S100A9 exerts insulin-independent antidiabetic and anti-inflammatory effects

Abstract

Type 1 diabetes mellitus (T1DM) is characterized by insulin deficiency leading to hyperglycemia and several metabolic defects. Insulin therapy remains the cornerstone of T1DM management, yet it increases the risk of life-threatening hypoglycemia and the development of major comorbidities. Here, we report an insulin signaling–independent pathway able to improve glycemic control in T1DM rodents. Co-treatment with recombinant S100 calcium-binding protein A9 (S100A9) enabled increased adherence to glycemic targets with half as much insulin and without causing hypoglycemia. Mechanistically, we demonstrate that the hyperglycemia-suppressing action of S100A9 is due to a Toll-like receptor 4–dependent increase in glucose uptake in specific skeletal muscles (i.e., soleus and diaphragm). In addition, we found that T1DM mice have abnormal systemic inflammation, which is resolved by S100A9 therapy alone (or in combination with low insulin), hence uncovering a potent anti-inflammatory action of S100A9 in T1DM. In summary, our findings reveal the S100A9-TLR4 skeletal muscle axis as a promising therapeutic target for improving T1DM treatment.

Advances in the study of S100A9 in cardiovascular diseases

“… 47 , 48 However, in abnormal systemic inflammation, S100A9 can exhibit an anti‐inflammatory action to avoid tissue damage caused by overwhelming inflammation. 49 Other studies suggest that S100A8/A9 heterodimer and S100A8/S100A9‐tetramers also exert anti‐inflammatory effects, in the context of MI, psoriasis and arthritis lesions. 50 , 51 Furthermore, S100A9 has implicated in regulating cell proliferation, migration, and invasion in the context of chronic inflammation associated with cancer.…”