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      Ywhaz/14-3-3ζ Deletion Improves Glucose Tolerance Through a GLP-1-Dependent Mechanism

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          Abstract

          Multiple signaling pathways mediate the actions of metabolic hormones to control glucose homeostasis, but the proteins that coordinate such networks are poorly understood. We previously identified the molecular scaffold protein, 14-3-3ζ, as a critical regulator of in vitro β-cell survival and adipogenesis, but its metabolic roles in glucose homeostasis have not been studied in depth. Herein, we report that Ywhaz gene knockout mice (14-3-3ζKO) exhibited elevated fasting insulin levels while maintaining normal β-cell responsiveness to glucose when compared with wild-type littermate controls. In contrast with our observations after an ip glucose bolus, glucose tolerance was significantly improved in 14-3-3ζKO mice after an oral glucose gavage. This improvement in glucose tolerance was associated with significantly elevated fasting glucagon-like peptide-1 (GLP-1) levels. 14-3-3ζ knockdown in GLUTag L cells elevated GLP-1 synthesis and increased GLP-1 release. Systemic inhibition of the GLP-1 receptor attenuated the improvement in oral glucose tolerance that was seen in 14-3-3ζKO mice. When taken together these findings demonstrate novel roles of 14-3-3ζ in the regulation of glucose homeostasis and suggest that modulating 14-3-3ζ levels in intestinal L cells may have beneficial metabolic effects through GLP-1-dependent mechanisms.

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          Most cited references 36

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          The 14-3-3 proteins: integrators of diverse signaling cues that impact cell fate and cancer development.

          The highly conserved 14-3-3 protein family has risen to a position of importance in cell biology owing to its involvement in vital cellular processes, such as metabolism, protein trafficking, signal transduction, apoptosis and cell-cycle regulation. The 14-3-3 proteins are phospho-serine/phospho-threonine binding proteins that interact with a diverse array of binding partners. Because many 14-3-3 interactions are phosphorylation-dependent, 14-3-3 has been tightly integrated into the core phospho-regulatory pathways that are crucial for normal growth and development and that often become dysregulated in human disease states such as cancer. This review examines the recent advances that further elucidate the role of 14-3-3 proteins as integrators of diverse signaling cues that influence cell fate decisions and tumorigenesis.
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            Signaling Through Scaffold, Anchoring, and Adaptor Proteins

             T. Pawson (1997)
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              Pancreatic β-cell identity, glucose sensing and the control of insulin secretion.

              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.
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                Author and article information

                Journal
                Endocrinology
                The Endocrine Society
                0013-7227
                1945-7170
                July 01 2016
                July 01 2016
                May 11 2016
                : 157
                : 7
                : 2649-2659
                Affiliations
                [1 ]Department of Cellular and Physiological Sciences (G.E.L., M.P., J.D.J.), University of British Columbia, Vancouver, BC, Canada;
                [2 ]ALPCO (J.E.L.), Salem, New Hampshire;
                [3 ]The Centre for Cancer Biology (H.S.R., A.F.L.), South Australia Pathology and University of South Australia, Adelaide, Australia
                Article
                10.1210/en.2016-1016
                © 2016

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