Loss of Znt8 function in diabetes mellitus: risk or benefit?

Barragán-Álvarez, Carla P; Padilla-Camberos, Eduardo; Díaz, Néstor Fabián; Cota-Coronado, Agustín; Hernández-Jiménez, Claudia; Bravo-Reyna, Carlos; Díaz-Martínez, N.E.

doi:10.1007/s11010-021-04114-4

Cited by 9 publications

(4 citation statements)

References 133 publications

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“…Beyond inborn errors of metabolism, several SLCs have been associated with predisposition to or increased severity of multi-factorial diseases (reviewed previously by Lin et al, 2015 ), such as type II diabetes ( Barragán-Álvarez et al, 2021 ), hypertension ( Boedtkjer et al, 2011 ; International Consortium for Blood Pressure Genome-Wide Association Studies et al, 2011 ), obesity ( Le et al, 2021 ; Hodges et al, 2022 ), depression ( Santarelli et al, 2015 ), cancer ( Nimmanon et al, 2017 ; Fang et al, 2021 ; Han et al, 2021 ; Mao et al, 2021 ) and aging ( Crocco et al, 2018 ). For example, at synapses and in astroglia, the SLC1 ( Xu et al, 2016 ) and SLC6 ( Kristensen et al, 2011 ) families of amino acid transporters are responsible for the removal of neurotransmitters from the synaptic cleft, quenching postsynaptic effects after neurotransmission, and balancing excitatory and inhibitory neurotransmitters ( Aykac and Sehirli, 2020 ).…”

Section: Structure Function and Physiological Roles Of Membrane Trans...mentioning

confidence: 99%

Membrane transporters in cell physiology, cancer metabolism and drug response

Alam,

Doherty,

Ortega-Prieto

et al. 2023

Disease Models &Amp; Mechanisms

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By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only the uptake and efflux of nutrients, but also the metabolic state of the cell. With more than 450 members, the Solute Carriers (SLCs) are the largest transporter super-family, clustering into families with different substrate specificities and regulatory properties. Cells of different types are, therefore, able to tailor their transporter expression signatures depending on their metabolic requirements, and the physiological importance of these proteins is illustrated by their mis-regulation in a number of disease states. In cancer, transporter expression is heterogeneous, and the SLC family has been shown to facilitate the accumulation of biomass, influence redox homeostasis, and also mediate metabolic crosstalk with other cell types within the tumour microenvironment. This Review explores the roles of membrane transporters in physiological and malignant settings, and how these roles can affect drug response, through either indirect modulation of sensitivity or the direct transport of small-molecule therapeutic compounds into cells.

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Section: Structure Function and Physiological Roles Of Membrane Trans...mentioning

confidence: 99%

Membrane transporters in cell physiology, cancer metabolism and drug response

Alam,

Doherty,

Ortega-Prieto

et al. 2023

Disease Models &Amp; Mechanisms

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“…Moreover, ZnT8 depletion targeting has been shown to produce detrimental consequences [327], including, but not limited to, increased sensitivity to a high-fat diet [174], obesity susceptibility [328], impaired glucose tolerance, and increased basal insulin clearance [329], and elevated circulating serotonin (5-hydroxytryptamine) [177]. These adverse consequences of loss of ZnT8 are reviewed in [330], and notably occur through potential extra-pancreatic function of ZnT8 that does not seem to be compensated by ZnT7 [331]. Altogether, these results show potential clinical benefits of targeting ZnT8 in diabetes, but also negative effects associated with T2D prevention using ZnT8 inhibitors.…”

Section: Znt8 (Slc30a8)mentioning

confidence: 99%

Impact of Zinc Transport Mechanisms on Embryonic and Brain Development

Willekens

Runnels

2022

Nutrients

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The trace element zinc (Zn) binds to over ten percent of proteins in eukaryotic cells. Zn flexible chemistry allows it to regulate the activity of hundreds of enzymes and influence scores of metabolic processes in cells throughout the body. Deficiency of Zn in humans has a profound effect on development and in adults later in life, particularly in the brain, where Zn deficiency is linked to several neurological disorders. In this review, we will summarize the importance of Zn during development through a description of the outcomes of both genetic and early dietary Zn deficiency, focusing on the pathological consequences on the whole body and brain. The epidemiology and the symptomology of Zn deficiency in humans will be described, including the most studied inherited Zn deficiency disease, Acrodermatitis enteropathica. In addition, we will give an overview of the different forms and animal models of Zn deficiency, as well as the 24 Zn transporters, distributed into two families: the ZIPs and the ZnTs, which control the balance of Zn throughout the body. Lastly, we will describe the TRPM7 ion channel, which was recently shown to contribute to intestinal Zn absorption and has its own significant impact on early embryonic development.

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“…The current literature on ZnT8-mediated Zn 2+ homeostasis is deep and interesting, owing to the existence of multiple T2D susceptibility loci covering the SLC30A8 gene [ 260 , 261 , 262 ]. Importantly, loss of function mutations at residue 325 tend to favor a reduced risk of T2D, and opposite deleterious effects are seen with a gain of function at this residue.…”

Section: Luminal Components Of the Insulin Secretory Granulementioning

confidence: 99%

Inside the Insulin Secretory Granule

et al. 2021

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The pancreatic β-cell is purpose-built for the production and secretion of insulin, the only hormone that can remove glucose from the bloodstream. Insulin is kept inside miniature membrane-bound storage compartments known as secretory granules (SGs), and these specialized organelles can readily fuse with the plasma membrane upon cellular stimulation to release insulin. Insulin is synthesized in the endoplasmic reticulum (ER) as a biologically inactive precursor, proinsulin, along with several other proteins that will also become members of the insulin SG. Their coordinated synthesis enables synchronized transit through the ER and Golgi apparatus for congregation at the trans-Golgi network, the initiating site of SG biogenesis. Here, proinsulin and its constituents enter the SG where conditions are optimized for proinsulin processing into insulin and subsequent insulin storage. A healthy β-cell is continually generating SGs to supply insulin in vast excess to what is secreted. Conversely, in type 2 diabetes (T2D), the inability of failing β-cells to secrete may be due to the limited biosynthesis of new insulin. Factors that drive the formation and maturation of SGs and thus the production of insulin are therefore critical for systemic glucose control. Here, we detail the formative hours of the insulin SG from the luminal perspective. We do this by mapping the journey of individual members of the SG as they contribute to its genesis.

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Loss of Znt8 function in diabetes mellitus: risk or benefit?

Cited by 9 publications

References 133 publications

Membrane transporters in cell physiology, cancer metabolism and drug response

Membrane transporters in cell physiology, cancer metabolism and drug response

Impact of Zinc Transport Mechanisms on Embryonic and Brain Development

Inside the Insulin Secretory Granule

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