At the Biddinger Lab we are working to identify the key targets and pathways, beyond glucose, that are regulated by insulin that and necessary to prevent atherosclerosis, NAFLD, and other complications of insulin resistance. Here are a few of our stories.
TMAO
Obesity and the related disorders of metabolic syndrome and Type 2 diabetes lead to cardiovascular disease. Indeed, cardiovascular disease is the most important cause of death in diabetic patients. 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 further found that TMAO exerts its effects by binding to the ER stress kinase PERK. We are excited about the 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.
Lipogenesis
In the normal liver, insulin suppresses glucose production, but it also stimulates lipogenesis (the synthesis of fatty acids). With the development of obesity, insulin loses its ability to control glucose production. Paradoxically, however, it continues to drive lipogenesis, leading to non-alcoholic fatty liver disease (NAFLD). The Biddinger lab is working to understand how insulin retains its ability to drive lipogenesis. In parallel, we are studying how diet, particularly the excessive consumption of fructose, may contribute. It is our hope that these studies will lead us to more effective therapies for NAFLD, which is rapidly becoming one of the most common causes of liver disease in our nation
Cholesterol Synthesis
We found that the most profound effect of insulin, at the transcriptional level, is the induction of the cholesterol synthesis genes. Indeed, patients with type 1 diabetes, and low levels of insulin have low levels of cholesterol synthesis,
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Sudha Biddinger, MD/PhD
Harvard Medical School Children's Hospital Boston |