Multi-Tissue Acceleration of the Mitochondrial Phosphoenolpyruvate Cycle Improves Whole-Body Metabolic Health

Abulizi, Abudukadier; Cardone, Rebecca L.; Stark, Romana; Lewandowski, Sophie L.; Zhao, Xiaojie; Hillion, Joëlle; Ma, Lu‐Fang; Sehgal, Raghav; Alves, Tiago C.; Thomas, Craig J.; Kung, Charles; Wang, Bei; Siebel, Stephan; Andrews, Zane B.; Mason, Graeme F.; Rinehart, Jesse; Merrins, Matthew J.; Kibbey, Richard G.

doi:10.1016/j.cmet.2020.10.006

Cited by 57 publications

(62 citation statements)

References 59 publications

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“…GSH, glutathione; S-AMP, adenylosuccinate. This figure is available as part of a downloadable slideset [68], the pyruvate-isocitrate cycle [69][70][71], the phosphoenolpyruvate (PEP) cycle [72,73] and the glycerolipid/NEFA cycle [74,75] (Fig. 2).…”

Section: Me3mentioning

confidence: 99%

Maturation of beta cells: lessons from in vivo and in vitro models

Barsby

Otonkoski

2022

Diabetologia

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The ability to maintain normoglycaemia, through glucose-sensitive insulin release, is a key aspect of postnatal beta cell function. However, terminally differentiated beta cell identity does not necessarily imply functional maturity. Beta cell maturation is therefore a continuation of beta cell development, albeit a process that occurs postnatally in mammals. Although many important features have been identified in the study of beta cell maturation, as of yet no unified mechanistic model of beta cell functional maturity exists. Here, we review recent findings about the underlying mechanisms of beta cell functional maturation. These findings include systemic hormonal and nutritional triggers that operate through energy-sensing machinery shifts within beta cells, resulting in primed metabolic states that allow for appropriate glucose trafficking and, ultimately, insulin release. We also draw attention to the expansive synergistic nature of these pathways and emphasise that beta cell maturation is dependent on overlapping regulatory and metabolic networks. Graphical abstract

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Section: Me3mentioning

confidence: 99%

Maturation of beta cells: lessons from in vivo and in vitro models

Barsby

Otonkoski

2022

Diabetologia

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“…The reduction of glutathione by the NADPH dependent enzyme, glutathione reductase, provides a redox shuttle to activate the deSUMOylating enzyme, SUMO specific peptidase-1 (SENP1), which acts on the exocytic SNARE machinery [ 55 ], including synaptotagmin 7, syntaxin 1A and the syntaxin 1A inhibitor, tomosyn, to amplify insulin secretion [ 62 , 63 , 64 , 65 ]. In addition to this redox-supported pathway, mitochondria oscillate between anaplerotic and oxidative states, which is used to generate phosphoenolpyruvate (PEP) from malate via the mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK) [ 66 , 67 , 68 ]. Mitochondria to cytosol shuttling of PEP through an unknown mitochondrial carrier is then utilized by pyruvate kinase to generate ATP.…”

Section: Nutrient-regulated Insulin Secretionmentioning

confidence: 99%

Nutrient Regulation of Pancreatic Islet β-Cell Secretory Capacity and Insulin Production

et al. 2022

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Pancreatic islet β-cells exhibit tremendous plasticity for secretory adaptations that coordinate insulin production and release with nutritional demands. This essential feature of the β-cell can allow for compensatory changes that increase secretory output to overcome insulin resistance early in Type 2 diabetes (T2D). Nutrient-stimulated increases in proinsulin biosynthesis may initiate this β-cell adaptive compensation; however, the molecular regulators of secretory expansion that accommodate the increased biosynthetic burden of packaging and producing additional insulin granules, such as enhanced ER and Golgi functions, remain poorly defined. As these adaptive mechanisms fail and T2D progresses, the β-cell succumbs to metabolic defects resulting in alterations to glucose metabolism and a decline in nutrient-regulated secretory functions, including impaired proinsulin processing and a deficit in mature insulin-containing secretory granules. In this review, we will discuss how the adaptative plasticity of the pancreatic islet β-cell’s secretory program allows insulin production to be carefully matched with nutrient availability and peripheral cues for insulin signaling. Furthermore, we will highlight potential defects in the secretory pathway that limit or delay insulin granule biosynthesis, which may contribute to the decline in β-cell function during the pathogenesis of T2D.

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“…Deletion of the gene in mice leads to a severe defect in insulin secretion ( 27 ) as shown by Richard Kibbey’s laboratory at Yale University. Subsequent studies have proposed that formation of phosphoenolpyruvate promotes cycling through the pyruvate kinase reaction and this is intimately connected with the closure of the ATP channel ( 28 , 29 ).…”

Section: Insulin Secretionmentioning

confidence: 99%