Diabetes has reached epidemic proportions in our society. The classic understanding of Type 2 diabetes revolves around glucose: insulin fails to suppress glucose levels in the plasma, leading to oxidative stress and inflammation that ultimately result in atherosclerosis. However, the normalization of blood glucose levels fails to prevent atherosclerosis, which remains the leading cause of death among diabetic patients. It also fails to prevent non-alcoholic fatty liver disease. We therefore postulate that there are other metabolic derangements, perhaps some that have yet to be discovered, that are the key drivers of diabetes associated disease. Our goal is to progress beyond the conventional, glucocentric view of diabetes by finding these other derangements, and thereby enable the development of more effective treatments for our diabetic patients.
One example of our work is the elucidation of the diabetes/FMO3/TMAO pathway. By performing transcriptional and metabolite profiling in insulin resistant mice, we identified the enzyme flavin-containing monooxygenase 3 (FMO3) and its product, the metabolite trimethylamine N-oxide (TMAO) as targets of insulin. In diabetic mice, FMO3 and TMAO are markedly increased. Moreover, knockdown of FMO3 prevented the development of hyperglycemia, hyperlipidemia and atherosclerosis. We are excited about the diabetes/FMO3/TMAO pathway for several reasons. First, the magnitude of the effects of FMO3 are striking, with knockdown of FMO3 completely normalizing most aspects of metabolic homeostasis in insulin resistant mice. Second, the fact that FMO3 and TMAO were identified through non-biased screens suggests that the defects in these pathways are central to diabetes, revealed only now that the necessary profiling tools have become available. Finally, even at this early stage, it appears that FMO3 and TMAO are also increased in diabetic humans. Ongoing work is directed at understanding exactly how FMO3 and TMAO exert their negative effects, and whether this pathway could be manipulated for therapeutic use in our patients.