Interplay between genes and environment in insulin resistance and metabolic syndrome: the unique role of the gut microbiome
C. Ronald Kahn is an internationally recognized scientist who has helped define the field of insulin signal transduction and mechanisms of altered signaling in disease. His laboratory discovered the insulin-receptor tyrosine kinase, identified its first two major substrates, and showed how they are linked to other intracellular molecules to create a complex signaling network through which insulin exerts multiple effects on metabolism and growth. His laboratory demonstrated how this network is altered in insulin-resistant states, such as in type 2 diabetes and obesity, and the impact of genetics and environment on these signaling functions. Early in his career, Dr. Kahn was a clinical associate (fellow) in NIH’s Clinical Center. He later became head of the Section on Cellular and Molecular Physiology of the Diabetes Branch in NIDDK. In 1981, he moved to Boston to become Research Director of the Joslin Diabetes Center and a faculty member at Harvard Medical School. He has won many awards and honors for his work including election to the National Academy of Sciences and the Institute of Medicine.
Both type 2 diabetes and obesity are the result of complex interactions between genes and environment and between adipose tissue (fat) and other tissues of the body. For example, fat releases adipokines that influence insulin action in other tissues; there are increasingly complex effects of the brain and adipose tissue on the control of metabolism. Our studies in three different commercial mouse lines have revealed new classes of insulin action and new mechanisms of tissue cross talk in the pathogenesis of obesity and diabetes, as well as the impact of genes, environment, and the gut microbiome on disease pathogenesis.
The analysis of the composition of gut microbiota reveals profound differences in the relative amounts of bacterial species in the intestine in the three mouse lines and their environmentally conditioned equivalents. The composition of each strain’s microbiome uniquely correlates with the genetic background, different diets, and different environmental histories. These changes in microbiota are also associated with changes in the production of the inflammatory mediators by the gut and to the production and secretion of gut hormones known to influence energy intake and metabolic homeostasis. Dr. Kahn’s lab is the first to unravel how diet, genetic background, as well as original housing conditions, each independently contribute to shaping the composition of the gut flora. That composition drives the susceptibility of mice to diet-induced obesity, which can be reprogrammed by simply exposing mice to new environmental factors.
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