Type 1 Diabetes (T1D) results from the loss of insulin-producing pancreatic β-cells, leading to insulin deficiency (ID). ID is characterized by profound metabolic derangements such as hyperglycemia, hypertriglyceridemia, and hyperketonemia, the latter of which can result in the life-threatening condition of diabetic ketoacidosis. Daily insulin administration is the cornerstone therapy for ID. However, insulin treatment is often sub-optimal due to its narrow therapeutic range. Insufficient insulin can lead to hyperglycemia, increasing the risk of long-term complications, while over-administration raises the danger of life-threatening hypoglycemia. Additionally, insulin's lipogenic effects can cause dyslipidemia. Critically, inadequate insulin levels also put T1D patients at risk of diabetic ketoacidosis. Hence, there is a need for new therapeutic strategies in the clinical management of T1D.
We have previously identified numerous anti-diabetic actions of the Ca2+-binding protein S100A9. Enhancing S100A9 is sufficient to improve hyperglycemia and double the lifespan of ID rodents. It also exerts potent lipid-improving effects, notably the normalization of diabetic ketogenesis via acting on Toll-Like Receptor 4 (TLR4) signaling.
These findings prompt further studies aimed at evaluating the therapeutic potential of S100A9-based treatment. The goal of my PhD thesis is to further explore S100A9’s cellular and molecular underpinnings to unveil novel insulin-independent mechanisms of metabolic regulation.
We recapitulated ID in a murine model by administering Diphtheria Toxin (DT) injections in a mouse model with selective expression of the DT receptor in pancreatic β-cells (RIP-DTR mice). Treatment with recombinant S100A9 improved adherence to glycaemic targets with only half as much insulin and without any life-threatening episodes of hypoglycemia. The glucose-lowering action of S100A9 is due to an enhancement of glucose uptake in the skeletal muscle via TLR4, without any changes in endogenous glucose production or insulin sensitivity. Moreover, we uncovered a potent anti-inflammatory action of S100A9 treatment in ID, partly but not entirely mediated via TLR4.
In addition, my thesis project aims to elucidate the effect of S100A9 on the cross-talk between hepatic parenchymal and non-parenchymal cells. Using a Cre-conditional reactivatable TLR4 Knock Out mouse model, we demonstrated the re-expression of TLR4 in the liver-resident Kupffer cells (KCs), is sufficient for S100A9 to rescue hypertriglyceridemia and hyperketonemia. Additionally, proteomic analysis revealed considerable S100A9-induced re-shaping of the KC proteome, affecting processes such as lipid and amino acid metabolism and revealing potential candidates mediating the intra-hepatic communication improving ID-derived dyslipidemia.
Overall, we underscore the significant potential of S100A9 as an adjuvant in insulin therapy, presenting a proof of concept for developing S100A9-based therapeutic approaches. Furthermore, our data reveal pleiotropic insulin-independent therapeutic effects of S100A9 in ID via TLR4-dependent mechanisms (in the skeletal muscle and in the liver) and offer considerable potential for the development of innovative treatments for T1D.
