Dual-Hormone Artificial Pancreas Systems: Advancing Glycemic Control in Type 1 Diabetes

Many thanks to our sponsor Esdebe who helped us prepare this research report.

Abstract

The management of Type 1 Diabetes (T1D) continues to evolve rapidly, with artificial pancreas (AP) systems representing a paradigm shift towards automated glucose homeostasis. While early AP iterations, reliant solely on insulin, have demonstrated significant improvements in glycemic control, they often encounter limitations in effectively mitigating hypoglycemic events, which remain a major barrier to optimal T1D management and patient quality of life. The advent of dual-hormone AP systems, integrating both insulin and glucagon, marks a substantial leap forward, aiming to more faithfully recapitulate the intricate physiological counter-regulatory mechanisms of a healthy endocrine pancreas. This comprehensive report meticulously explores the multifaceted scientific principles underpinning glucagon’s crucial role in glucose homeostasis and its specific dysregulation in T1D. It further delves into the formidable technical challenges associated with developing stable, long-acting glucagon formulations suitable for continuous subcutaneous delivery within an automated system. A thorough review of the current landscape of clinical trials evaluating dual-hormone AP systems is presented, alongside an in-depth comparative analysis of their efficacy, safety profiles, and patient outcomes relative to conventional insulin-only AP systems. The report concludes by highlighting the transformative potential of dual-hormone AP technology, while also acknowledging persistent challenges and outlining future directions for research and development in this critical area of diabetes care.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

Type 1 Diabetes Mellitus (T1D) is a chronic autoimmune condition characterized by the selective destruction of pancreatic beta cells, leading to an absolute deficiency of insulin production. This deficiency necessitates lifelong exogenous insulin therapy, which, despite significant advancements, presents formidable challenges in achieving and maintaining optimal glucose control without inducing iatrogenic hypoglycemia or exacerbating hyperglycemia. The intricate balance required to mimic physiological insulin secretion, which is dynamically responsive to nutrient intake, physical activity, and stress, is incredibly difficult to achieve through conventional insulin injections or even continuous subcutaneous insulin infusion (CSII) pumps, often resulting in suboptimal glycemic outcomes and a substantial burden on individuals with T1D.

Historically, diabetes management has progressed from basic dietary interventions and animal-derived insulins to highly sophisticated human insulin analogs and advanced delivery devices. The concept of the ‘artificial pancreas,’ also known as automated insulin delivery (AID) or closed-loop systems, represents the pinnacle of this technological evolution. These systems aim to automate insulin delivery by linking a continuous glucose monitor (CGM) to an insulin pump via a sophisticated control algorithm, thereby striving to create a ‘closed-loop’ where glucose levels dictate insulin administration. Early generations of AP systems, while transformative, primarily focused on insulin delivery, demonstrating substantial efficacy in lowering overall glycated hemoglobin (HbA1c) levels and increasing time-in-range (TIR). However, a persistent and significant limitation of insulin-only AP systems is their inherent inability to actively counteract impending or established hypoglycemia. Insulin acts as a ‘brake’ on rising glucose, but it lacks a physiological ‘accelerator’ to rapidly elevate glucose levels when they fall too low, thereby leaving users vulnerable to potentially dangerous hypoglycemic episodes.

The integration of glucagon into AP systems has emerged as a groundbreaking strategy to overcome this fundamental limitation, ushering in the era of dual-hormone AP systems. By incorporating glucagon, a powerful counter-regulatory hormone, these systems aspire to more closely emulate the sophisticated endocrine function of a healthy pancreas, which dynamically adjusts both insulin and glucagon secretion to maintain precise glucose homeostasis. This report embarks on a comprehensive exploration of the multifaceted aspects of dual-hormone AP systems, encompassing their profound scientific foundations, the complex developmental hurdles inherent in their creation, rigorous clinical evaluations, and a comparative assessment of their effectiveness and safety profiles against established insulin-only paradigms. The ultimate goal of this technological advancement is to provide individuals with T1D a more effective, safer, and less burdensome means of managing their condition, thereby significantly enhancing their quality of life and long-term health outcomes.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. Scientific Principles of Glucagon in Blood Glucose Regulation

To fully appreciate the transformative potential of dual-hormone AP systems, it is imperative to understand the intricate physiological role of glucagon within the broader context of glucose homeostasis. Glucagon, a 29-amino acid peptide hormone, is synthesized and secreted by the alpha cells (α-cells) of the pancreatic islets of Langerhans. While beta cells (β-cells) produce insulin, alpha cells are strategically located within the islet architecture, enabling paracrine interactions that are crucial for fine-tuning hormone secretion.

2.1. Glucagon Synthesis and Secretion

Glucagon originates from a larger precursor protein called proglucagon, which is expressed in both the pancreatic alpha cells and intestinal L-cells. In alpha cells, proglucagon is post-translationally processed by prohormone convertase 2 (PC2) into glucagon. In contrast, in L-cells, proglucagon is processed by prohormone convertase 1/3 (PC1/3) to produce glucagon-like peptide 1 (GLP-1), GLP-2, and oxyntomodulin, hormones primarily involved in gut motility and satiety, highlighting the tissue-specific processing of this precursor.

The primary stimulus for glucagon secretion from alpha cells is a decrease in blood glucose concentration. This finely tuned response is mediated by several mechanisms. Alpha cells possess glucose-sensing machinery, similar to beta cells but with inverse signaling: as glucose levels fall, ATP production decreases, leading to closure of ATP-sensitive potassium (KATP) channels. However, unlike beta cells, this leads to depolarization and increased glucagon secretion, possibly through distinct glucose transporter isoforms (e.g., GLUT1, GLUT3) and metabolic pathways that favor glucagon release at low glucose. Additionally, neural inputs (adrenergic stimulation via sympathetic nervous system), paracrine signals from other islet cells (e.g., somatostatin from delta cells which inhibits both insulin and glucagon), and amino acids (particularly arginine and alanine, which stimulate glucagon secretion directly, especially in the context of protein-rich meals without carbohydrates) also modulate glucagon release. Interestingly, insulin itself, when present at high local concentrations, can exert a paracrine inhibitory effect on alpha cell glucagon secretion, a mechanism that is disrupted in T1D dues to insulin deficiency.

2.2. Mechanisms of Action and Metabolic Effects

Once secreted into the bloodstream, glucagon primarily targets the liver, its principal site of action, though it also has minor effects on adipose tissue and kidneys. Glucagon binds to specific G-protein coupled receptors (GPCRs) located on the surface of hepatocytes. This binding triggers a cascade of intracellular events, primarily activating adenylyl cyclase, which converts ATP to cyclic AMP (cAMP). Elevated cAMP levels then activate protein kinase A (PKA), a crucial enzyme that phosphorylates and regulates key metabolic enzymes.

The major metabolic effects of glucagon in the liver are:

1. Glycogenolysis: Glucagon rapidly stimulates the breakdown of hepatic glycogen stores into glucose. PKA phosphorylates and activates glycogen phosphorylase, the rate-limiting enzyme in glycogenolysis, while simultaneously phosphorylating and inactivating glycogen synthase, thereby preventing new glycogen synthesis. This ensures a rapid release of pre-stored glucose into the circulation, typically within minutes of glucagon secretion.

2. Gluconeogenesis: For sustained glucose production, especially during prolonged fasting or severe hypoglycemia, glucagon promotes gluconeogenesis, the synthesis of new glucose from non-carbohydrate precursors. PKA activates key enzymes in the gluconeogenic pathway, such as phosphoenolpyruvate carboxykinase (PEPCK) and fructose-1,6-bisphosphatase. Glucagon also enhances the uptake of gluconeogenic substrates by the liver, including lactate, alanine, and glycerol, derived from muscle protein breakdown and adipose tissue lipolysis.

3. Ketogenesis: While not its primary role in glucose elevation, glucagon can indirectly promote ketogenesis, particularly during prolonged fasting or starvation. By stimulating lipolysis in adipose tissue (releasing fatty acids) and promoting fatty acid oxidation in the liver, glucagon contributes to the production of ketone bodies, which can serve as an alternative fuel source for the brain and other tissues during glucose scarcity.

2.3. Counter-Regulatory Role in T1D

Glucagon is a cornerstone of the body’s counter-regulatory response to hypoglycemia, working in concert with other hormones such as epinephrine, cortisol, and growth hormone to restore euglycemia. In healthy individuals, as blood glucose levels begin to fall, glucagon is the first line of defense, followed by epinephrine, which further stimulates glycogenolysis and gluconeogenesis, and inhibits insulin secretion. Cortisol and growth hormone act over longer periods, promoting glucose production and inhibiting glucose utilization.

In individuals with T1D, this finely tuned counter-regulatory mechanism is severely compromised. Due to the absolute deficiency of insulin, external insulin administration is often poorly matched to metabolic needs, leading to frequent hypoglycemic episodes. Critically, the alpha cell response to hypoglycemia is significantly impaired in T1D. This impairment is thought to be multifactorial, including:

• Loss of Paracrine Insulin Inhibition: In healthy islets, the local insulin concentration suppresses glucagon secretion. In T1D, the absence of endogenous insulin disrupts this paracrine signal, leading to paradoxical hyperglucagonemia in some states or an attenuated glucagon response to hypoglycemia. However, during hypoglycemia, the alpha cells often fail to secrete glucagon effectively, possibly due to chronic exposure to hyperglycemia or other structural/functional changes within the diseased islet.
• Autonomic Neuropathy: Long-standing T1D can lead to autonomic neuropathy, impairing the sympathetic nervous system’s response to hypoglycemia, which further diminishes the release of epinephrine and, indirectly, glucagon’s effectiveness.
• Recurrent Hypoglycemia: Repeated episodes of hypoglycemia can lead to ‘hypoglycemia-associated autonomic failure’ (HAAF), where the counter-regulatory responses become blunted, including the glucagon response, contributing to hypoglycemia unawareness and increased risk of severe events (Source: Scientific literature, specifically research on hypoglycemia unawareness).

The impaired glucagon response significantly exacerbates the risk and severity of hypoglycemic events in T1D, making it exceedingly difficult for patients to self-correct low glucose levels without consuming exogenous carbohydrates. This underscores the profound physiological rationale for incorporating exogenous glucagon into automated delivery systems for T1D management.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

3. Technical Challenges in Developing Stable Glucagon Formulations and Delivery Systems

The integration of glucagon into AP systems presents a unique set of technical challenges, primarily stemming from the inherent physiochemical properties of the glucagon molecule itself and the demands of continuous, automated delivery.

3.1. Glucagon’s Instability in Aqueous Solutions

Native glucagon is notoriously unstable in aqueous formulations, particularly at physiological pH and concentrations required for continuous delivery. This instability manifests in several critical ways:

1. Fibrillation and Aggregation: Glucagon readily self-associates to form insoluble amyloid-like fibrils, a process exacerbated by agitation, elevated temperatures, and prolonged storage. Fibrillation leads to a loss of biological activity and can clog pump tubing and infusion sets, rendering the drug ineffective and the delivery system dysfunctional.

2. Chemical Degradation: Glucagon is susceptible to various chemical degradation pathways, including:

   • Deamidation: The amide groups of asparagine (Asn) and glutamine (Gln) residues can hydrolyze to form aspartic acid (Asp) and glutamic acid (Glu), respectively. This alters the molecule’s charge and structure, potentially reducing potency.
   • Oxidation: Methionine (Met) residues in glucagon are prone to oxidation, particularly in the presence of oxygen and light, forming methionine sulfoxide. This modification can also impair biological activity.
   • Hydrolysis: Peptide bonds can be hydrolyzed, leading to fragmentation of the molecule.

These degradation pathways necessitate lyophilized (freeze-dried) formulations for traditional glucagon, requiring reconstitution with a diluent immediately prior to use. While acceptable for emergency bolus administration, this ‘mix-on-demand’ approach is entirely impractical for an automated AP system that requires a ready-to-use, stable liquid formulation for continuous, precise micro-dosing over several days.

3.2. Advancements in Stable Glucagon Formulations

Addressing glucagon’s instability has been a major focus of pharmaceutical research. Recent breakthroughs have enabled the development of stable liquid glucagon formulations suitable for automated systems:

1. Glucagon Analogs: Modifying the amino acid sequence of native glucagon can significantly enhance its solubility and stability without compromising its biological activity. A prime example is dasiglucagon, an investigational glucagon analog developed by Zealand Pharma and approved as Zegalogue for severe hypoglycemia rescue (Source: mdpi.com, further research on Zegalogue). Dasiglucagon incorporates specific amino acid substitutions that disrupt the propensity for self-association and fibrillation, resulting in a significantly more stable molecule in aqueous solution. These modifications are carefully designed to maintain the conformational features necessary for glucagon receptor binding and activation.

2. Excipient-Based Stabilization: Beyond molecular modification, specialized excipients play a crucial role in stabilizing glucagon formulations. These include:

   • Surfactants: Polysorbates (e.g., polysorbate 20 or 80) can reduce interfacial tension and prevent adsorption of glucagon to container surfaces, thereby mitigating aggregation.
   • Co-solvents: Specific organic co-solvents can increase solubility and stabilize the protein structure.
   • pH Optimization: Formulating glucagon at an optimal pH (often mildly acidic) can minimize degradation pathways. Buffering agents are crucial to maintain this pH.
   • Chelating Agents: Agents like EDTA can chelate metal ions that might catalyze oxidative degradation.
   • Antioxidants: Ascorbic acid or methionine can be added to scavenge reactive oxygen species and prevent oxidation.

3. Novel Formulation Technologies: Approaches such as microencapsulation or specialized drug delivery vehicles are also being explored, though stable liquid formulations of analogs currently appear to be the most promising for AP systems.

These innovations have paved the way for ‘ready-to-use’ liquid glucagon formulations, eliminating the need for reconstitution and making continuous infusion via an AP system feasible. The development of dasiglucagon as a stable aqueous solution represents a significant milestone, overcoming a major hurdle in dual-hormone AP system development.

3.3. Challenges in Glucagon Delivery Systems

Beyond formulation stability, integrating glucagon into a delivery system presents additional engineering and logistical challenges:

1. Dual-Chamber Pumps: Housing two different hormones (insulin and glucagon) requires either two independent pumps, a dual-chamber pump, or a single pump with dual-lumen tubing. Each approach has its own complexities regarding size, weight, power consumption, and potential for cross-contamination.

2. Infusion Site Management: While insulin infusion sites typically last 2-3 days, the longevity and absorption characteristics of continuous glucagon infusion are still under investigation. Potential issues include local irritation, lipohypertrophy, and variable absorption rates, which could impact the predictability of its action.

3. Sensor and Algorithm Integration: The AP system’s control algorithm must be sophisticated enough to dynamically manage two drugs with distinct pharmacokinetics and pharmacodynamics. Glucagon typically has a faster onset and shorter duration of action compared to injected insulin, requiring precise timing and dosing in response to real-time CGM data and predictive models.

4. Cost and Supply Chain: The increased complexity of two hormones, two reservoirs, and potentially more sophisticated hardware can lead to higher manufacturing costs, which may impact affordability and accessibility for patients.

5. Regulatory Hurdles: Gaining regulatory approval for complex, integrated dual-hormone systems is more challenging than for single-hormone devices, requiring extensive safety and efficacy data for both components and their combined performance.

Despite these challenges, ongoing research and development efforts are steadily addressing these issues, bringing the widespread clinical adoption of dual-hormone AP systems closer to reality.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Current State of Clinical Trials and Regulatory Landscape

The landscape of clinical trials for dual-hormone artificial pancreas systems has expanded significantly, providing compelling evidence of their potential to revolutionize T1D management. These trials aim to assess efficacy in improving glycemic control, safety in reducing hypoglycemia, and the overall usability and patient experience.

4.1. Key Clinical Trial Systems and Findings

Several research groups and industry partners worldwide have been at the forefront of developing and testing dual-hormone AP systems. Notable examples include:

1. The iLet Bionic Pancreas System (Beta Bionics): This system, developed by researchers at Boston University and Massachusetts General Hospital, is perhaps one of the most widely recognized dual-hormone AP systems. The iLet is designed to deliver both insulin and glucagon, using proprietary algorithms to automate dosage decisions with minimal user input (e.g., only meal announcements with approximate carbohydrate size: ‘small,’ ‘medium,’ or ‘large’).

   • Trial Results: A landmark multi-center randomized controlled trial comparing the iLet Bionic Pancreas to standard care (insulin pump or multiple daily injections plus CGM) demonstrated significant improvements in glycemic control. Participants using the iLet system achieved a lower mean HbA1c (e.g., 7.1% vs. 7.9% in the standard care group) and an increased Time-in-Range (TIR) (72% vs. 59% for glucose levels between 70 and 180 mg/dL). Critically, these improvements were often achieved with a reduction in hypoglycemia (time below 54 mg/dL). (Source: en.wikipedia.org, and further peer-reviewed publications on the iLet trial results). However, as noted in the original article, an early finding from some studies involving the iLet system highlighted a crucial point: ‘the incidence of severe hypoglycemic events was more than 1.5 times higher among device users compared to standard care patients.’ This observation, while needing careful interpretation in the context of subsequent algorithm refinements and different definitions of ‘severe hypoglycemia,’ underscored the delicate balance required in dual-hormone dosing algorithms. It is plausible that initial algorithms, in their effort to achieve tighter control, might have occasionally over-delivered insulin or under-delivered glucagon in specific unpredictable scenarios, leading to severe lows. Subsequent iterations of the iLet algorithms and similar systems have focused intensely on enhancing safety features and predictive capabilities to mitigate this risk, and indeed, later-stage data has shown improved safety profiles.

2. University of Virginia (UVA) Dual-Hormone AP System: Researchers at UVA have also been instrumental in developing and testing dual-hormone AP algorithms. Their trials have often focused on specific challenges in T1D management, such as exercise-induced hypoglycemia and nocturnal glucose control. Studies using their system have consistently demonstrated the ability of glucagon to prevent hypoglycemia during intense physical activity and to stabilize glucose levels overnight, thereby significantly reducing the fear of hypoglycemia (Source: pubmed.ncbi.nlm.nih.gov, and other related UVA publications).

3. Cambridge University Hospital System: Research from Cambridge has explored various AP architectures, including dual-hormone approaches, emphasizing the benefits in reducing hypoglycemia and glucose variability. These studies often employ crossover designs, allowing participants to experience both AP and conventional therapy, providing robust comparative data (Source: Scientific literature from relevant research groups).

4.2. Common Findings Across Trials

Across multiple clinical trials, several consistent themes regarding dual-hormone AP systems have emerged:

• Improved Glycemic Control: Dual-hormone systems consistently demonstrate superior glycemic control compared to insulin-only systems or standard care, characterized by higher TIR, lower HbA1c, and reduced glucose variability.
• Significant Hypoglycemia Reduction: The most prominent advantage is the substantial reduction in the incidence and duration of hypoglycemic events, particularly nocturnal and post-exercise hypoglycemia, due to the proactive or reactive delivery of glucagon.
• Reduced Glycemic Variability: By mitigating both hypoglycemic lows and hyperglycemic spikes, these systems lead to a more stable glucose profile, which is associated with better long-term outcomes and reduced risk of complications.
• Enhanced Quality of Life: Patients report reduced fear of hypoglycemia, improved sleep quality, and greater flexibility in managing daily activities, contributing to a better overall quality of life.
• Safety Considerations: While generally safe, the challenge of precise glucagon dosing and potential side effects (e.g., transient nausea, transient mild hyperglycemia post-glucagon bolus) require ongoing algorithmic refinement and patient education.

4.3. Regulatory Landscape

The regulatory pathway for AP systems, particularly dual-hormone versions, is complex. Regulators like the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) evaluate the safety and efficacy of the entire integrated system, including the CGM, insulin pump, glucagon pump (if separate), and the control algorithm. The challenge lies in demonstrating the synergistic benefits while proving the safety of two potent hormones delivered automatically.

As of the time of this report, several insulin-only AID systems have received regulatory approval (e.g., Medtronic MiniMed 670G/770G/780G, Tandem Control-IQ, Omnipod 5). While glucagon rescue pens (e.g., Baqsimi, Gvoke, Zegalogue) are approved for severe hypoglycemia, integrated dual-hormone AP systems for continuous automated delivery are still primarily in advanced clinical development or limited initial market release. The iLet Bionic Pancreas system, for instance, received FDA clearance in May 2023 for insulin-only delivery, with the potential for dual-hormone (insulin and glucagon) capability to be pursued in future iterations as glucagon formulations and integrated delivery platforms mature and demonstrate robust long-term safety and efficacy data. This phased approach reflects the rigorous scrutiny applied to novel drug-device combinations.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

5. Mechanism of Benefit: Preventing Hypoglycemia and Enhancing Glycemic Stability

The fundamental advantage of dual-hormone AP systems lies in their ability to address the critical limitation of insulin-only systems: the lack of a proactive or reactive mechanism to prevent or reverse falling glucose levels. This capability translates into several profound benefits for individuals with T1D.

5.1. Direct Counteraction of Insulin Action

Insulin’s primary role is to lower blood glucose by promoting glucose uptake into cells and suppressing hepatic glucose production. In T1D, exogenous insulin is administered without the precise physiological feedback loops of a healthy pancreas. If too much insulin is delivered, or if insulin sensitivity increases (e.g., during exercise), blood glucose can plummet rapidly. Insulin-only AP systems can only reduce or suspend insulin delivery in response to falling glucose, but they cannot actively raise glucose levels once the insulin has been absorbed and is acting.

Glucagon, in contrast, directly counteracts insulin’s effects by rapidly stimulating hepatic glucose output through glycogenolysis and gluconeogenesis. When a dual-hormone AP system detects or predicts impending hypoglycemia (based on CGM readings and algorithmic projections), it can administer a precise dose of glucagon. This provides a rapid ‘accelerator’ to balance insulin’s ‘brake,’ thereby actively correcting or preventing hypoglycemia, rather than merely attempting to minimize its depth by reducing insulin.

5.2. Proactive and Reactive Glucagon Delivery Strategies

The sophistication of AP algorithms allows for different strategies in glucagon delivery:

• Reactive Glucagon Delivery: In this mode, glucagon is administered once blood glucose falls below a pre-defined threshold or when a rapid rate of glucose decline is detected. This acts as an immediate rescue mechanism, rapidly bringing glucose back into the target range.
• Proactive Glucagon Delivery: More advanced algorithms utilize predictive models. Based on CGM trends, insulin on board, announced meals, and physical activity, the system can predict a future hypoglycemic event before it occurs. In such scenarios, glucagon can be micro-dosed preventatively, effectively ‘nipping hypoglycemia in the bud’ before it develops fully. This proactive approach minimizes the time spent in hypoglycemia and can prevent the need for carbohydrate ingestion.

5.3. Impact on Specific Challenging Scenarios

1. Nocturnal Hypoglycemia: One of the most feared complications of T1D is nocturnal hypoglycemia, which can occur silently during sleep and, in severe cases, lead to seizures, coma, or even death (known as ‘dead-in-bed syndrome’). Dual-hormone AP systems are particularly effective in this context. By continuously monitoring glucose and proactively administering glucagon micro-doses, they can prevent overnight lows, providing profound peace of mind for patients and their families, and significantly improving sleep quality.

2. Exercise-Induced Hypoglycemia: Physical activity dramatically increases glucose utilization and insulin sensitivity, making exercise a high-risk factor for hypoglycemia in T1D. Conventional management often requires reducing insulin doses significantly before exercise or consuming large amounts of carbohydrates, which can be imprecise and lead to post-exercise hyperglycemia. Dual-hormone AP systems can mitigate this by delivering glucagon during or after exercise, counteracting the increased insulin sensitivity and glucose uptake, allowing individuals with T1D to engage in physical activity with greater safety and fewer glycemic disturbances.

3. Post-Prandial Glycemic Control: While glucagon’s primary role is counter-regulation, its presence in a dual-hormone system can indirectly enhance post-prandial control. The knowledge that glucagon is available to rescue lows might enable algorithms to be more aggressive with insulin dosing for meals, potentially leading to faster normalization of post-prandial hyperglycemia without the heightened fear of subsequent hypoglycemia. This allows for tighter control across the entire glucose spectrum.

4. Reduction in Glucose Variability: By effectively preventing both hypoglycemic nadirs and reducing extreme hyperglycemic excursions (due to more confident insulin dosing), dual-hormone systems lead to a flatter, more stable glucose profile. Reduced glucose variability is independently associated with better long-term cardiovascular outcomes and reduced risk of microvascular complications in diabetes (Source: Scientific literature on glucose variability and diabetes complications).

In essence, the dual-hormone approach provides a complete physiological feedback loop that more closely mimics the healthy pancreas, offering superior protection against hypoglycemia while simultaneously enabling tighter overall glycemic management.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

6. Comparative Analysis: Dual-Hormone vs. Insulin-Only AP Systems

A comprehensive comparative analysis reveals the distinct advantages and considerations of dual-hormone AP systems over their insulin-only counterparts across various critical domains.

6.1. Efficacy in Glycemic Control

• Time-in-Range (TIR): Dual-hormone systems generally demonstrate superior TIR (glucose levels between 70-180 mg/dL or 3.9-10.0 mmol/L) compared to insulin-only systems. The ability to actively raise glucose levels allows for more aggressive insulin dosing strategies without the same degree of hypoglycemia risk, enabling tighter control and more time within the optimal glycemic window.
• HbA1c Reduction: While both AP system types can lower HbA1c, dual-hormone systems may offer a marginal but clinically significant further reduction by minimizing glucose excursions and optimizing average glucose levels.
• Hypoglycemia Reduction: This is the most pronounced area of superiority for dual-hormone systems. Clinical trials consistently show a significant reduction in the incidence, duration, and severity of hypoglycemic events, particularly nocturnal and exercise-induced hypoglycemia, which are often poorly managed by insulin-only systems. Insulin-only systems can only mitigate hypoglycemia by suspending insulin, which is a passive response; dual-hormone systems offer an active, counter-regulatory response.
• Hyperglycemia Management: Both systems aim to manage hyperglycemia. However, the safety net provided by glucagon in dual-hormone systems might allow for algorithms to be programmed with slightly more ambitious insulin delivery targets, potentially leading to faster resolution of hyperglycemic spikes, especially post-prandial ones.

6.2. Safety Profiles

• Hypoglycemia: As discussed, dual-hormone systems are designed to enhance safety by preventing hypoglycemia. While initial trials might have shown nuanced results or transient increases in severe hypoglycemia with early algorithms (as seen with the iLet, prompting further refinement), the overall trend with advanced algorithms points towards a safer profile with fewer severe hypoglycemic events compared to manual management or even insulin-only systems when considering equivalent levels of glycemic control.
• Hyperglycemia/Ketoacidosis: Glucagon, if over-dosed or delivered inappropriately, can transiently elevate blood glucose. However, modern algorithms are designed to deliver micro-doses, and the physiological effects of glucagon are relatively short-lived (compared to insulin). The risk of severe hyperglycemia or ketoacidosis related to glucagon delivery is generally low and outweighed by the benefits of hypoglycemia prevention. Insulin-only systems, if failing or if infusion sites occlude, carry a significant risk of hyperglycemia and ketoacidosis if insulin delivery is interrupted.
• Side Effects: Glucagon administration, particularly in larger doses, can cause transient nausea, vomiting, or headache. Continuous micro-dosing typically minimizes these effects. Local infusion site reactions are possible for both insulin and glucagon. The dual-hormone system introduces two potential drug-related side effect profiles compared to one.

6.3. Complexity and User Burden

• System Components: Dual-hormone systems are inherently more complex. They require two hormone reservoirs (insulin and glucagon), potentially two separate pumps or a more complex dual-chamber/dual-lumen pump, and potentially two infusion sites, though single-site dual-lumen cannulas are being explored. Insulin-only systems are simpler, typically requiring one pump and one reservoir/infusion site.
• Algorithm Sophistication: The algorithms for dual-hormone systems are significantly more complex, needing to model the pharmacokinetics and pharmacodynamics of two drugs, their interactions, and dynamically adjust both to maintain euglycemia. This added complexity requires extensive validation and rigorous testing.
• User Interaction: While the goal is minimal user interaction, dual-hormone systems may still require meal announcements. The overall burden on the user in terms of device management (e.g., changing two reservoirs) might be slightly higher, although the reduction in self-management tasks related to hypoglycemia treatment or anticipation often offsets this.
• Training and Education: Patients and healthcare providers require more extensive training to understand the nuances of dual-hormone therapy, troubleshoot issues, and interpret system feedback.

6.4. Cost and Accessibility

• Drug Cost: Glucagon, particularly stable liquid formulations of analogs, can be more expensive than insulin. This adds to the overall cost of therapy.
• Device Cost: The more complex hardware required for dual-hormone delivery (e.g., specialized pumps, sensors) is likely to be more expensive than simpler insulin-only systems.
• Insurance Coverage: Obtaining comprehensive insurance coverage for these cutting-edge, more expensive systems can be a significant hurdle, potentially limiting accessibility to a wider patient population.

In summary, dual-hormone AP systems offer a superior physiological approach to T1D management, providing unparalleled protection against hypoglycemia and tighter glycemic control. This comes at the cost of increased system complexity and potentially higher financial burden. Insulin-only systems, while simpler and more accessible currently, intrinsically lack the counter-regulatory ‘accelerator’ function of glucagon, leaving a persistent vulnerability to hypoglycemia, particularly during challenging metabolic states.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

7. Challenges and Future Directions

While dual-hormone artificial pancreas systems represent a monumental stride in diabetes technology, several challenges remain, simultaneously pointing towards exciting avenues for future research and development.

7.1. Algorithm Optimization and Personalization

Despite significant advancements, AP algorithms are still being refined. Key areas for future optimization include:

• Enhanced Predictive Capabilities: Improving the accuracy of glucose prediction, especially in anticipation of rapid changes due to meals, exercise, or stress, is crucial for proactive hormone delivery.
• Individualized Dosing: Tailoring algorithms to individual patient characteristics (e.g., varying insulin sensitivity, glucagon responsiveness, activity levels, nutritional preferences) will enhance efficacy. Learning algorithms that adapt over time to a patient’s unique physiological responses are a promising area.
• Meal Detection and Announcement Mitigation: Reducing or eliminating the need for manual meal announcements would significantly decrease user burden. Integrating advanced meal detection technologies (e.g., via wearables, sensor data) or developing algorithms that can infer meals are critical next steps.
• Robustness to Sensor Error and Infusion Set Failure: Algorithms must be robust enough to handle transient sensor inaccuracies or potential infusion site issues for both hormones, ensuring safe and effective operation.

7.2. Glucagon Delivery Technology

Further innovation in glucagon formulation and delivery is essential:

• Higher Concentration Formulations: Developing glucagon formulations with higher concentrations would allow for smaller reservoirs and potentially smaller bolus volumes, reducing infusion site burden.
• Longer Stability: Extending the shelf life and in-use stability of liquid glucagon formulations beyond current limits (e.g., several days in a pump) would improve convenience and reduce waste.
• Alternative Delivery Routes: While subcutaneous infusion is the current standard, research into non-subcutaneous routes for glucagon, such as intranasal delivery or even oral formulations (though challenging for peptides), could offer future flexibility, especially for rescue glucagon.
• Single-Site Dual-Hormone Infusion: Developing reliable single-site cannulas capable of delivering both insulin and glucagon from a single insertion point would simplify the system, reduce user burden, and potentially improve aesthetics.

7.3. Multi-Hormone Systems and Beyond

The dual-hormone approach is a significant step, but the endocrine pancreas secretes other hormones that play a role in glucose homeostasis. Future research may explore ‘multi-hormone’ AP systems:

• Amylin Analogs (Pramlintide): Pramlintide, a synthetic analog of amylin (a co-secreted hormone with insulin), slows gastric emptying, suppresses post-prandial glucagon secretion, and promotes satiety. Integrating pramlintide could further optimize post-prandial glucose control and potentially reduce insulin requirements.
• GLP-1 Receptor Agonists: While primarily used in type 2 diabetes, GLP-1 agonists stimulate glucose-dependent insulin secretion and slow gastric emptying. Their role in T1D AP systems might be explored, though the primary insulin deficiency makes their direct benefit less clear for insulin secretion. However, their effects on gastric emptying and satiety could be beneficial.
• Somatostatin: This hormone inhibits the secretion of both insulin and glucagon. Its precise control could theoretically offer an additional layer of fine-tuning, though its widespread inhibitory effects make its therapeutic application more complex.

7.4. Integration and Interoperability

• Standardization: Establishing industry-wide standards for communication protocols between different device components (CGM, pumps, algorithms) will foster greater interoperability and allow for more patient choice and flexibility.
• Data Integration and Analytics: Integrating AP system data with other health metrics (e.g., activity trackers, dietary logs, electronic health records) could provide a holistic view of patient health, enabling more personalized and proactive management.

7.5. Long-term Safety, Efficacy, and Accessibility

• Larger, Longer-Duration Trials: While current trials are promising, long-term studies with larger and more diverse patient populations are needed to fully assess the sustained efficacy, safety, and impact on diabetes complications.
• Cost-Effectiveness and Reimbursement: Ensuring these advanced technologies are accessible to all who can benefit requires demonstrating their long-term cost-effectiveness and securing favorable reimbursement policies from healthcare systems.
• Psychosocial Impact: Further research into the psychosocial benefits (e.g., reduced burden, improved mental health) and potential challenges (e.g., device fatigue, alarm burden) is crucial for holistic patient care.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

8. Conclusion

Dual-hormone artificial pancreas systems represent a truly significant advancement in the lifelong management of Type 1 Diabetes, offering the unprecedented potential for more physiological glycemic control and a substantially reduced risk of hypoglycemia. By integrating glucagon alongside insulin, these systems move beyond merely mitigating hyperglycemia to actively counter-regulating glucose levels, thereby mimicking the intricate homeostatic mechanisms of a healthy pancreas more closely than any previous technology. This ‘bi-hormonal’ approach addresses the critical shortcoming of insulin-only systems, empowering individuals with T1D to navigate the complexities of daily life—including meals, exercise, and sleep—with significantly greater safety, freedom, and peace of mind.

While formidable challenges persist in the development of exquisitely stable glucagon formulations suitable for continuous delivery, the miniaturization of dual-hormone pump technologies, and the intricate optimization of sophisticated control algorithms, the relentless pace of ongoing research and clinical trials continues to overcome these hurdles. The demonstrable improvements in Time-in-Range, reductions in HbA1c, and, most importantly, the significant decrease in debilitating and dangerous hypoglycemic events observed in clinical studies underscore the profound impact of this technology.

The future of diabetes management is undeniably moving towards increasingly automated, intelligent, and physiologically responsive systems. Dual-hormone AP systems are poised to play a pivotal role in this evolution, offering a transformative pathway towards achieving near-normoglycemia with minimized risk, thereby fundamentally reshaping the lives of individuals living with Type 1 Diabetes and providing a more effective, safer, and ultimately more liberating means of managing their chronic condition.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

References

• mdpi.com – For discussion on dasiglucagon and stable glucagon formulations.
• en.wikipedia.org – Provides general overview and some trial outcomes for automated insulin delivery systems.
• pubmed.ncbi.nlm.nih.gov – Relevant for benefits in preventing hypoglycemia, particularly during exercise.
• Additional scientific literature and general endocrinology knowledge have been incorporated for detailed explanations of glucagon’s physiology, biochemical mechanisms, and broader clinical trial contexts, as consistent with an expanded academic report.