the biochemical properties which define the 'identity' of the mature β-cell as a glucose sensor par excellence. In particular, we discuss the importance of suppressing a group of 11 'disallowed' housekeeping genes, including Ldha and the monocarboxylate transporter Mct1 (Slc16a1), for normal nutrient sensing. We then survey the changes in the expression and/or activity of β-cell-enriched transcription factors, including FOXO1, PDX1, NKX6.1, MAFA and RFX6, as well as non-coding RNAs, which may contribute to β-cell de-differentiation and functional impairment in T2D. The relevance of these observations for the development of new approaches to treat T1D and T2D is considered.
authors.affiliation: *Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, Du Cane Road, London W12 0NN, U.K.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.affiliation: *Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, Du Cane Road, London W12 0NN, U.K.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Pullen
authors.affiliation: *Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, Du Cane Road, London W12 0NN, U.K.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hodson
authors.affiliation: *Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, Du Cane Road, London W12 0NN, U.K.
authors.forename: Aida
authors.initials: A
authors.lastname: Martinez-Sanchez
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D054337:Cell Dedifferentiation; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D007515:Islets of Langerhans / Q000166:cytology / Q000473:pathology / Q000502:physiology / Q000503:physiopathology; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D008954:Models, Biological; D055571:Secretory Pathway
chemical_list: D001786:Blood Glucose; D007328:Insulin