Recent advances in pancreatic β‐cell dysfunction in type 2 diabetes mellitus: Intracellular stress and dedifferentiation

INTRODUCTION

Type 2 diabetes mellitus is characterized by insulin resistance and pancreatic β‐cell dysfunction. The compensatory mechanisms of β‐cells against insulin resistance eventually fail, leading to persistent hyperglycemia. The reduction in β‐cell mass in patients with type 2 diabetes mellitus has been understood primarily as irreversible cell death due to apoptosis ¹ ; however, recently, attention has shifted to the involvement of the loss of cellular identity, namely dedifferentiation, in this process. This review focuses on the molecular mechanisms of β‐cell dysfunction, particularly on the protection of β‐cells from intracellular stress and dedifferentiation, and outlines future therapeutic strategies.

INTRACELLULAR STRESS

In addition to external factors such as hyperglycemia, β‐cells are vulnerable to multiple forms of intracellular stress, including oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. Below, we describe several new molecular mechanisms and pathways for protecting β‐cell function as potential targets for future diabetes treatment.

First, the long‐term exposure of pancreatic β‐cells to hyperglycemia induces ER stress, which inhibits insulin secretion by suppressing translation through the protein misfolding response. However, it was unknown whether sustained hyperglycemia is involved in translational regulation at an earlier stage than ER stress induction. Cheruiyot et al ² . demonstrated that exposing pancreatic islets and MIN6 cells to sustained high glucose under conditions without an increase in ER stress markers suppresses the translation of specific messenger ribonucleic acids required for insulin secretion. This finding holds the potential to identify targets for new therapeutic strategies to suppress the progression of β‐cell dysfunction in the early stages of diabetes.

Next, it is well known that oxidative stress induces β‐cell dysfunction via mitochondrial dysfunction. A recent report showed that oxidative stress inhibits mitophagy in β‐cells by downregulating the expression of prohibitin 2 (PHB2), a mitochondrial inner membrane protein. However, nuclear factor erythroid 2‐related factor 2 (Nrf2), which regulates antioxidant protein expression, has been identified as an upstream regulator of PHB2 in β‐cells, and the antioxidant N‐acetyl cysteine increases β‐cell mitophagy by activating the Nrf2/PHB2 pathway ³ .

Furthermore, mitochondrial aldehyde dehydrogenase 2 (Aldh2) is also involved in β‐cell protection by detoxifying harmful lipid peroxidation products, for example, 4‐hydroxynonenal, generated within mitochondria. One mechanism of toxicity of the chemotherapeutic agent doxorubicin involves the release of ceramide, which inhibits AKT serine/threonine kinase phosphorylation via casein kinase 2 and induces the degradation of mitochondrial Aldh2, thereby causing β‐cell dysfunction ⁴ .

Glucokinase activation has β‐cell protective effects, including improving ER stress‐mediated apoptosis ⁵ . However, it is now suggested that its efficacy is not sustained over the long term and chronic glucokinase activation may actually induce β‐cell failure. Indeed, in glucokinase heterozygous‐deficient mice fed a high‐fat, high‐sugar diet, glucose tolerance does not deteriorate at advanced ages, and β‐cell mass actually shows an increasing trend ⁶ .

DEDIFFERENTIATION

In recent years, the nature of β‐cell dysfunction has been redefined not merely as cell death but also as a loss of cellular identity (i.e., dedifferentiation). Focusing on the transcription factor forkhead box O1 (FoxO1), Talchai et al ⁷ . conducted lineage tracing experiments using β‐cell‐specific FoxO1‐deficient mice subjected to metabolic stress, such as aging or multiple pregnancies, and demonstrated that the reduction in β‐cell mass is due to dedifferentiation rather than cell death. They found that dedifferentiated β‐cells transform into precursor‐like cells, with some differentiating into glucagon‐positive α‐cell‐like cells. Similar phenomena have been confirmed in diabetic model mice and human diabetic islets ⁷ , ⁸ , suggesting that β‐cell dysfunction may represent a reversible cellular state change.

FoxO1 plays a central role in the molecular mechanisms of dedifferentiation. Under metabolic stress, FoxO1 translocates into the nucleus; if the stress persists, its expression decreases, and β‐cells transition to an undifferentiated state ⁷ . Epigenetic regulation is also involved in this process, and Fu et al. identified ubiquitin‐like with PHD and ring finger domains 1 (Uhrf1) as a key regulator. They demonstrated that Uhrf1 knockdown promotes H3K27me3 and H3K9me3 and suppresses H3K4me3 at the FoxO1 promoter in INS‐1 cells (rat insulinoma cell line), resulting in decreased FoxO1 expression and β‐cell dedifferentiation ⁹ .

Furthermore, the link between intracellular stress and dedifferentiation is becoming increasingly clear. Wolfram syndrome, a rare inherited disorder caused by mutations in the wolframin ER transmembrane glycoprotein (Wfs1) gene, was previously thought to lead to insulin‐dependent diabetes due to apoptosis triggered by increased ER stress. However, Shiinoki et al ¹⁰ . demonstrated that diabetes develops due to a reduction in the number of functional β‐cells caused by dedifferentiation in addition to apoptosis. Furthermore, the researchers generated Wfs1/thioredoxin‐interacting protein (Txnip) double‐deficient mice, in which the stress‐response molecule Txnip, which is highly expressed in β‐cells of Wfs1‐deficient mice, is also absent. As a result, dedifferentiation is suppressed and insulin secretion is restored.

TREATMENT

Conventional treatments, such as glucagon‐like peptide‐1 (GLP‐1) receptor agonists, dipeptidyl peptidase‐4 inhibitors, and peroxisome proliferator‐activated receptor γ agonists, have been shown to improve β‐cell function, including activation of the GLP‐1 receptor promotes β‐cell proliferation ¹¹ . Recently, imeglimin has attracted attention as a new oral hypoglycemic agent that targets intracellular stress. Under ER stress, eukaryotic initiation factor 2α (eIF2α) is phosphorylated, inhibiting protein translation; however, imeglimin increases growth arrest and DNA‐damage‐inducible gene 34 and activating transcription factor 3 levels, leading to eIF2α dephosphorylation via negative feedback, thereby preserving β‐cell survival through the restoration of protein translation ¹² .

Furthermore, as a novel approach targeting cell fate regulation, it has been proposed that FoxO1 inhibition can convert intestinal epithelial cells into insulin‐producing cells ¹³ . In human intestinal organoid cultures, cells differentiating into β‐cells were identified as serotonin‐producing enterochromaffin cells, and it was demonstrated that FoxO1 inhibition causes enterochromaffin cells to differentiate into β‐cell‐like cells and acquire insulin secretory capacity ¹⁴ . Furthermore, in multiple insulin‐deficient diabetic mouse models, including non‐obese diabetic, Akita, and streptozotocin‐treated mice, the administration of FoxO1 inhibitors alone or in combination with Notch inhibitors or transforming growth factor‐β inhibitors generates insulin‐immunoreactive intestinal cells and improves blood glucose levels ¹⁵ . This is a field in which further long‐term safety studies are anticipated.

In conclusion, it has become clear that intracellular stress and dedifferentiation are interrelated pathophysiological mechanisms at the core of β‐cell dysfunction (Figure 1). Future research should integrate our understanding of these mechanisms and aim to correct stress responses while maintaining and restoring cellular function.

Figure 1.

Mechanisms of pancreatic β‐cell failure regulated by intracellular stress and dedifferentiation. Aldh2, aldehyde dehydrogenase 2; ER, endoplasmic reticulum; FoxO1, Forkhead box O1; Pfkfb3, 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase 3; PHB2, prohibitin 2; Scgn, secretagogin; Txnip, thioredoxin‐interacting protein; Uhrf1, Ubiquitin‐like with PHD and ring finger domains 1.

DISCLOSURE

The authors declare no conflicts of interest.

Approval of the research protocol: N/A.

Informed consent: N/A.

Approval date of registry and registration no. of the study/trial: N/A.

Animal studies: N/A.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.