Targeting Ras homolog enriched in brain 1 to restore β-cell mass and function: A potential therapeutic strategy for diabetes

Abstract

This editorial highlighted the central role of pancreatic β-cell dysfunction in the pathogenesis of diabetes mellitus and discussed the emerging significance of Ras homolog enriched in brain 1 (Rheb1) as a key regulator of β-cell mass and insulin-secretory capacity. While molecular mechanisms governing β-cell homeostasis remain incompletely defined, Yang et al have recently demonstrated that Rheb1 could promote β-cell proliferation through dual activation of mechanistic target of rapamycin complex 1 and AMP-activated protein kinase signaling pathways, rather than relying solely on mechanistic target of rapamycin complex 1. Notably, Rheb1 expression is higher in pancreatic islets from younger individuals and upregulates hepatocyte nuclear factor 4 alpha, which is recognized as a transcription factor essential for β-cell identity and insulin production. These insights position Rheb1 as a pivotal regulator of β-cell growth and metabolic function, with potential therapeutic implications for diabetes. Targeting Rheb1 may shift treatment paradigms from conventional glucose-lowering strategies toward β-cell restoration, providing a novel approach to preserve or enhance functional β-cell mass in diabetic patients. Further investigation into Rheb1’s upstream regulators and downstream effectors may provide innovative therapeutic directions.

Key Words: Diabetes mellitus; β cell dysfunction; Ras homolog enriched in brain 1; Mechanistic target of rapamycin complex 1 pathway; AMP-activated protein kinase pathway; Hepatocyte nuclear factor 4 alpha

Core Tip: Dysregulation of β-cell mass and function contributes to the development and progression of diabetes mellitus. In a recent study, Yang et al identified Ras homolog enriched in brain 1 (Rheb1) as a critical regulator of β-cell proliferation via both mechanistic target of rapamycin complex 1 and AMP-activated protein kinase signaling pathways. Rheb1 also enhances hepatocyte nuclear factor 4 alpha expression, further supporting its role in maintaining β-cell functionality. These results reveal an intricate signaling network through by Rheb1 supports β-cell growth and survival, highlighting its potential as a therapeutic target for diabetes management. Further research is warranted to explore the translational applications of these findings.

INTRODUCTION

Diabetes mellitus represents one of the most pressing global health challenges, with rising prevalence and substantial socioeconomic burdens. A central feature in the pathogenesis of both type 1 and type 2 diabetes is the progressive loss of functional pancreatic β-cells, driven by mechanisms such as autoimmune destruction, metabolic stress-induced dysfunction, dedifferentiation, and apoptosis[1]. Despite decades of research, most current therapies have concentrated on glycemic control through exogenous insulin or insulin sensitizers rather than addressing the root cause, including the decline in functional β-cell mass[2].

To overcome this limitation, regenerative strategies targeting β cell preservation, proliferation, or functional restoration have emerged as a promising therapeutic frontier. Multiple molecular regulators, such as pancreatic and duodenal homeobox 1, which is essential for β-cell development and maintenance, and neurogenin 3 (a key inducer of endocrine differentiation) have been investigated for their capacity to expand β-cell mass[3,4]. However, these targets mainly face limitations, including limited proliferative efficacy and difficulties in achieving precise modulation without unintended off-target effects.

In this context, Yang et al[5] introduced Ras homolog enriched in brain 1 (Rheb1) as a novel and multifaceted regulator of β-cell expansion and function. In contrast to single-pathway targets, Rheb1 uniquely engages both mechanistic target of rapamycin complex 1 (mTORC1) and AMP-activated protein kinase (AMPK) signaling pathways, coupling nutrient-sensing mechanisms with energy homeostasis to promote β-cell proliferation. Furthermore, Rheb1 upregulates hepatocyte nuclear factor 4 alpha (HNF4α), which is a transcription factor essential for maintaining β cell identity and insulin secretion. These findings position Rheb1 as a compelling candidate for therapeutic intervention, potentially providing broader and more sustainable benefits compared with existing molecular targets (Figure 1).

Figure 1 Schematic of Ras homolog enriched in brain 1 activating mechanistic target of rapamycin complex 1/AMP-activated protein kinase to regulate hepatocyte nuclear factor 4 alpha-dependent β cell proliferation, insulin transcription, identity, and metabolic homeostasis, driving functional β cell expansion. Rheb1: Ras homolog enriched in brain 1; mTORC1: Mechanistic target of rapamycin complex 1; AMPK: AMP-activated protein kinase; HNF4α: Hepatocyte nuclear factor 4 alpha.

Nevertheless, translating these insights into clinical applications remains challenging due to obstacles, such as ensuring tissue-specific delivery, mitigating oncogenic risks associated with sustained mTORC1 activation, and navigating the delicate balance between promoting proliferation and preserving β-cell functional maturation. This editorial critically examined Rheb1’s role in β-cell biology within the larger landscape of regenerative strategies, while addressing the challenges and opportunities for its therapeutic development (Figure 2).

Figure 2 A schematic diagram showing Ras homolog enriched in brain 1-high-expression-mediated β-cell proliferation/function enhancement via dual pathway activation and hepatocyte nuclear factor 4 alpha upregulation, with translational research pipeline. Rheb1: Ras homolog enriched in brain 1; mTORC1: Mechanistic target of rapamycin complex 1; AMPK: AMP-activated protein kinase; HNF4α: Hepatocyte nuclear factor 4 alpha.

RHEB1: BRIDGING PROLIFERATION AND METABOLIC SIGNALING IN β CELLS

Over the past decade, research into Rheb1’s role in β cell biology has significantly advanced. Initially characterized in 2005 as a potent activator of mTORC1[6], Rheb1 was primarily studied in the context of cancer and nutrient sensing before assessing its potential role in β cells. Early studies (2010-2015) examining mTORC1 activation in β cells reported conflicting results, while some studies demonstrated enhanced proliferation, others found that chronic mTORC1 activation could lead to β-cell exhaustion and impaired function[7]. These discrepancies highlighted the need to understand mTORC1 regulation in a more robust context. Rheb1, as a member of the Ras superfamily of GTPases, gained particular attention when transcriptomic analyses revealed its differential expression patterns in human islets across developmental stages. This temporal expression profile indicates a potential role of Rheb1 in β cell growth regulation. Yang et al[5] evidenced that Rheb1 is highly expressed in islets from younger individuals and promotes β-cell proliferation through a novel dual-pathway mechanism.

The unique capacity of Rheb1 to concurrently activate both mTORC1 and AMPK signaling pathways challenges the traditional view of these pathways as mutually antagonistic. While mTORC1 primarily promotes cell cycle progression and anabolic processes, AMPK modulates catabolic responses under energy-deprived conditions[8]. This dual-pathway coordination overcomes a fundamental limitation of interventions, targeting a single signaling pathway, as evidenced by the constrained proliferative outcomes observed with rapamycin-mediated mTORC1 suppression and the transient effects of AMPK-specific activation.

The identification of Rheb1’s dual activation of growth-promoting and homeostatic pathways provides a potential explanation for previous therapeutic limitations. By concurrently stimulating mTORC1 and AMPK signaling pathways, Rheb1 may sustain a metabolic balance, promoting β-cell proliferation without compromising function[9]. This delicate balance is particularly crucial for β cells, which must constantly adapt to fluctuating nutrient levels while maintaining precise insulin secretion capacity.

However, some studies have reported minimal effects of Rheb1 manipulation in certain β cell models, demonstrating that its regulatory role may be context-dependent. These contrasting findings emphasize the need for further research into the specific conditions under which Rheb1 exerts its proliferative effects. Nevertheless, the unique signaling convergence mediated by Rheb1 positions it as a multifunctional regulator capable of coordinating proliferative expansion while minimizing detrimental stress responses or dedifferentiation[10].

MAINTAINING FUNCTIONAL β-CELL IDENTITY THROUGH HNF4α

Beyond increasing β-cell numbers, preserving functional maturity and identity is essential for any regenerative approach to be clinically effective. Immature or dedifferentiated β cells mainly exhibit impaired insulin secretion, leading to glycemic instability[11]. Current therapies, such as GLP-1 analogs, mainly enhance the function of residual β cells without expanding their population, whereas stem cell-derived islet transplantation remains limited by donor scarcity and immune rejection. Yang et al[5] found that Rheb1 upregulates HNF4α a nuclear transcription factor critical for maintaining β-cell identity, regulating insulin gene transcription, and ensuring proper glucose-stimulated insulin secretion. Mutations in HNF4α gene cause maturity-onset diabetes of the young type 1, highlighting its central role in β-cell-specific gene expression. This mechanism contrasts with other proliferative approaches that risk losing β cell identity markers during expansion.

The ability of Rheb1 to simultaneously enhance proliferation while maintaining functional gene expression programs marks it as a particularly valuable therapeutic target[12]. It addresses a fundamental limitation of many regenerative approaches, which may promote proliferation at the cost of cellular identity and insulin secretory function. Nevertheless, the potential tumorigenic risk associated with sustained mTORC1 activation via Rheb1 warrants cautious evaluation, particularly given the oncogenic potential of other Ras family members.

THERAPEUTIC POTENTIAL: A NEW PARADIGM IN β-CELL REGENERATION

Targeting Rheb1 provides a novel and multifaceted strategy for diabetes therapy. In contrast to traditional pharmacologic agents that aim to reduce blood glucose level or enhance insulin action, Rheb1-based interventions could potentially restore intrinsic β-cell mass and functionality, reducing or eliminating the need for lifelong insulin therapy[13]. This represents a fundamental shift from current standard-of-care treatments to a potentially curative approach.

Moreover, the molecular accessibility of Rheb1-related signaling pathways presents multiple pharmacologic targets. Both mTORC1 and AMPK are well-characterized targets with existing small-molecule modulators and biologics already in clinical use or under active development[14-16]. For instance, rapamycin analogs that selectively inhibit mTORC1 and metformin, a widely used AMPK activator, may serve as foundational components for Rheb1-targeted strategies. These agents can promote more rapid clinical translation compared with the development of entirely novel therapeutic classes. Modulating Rheb1 itself, or downstream effectors, such as HNF4α, may thus be feasible within a relatively short translational window. However, the field must draw lessons from the limitations of prior regenerative strategies, such as β-cell exhaustion resulting from sustained GLP-1 receptor stimulation and the inconsistent functional maturation found in stem cell-derived β cells[17].

Additional attention must be given to the context-specific effects of Rheb1 activation. Overactivation of mTORC1 has been linked to β-cell exhaustion and endoplasmic reticulum stress, while long-term AMPK stimulation may impair anabolic capacity essential for insulin production[18,19]. Additionally, the proliferative effects of Rheb1 activation could theoretically increase cancer risk, particularly in tissues with high basal mTORC1 activity. Thus, future therapies will require precise tuning of Rheb1 activity, potentially through tissue-specific gene modulation, small interfering RNAs, or targeted delivery systems, in order to optimize efficacy while minimizing systemic risks. Combination approaches involving transient Rheb1 activation alongside differentiation-promoting factors may provide a means to balance β-cell proliferation with the preservation of functional maturity.

ADVANCING RHEB1 THERAPEUTICS FOR DIABETES

Translating Rheb1 into clinical applications requires developing targeted delivery systems that can safely modulate its activity in pancreatic β cells. Promising approaches include β cell-specific nanoparticles, engineered viral vectors, and modified small molecules that can precisely regulate Rheb1-mTORC1-AMPK signaling[20]. These technologies must overcome key challenges in tissue specificity, dosage control, and long-term safety before clinical use. Rheb1-based therapies could revolutionize diabetes prevention by enabling early intervention. Identifying at-risk individuals through molecular profiling of Rheb1 pathway activity may allow treatment during the critical β cell compensation phase. Developing reliable biomarkers from blood samples and imaging techniques will be essential for implementing this precision medicine approach.

Several important scientific questions remain to be addressed to advance Rheb1-based therapeutics. Fundamental priorities include elucidating how various diabetic states modulate Rheb1 signaling and identifying optimal therapeutic windows during disease progression. Ongoing safety studies are essential to evaluate strategies to mitigate risks, such as β-cell over-proliferation, including the use of drug-inducible expression systems and combination regimens to enhance precision and control.

Cutting-edge research platforms are rapidly advancing the development of Rheb1-based therapeutics. Complicated animal models, human islet-on-chip systems, and single-cell technologies are yielding deeper insights into Rheb1’s role in β-cell biology[21-23]. Computational modeling and artificial intelligence are employed to optimize drug design and predict therapeutic responses. Visual tools, such as molecular network diagrams and pathway schematics, are increasingly utilized to clarify Rheb1’s regulatory role and promote communication of these complex concepts.

CONCLUSION

The identification of Rheb1 as a multifunctional regulator of β-cell proliferation, metabolic function, and identity maintenance has provided important insights for the therapy of diabetes. In contrast to single-pathway targets, Rheb1’s unique capacity to coordinately activate both mTORC1 and AMPK signaling pathways, while simultaneously upregulating HNF4α, positions it as a particularly promising molecular target for β-cell restoration. These dual mechanisms address the critical need for therapies that can simultaneously expand β-cell mass while preserving functional maturity. However, key translational challenges remain, including the development of tissue-specific delivery systems, mitigation of potential oncogenic risks from chronic pathway activation, and establishment of optimal treatment windows. As the field progresses from symptomatic management to regenerative approaches, Rheb1-targeted therapies provide the potential for transformative, disease-modifying interventions that directly address the fundamental pathophysiology of diabetes, including the loss of functional β-cell mass. Future research should concentrate on overcoming these translational barriers while further elucidating Rheb1’s context-dependent regulatory role across diabetes subtypes.