mTORC in β cells: more Than Only Recognizing Comestibles

Maedler, Kathrin; Ardestani, Amin

doi:10.1083/jcb.201704179

Cited by 11 publications

(8 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…b cell-specific activation of mTORC1 in genetic mouse models found that hyperactivation of mTORC1 signaling resulted in increased b cell function and improved glucose tolerance (Blandino-Rosano et al, 2017;Hamada et al, 2009;Mori et al, 2009;Rachdi et al, 2008;Shigeyama et al, 2008). Consistently, b cell-specific ablation of mTORC1 resulted in lower insulin secretion caused by mitochondrial dysfunction and oxidative stress, indicating that mTORC1 activity is essential for b cell function and maturation (Sinagoga et al, 2017;Chau et al, 2017;Ardestani et al, 2018;Maedler and Ardestani, 2017;Ni et al, 2017;Blandino-Rosano et al, 2017;Alejandro et al, 2017). In contrast, other findings show that chronically increased mTORC1 activity can induce b cell failure (Mori et al, 2009;Sun et al, 2010;Swisa et al, 2015;Elghazi et al, 2010;Bartolome and Guillé n, 2014;Koyanagi et al, 2011;Jaafar et al, 2019).…”

Section: Context and Significancementioning

confidence: 93%

A Nutrient-Sensing Transition at Birth Triggers Glucose-Responsive Insulin Secretion

et al. 2020

View full text Add to dashboard Cite

show abstract

Section: Context and Significancementioning

confidence: 93%

A Nutrient-Sensing Transition at Birth Triggers Glucose-Responsive Insulin Secretion

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Although no studies have been conducted in β cell, mTORC1 is ordinarily inhibited under oxidative stress, potentially through the activation of AMPK [82]. The inactivation of mTORC1 may have several detrimental effects (Figure 2), the first of which is the increased expression of Thioredoxininteracting protein (TXNIP) and shuttling of it into the mitochondria under oxidative stress conditions [85][86][87]. TXNIP is a ubiquitously expressed protein that influences cellular redox balance through negatively regulating the TXN antioxidant systems [88].…”

Section: Mtor Inhibitionmentioning

confidence: 99%

“…For example, it has been demonstrated that β-cell-specific loss of mTORC1 causes DM and β-cell failure due to defects in proliferation, autophagy, apoptosis, and insulin secretion in mice [96]. 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].…”

Section: Mtor Inhibitionmentioning

confidence: 99%

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

Eguchi

Vaziri

Dafoe

et al. 2021

IJMS

184

View full text Add to dashboard Cite

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.

show abstract

“…Other researchers suggest that the role of glucose and amino acids in the activation of mTORC1 is mediated by an increase in mitochondrial metabolism, even in MIN6 cells. Several studies confirm the link between mTOR signaling, mitochondrial activity, and insulin production [46,61,62]. Nevertheless, to determine the exact molecular pathways that bring about the effects of BF142 requires further investigations.…”

Section: Plos Onementioning

confidence: 97%

Glycogen phosphorylase inhibitor, 2,3‐bis[(2E)‐3‐(4‐hydroxyphenyl)prop‐2‐enamido] butanedioic acid (BF142), improves baseline insulin secretion of MIN6 insulinoma cells

et al. 2020

View full text Add to dashboard Cite

Type 2 diabetes mellitus (T2DM), one of the most common metabolic diseases, is characterized by insulin resistance and inadequate insulin secretion of β cells. Glycogen phosphorylase (GP) is the key enzyme in glycogen breakdown, and contributes to hepatic glucose production during fasting or during insulin resistance. Pharmacological GP inhibitors are potential glucose lowering agents, which may be used in T2DM therapy. A natural product isolated from the cultured broth of the fungal strain No. 138354, called 2,3-bis(4-hydroxycinnamoyloxy)glutaric acid (FR258900), was discovered a decade ago. In vivo studies showed that FR258900 significantly reduced blood glucose levels in diabetic mice. We previously showed that GP inhibitors can potently enhance the function of β cells. The purpose of this study was to assess whether an analogue of FR258900 can influence β cell function. BF142 (Meso-Dimethyl 2,3-bis[(E)-3-(4-acetoxyphenyl)prop-2-enamido]butanedioate) treatment activated the glucose-stimulated insulin secretion pathway, as indicated by enhanced glycolysis, increased mitochondrial oxidation, significantly increased ATP production, and elevated calcium influx in MIN6 cells. Furthermore, BF142 induced mTORC1-specific phosphorylation of S6K, increased levels of PDX1 and insulin protein, and increased insulin secretion. Our data suggest that BF142 can influence β cell function and can support the insulin producing ability of β cells.

show abstract

mTORC in β cells: more Than Only Recognizing Comestibles

Abstract: Maedler and Ardestani discuss recent work from Chau et al. on the role of mTOR for β cell survival in diabetes.

Cited by 11 publications

References 10 publications

A Nutrient-Sensing Transition at Birth Triggers Glucose-Responsive Insulin Secretion

A Nutrient-Sensing Transition at Birth Triggers Glucose-Responsive Insulin Secretion

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

Glycogen phosphorylase inhibitor, 2,3‐bis[(2E)‐3‐(4‐hydroxyphenyl)prop‐2‐enamido] butanedioic acid (BF142), improves baseline insulin secretion of MIN6 insulinoma cells

Contact Info

Product

Resources

About