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Ron Kahn Laboratory

Location: Joslin Diabetes Center, Laboratory of Ron Kahn, Room 605, One Joslin Place, Boston, MA 02215


Our laboratory focuses on two major areas: 1) understanding the molecular mechanism of insulin and IGF-1 action and their alterations in pathologic states; and 2) the developmental heterogeneity of adipose tissue and its role in diabetes, metabolic syndrome and longevity. To achieve these goals, we use a wide variety of methods ranging from basic cell biology to creation and analysis of tissue-specific knockouts mice, and analysis of human cells and tissues.

The insulin and IGF-1 receptor tyrosine kinases are major regulators of metabolism and growth, and sites of both physiological and disease regulation. Following stimulation, the insulin receptor phosphorylates as many as 10 different intracellular substrate proteins, each of which dock to a number of other intracellular proteins through SH2 and non-SH2 mediated interactions. This results in stimulation of both the PI 3-kinase pathway and the Ras-MAP kinase pathway, as well as activation of many serine and threonine kinases involved in control of metabolism and glucose uptake. To understand the complementarity and redundancy between these various complex pathways, we have utilized cellular transfection models, mouse knockout models and cells derived from knockout mice. We have used this approach to define the differential role of both receptors, their substrates (the IRS proteins) and various components of PI 3-kinase and its downstream target. These studies indicate that the insulin signaling network is a finely tuned network with critical nodes of signal divergence and regulation. Through the use of tissue-specific knockouts created using Cre-lox recombination, the role of each of these pathways in specific insulin actions in specific tissues has been determined. This includes the actions of insulin in both classical targets, like liver, muscle and fat, and non-classical targets, like the brain. We have shown how these genetic modifications are further modulated by acquired alterations and by genetic background in the mouse. We are also studying how these pathways affect longevity and how they are altered in type 2 diabetes, obesity and metabolic syndrome.

The second major focus of the laboratory is defining the developmental origins and heterogeneity of white and brown fat. This is based on the important difference in fat in various depots on development of insulin resistance and energy balance. We have shown that fundamental developmental genes play a role in this process, and that fat cells in different depots have cell autonomous differences in function which affect whole body metabolism. The difference between energy burning brown fat and energy storing white fat also affects metabolism. The role of this heterogeneity and insulin action on mitochondrial function is also being explored at a cellular and molecular level, since mitochondrial function is altered in diabetes and may play an important role in longevity.





Last updated: 2013-05-15T15:34:10.178-04:00

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The eagle-i Consortium is supported by NIH Grant #5U24RR029825-02 / Copyright 2016