Researchers exploring type 1 diabetes have uncovered distinct genetic subtypes and potential new avenues for treatment. Recent genetic association findings point toward biological differences between specific HLA risk patterns, while separate observational data suggest that GLP-1 receptor agonists could offer cardiovascular and kidney benefits for patients living with the condition.
Identifying distinctive types of conditions like diabetes is helpful in two ways. It means treatments can be personalized more precisely to individuals, and gives researchers a better idea of how to make those treatments more effective going forward.
Living with type 1 diabetes remains a lifelong balancing act of blood sugar management, yet the underlying biological pathways driving the condition have long presented complex clinical puzzles. New research highlights both genetic distinctions within the disease and potential adjunctive therapies that could shift long-term care management.
Genetic Association Study Points to Distinct Subtypes
When examining genetic susceptibility to type 1 diabetes, two genetic patterns called HLA-DR3 and HLA-DR4 are associated with a higher risk of the disease. However, while the end result is the same (type 1 diabetes), the early signs differ between the two patterns.
To investigate further, researchers from the US and UK ran the first-ever genome-wide association study (GWAS) separating type 1 diabetes patients by these two genetic signatures (technically known as haplotypes).
The purpose of a GWAS is to find areas of DNA potentially linked to a disease, and there were enough genetic differences between HLA-DR3 and HLA-DR4 participants in a sample of 9,091 people with type 1 diabetes and 14,157 controls to suggest we may be looking at two distinct subtypes.
The results have been published in Diabetologia.
“Type 1 diabetes is a complex disease characterized by autoimmune destruction of beta cells, but the underlying etiology is not well understood,” write the researchers in their published paper. “The timing of progression to clinical diabetes varies widely across individuals, ranging from very early in childhood to adult onset.”
While the HLA-DR3 and HLA-DR4 genetic profiles and early signs had hinted at two types of type 1 diabetes, the new findings point to different biological machinery and mechanisms being involved as well.
The HLA-DR3 results pointed towards immune cells called mast cells, linked to allergies and inflammation, which keep watch for potential infection and foreign invasion.
With the HLA-DR4 genetic pattern, the body’s T cells were more strongly implicated. These immune cells directly attack other cells when ordered to, and in the case of type 1 diabetes, are known to destroy the beta cells in the pancreas.
“This reveals that type 1 diabetes in a DR3 and DR4 background may represent heterogeneous sub-forms of type 1 diabetes at the genetic level,” write the researchers.
To add some perspective, the researchers say the genes driving type 1 diabetes in HLA-DR3 cases compared to HLA-DR4 cases are as distinct and separate as they are when comparing schizophrenia and bipolar disorder.
Evaluating Cardiovascular and Kidney Outcomes with GLP-1 Receptor Agonists
A major real-world analysis suggests GLP-1 receptor agonists could offer heart, kidney, and weight benefits in type 1 diabetes without raising hospitalization risk for diabetic ketoacidosis or severe hypoglycemia.
In a recent study published in the journal Nature Medicine, researchers used target trial emulation
to analyze a decade of clinical data on the long-term outcomes associated with glucagon-like peptide-1 receptor agonists (GLP-1RAs) in type 1 diabetes (T1D).
The study dataset comprised more than 174,000 patients and found that patients using GLP-1RAs demonstrated a 15% reduced risk of major cardiovascular events and a 19% lower risk of end-stage kidney disease. Furthermore, the study found no increased risk of hospitalization for side effects like diabetic ketoacidosis or severe hypoglycemia, suggesting that GLP-1RAs may represent a promising adjunctive therapy warranting further study in T1D management.
Decades of research and patient reports have established that living with type 1 diabetes is a lifelong balancing act. Even in laboratory-controlled settings with perfect insulin management, the cumulative toll on the body has been found to be significant. Previous analyses have shown that by middle age, ~31% of individuals with T1D develop major adverse cardiovascular events (MACEs), and 7% report clinically confirmed end-stage kidney disease (ESKD). Furthermore, while the primary focus of conventional T1D interventions has been on glycemic (blood sugar) control, only about 20-30% of patients in the United States (U.S.) meet these targets.
While glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) have become important treatments for type 2 diabetes (T2D) and obesity, their long-term impact on type 1 diabetes has remained understudied due to T1D patients being excluded from landmark clinical trials for GLP-1RA drugs.
Implications for Future Research and Patient Care
Both sets of findings emphasize the need for a more personalized approach to managing type 1 diabetes. Understanding genetic heterogeneity across genetic signatures and evaluating real-world therapeutic interventions provides researchers with a better idea of how to make treatments more effective going forward.
Findings are promising, but randomized trials are still needed because the study is observational.
