Exploring the groundbreaking science behind targeting glucagon as a new approach to type 2 diabetes therapy
For decades, the conversation around diabetes has centered almost exclusively on insulin—the blood sugar-lowering hormone produced by pancreatic beta cells. The standard treatment approach has focused on either replacing insulin or helping the body use it more effectively. But what if we've been missing half the picture? Emerging research reveals that diabetes is actually a bihormonal disorder involving both insulin deficiency and glucagon excess 1 . This paradigm shift opens up exciting new possibilities for treatment, including drugs that target glucagon—the hormone that raises blood sugar—rather than focusing solely on insulin.
Every form of diabetes is now known to be associated with hyperglucagonemia (excess glucagon), and suppressing this excess effectively eliminates hyperglycemia 1 .
The discovery of glucagon's crucial role in diabetes represents a fundamental change in our understanding of this widespread condition. This article explores the groundbreaking science behind glucagon antagonism, a revolutionary approach that could transform how we treat type 2 diabetes and offer new hope to millions worldwide.
Diabetes is not just an insulin deficiency disease but a bihormonal disorder involving both insufficient insulin and excessive glucagon action.
The story of glucagon begins surprisingly alongside insulin itself. Back in 1922, when Frederick Banting, Charles Best, and James Collip were first experimenting with pancreatic extracts to treat diabetes, they noticed something peculiar: some of their crude insulin preparations would briefly raise blood sugar in dogs before lowering it 1 . This puzzling observation was the first glimpse of what would later be identified as glucagon—a 29-amino acid peptide hormone that opposes insulin's action 1 .
First observation of glucagon's effects alongside insulin discovery
Development of radioimmunoassay enables proper glucagon measurement
Roger Unger proposes the bihormonal theory of diabetes
The modern understanding of diabetes as a bihormonal disorder gained traction through the work of researchers like Roger Unger, who demonstrated that both insufficient insulin and excessive glucagon action contribute to diabetic hyperglycemia 1 . This theory elegantly explains why patients with diabetes experience dangerous blood sugar spikes even when they haven't eaten—their livers continue to overproduce glucose due to unopposed glucagon action.
Glucagon exerts its blood sugar-raising effects primarily through its receptor in the liver—a G-protein-coupled receptor (GPCR) that triggers a cascade of events leading to increased glucose production 1 . When glucagon binds to its receptor, it activates adenylyl cyclase, leading to increased production of cyclic AMP (cAMP), which in turn activates protein kinase A and downstream transcription factors that boost the expression of key enzymes in glucose production 1 .
Glucagon receptor antagonists (GRAs) work by blocking this process through various mechanisms:
One of the most promising glucagon antagonists to emerge is Eli Lilly's LY2409021. In what remains the largest and longest trial for safety and efficacy of a GRA ever performed, this small-molecule antagonist demonstrated significant glucose-lowering effects without some of the cholesterol-related side effects that hampered earlier candidates 1 .
In 2012, researchers at Merck reported on a novel small-molecule glucagon receptor antagonist called GRA1 in the journal PLOS ONE . This comprehensive preclinical study aimed to characterize the anti-diabetic efficacy and safety profile of this promising compound.
The research team employed multiple innovative approaches:
Using CHO cells expressing human glucagon receptors
Human liver cells for glycogenolysis assays
NMR imaging to monitor glycogen
Diabetic mouse models and rhesus monkeys
The findings from the GRA1 study demonstrated robust glucose-lowering effects across multiple models. In human hepatocytes, GRA1 dose-dependently inhibited glucagon-stimulated glycogenolysis, with significant effects observed at micromolar concentrations . In the perfused liver model, GRA1 completely blocked glucagon's ability to stimulate glycogen breakdown .
Perhaps most impressively, in various diabetic mouse models, both acute and chronic administration of GRA1 significantly reduced blood glucose concentrations . The researchers also observed moderate increases in plasma glucagon and glucagon-like peptide-1 (GLP-1)—an effect that might provide additional benefits for blood sugar control.
| Model System | Intervention | Key Finding | Significance |
|---|---|---|---|
| Primary human hepatocytes | GRA1 (0.3-10 µM) | Dose-dependent inhibition of glucagon-stimulated glycogenolysis | Direct evidence of target engagement in human cells |
| Perfused hGCGR mouse liver | GRA1 (0.1-3.0 µM) | Complete blockade of glucagon-induced glycogenolysis | Demonstrated efficacy in intact organ system |
| hGCGR diabetic mice | Chronic oral GRA1 | Significant reduction in blood glucose | Proof-of-concept for in vivo efficacy |
| Rhesus monkeys | Oral GRA1 | Blocked hyperglycemic response to exogenous glucagon | Translation to non-human primates |
An unexpected but important finding emerged from hepatic gene-expression profiling in monkeys treated with GRA1. The researchers observed down-regulation of genes involved in amino acid catabolism, accompanied by increased amino acid levels in the circulation . This finding revealed an previously underappreciated connection between glucagon signaling and amino acid metabolism, suggesting potential side effects that would need monitoring in clinical trials.
| Amino Acid | Change with GRA1 Treatment | Potential Implications |
|---|---|---|
| Alanine | Increased | Major gluconeogenic substrate |
| Glutamine | Increased | Important nitrogen transport |
| Branched-chain amino acids | Increased | Linked to insulin resistance |
| Glucogenic amino acids | Generally increased | Result of reduced hepatic catabolism |
The development of glucagon receptor antagonists has relied on specialized research tools and reagents that enable precise investigation of glucagon signaling and its inhibition. Here are some key components of the glucagon research toolkit:
| Tool/Reagent | Function/Application | Examples from Research |
|---|---|---|
| Cell lines expressing hGCGR | Screening potential antagonists | CHO cells stably transfected with human glucagon receptor |
| Radiolabeled glucagon | Measuring receptor binding affinity | ¹²⁵I-glucagon competitive binding assays |
| cAMP detection assays | Assessing functional antagonism | Measuring inhibition of glucagon-induced cAMP production |
| Transgenic animal models | In vivo efficacy studies | hGCGR mice expressing human instead of murine receptor |
| Primary human hepatocytes | Studying human-specific effects | Glycogenolysis assays in human liver cells |
| GCGR knockout mice | Understanding glucagon biology | Global deletion models showing glucose-lowering effects 5 |
Despite the promising efficacy of glucagon receptor antagonists, several safety concerns have emerged that require careful attention. The most common side effect observed across multiple GRA candidates has been elevated liver enzymes (particularly ALT and AST), as seen in trials with LY2409021 where some patients showed levels more than three times the upper limit of normal 1 . However, these increases typically weren't accompanied by rises in bilirubin or alkaline phosphatase, suggesting they might not indicate serious liver injury 1 .
Rather than abandoning glucagon modulation entirely due to safety concerns, researchers are exploring more sophisticated approaches. One promising strategy involves dual and triple receptor agonists that combine glucagon receptor activation with targeting of related receptors like GLP-1 and GIP 3 5 .
These multi-target drugs represent a paradigm shift in metabolic disease treatment. For instance, dual GLP-1/glucagon receptor agonists aim to harness glucagon's beneficial effects on energy expenditure and weight loss while counteracting its hyperglycemic effects through simultaneous GLP-1 receptor activation 5 . Similarly, triple agonists targeting GLP-1, GIP, and glucagon receptors have shown unprecedented weight loss effects in early-stage trials 3 .
The journey to develop effective glucagon receptor antagonists exemplifies both the challenges and promises of modern drug development. While previous attempts to bring GRAs to market have stumbled over safety concerns, each failure has provided valuable insights that inform the next generation of therapies.
The emerging understanding of diabetes as a bihormonal disorder has fundamentally expanded our approach to treatment, moving beyond solely insulin-centric strategies. As researchers continue to unravel the complexities of glucagon biology and develop more sophisticated multi-target therapies, we move closer to a future where diabetes can be managed more effectively and with fewer side effects.
The story of glucagon antagonism reminds us that sometimes the most promising therapeutic targets have been hiding in plain sight, waiting for science to advance enough to reveal their potential. As we approach the centenary of glucagon's discovery, we may finally be on the verge of fully harnessing its therapeutic potential for the benefit of millions living with diabetes worldwide.