Molecular determinants of insulin action.
Insulin elicits an array of biologic responses. Insulin exerts a regulatory role in almost all cells of the body and is the primary hormone responsible for signaling the storage and utilization of basic nutrients. On the molecular level, the actions of insulin are initiated by binding of insulin to the insulin receptor. Interaction of the alpha and beta subunits of the receptor results in tyrosine kinase activity, which is integral to the initiation of cascades of phosphorylation/dephosphorylation reactions that mediate a large number of the actions of insulin. Insulin-receptor substrate 1 may be central to phosphorylation reactions through a role in serine and threonine kinase activity. Insulin action may also involve the generation of low-molecular-weight mediators capable of modulating intracellular enzymes. The regulation of glucose transport is a primary feature of the physiologic role of insulin and is performed by a family of glucose-transporter proteins with different characteristics. One mechanism by which insulin exerts its effect on glucose transport is the stimulation of the translocation of the glucose transporter to the plasma membrane. Degradation of insulin occurs through diverse mechanisms at numerous sites in the body. Reversal of the insulin signal at the cellular level may be accomplished by a class of enzymes termed phosphotyrosine phosphatases, which may play a role in certain pathophysiologic states. Important roles for insulin-receptor kinase, glucose transporters, insulin-receptor substrate 1, and various intracellular enzymes in the actions of insulin have been demonstrated; nonetheless, the formulation of potential therapeutic strategies directed at particular stages of the insulin action cascade will require further elucidation of its components.
Kahn
C R
CR
Harvard Medical Center, Brigham and Women's Hospital, Boston, Massachusetts.
Goldfine
A B
AB
D000595:Amino Acid Sequence; D000818:Animals; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000502:physiology*; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D017433:Protein Structure, Secondary; D011972:Receptor, Insulin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
D007328:Insulin; D009004:Monosaccharide Transport Proteins; D011972:Receptor, Insulin