Imeglimin to the Rescue: Enhanced CHOP/GADD34/eIF2α Signaling Axis Promotes β-Cell Survival

Jo, Seokwon; Alejandro, Emilyn U.

doi:10.2337/dbi21-0035

Cited by 3 publications

(1 citation statement)

References 23 publications

(19 reference statements)

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“…This connection establishes the ATF4 -> GADD34 -> ATF4 positive feedback loop in the control network (see number "3" connections on Figure 3) [127]. It has also been shown that CHOP had a positive effect on GADD34 [132][133][134] upon ER stress, resulting in another positive feedback loop, i.e., ATF4 -> CHOP -> GADD34 -> ATF4 (see number "4" connections on Figure 3) [127].…”

Section: Crosslinks Inside and Between The Upr Arms And Their Roles U...mentioning

confidence: 91%

Mechanism of Decision Making between Autophagy and Apoptosis Induction upon Endoplasmic Reticulum Stress

Kapuy

2024

IJMS

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Dynamic regulation of the cellular proteome is mainly controlled in the endoplasmic reticulum (ER). Accumulation of misfolded proteins due to ER stress leads to the activation of unfolded protein response (UPR). The primary role of UPR is to reduce the bulk of damages and try to drive back the system to the former or a new homeostatic state by autophagy, while an excessive level of stress results in apoptosis. It has already been proven that the proper order and characteristic features of both surviving and self-killing mechanisms are controlled by negative and positive feedback loops, respectively. The new results suggest that these feedback loops are found not only within but also between branches of the UPR, fine-tuning the response to ER stress. In this review, we summarize the recent knowledge of the dynamical characteristic of endoplasmic reticulum stress response mechanism by using both theoretical and molecular biological techniques. In addition, this review pays special attention to describing the mechanism of action of the dynamical features of the feedback loops controlling cellular life-and-death decision upon ER stress. Since ER stress appears in diseases that are common worldwide, a more detailed understanding of the behaviour of the stress response is of medical importance.

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Section: Crosslinks Inside and Between The Upr Arms And Their Roles U...mentioning

confidence: 91%

Mechanism of Decision Making between Autophagy and Apoptosis Induction upon Endoplasmic Reticulum Stress

Kapuy

2024

IJMS

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Exploring new mechanisms of Imeglimin in diabetes treatment: Amelioration of mitochondrial dysfunction

Li,

Lou,

Liu

et al. 2024

Biomedicine & Pharmacotherapy

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Imeglimin enhances glucagon secretion through an indirect mechanism and improves fatty liver in high‐fat, high‐sucrose diet‐fed mice

Kikuchi,

Ikeuchi,

Kobayashi

et al. 2024

J of Diabetes Invest

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Aims/IntroductionImeglimin is a recently approved oral antidiabetic agent that improves insulin resistance, and promotes insulin secretion from pancreatic β‐cells. Here, we investigated the effects of imeglimin on glucagon secretion from pancreatic α‐cells.Materials and MethodsExperiments were carried out in high‐fat, high‐sucrose diet‐fed mice. The effects of imeglimin were examined using insulin and glucose tolerance tests, glucose clamp studies, and measurements of glucagon secretion from isolated islets. Glucagon was measured using both the standard and the sequential protocol of Mercodia sandwich enzyme‐linked immunosorbent assay; the latter eliminates cross‐reactivities with other proglucagon‐derived peptides.ResultsPlasma glucagon, insulin and glucagon‐like peptide‐1 levels were increased by imeglimin administration in high‐fat, high‐sucrose diet‐fed mice. Glucose clamp experiments showed that the glucagon increase was not caused by reduced blood glucose levels. After both single and long‐term administration of imeglimin, glucagon secretions were significantly enhanced during glucose tolerance tests. Milder enhancement was observed when using the sequential protocol. Long‐term administration of imeglimin did not alter α‐cell mass. Intraperitoneal imeglimin administration did not affect glucagon secretion, despite significantly decreased blood glucose levels. Imeglimin did not enhance glucagon secretion from isolated islets. Imeglimin administration improved fatty liver by suppressing de novo lipogenesis through decreasing sterol regulatory element binding protein‐1c and carbohydrate response element binding protein and their target genes, while enhancing fatty acid oxidation through increasing carnitine palmitoyltransferase I.ConclusionsOverall, the present results showed that imeglimin enhances glucagon secretion through an indirect mechanism. Our findings also showed that glucagon secretion promoted by imeglimin could contribute to improvement of fatty liver through suppressing de novo lipogenesis and enhancing fatty acid oxidation.

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Imeglimin to the Rescue: Enhanced CHOP/GADD34/eIF2α Signaling Axis Promotes β-Cell Survival

Cited by 3 publications

References 23 publications

Mechanism of Decision Making between Autophagy and Apoptosis Induction upon Endoplasmic Reticulum Stress

Mechanism of Decision Making between Autophagy and Apoptosis Induction upon Endoplasmic Reticulum Stress

Exploring new mechanisms of Imeglimin in diabetes treatment: Amelioration of mitochondrial dysfunction

Imeglimin enhances glucagon secretion through an indirect mechanism and improves fatty liver in high‐fat, high‐sucrose diet‐fed mice

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