An iconoclastic view of diabetes: novel metabolic pathways and metabolites that drive the diabetic phenotype
DAlmost 33% of adult Americans develop pre-diabetes or diabetes.
ØDiabetes leads to morbidity and mortality in the form of kidney failure, blindness, fatty liver disease, gallstones and atherosclerosis.
ØDiabetes is clinically defined by high levels of glucose in the blood. However, normalizing blood glucose levels does not uniformly prevent the different morbidities associated with diabetes.
ØTo us, the classic understanding of diabetes is “glucocentric” and incomplete. We believe that there are other dysregulated metabolic pathways in diabetes, some of which have yet to be discovered, that are more important than hyperglycemia, particularly for certain forms of diabetes associated morbidity such as atherosclerosis. Our goal is to find these metabolic derangements and thereby enable the development of better treatments for our diabetic patients.
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. We have found that insulin resistance, a central feature of obesity, is sufficient to cause high cholesterol levels in the blood and atherosclerosis. The Biddinger lab is currently dissecting, at the molecular level, the mechanisms by which insulin resistance produces atherosclerosis.
Over 100 years ago, Sir William Osler documented the association between obesity and gallstones. Since then, many studies have confirmed the increased prevalence of gallstones in obese individuals, but how obesity could cause gallstones remained a mystery. In 2008, we showed that insulin resistance, a central feature of obesity, promotes gallstone formation by increasing biliary cholesterol secretion and altering the composition of the bile such that it becomes more likely to form gallstones. The Biddinger lab is now taking on further studies to identify the specific regulatory molecules which mediate the effects of insulin on biliary lipid metabolism.
Over the past century, our intake of fructose has dramatically increased. This is correlated with increases in obesity, fatty liver disease, and other disorders. This has led to the suggestion that fructose intake should be limited. But is fructose itself harmful? The Biddinger lab, using a combination of metabolomics, genetic and transcriptional profiling approaches, is trying to determine the specific metabolic effects of fructose. It is our expectation that this will lead to more rational dietary advice.
Sudha Biddinger, MD/PhD
Harvard Medical School
Children's Hospital Boston