Protein Discovery Offers Potential Path to Reversing Type 2 Diabetes

A newly discovered role for the protein SerpinB2 in maintaining immune cell health within fat tissue could pave the way for novel treatments for type 2 diabetes and obesity. Researchers at the University of Pittsburgh School of Medicine have found that SerpinB2 is crucial for the survival of tissue-resident macrophages, which play a key role in controlling inflammation and insulin sensitivity.

The Role of Macrophages and SerpinB2

Macrophages are immune cells that reside in adipose (fat) tissue. Unlike macrophages derived from circulating monocytes, these tissue-resident macrophages are enriched with mitochondrial antioxidant enzymes, helping to restrain inflammation and promote metabolic homeostasis. SerpinB2, a protein involved in the blood coagulation cascade, is highly expressed in these resident macrophages and is vital for their survival.

The research, published in Nature Communications, demonstrates that SerpinB2 regulates mitochondrial oxidative phosphorylation and prevents the release of cytochrome c – a trigger for cell death – from the mitochondria. This protective effect is achieved through the promotion of glutathione production, a key antioxidant.

Inflammation and SerpinB2 Decline in Obesity and Diabetes

Chronic inflammation, such as that seen in obesity, diminishes SerpinB2 expression in macrophages within visceral adipose tissue (VAT) in both patients and mice. This decline leads to the death of these beneficial macrophages, disrupting the balance in fat tissue and contributing to insulin resistance. Studies show that as weight increases, inflammation rises and SerpinB2 levels fall, leading to macrophage die-off.

Specifically, elevated levels of interferon-γ, a cytokine often increased in diabetes, induce Ikaros, a transcriptional suppressor. Ikaros then binds to the SerpinB2 promoter, reducing its expression. This creates a vicious cycle where inflammation further reduces SerpinB2 levels, leading to more inflammation.

Restoring Macrophage Survival and Improving Metabolic Health

Researchers found that selectively depleting the IFN-γ receptor in myeloid cells, or supplementing SerpinB2-deficient mice with N-acetylcysteine (NAC) – a glutathione precursor – restored VAT resident macrophage survival. This, in turn, decreased adipocyte (fat cell) size and improved glucose tolerance and insulin sensitivity. The University of Pittsburgh team demonstrated that bolstering antioxidant defenses could protect macrophages.

Implications for Future Treatments

These findings suggest that enhancing the antioxidant function of tissue-resident macrophages could be a promising therapeutic strategy for preventing and treating chronic inflammation and type 2 diabetes. Researchers believe this approach could potentially replace or complement existing treatments like GLP-1 weight maintenance drugs, which can lose effectiveness over time. Further research is needed to fully understand the regulation of SerpinB2 and its potential as a drug target.

Key Takeaways

• SerpinB2 is essential for the survival of tissue-resident macrophages in adipose tissue.
• Chronic inflammation, particularly in obesity, reduces SerpinB2 expression, leading to macrophage death.
• Restoring SerpinB2 levels or bolstering antioxidant defenses can improve macrophage survival, reduce inflammation and enhance insulin sensitivity.
• Targeting SerpinB2 could offer a new approach to treating and preventing type 2 diabetes.