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      Impact of islet architecture on β-cell heterogeneity, plasticity and function

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          Abstract

          Although β-cell heterogeneity was discovered more than 50 years ago, the underlying principles have been explored only during the past decade. Islet-cell heterogeneity arises during pancreatic development and might reflect the existence of distinct populations of progenitor cells and the developmental pathways of endocrine cells. Heterogeneity can also be acquired in the postnatal period owing to β-cell plasticity or changes in islet architecture. Furthermore, β-cell neogenesis, replication and dedifferentiation represent alternative sources of β-cell heterogeneity. In addition to a physiological role, β-cell heterogeneity influences the development of diabetes mellitus and its response to treatment. Identifying phenotypic and functional markers to discriminate distinct β-cell subpopulations and the mechanisms underpinning their regulation is warranted to advance current knowledge of β-cell function and to design novel regenerative strategies that target subpopulations of β cells. In this context, the Wnt/planar cell polarity (PCP) effector molecule Flattop can distinguish two unique β-cell subpopulations with specific transcriptional signatures, functional properties and differential responses to environmental stimuli. In vivo targeting of these β-cell subpopulations might, therefore, represent an alternative strategy for the future treatment of diabetes mellitus.

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          Most cited references 113

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          Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure.

          Diabetes is associated with β cell failure. But it remains unclear whether the latter results from reduced β cell number or function. FoxO1 integrates β cell proliferation with adaptive β cell function. We interrogated the contribution of these two processes to β cell dysfunction, using mice lacking FoxO1 in β cells. FoxO1 ablation caused hyperglycemia with reduced β cell mass following physiologic stress, such as multiparity and aging. Surprisingly, lineage-tracing experiments demonstrated that loss of β cell mass was due to β cell dedifferentiation, not death. Dedifferentiated β cells reverted to progenitor-like cells expressing Neurogenin3, Oct4, Nanog, and L-Myc. A subset of FoxO1-deficient β cells adopted the α cell fate, resulting in hyperglucagonemia. Strikingly, we identify the same sequence of events as a feature of different models of murine diabetes. We propose that dedifferentiation trumps endocrine cell death in the natural history of β cell failure and suggest that treatment of β cell dysfunction should restore differentiation, rather than promoting β cell replication. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Five stages of evolving beta-cell dysfunction during progression to diabetes.

            This article proposes five stages in the progression of diabetes, each of which is characterized by different changes in beta-cell mass, phenotype, and function. Stage 1 is compensation: insulin secretion increases to maintain normoglycemia in the face of insulin resistance and/or decreasing beta-cell mass. This stage is characterized by maintenance of differentiated function with intact acute glucose-stimulated insulin secretion (GSIS). Stage 2 occurs when glucose levels start to rise, reaching approximately 5.0-6.5 mmol/l; this is a stable state of beta-cell adaptation with loss of beta-cell mass and disruption of function as evidenced by diminished GSIS and beta-cell dedifferentiation. Stage 3 is a transient unstable period of early decompensation in which glucose levels rise relatively rapidly to the frank diabetes of stage 4, which is characterized as stable decompensation with more severe beta-cell dedifferentiation. Finally, stage 5 is characterized by severe decompensation representing a profound reduction in beta-cell mass with progression to ketosis. Movement across stages 1-4 can be in either direction. For example, individuals with treated type 2 diabetes can move from stage 4 to stage 1 or stage 2. For type 1 diabetes, as remission develops, progression from stage 4 to stage 2 is typically found. Delineation of these stages provides insight into the pathophysiology of both progression and remission of diabetes.
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              Autonomic regulation of islet hormone secretion--implications for health and disease.

               B. Ahrén (2000)
              The pancreatic islets are richly innervated by parasympathetic, sympathetic and sensory nerves. Several different neurotransmitters are stored within the terminals of these nerves, both the classical neurotransmitters, acetylcholine and noradrenaline, and several neuropeptides. The neuropeptides, vasoactive intestinal polypeptide, pituitary adenlyate cyclase activating polypeptide and gastrin releasing peptide are constituents of the parasympathetic nerves, whereas the neuropeptides galanin and neuropeptide Y are localised to sympathetic nerve terminals. Furthermore, the neuropeptide calcitonin gene-related peptide is localised to sensory nerves and cholecystokinin is also an islet neuropeptide, although the nature of the cholecystokinin nerves is not established. Stimulation of the autonomic nerves and treatment with neurotransmitters affect islet hormone secretion. Thus, insulin secretion is stimulated by parasympathetic nerves or their neurotransmitters and inhibited by sympathetic nerves or their neurotransmitters. The islet autonomic nerves seem to be of physiological importance in mediating the cephalic phase of insulin secretion, in synchronising the islets to function as a unit allowing oscillations of islet hormone secretion, and in optimising islet hormone secretion during metabolic stress, e.g. hypoglycaemia and neuroglycopenia. The autonomic nerves could also be involved in the islet adaptation to insulin resistance with possible implication for the development of glucose intolerance and Type II (non-insulin-dependent) diabetes mellitus. It is concluded that islet innervation, through the contribution of all branches of the autonomic nerves and several different neurotransmitters is of importance both for the physiology and pathophysiology of the islets.
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                Author and article information

                Journal
                Nature Reviews Endocrinology
                Nat Rev Endocrinol
                Springer Science and Business Media LLC
                1759-5029
                1759-5037
                December 2016
                September 2 2016
                December 2016
                : 12
                : 12
                : 695-709
                Article
                10.1038/nrendo.2016.147
                27585958
                © 2016

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