| 1. |
- Halban, Philippe A, et al.
(författare)
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β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment.
- 2014
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 37:6, s. 1751-1758
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Tidskriftsartikel (refereegranskat)abstract
- This article examines the foundation of β-cell failure in type 2 diabetes (T2D) and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and treatment.RESEARCH DESIGN AND METHODS: A group of experts participated in a conference on 14-16 October 2013 cosponsored by the Endocrine Society and the American Diabetes Association. A writing group prepared this summary and recommendations.RESULTS: The writing group based this article on conference presentations, discussion, and debate. Topics covered include genetic predisposition, foundations of β-cell failure, natural history of β-cell failure, and impact of therapeutic interventions.CONCLUSIONS: β-Cell failure is central to the development and progression of T2D. It antedates and predicts diabetes onset and progression, is in part genetically determined, and often can be identified with accuracy even though current tests are cumbersome and not well standardized. Multiple pathways underlie decreased β-cell function and mass, some of which may be shared and may also be a consequence of processes that initially caused dysfunction. Goals for future research include to 1) impact the natural history of β-cell failure; 2) identify and characterize genetic loci for T2D; 3) target β-cell signaling, metabolic, and genetic pathways to improve function/mass; 4) develop alternative sources of β-cells for cell-based therapy; 5) focus on metabolic environment to provide indirect benefit to β-cells; 6) improve understanding of the physiology of responses to bypass surgery; and 7) identify circulating factors and neuronal circuits underlying the axis of communication between the brain and β-cells.
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| 2. |
- Halban, Philippe A, et al.
(författare)
-
β-cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment.
- 2014
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 99:6, s. 1983-1992
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Tidskriftsartikel (refereegranskat)abstract
- Objective: This report examines the foundation of β-cell failure in type 2 diabetes and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and treatment. Participants: A group of experts participated in a conference on October 14-16, 2013 cosponsored by The Endocrine Society and the American Diabetes Association. A writing group prepared this summary and recommendations. Evidence: The writing group based this report on conference presentations, discussion, and debate. Topics covered include genetic predisposition, the foundations of β-cell failure, natural history of β-cell failure, and impact of therapeutic interventions. Conclusions: β-cell failure is central to the development and progression of type 2 diabetes. It antedates and predicts diabetes onset and progression, is in part genetically determined, and often can be identified with accuracy even though current tests are cumbersome and not well standardized. Multiple pathways underlie decreased β-cell function and mass, some of which may be shared and may also be a consequence of processes that initially caused dysfunction. Goals for future research include: 1) Impact the natural history of β-cell failure; 2) Identify and characterize genetic loci for type 2 diabetes; 3) Target β-cell signaling, metabolic, and genetic pathways to improve function/mass; 4) Develop alternative sources of β-cells for cell-based therapy; 5) Focus on metabolic environment to provide indirect benefit to β-cells; 6) Improve understanding of the physiology of responses to bypass surgery; 7) Identify circulating factors and neuronal circuits underlying the axis of communication between the brain and β-cells.
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| 3. |
- Raum, Jeffrey C, et al.
(författare)
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Islet {beta}-cell-specific MafA transcription requires the 5'-flanking conserved Region 3 control domain.
- 2010
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Ingår i: Molecular and Cellular Biology. - 0270-7306. ; 30:17, s. 4234-4244
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Tidskriftsartikel (refereegranskat)abstract
- MafA is a key transcriptional activator of islet beta cells and its exclusive expression within beta cells of the developing and adult pancreas is distinct amongst pancreatic regulators. Region 3 (base pairs -8118/-7750 relative to the transcription start site), one of six conserved 5' cis-domains of the MafA promoter, is capable of directing beta-cell-line-selective expression. Transgenic reporters of Region 3 alone (R3), sequences spanning Regions 1-6 (R1-6; base pairs -10428/+230), and R1-6 lacking Region 3 (R1-6(DeltaR3)) were generated. Only the R1-6 transgene was active in MafA(+) insulin(+) cells during development and in adults. R1-6 also mediated glucose-induced MafA expression. Conversely, pancreatic expression was not observed with the R3 or R1-6(DeltaR3) lines, although much of the non-pancreatic expression pattern was shared between the R1-6 and R1-6(DeltaR3) lines. Further support for the importance of Region 3 was shown as the islet regulators Nkx6.1 and Pax6, but not NeuroD1 activated MafA using gel shift, chromatin immunoprecipitation (ChIP), transfection assays, and in vivo mouse knockout models. Lastly ChIP demonstrated that Pax6 and Pdx-1 bound also to Regions 1 and 6, potentially functioning in pancreatic and non-pancreatic expression. These data highlight the nature of the cis- and trans-acting factors controlling the beta-3cell-specific expression of MafA.
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| 4. |
- Roybon, Laurent, et al.
(författare)
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GABAergic Differentiation Induced by Mash1 Is Compromised by the bHLH Proteins Neurogenin2, NeuroD1, and NeuroD2.
- 2010
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Ingår i: Cerebral Cortex. - : Oxford University Press (OUP). - 1460-2199 .- 1047-3211. ; 20, s. 1234-1244
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Tidskriftsartikel (refereegranskat)abstract
- During forebrain development, Mash1 directs gamma-aminobutyric acid (GABA)ergic neuron differentiation ventrally in the ganglionic eminences. Repression of Mash1 in the cortex is necessary to prevent the formation of GABAergic interneurons. Negative regulation of Mash1 has been attributed to members of the Neurogenin family; the genetic ablation of Neurogenin2 (Ngn2) leads to the derepression of Mash1 and the formation of ectopic GABAergic neurons in the cortex. We have developed an in vitro system to clarify the importance of NeuroD proteins in the Mash1 regulatory pathway. Using a neurosphere culture system, we show that the downstream effectors of the Ngn2 pathway NeuroD1 and NeuroD2 can abrogate GABAergic differentiation directed by Mash1. The ectopic expression of either of these genes in Mash1-expressing cells derived from the lateral ganglionic eminence, independently downregulate Mash1 expression without affecting expression of distal less homeodomain genes. This results in a complete loss of the GABAergic phenotype. Moreover, we demonstrate that ectopic expression of Mash1 in cortical progenitors is sufficient to phenocopy the loss of Ngn2 and strongly enhances ectopic GABAergic differentiation. Collectively, our results define the compensatory and cross-regulatory mechanisms that exist among basic helix-loop-helix transcription factors during neuronal fate specification.
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| 5. |
- Roybon, Laurent, et al.
(författare)
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The Origin, Development and Molecular Diversity of Rodent Olfactory Bulb Glutamatergic Neurons Distinguished by Expression of Transcription Factor NeuroD1.
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:6
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Tidskriftsartikel (refereegranskat)abstract
- Production of olfactory bulb neurons occurs continuously in the rodent brain. Little is known, however, about cellular diversity in the glutamatergic neuron subpopulation. In the central nervous system, the basic helix-loop-helix transcription factor NeuroD1 (ND1) is commonly associated with glutamatergic neuron development. In this study, we utilized ND1 to identify the different subpopulations of olfactory bulb glutamategic neurons and their progenitors, both in the embryo and postnatally. Using knock-in mice, transgenic mice and retroviral transgene delivery, we demonstrate the existence of several different populations of glutamatergic olfactory bulb neurons, the progenitors of which are ND1+ and ND1- lineage-restricted, and are temporally and regionally separated. We show that the first olfactory bulb glutamatergic neurons produced - the mitral cells - can be divided into molecularly diverse subpopulations. Our findings illustrate the complexity of neuronal diversity in the olfactory bulb and that seemingly homogenous neuronal populations can consist of multiple subpopulations with unique molecular signatures of transcription factors and expressing neuronal subtype-specific markers.
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