Risk of Type 1 Diabetes with ENPP1 Inhibitors like RBS 2418
There is currently no established evidence that ENPP1 inhibitors like RBS 2418 increase the risk of developing type 1 diabetes, as these agents are not mentioned in current diabetes guidelines regarding risk factors for type 1 diabetes development.
Background on ENPP1 and Diabetes
ENPP1 (Ectonucleotide Pyrophosphatase/Phosphodiesterase 1) is a protein that has been studied primarily in relation to insulin resistance and type 2 diabetes, not type 1 diabetes. The relationship between ENPP1 and diabetes involves:
- ENPP1 functions as an inhibitor of insulin receptor signaling 1
- The K121Q polymorphism in the ENPP1 gene has been associated with insulin resistance in some populations 2, 3
- However, studies have shown conflicting results regarding ENPP1 variants and type 2 diabetes risk 4
Current Evidence on Type 1 Diabetes Risk
According to the most recent American Diabetes Association (ADA) Standards of Care (2024), the known risk factors for type 1 diabetes include:
- Genetic predisposition (particularly HLA haplotypes)
- Environmental triggers (including certain viral infections)
- Family history (though 90% of individuals who develop type 1 diabetes don't have a known relative with the disease) 5
The 2024 ADA guidelines specifically state that "there are currently no approved therapies for preservation of C-peptide or delaying the progression of clinical type 1 diabetes" 5. This indicates that ENPP1 inhibitors are not currently recognized as either increasing or decreasing type 1 diabetes risk.
Mechanisms of Type 1 Diabetes Development
Type 1 diabetes is primarily an autoimmune condition characterized by:
- Autoimmune destruction of pancreatic β-cells
- Multiple genetic predispositions
- Environmental factors that remain poorly defined 5
The pathophysiology of type 1 diabetes differs significantly from type 2 diabetes, which is characterized by insulin resistance - the pathway where ENPP1 is known to play a role.
Clinical Implications
For healthcare providers considering the use of ENPP1 inhibitors:
- Monitor patients for typical signs of new-onset diabetes (polyuria, polydipsia, unexplained weight loss)
- Consider baseline and follow-up testing of pancreatic autoantibodies in high-risk individuals
- Be aware that while ENPP1 inhibition theoretically could improve insulin sensitivity, there's no evidence suggesting it would trigger autoimmune destruction of β-cells
Conclusion
While ENPP1 inhibitors like RBS 2418 may have effects on insulin signaling pathways, current diabetes guidelines and research do not identify them as agents that increase the risk of developing type 1 diabetes. The primary concern with ENPP1 has been its relationship to insulin resistance in type 2 diabetes, not autoimmune-mediated type 1 diabetes.
As with any newer class of medications, continued pharmacovigilance and post-marketing surveillance will be important to identify any unexpected associations with autoimmune conditions including type 1 diabetes.