The Role of Inflammation in Type 1 Diabetes
The Centers for Disease Control estimates that 1.7 million adults and 300,000 children have type 1 diabetes, a chronic pancreatic condition where the immune system destroys insulin-producing cells. How and why this occurs is unknown. The Subramanian Lab, with NIH funding, is investigating what they believe to be the critical role of the immune protein NLRP3 in this process. Understanding this could unlock new avenues for treatment and prevention.
Members of Dr. Naeha Subramanian’s lab hold a slide with a section of mouse pancreas. It is being imaged for T1D research. Photo credit: Scott Eklund / Red Box Pictures.
ISB’s Naeha Subramanian, PhD, studies the very earliest sentinels of our immune defenses — the cells and molecules that make up the innate immune system. While innate immunity provides an important first line of defense against dangerous pathogens, disruptions in this system can contribute to chronic diseases, including autoimmune diseases and cancer. In type 1 diabetes, an autoimmune disease, the immune system mistakenly attacks and destroys cells in the pancreas that produce the hormone insulin, impairing the body’s ability to regulate blood sugar levels. Subramanian and her laboratory team are studying how subtle changes in an innate immune protein called NLRP3 may worsen type 1 diabetes by promoting chronic inflammation.
- Funded by National Institute of Allergy and Infectious Diseases
- Led by Naeha Subramanian, PhD
- Key collaborators:
- Ram Savan, PhD, University of Washington
- Karen Cerosaletti, PhD, Benaroya Research Institute
How an immune protein affects type 1 diabetes progression
In previous work, Subramanian and colleagues discovered that even small shifts in the levels of certain innate immune proteins can push the body toward complex diseases like cancer. The researchers found that certain genetic mutations associated with type 1 diabetes appear to slightly increase NLRP3 levels, so they decided to investigate whether small changes in NLRP3 could influence the onset or progression of type 1 diabetes in mice genetically predisposed to develop the disease.
Normally, NLRP3 remains inactive unless it detects a potential threat. When triggered by a bacterium or virus, for instance, it activates and assembles with other immune proteins to form a wheel-shaped protein complex called an inflammasome. This structure then activates inflammatory molecules that help clear infections. However, if this inflammatory response remains active for too long or occurs spontaneously without an actual infection, it can lead to harmful conditions including autoimmune disease.
Subramanian and her collaborators found that in female mice predisposed to develop type 1 diabetes, those lacking NLRP3 entirely or having only half the normal levels of the protein still developed diabetes at the expected time, but the disease progressed more slowly. These mice maintained lower blood sugar levels and healthier body weight compared to those with normal NLRP3 levels. Interestingly, reducing NLRP3 levels in male mice had no effect on disease progression, leading the researchers to suspect that NLRP3 interacts with sex-specific factors to exert its effects in type 1 diabetes.
Subramanian and her team are now working to understand the biology that drives NLRP3’s effects in type 1 diabetes and why its action appears to be specific to female animals. They also aim to determine in which immune cells NLRP3 acts during disease progression, and whether its impact on type 1 diabetes stems from its role in the inflammasome or a previously unrecognized function.
Because NLRP3 has been linked to multiple diseases, including Alzheimer’s disease and cancer, pharmaceutical companies have developed NLRP3 inhibitors, several of which are currently being tested in clinical trials. Subramanian also plans to test some of these drugs in type 1 diabetes mouse models to assess whether they can slow disease progression. A deeper understanding of how this immune protein influences type 1 diabetes could ultimately lead to new treatments, potentially slowing or even halting disease progression.
Contact Dr. Naeha Subramanian
Associate Professor
ISB