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

Pancreatic β-cells are the main source of insulin in the body, and this hormone is required to maintain glucose homeostasis and normal metabolic health. Circulating insulin level is impacted by total β-cell mass in the pancreas, which is maintained by the ability of the β-cells to self-duplicate and survive from various stressors, such as apoptosis and endoplasmic reticulum (ER) stress. Given the inherently low rate of turnover in β-cells (1,2), apoptosis can play a key pathogenic role in the development of diabetes. While many factors contribute to the death of β-cells, such as inflammation and oxidative stress, ER homeostasis through the unfolded protein response (UPR) elements are of the utmost importance (3). As the insulin factory of the body, β-cells allocate a significant amount of energy on insulin synthesis in the ER, and the quantity of insulin produced is partly dependent on the processes that shape ER synthetic capacity (4). Current literature argues that induction of UPR in the face of ER stress represents a cell’s functional adaptation to cellular stress, but, unchecked, it can ultimately cause the demise of a cell if the stressor is not remedied in a timely manner.

The current molecular arsenal to combat β-cell death is very limited. Imeglimin is an investigational oral medication, emerging as a potent antidiabetic drug. In current preclinical models, imeglimin promotes β-cell proliferation while suppressing apoptosis in Zucker diabetic fatty rats (5) as well as improving islet glucose-stimulated insulin secretion in a dose-dependent manner in C57/BL6 mice (6,7). While these findings provide insight into the role of imeglimin as a promoter of optimal β-cell health and insulin release, the molecular mechanisms of how it maintains and preserves β-cell mass is less understood.

In this issue of Diabetes, Li et al. (8) explore the mechanisms of how imeglimin works as an antidiabetic drug and specifically dissect its effects in suppressing β-cell apoptosis through modulation of UPR regulation, using various mouse models and human islets. First, the authors show the positive effects of imeglimin on β-cell function by measuring insulin release in response to glucose and then the ability of the β-cells to proliferate with the drug. Li et al. demonstrate that imeglimin promotes β-cell survival, confirming findings by others (5,9). To identify the molecular mechanisms of how imeglimin promotes cell survival, the authors started with an unbiased gene expression microarray experiment in primary mouse islets treated with imeglimin and identified 245 upregulated and 451 downregulated genes. From this study, increases in several ER stress–related genes (e.g., CHOP and GADD34) were evident, indicating a role of ER moderators as mechanisms driving the improvements in β-cell survival. Imeglimin effectively prevented β-cell apoptosis and increased β-cell mass in an ER stress mouse model (Akita) in vivo as well as in primary human or mouse islets treated with the ER stress inducer thapsigargin (Tg) in vitro. Li et al. further demonstrated that Tg-induced ER stress was sufficient to increase gene and protein expression of ER stress markers (e.g., CHOP, Atf3, and GADD34), with further increase observed with imeglimin treatment. The authors concluded that the enhanced ER stress with imeglimin treatment positively impacts β-cell physiology.

The findings in Li et al. (8) reveal new insights into the effects of ER UPR activation and that the level of activation determines specific biological outcomes (Fig. 1). To get a fuller picture, they next focused on the relationship between CHOP and its downstream targets, GADD34 and eIF2α. Phosphorylation of eIF2α, a protein translation regulator and a modulator of the integrated stress response (ISR), is an important step in ER stress–mediated gene expression and halts global protein synthesis (i.e., CHOP and GADD34) while upregulating ISR-related translation (10). This is maintained by a negative feedback loop where GADD34 targets protein phosphatase 1a to promote dephosphorylation of eIF2α (11). In their study, Li et al. suggest that an increase in GADD34 expression causes dephosphorylation of eIF2α and therefore restoration of global translation by imeglimin. To support their finding, the treatment of ISRIB, a small-molecule inhibitor of ISR and phospho-eIF2α, alone was effective in preventing Tg-mediated β-cell apoptosis, and cotreatment with imeglimin had no further effects. Together, these data implicate the eIF2α pathway in mediating imeglimin-mediated β-cell survival. However, it is important to note that while imeglimin consistently showed its rescue effects in various animal models, ISRIB had minimal effect on human islets. As further supporting data, guanabenz, a GADD34 inhibitor, prevented improvements in β-cell survival by imeglimin, suggesting that the GADD34-mediated pathway is also a critical player in imeglimin’s prosurvival effect. Finally, Li et al. associate CHOP, a well-known proapoptotic factor that is often linked with β-cell death, with a regulator of cell survival in their model (10). Surprisingly, despite a reduction in apoptosis level, imeglimin treatment upregulated CHOP across all models they tested. Furthermore, the authors used islet from CHOP null mice to show its requirement for the prosurvival effects of imeglimin. However, in this experiment, it is important to note that Tg alone caused a nonsignificant trend in apoptotic level on CHOP null islets; therefore, data on the contribution of CHOP in this context is less interpretable. Future studies investigating the direct association of CHOP with its downstream targets by either overexpression or acute knockdown may shed light on the critical role of this protein in imeglimin’s prosurvival effects in β-cells.

In summary, Li et al. (8) show important mechanistic insights into the role of imeglimin as a novel antidiabetic drug and highlights an interesting perspective into the ER homeostatic regulation of β-cell survival. Many published reports have associated the induction of CHOP with increased β-cell apoptosis, as islets from multiple diabetes models show increased CHOP expression and CHOP null β-cells resist apoptosis from stressors (12–14). However, Li et al. point to a potentially new paradigm in the complex and dynamic regulation of CHOP-ER homeostasis in β-cell survival, where an increase in CHOP and GADD34 expression and dephosphorylation of eIF2α ameliorates cell death. Inactivation of the CHOP/GADD34/eIF2α negative feedback loop to maintain translational inhibition has been implicated as a protective mechanism to relieve proteostatic load under stress (15), but inversely, GADD34/eIF2α loop activation was shown to mitigate death in other models (16). This raises important questions on the duality of ER stress and the role of CHOP as a proapoptotic and prosurvival protein. ER stress and UPR inductions are a critical node of β-cell proliferation and survival (17,18). How does the presence, degree, or duration of ER stress contribute to β-cell physiology? Is there a range of CHOP expression where it plays a protective versus apoptotic role? Much work remains to be done to clarify the many gaps in our understanding of how increased CHOP or ER stress balances between cell death and survival. Lastly, the effects of imeglimin in promoting β-cell function and mass to support insulin secretion are becoming clear, along with other work showing improvements in peripheral insulin sensitivity (8,19). Its efficacy as an antidiabetic is promising, as Japan has recently approved it for clinical use in treatment of type 2 diabetes based on the successful phase 3 of the Trials of Imeglimin for Efficacy and Safety (TIMES) (20,21). With further distribution and drug approval, imeglimin may become a valuable addition to the arsenal to combat the epidemic of diabetes worldwide.