Raptor determines β-cell identity and plasticity independent of hyperglycemia in mice

Yin, Qinglei; Ni, Qicheng; Wang, Yichen; Zhang, Hongli; Li, Wenyi; Nie, Aifang; Wang, Shu; Gu, Yuchao; Wang, Qidi; Ning, Guang

doi:10.1038/s41467-020-15935-0

Cited by 26 publications

(19 citation statements)

References 69 publications

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“…Furthermore, β cell specific mTOR KO mice as well as mTOR deficient β cell line has revealed compromised mitochondrial membrane potential and respiration, which lead to impaired ATP production, lower intracellular Ca 2+ levels, impaired insulin secretion, and ROS production [87]. mTOR has also been shown to be important to maintain β cell mature identity and to suppress α cell enriched genes including MAF BZIP transcription factor B (MafB), suggesting a potential role of oxidative stress in β cell dedifferentiation [97]. It is clear that downregulation of mTOR in β cells could potentially have a major detrimental impact on its function and viability.…”

Section: Mtor Inhibitionmentioning

confidence: 99%

The Role of Oxidative Stress in Pancreatic β Cell Dysfunction in Diabetes

Eguchi

Vaziri

Dafoe

et al. 2021

IJMS

131

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Diabetes is a chronic metabolic disorder characterized by inappropriately elevated glucose levels as a result of impaired pancreatic β cell function and insulin resistance. Extensive studies have been conducted to elucidate the mechanism involved in the development of β cell failure and death under diabetic conditions such as hyperglycemia, hyperlipidemia, and inflammation. Of the plethora of proposed mechanisms, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and oxidative stress have been shown to play a central role in promoting β cell dysfunction. It has become more evident in recent years that these 3 factors are closely interrelated and importantly aggravate each other. Oxidative stress in particular is of great interest to β cell health and survival as it has been shown that β cells exhibit lower antioxidative capacity. Therefore, this review will focus on discussing factors that contribute to the development of oxidative stress in pancreatic β cells and explore the downstream effects of oxidative stress on β cell function and health. Furthermore, antioxidative capacity of β cells to counteract these effects will be discussed along with new approaches focused on preserving β cells under oxidative conditions.

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Section: Mtor Inhibitionmentioning

confidence: 99%

The Role of Oxidative Stress in Pancreatic β Cell Dysfunction in Diabetes

Eguchi

Vaziri

Dafoe

et al. 2021

IJMS

131

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“…Thus, the mitochondrial abnormalities in Mfn1/2-deficient βcells appear to affect β-cell identity, leading to metabolic derangement and defective secretion. We note that the progressive hyperglycaemia that ensues may further aggravate dedifferentiation (Brereton, Iberl et al 2014) and lead to changes in β-cell transcription factor expression (Yin, Ni et al 2020). No changes in inactivated ("disallowed") β-cell gene levels were detected in Mfn1/2-deficient mice, suggesting that mitochondrial structure alterations do not affect disallowed gene expression, at least in young mice.…”

Section: Discussionmentioning

confidence: 78%

Mitofusins Mfn1 and Mfn2 are required to preserve glucose-but not incretin- stimulated beta cell connectivity and insulin secretion

Georgiadou

Muralidharan

Martínez

et al. 2020

Preprint

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Background and aims: Mitochondria are highly dynamic organelles, fundamental to cellular energy homeostasis. Mitochondrial metabolism of glucose is essential for the initiation of insulin release from pancreatic beta cells. Whether mitochondrial ultrastructure, and the proteins controlling fission and fusion, are important for glucose recognition are unclear. Mitochondrial fusion is supported by proteins including mitofusin 1 (MFN1), mitofusin 2 (MFN2) and optic atrophy (OPA1), and fission by dynamin-related protein 1 (DRP1). Here, we generated mice with beta cell-selective, adult-restricted deletion of Mfn1 and Mfn2 (bMfn1/2-KO), and explored the impact on insulin secretion and glucose homeostasis in vivo and in vitro. Materials and methods: C57BL/6J mice bearing Mfn1 and Mfn2 alleles with loxP sites, were crossed to animals carrying an inducible Cre recombinase at the Pdx1 locus (Pdx CreERT ). Isolated islets were used for live beta cell fluorescence imaging of cytosolic (Cal-520) or mitochondrial (Pericam) free Ca 2+ concentration and membrane potential (TMRE). Mitochondrial network characteristics were quantified using super resolution fluorescence and transmission electron microscopy. Beta cellbeta cell connectivity was assessed using the Pearson (R) analysis and Monte Carlo simulation in intact mouse islets. Intravital imaging was performed in mice injected with an adeno-associated virus to express the cytosolic Ca 2+ sensor GCaMP6s selectively in beta cells and TMRM to visualise mitochondria using multiphoton microscopy. Results: bMfn1/2-KO mice displayed higher fasting glycaemia than control littermates at 14 weeks (8.6 vs 6.4 mmol/L, p>0.05) and a >five-fold decrease in plasma insulin post-intraperitoneal glucose injection (5-15 min, p<0.0001). Mitochondrial length, and glucose-induced Ca 2+ accumulation, mitochondrial hyperpolarisation and beta cell connectivity were all significantly reduced in bMfn1/2-KO mouse islets. Examined by intravital imaging of the exteriorised pancreas, antiparallel changes in cytosolic Ca 2+ and mitochondrial membrane potential, observed in control animals in vivo, were suppressed after Mfn1/2 deletion. 3 Conclusion: Mitochondrial fusion and fission cycles are essential in the beta cell to maintain normal mitochondrial bioenergetics and glucose sensing both in vitro and in the living mouse. Such cycles may be disrupted in some forms of diabetes to impair mitochondrial function and, consequently, insulin secretion. R Pearson correlation coefficient TMRE Tetramethylrhodamine ethyl ester TMRM Tetramethylrhodamine methyl ester WT Wild-type

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“…Although there are scarce data on changes in gene expression induced by excessive GV, there is a large pool of studies on gene profiling related to hyperglycemia. Using high-throughput technologies, differential gene expression was measured under hyperglycemic conditions in beta cells [140,141], pancreatic cells [142], hepatic cells [143,144], endothelial cells [145], myotubes [146], cardiomyocytes [147], vascular smooth muscle cells [148,149], adipose progenitor cells [150], kidney cells [151], renal tubular epithelial cells [152], retina [153,154], immune cells [155,156] and others. The genes that demonstrate an altered expression in hyperglycemia are mostly involved in glucose metabolism, inflammation and immune processes, endothelial dysfunction, angiogenesis, oxidative stress, mitochondrial dysfunction, hypoxia and cell death.…”

Section: Gene Expressionmentioning

confidence: 99%

Glucose Variability: How Does It Work?

Климонтов

Saik

Korbut

2021

IJMS

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A growing body of evidence points to the role of glucose variability (GV) in the development of the microvascular and macrovascular complications of diabetes. In this review, we summarize data on GV-induced biochemical, cellular and molecular events involved in the pathogenesis of diabetic complications. Current data indicate that the deteriorating effect of GV on target organs can be realized through oxidative stress, glycation, chronic low-grade inflammation, endothelial dysfunction, platelet activation, impaired angiogenesis and renal fibrosis. The effects of GV on oxidative stress, inflammation, endothelial dysfunction and hypercoagulability could be aggravated by hypoglycemia, associated with high GV. Oscillating hyperglycemia contributes to beta cell dysfunction, which leads to a further increase in GV and completes the vicious circle. In cells, the GV-induced cytotoxic effect includes mitochondrial dysfunction, endoplasmic reticulum stress and disturbances in autophagic flux, which are accompanied by reduced viability, activation of apoptosis and abnormalities in cell proliferation. These effects are realized through the up- and down-regulation of a large number of genes and the activity of signaling pathways such as PI3K/Akt, NF-κB, MAPK (ERK), JNK and TGF-β/Smad. Epigenetic modifications mediate the postponed effects of glucose fluctuations. The multiple deteriorative effects of GV provide further support for considering it as a therapeutic target in diabetes.

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Raptor determines β-cell identity and plasticity independent of hyperglycemia in mice

Cited by 26 publications

References 69 publications

The Role of Oxidative Stress in Pancreatic β Cell Dysfunction in Diabetes

The Role of Oxidative Stress in Pancreatic β Cell Dysfunction in Diabetes

Mitofusins Mfn1 and Mfn2 are required to preserve glucose-but not incretin- stimulated beta cell connectivity and insulin secretion

Glucose Variability: How Does It Work?

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