Significance of DPP-4 Inhibition for Glucose Modulation and Its Bioimaging with Small Molecular Probes

Diabetes mellitus is a metabolic disease that results from a reduced response to insulin, or a lack of it, either due to a deficiency of insulin or a diminished effectiveness of the insulin. The pharmacological inhibition of human DPP-4 results in increased incretin activity, and this has beneficial effects on glucose control in type 2 diabetes mellitus. Contrary to this, certain species of the gut microbiome have been found to include DPP-4-like enzymes, which can degrade incretin hormones. They are reported in biochemical and animal studies to have potential metabolic relevance but are associated in human studies and have not been proven to be a factor in the response to clinical treatment. The present narrative review covers the reported pharmacology of human DPP-4, setting up the data on the microbial enzyme, as well as two detection methods based on fluorescence and natural compounds tested as inhibitors. Fluorescent probes are versatile tools for enzyme activity assays, fluorescence imaging, and inhibitor screening, but may not be readily distinguishable as host vs. microbial and may lack clinical validation. There is evidence of natural inhibitors from computational predictions and biochemical and animal observations, but efficacy against microbial DPP-4 needs to be determined directly. Co-inhibition by host and microbe is thus a potential research approach and not a clinically proven therapy. Priorities for the future are source-selective assays; exposure of the enzyme to the intestinal barrier; assessment of safety and bioavailability for individual compounds; and controlled human studies.