Insulin is one of the most important regulators of biological functions. However, our present knowledge on the mechanisms of action of insulin is very limited. Insulin interacts with cells by binding to a specific surface receptor and, upon binding, generates specific biochemical signals that control various metabolic processes that occur inside the cell. One of the various signals used by insulin is the generation of small chemical mediators. These mediators are complex sugars that act by regulating a number of biochemical functions that determine the metabolism of glucose, fat and other cellular components. However, the mechanisms by which insulin regulates the generation of these mediators are not understood. Members of a family of regulatory proteins (G proteins) are involved in the generation of insulin mediators. It is not clear, however, how the insulin receptor communicates with these proteins. Several alternative hypotheses exist. For instance, upon binding of insulin, the receptor becomes activated and may change the structure of other proteins by attaching phosphate groups in specific sites located in the target protein. Alternatively, the activated receptor may interact directly with these regulatory proteins, modifying them transitorily and inducing their activation without generating any long term chemical changes in the protein. These and other possibilities will be examined by taking advantage of several types of modified insulin receptors generated by recombinant DNA technology in which specific functions have been impaired. It is possible that the major defects associated with the resistance of Type 2 diabetics to insulin may be related to the mechanisms by which insulin transmits signals to the interior of the cell. This proposal addresses directly some important questions on the biochemical events that lead to the generation of insulin mediators and the work proposed here should increase our understanding of the molecular defects that lead to the diabetic state.//
