Rheb1 signaling and the fate of pancreatic β cells: Toward a new frontier in diabetes therapy

Abstract

A recent study in the World Journal of Diabetes by Yang et al explored how Rheb1 signaling influenced pancreatic β cell fate and its potential as a therapeutic target. This invited commentary by a senior diabetes researcher discussed the findings of Yang et al in the context of current knowledge on β cell biology, providing critical insight into the role of Rheb1 in β cell survival and function and the prospects for diabetes treatment. Key outcomes of the study were interpreted alongside established literature on Rheb1- mechanistic target of rapamycin signaling in islet cells. Rheb1 emerges as a pivotal regulator of β cell growth and insulin secretory function, aligning with evidence that β cell-specific Rheb1 deletion impairs β cell mass and glucose-stimulated insulin secretion. The commentary highlighted how modulating this pathway could preserve or restore the β cell population in diabetes while cautioning about potential off-target effects (e.g. in α cells). Targeting Rheb1 signaling represents a promising new frontier in diabetes therapy to enhance β cell resilience; however, a balanced approach addressing both its benefits and risks is essential. This letter discussed the scientific implications and future research directions needed to translate Rheb1 modulation into clinical application for diabetes.

Key Words: Pancreatic β cell fate; Rheb1 signaling; mTOR pathway; Diabetes therapy; Β cell survival

Core Tip: Rheb1 is a critical regulator of pancreatic β cell survival and insulin secretion, acting through the mechanistic target of rapamycin complex 1 pathway to support β cell mass and function. This invited commentary evaluated how Rheb1-driven signaling modulates β cell fate and assesses its promise as a therapeutic target in diabetes. While enhancing Rheb1 activity could preserve or expand functional β cell mass, careful modulation is required to avoid unintended effects such as α cell overactivity. Understanding the dualistic nature of Rheb1 signaling in islet cell populations will be key to harnessing this pathway for future diabetes treatments.

TO THE EDITOR

The study by Yang et al[1] recently published in the World Journal of Diabetes provides compelling new insights into the role of Rheb1 signaling in pancreatic β cells. The authors examined how manipulating Rheb1, a small GTPase upstream of the mechanistic target of rapamycin complex (mTORC1) pathway, can influence β cell fate decisions, potentially offering novel therapeutic avenues for diabetes. This work is significant given the central importance of functional β cell mass in the pathogenesis of both type 1 and type 2 diabetes. Loss of insulin-producing β cells through apoptosis or functional decline underlies the progressive failure of glycemic control in diabetes. Strategies to safeguard or replenish β cells are therefore highly sought after in diabetes research. In this context the focus of Yang et al[1] on Rheb1 signaling as a lever to modulate β cell fate is timely and thought-provoking.

Rheb1 signaling in β cell function and survival

The study under discussion built on growing evidence that nutrient-sensing pathways, particularly the Rheb1-mTORC1 signaling axis, are critical regulators of β cell physiology. Rheb1 is known to be abundantly expressed in pancreatic islets[2,3] and to positively regulate mTORC1 activity, a pathway integral to cell growth, proliferation, and metabolism[4]. In murine models β cell-specific knockout of Rheb1 results in marked reductions in β cell size and mass due to suppressed β cell proliferation and increased apoptosis[3]. Yang et al[1] demonstrated that embryonic loss of Rheb1 in β cells leads to diabetes in mice, underscoring that Rheb1 is essential for maintaining an adequate β cell population.

Interestingly, when Rheb1 was deleted in adult β cells (after normal development), β cell mass remained grossly unchanged, but insulin secretion in response to glucose was significantly impaired[3]. This indicates that Rheb1 has dual roles: (1) Sustaining β cell survival and replication over the long term; and (2) Acutely enabling β cells to sense glucose and secrete insulin. Mechanistically, Rheb1 promotes glucose-stimulated insulin secretion by upregulating glucose transporter expression (GLUT1 in human β cells, GLUT2 in mouse β cells) via mTORC1-dependent signaling[3]. These findings, corroborated by Yang et al[1], paint Rheb1 as a master regulator of β cell fate, one that impacts both the quantity of β cells and their quality of function[1].

Yang et al[1] extended this paradigm by exploring the therapeutic potential of modulating Rheb1. The manuscript posits that enhancing Rheb1 signaling in pancreatic β cells could be harnessed to treat diabetes, essentially by preventing β cell loss or even promoting β cell regeneration. This idea is supported by prior observations that augmenting mTORC1 activity (to which Rheb1 is key) can drive β cell expansion in states of increased metabolic demand. For instance, nutrient and growth factor signals that activate mTORC1 are known to contribute to compensatory β cell hyperplasia in insulin-resistant conditions. Conversely, systemic mTORC1 inhibitors (like rapamycin used in transplant medicine) often induce glucose intolerance or diabetes as a side effect due in part to β cell dysfunction caused by mTORC1 suppression[3,5-7]. The convergence of these insights with the findings from Yang et al[1] highlights a fundamental concept: Adequate Rheb1/mTORC1 signaling is requisite for β cell health, and its strategic upregulation might counteract the β cell failure central to diabetes. Indeed, Rheb1 has been identified as a promising target for diabetes therapy in recent literature.

Therapeutic implications and future directions

If Rheb1 signaling is to be leveraged in diabetes treatment, several implications and challenges warrant careful discussion. First, specificity of the intervention is crucial. Rheb1 is expressed in multiple cell types within the islets of Langerhans, including α cells (glucagon-producing cells). While bolstering Rheb1 in β cells is desirable for enhancing insulin output, inadvertent activation of Rheb1 in α cells could be counterproductive. Lubaczeuski et al[8] recently showed that inducing Rheb1/mTORC1 hyperactivation in α cells led to hypersecretion of glucagon and an increase in α cell mass. This condition of hyperglucagonemia can aggravate hyperglycemia and counterbalance the benefits of increased insulin. Yang et al[1] rightly acknowledges this concern and suggests that any therapeutic strategy must target β cells selectively. Gene therapy or advanced drug delivery systems might be needed to confine Rheb1 modulation to β cells. Future research could explore β cell-specific promoters or targeting ligands that activate Rheb1 only in the intended cells, thereby minimizing off-target effects on α cells or other tissues[1,9-11]. Among delivery tools, adeno-associated virus serotype 8 has demonstrated high tropism for pancreatic islets in rodents. Use of the rat insulin promoter or human insulin promoter elements can restrict expression to β cells. Alternatively, ligand-decorated lipid nanoparticles targeting surface proteins (e.g., GLP1R) could provide non-viral specificity[12-14].

Second, the timing and degree of Rheb1 activation require optimization. β cell failure in type 2 diabetes develops in the context of chronic metabolic stress (glucotoxicity, lipotoxicity, and inflammatory signals). An open question is whether boosting Rheb1 signaling in already stressed β cells will rescue them or potentially push them into overdrive. Chronic mTORC1 hyperactivation can in some settings lead to cellular stress by inhibiting autophagic pathways and altering feedback loops in metabolism. Thus, how much and when to stimulate Rheb1 is a critical matter. Transient or moderate enhancement of Rheb1 might promote β cell survival and function, whereas excessive or sustained activation could have diminishing returns or even adverse effects[11]. Preclinical studies could employ inducible Rheb1 upregulation in diabetic animal models to determine the optimal window and magnitude of intervention to a balance in which β cells are supported but not exhausted. Additionally, combination therapies may be envisioned. For example, coupling Rheb1 pathway activation with agents that mitigate oxidative or ER stress in β cells could be used to create a more permissive environment for β cell regeneration[15-17].

Third, translating Rheb1 modulation into a practical therapy will likely involve innovative pharmacological strategies. Direct agonists of Rheb1 are not currently available since Rheb1 is a small GTP-binding protein normally regulated by upstream inhibitors (TSC1/TSC2 complex) and activators. One approach could be targeting the inhibitory TSC1/TSC2 complex in β cells. Inhibiting TSC1/2 would release Rheb1 from repression, thus activating mTORC1. Small-molecule inhibitors of TSC2 or compounds that disrupt the TSC-Rheb interaction might simulate Rheb1 activation[18,19]. Another approach might utilize incretin hormones or growth factors that naturally enhance β cell mTORC1 signaling. For instance, insulin/IGF-1 signaling and glucagon-like peptide-1 (GLP-1) agonists can activate PI3K-Akt pathways upstream of mTORC1, potentially boosting Rheb1 activity indirectly. It would be intriguing to investigate whether part of the known β cell protective effects of GLP-1 analogues or modern antidiabetic drugs (like GLP-1 receptor agonists and possibly SGLT2 inhibitors through metabolic remodeling) involve modulation of the Rheb1/mTORC1 axis[20-22]. AMPK, a key energy sensor, antagonizes mTORC1 and is downregulated in diabetic β cells, potentially tipping the Rheb1 balance. Similarly, Rheb1-mediated mTORC1 signaling intersects with Notch1, a pathway implicated in β cell dedifferentiation. Dual modulation of these axes may enhance therapeutic specificity[23-26].

Fourth, to strengthen the translational relevance of the proposed strategies, future research should focus on validating the selective activation of Rheb1 using β cell-specific delivery systems such as adeno-associated virus-mediated gene delivery or ligand-conjugated nanoparticles. In vitro β cell models or human islet organoids could serve as platforms to assess the impact of targeted Rheb1 modulation on insulin secretion and β cell proliferation[3]. In vivo models should be used to evaluate systemic safety with particular attention to α cell activity and chronic mTORC1 overactivation. Additionally, combining Rheb1 activation with GLP-1 analogs could be tested for synergistic effects. A comprehensive risk-benefit framework should guide future studies, considering both therapeutic potential and unintended consequences, including dysregulation of α cell function, metabolic imbalances, and feedback inhibition of insulin signaling. Such investigations would provide experimental validation for the conceptual model proposed herein and facilitate the development of safe, targeted therapies for diabetes[27,28].

Finally, rigorous safety and efficacy assessments will be paramount. As with any intervention on a fundamental growth pathway, there is a theoretical risk of neoplastic transformation if cell proliferation is overstimulated. Pancreatic β cells have a low baseline proliferative rate in adults and forcing them to divide carries uncertainties. Long-term studies in animal models will be needed to ensure that enhancing Rheb1 does not predispose to islet cell tumorigenesis or other proliferative lesions[29,30]. Preclinical safety studies should assess tumor suppressor gene expression (e.g., p53, p16^INK4a) and conduct metabolomic profiling to detect dysregulated anabolic flux. Carcinogenicity trials with extended follow-up in Rheb1-activated models are essential before human translation[31,32]. Moreover, the metabolic consequences of chronically altering β cell insulin output via Rheb1 should be evaluated: Would it improve overall glucose homeostasis sustainably, and how would it interact with peripheral insulin sensitivity? These questions frame a broad research agenda stemming from the pioneering proposal of Yang et al[3]. To support the translational validity of these hypotheses, future studies using inducible β cell-specific Rheb1 overexpression in STZ-induced or HFD-induced diabetic mouse models are warranted. In vitro validation using insulin-1 or EndoC-βH1 cell lines exposed to glucolipotoxic stress could assess whether moderate Rheb1 activation reverses β cell apoptosis or dysfunction[33-35].

CONCLUSION

Rheb1 signaling has emerged as a crucial nexus point in the control of pancreatic β cell fate, bridging nutrient-sensing pathways with the maintenance of β cell mass and function. Yang et al[1] makes a strong case that modulating Rheb1 activity can be a modus operandi to preserve and possibly restore the insulin-producing cell population in diabetes. This concept opens a new frontier in diabetes therapy, one that goes beyond managing blood sugar levels and aims to correct the underlying β cell deficiency. The commentary presented here underscores that while the prospects of targeting Rheb1 are exciting, a nuanced approach is essential. Future research should focus on developing cell-specific Rheb1 modulators, understanding the long-term effects of Rheb1 activation, and integrating this strategy with existing treatments. If these challenges can be met, Rheb1-based interventions might ultimately transform the landscape of diabetes care by offering patients therapies that protect and rejuvenate their own pancreatic β cells. To enhance translational relevance, future studies should incorporate human islet models such as pseudo-islets or pancreatic organoids. Single-cell RNA-sequencing of these systems following Rheb1 modulation may reveal subpopulation-specific responses and refine target selection.