Objective
The objective of this research is to develop a new approach to restore insulin production in people leaving with Type 1 diabetes (T1D) by reprogramming cells already present in the pancreas. Rather than replacing lost β-cells through transplants or stem cell-derived therapies, this project aims to convert surviving α-cells into insulin-producing, β-like cells using targeted molecular interventions.
The core objective of this research is to identify and overcome the molecular mechanisms that maintain α-cell identity and prevent their conversion into insulin-producing cells. We propose that α-cells are actively “locked” into their original role by specific genetic and epigenetic regulators. By disrupting these regulators, we aim to induce a more flexible, “permissive”, cellular state that allows α-cells to activate key features of β-cell identity, including insulin production.
By defining how α-cells sustain their identity at the molecular level, this research will stablish a mechanistic framework for identifying druggable targets capable of inducing insulin-production in human α-cells. This knowledge will enable the development of scalable, drug-based strategies to promote endogenous insulin production, advancing a regenerative approach to diabetes treatment that relies on a patient’s own pancreatic cells.
Background Rationale
Type 1 diabetes (T1D) is caused by the immune-mediated destruction of pancreatic β-cells, the only cells in the body capable of producing insulin in response to rising blood glucose levels. The loss of these cells leads to lifelong dependence on injected insulin. While insulin therapy is essential and life-saving, it cannot fully replicate the precise, real-time regulation of blood sugar provided by healthy pancreatic tissue. As a result, many individuals living with T1D experience significant glucose fluctuations and remain at risk for acute and long-term complications.
A major goal of diabetes research is therefore to restore insulin production within the body. Cell replacement strategies, including donor islet transplantation and stem cell-derived insulin-producing cells, have shown that restoring insulin-producing cells can normalize blood glucose levels. However, their widespread use is limited by challenges such as donor availability, complex manufacturing, and long-term treatment burden. These limitations have driven interest in regenerative strategies that use cells already present in the body.
In the pancreas, different hormone-producing cell types arise from common developmental origins and share related gene programs. Among these, α-cells, which normally produce the hormone glucagon, are particularly attractive for regenerative strategies. α-cells persist in the pancreas long after β-cells have been destroyed and are present in sufficient numbers to represent a meaningful therapeutic reservoir.
Importantly, both experimental studies and observations in humans suggest that α-cells retain a latent capacity to activate insulin-related programs under certain conditions. In some disease states and experimental models, α-cells have been observed to express insulin or adopt mixed cellular identities. These findings indicate that α-cells are not irreversibly committed to their original fate, but instead actively maintain their identity through molecular control mechanisms.
Understanding and modulating the biological systems that enforce cell identity could thus be the key to transform these cells into insulin-producers. If the molecular “barriers” that lock α-cells into a glucagon-producing state can be safely and transiently relaxed, α-cells may be redirected to become “β-like” cells. Such an approach could enable regeneration directly within the pancreas, using cells that are already present and integrated into the body’s glucose-sensing systems. Despite this promise, the specific mechanisms that stabilize α-cell identity, and how they can be selectively modulated, remain poorly understood. Identifying these mechanisms is a critical prerequisite for developing safe and effective regenerative therapies.
This research is grounded in the rationale that α-cell identity is actively maintained by specific genetic and epigenetic regulators, and that these regulators represent actionable targets for therapeutic intervention. By uncovering how α-cells preserve their identity and resist conversion, this research lays the foundation for drug-based strategies that harness the pancreas’s own cells to restore insulin production.
Description of Project
While modern insulin therapies and glucose-monitoring technologies have significantly improved daily Type 1 diabetes (T1D) management, they do not replace the body’s natural ability to produce insulin in response to changing blood sugar levels. As a result, people living with T1D remain at risk for dangerous hypoglycemia, long-term complications, and a reduced quality of life.
One of the most promising ways to fundamentally change T1D treatment is to restore the body’s own insulin production. Cell replacement therapies, such as islet transplantation or stem cell-derived β-cells, have demonstrated that replacing insulin-producing cells can reverse diabetes. However, these approaches face significant obstacles, including limited donor availability, high cost, immune rejection, and the need for lifelong immunosuppression or protective devices. These challenges limit their widespread use and highlight the need for alternative, more accessible solutions.
This project explores a different strategy: transforming the pancreas’s own remaining cells into new insulin-producing cells. Specifically, it focuses on α-cells, which normally produce the hormone glucagon. α-cells are an attractive target because they are abundant, resilient, and remain present in the pancreas even decades after the onset of T1D. Importantly, our studies with mice indicate that reducing α-cell numbers is well tolerated, suggesting that converting a fraction of them into insulin-producing cells could be safe and beneficial.
Over the past decade, we have discovered that pancreatic cells are more flexible than once believed. Under certain conditions, α-cells, and more broadly, all the islet non-β-cells, can naturally begin to produce insulin. Our group previously demonstrated (thanks to precious JDRF support, among others), that human α-cells can “learn” to make insulin by activating key β-cell genes. These reprogrammed α-cells can respond to glucose and restore normal blood sugar levels when transplanted into diabetic mice. However, these cells still produce less insulin than normal β-cells, indicating that important biological barriers prevent full conversion.
The goal of this project is to identify and overcome those barriers. We propose that α-cells actively maintain their identity through molecular “locks” that prevent them from becoming insulin-producing cells. This research focuses on key regulatory mechanisms, including a gene called ARX, which plays a central role in enforcing α-cell identity. By understanding how these molecular locks operate, we aim to learn how to loosen them safely and precisely.
Using advanced “single cell” technologies, we will study how α-cells maintain their identity and how disrupting these mechanisms creates a more flexible, “permissive” state that allows insulin production. Importantly, these studies will be carried out using primary human α-cells and well-controlled animal models, ensuring that the findings are directly relevant to human disease.
The final goal of this project is to translate this knowledge into drug-based strategies that are scalable and widely accessible. We aim at identifying small molecules that temporarily loosen the α-cell molecular “locks”, allowing them to produce insulin in a stable and controlled manner. If successful, this research could establish a new way to restore insulin production using a patient’s own pancreatic cells. Even partial recovery of insulin production could improve blood sugar stability, reduce complications, and improve quality of life for people living with T1D. By transforming surviving pancreatic cells into a renewable source of insulin, this work aims to move T1D treatment beyond management and toward restoring functional insulin production.
Anticipated Outcome
The anticipated long-term outcome of this research is the establishment of a new regenerative strategy for Type 1 diabetes (T1D) that restores insulin production by converting existing pancreatic cells into insulin-producing cells. Rather than relying on transplanted cells or lifelong external insulin therapy, this work aims to harness the regenerative potential of α-cells that naturally remain in the pancreas.
A primary expected outcome is the identification of the molecular mechanisms that actively prevent α-cells from producing insulin. By defining how genes and regulatory proteins enforce α-cell identity, this research will clarify why α-cells resist conversion into β-like cells despite their inherent plasticity. This knowledge will fill a critical gap in our understanding of pancreatic cell identity.
Another anticipated outcome is the demonstration that disrupting these molecular barriers creates permissive or transitional α-cell states that allow activation of insulin-producing gene programs. Even if full conversion into mature β-like-cells is not achieved in every α-cell, the identification of intermediate states will represent a major advance. Such states may be sufficient to support meaningful insulin production or may serve as essential stepping stones toward full functional maturation.
This project is also expected to generate important insights into the durability of reprogramming. By testing whether insulin production persists after removal of drug-based interventions, the research will determine whether α-cell identity can be stably remodeled rather than transiently altered. Durable insulin production is essential for any regenerative therapy to be clinically useful.
From a translational perspective, a key anticipated outcome is the identification of drug-based strategies capable of inducing insulin production in human α-cells. The discovery of small molecules that can safely and reversibly relax lineage restrictions would represent a major step toward a scalable and accessible therapy. Unlike gene therapies or cell transplants, drug-based approaches could be administered non-invasively, adjusted over time, and broadly distributed.
Importantly, this project is designed to deliver valuable outcomes even if pharmacologically-mediated α-to-β-cell reprogramming is not achieved within the project period. Identification of key regulatory barriers, permissive chromatin states, and candidate pharmacological targets will provide a foundation to inform future therapeutic development.
Overall, this work aims to open a new pathway toward durable, regenerative treatment options that reduce dependence on external insulin and improve quality of life in T1D individuals.
Relevance to T1D
By aiming to restore insulin production from endogenous pancreatic cells, this project addresses a critical unmet need in Type 1 Diabetes (T1D). Even modest levels of internally produced insulin can significantly improve glucose stability, reduce the frequency of dangerous hypoglycemic episodes, and lessen the daily burden of disease management. For individuals living with T1D, regaining any degree of insulin production could meaningfully improve health, safety and quality of life.
A key strength of this research is its focus on pancreatic α-cells. Unlike β-cells, which are largely destroyed by autoimmune attack, α-cells persist in the pancreas even decades after T1D diagnosis. They are abundant, resilient, and located within the same tissue environment that normally supports insulin secretion, making them a realistic and widely available target for regenerative approaches in people with established disease.
Crucially, the proposed approach is grounded in strong human proof-of-concept. Our group has demonstrated that human α-cells can be reprogrammed into glucose-responsive, insulin-producing cells. These reprogrammed cells restore normal blood sugar levels when transplanted into diabetic mice and maintain insulin production long term. This work provided the first demonstration that islet cell reprogramming is feasible in human pancreatic cells, overcoming a major translational barrier that has limited many regenerative strategies to animal models.
Despite this progress, reprogrammed human α-cells currently produce less insulin than native β-cells and retain a strong α-cell molecular signature, indicating that biological barriers limit full conversion. This project directly addresses this challenge by identifying and targeting the molecular mechanisms that lock α-cells in their original identity. By defining these mechanisms, we aim to develop drug-based strategies that safely loosen lineage constrains and enable efficient insulin production.
By advancing α-cell reprogramming from proof-of-concept toward a therapeutically viable strategy, this work seeks to open a new path toward improved metabolic stability and reduced disease burden for people living with Type 1 diabetes.