The International Diabetes Federation (IDF) estimates that 537 million adults (10.5%) globally had diabetes in 2021. This number is expected to reach 784 million by 2045. Type 2 diabetes mellitus (T2DM), caused by insulin resistance and islet cell destruction, accounts for more than 90% of diabetes patients, leading to a series of serious complications.
Currently, the treatment of T2DM primarily relies on insulin injections and oral hypoglycemic medications, imposing significant physiological, psychological, and economic burdens on patients due to the need for long-term administration.
In T2DM treatment, fibroblast growth factor 21 (FGF21), secreted by the human liver, and the secretion protein P9 from the human probiotic Akkermansia muciniphila hold great potential. FGF21 acts on adipocyte membranes through circulation. P9 binds to the intercellular adhesion molecule 2 (ICAM-2) receptor on intestinal secretory cells, promoting the secretion of glucagon-like peptide-1 (GLP-1). Together, P9 and FGF21 synergistically lower blood glucose by promoting insulin secretion and improving tissue insulin resistance.
To achieve a long-acting and non-invasive drug delivery method for diabetes treatment, we have chosen food-grade Lactobacillus as our chassis cells.
To address blood sugar fluctuations caused by eating, patients commonly inject insulin before meals. Skipping a meal can result in hypoglycemia. To tackle these challenges, we have designed a foodborne-stress induced secretion therapy (FIST). Plasmid A (with GroESL promoter) is activated by the concentration of bile in the intestines. The expressed protein consists of three components: FGF21, secretory peptide (SP), and cell-penetrating peptide (CPP). The SP promotes the release of lactobacilli-secreted proteins, while the CPP facilitates endocytosis of FGF21 into intestinal epithelial cells, allowing it to enter the circulation.
Merely regulating after meals is not sufficient, as the elevated baseline blood sugar levels in T2DM patients can also damage various target organs. Therefore, we designed a system for the constitutive expression and surface display of the P9 protein to supplement the hypoglycemic effects of FGF21. Due to the lower efficiency of constitutive expression in Lactobacillus compared to inducible expression, a cell membrane surface anchoring method is chosen to increase the quantity of P9, enhancing its binding to the ICAM-2 receptor on intestinal epithelial L cells.
We aim to provide a novel approach to diabetes treatment through the design of engineered Lactobacillus. This intelligent method, induced by foodborne stress, seeks to coordinate and enhance the body's own hypoglycemic mechanisms. Our goal is to achieve non-invasive, long-lasting, and more humanized relief, control, and even cure diabetes. This will contribute to the global promotion of a new concept of diabetes health management and help resolve the global diabetes pandemic.