Understanding Insulin Action: Principles and Molecular Mechanisms

1 Introduction.- 1.1 A short account of the discovery of insulin.- 1.2 An overview of insulin action and diabetes.- 2 Insulin: Chemistry, Synthesis and Secretion.- 2.1 The insulin molecule.- 2.1.1 Primary structure and evolutionary conservation.- 2.1.2 X-ray analysis and structure-activity relationships.- 2.2 Insulin synthesis.- 2.2.1 The insulin gene.- 2.2.2 Regulation of insulin gene expression.- 2.2.3 Physiological regulation of gene expression.- 2.2.4 Pathology of insulin gene expression.- 2.3 Insulin secretion.- 2.3.1 Morphology of the islets of Langerhans.- 2.3.2 Glucose metabolism in the P-cell.- 2.3.3 Role of Ca2+ in insulin secretion.- 2.3.4 Role of cAMP in insulin secretion.- 3 Pathophysiology of Insulin.- 3.1 Introduction.- 3.2 Metabolic effects of insulin.- 3.2.1 Effects on carbohydrate metabolism.- 3.2.2 Effects on fat metabolism.- 3.2.3 Effects on protein metabolism.- 3.2.4 Summary.- 3.3 Diabetes.- 3.3.1 Insulin-dependent diabetes mellitus (IDDM).- 3.3.2 Non-insulin-dependent diabetes mellitus (NIDDM).- 4 Molecular Mechanisms Involved in Insulin Action.- 4.1 Regulation of protein phosphorylation.- 4.1.1 Insulin-stimulated increases in protein phosphorylation.- 4.1.2 Insulin-stimulated decreases in protein phosphorylation.- 4.2 Insulin regulation of protein traffic.- 4.2.1 Insulin stimulation of glucose transport.- 4.2.2 Translocation of IGF-II receptors and other proteins.- 4.3 Regulation of gene expression.- 4.3.1 Effects of insulin on phosphoenolpyruvate carboxyl-kinase (PEPCK) gene expression.- 4.3.2 Effects of insulin on glyceraldehyde phosphate dehydrogenasel (GAPDH) mRNA.- 5 The Insulin Receptor.- 5.1 Receptor structure.- 5.1.1 Methods used in determining the structure of the insulin receptor.- 5.1.2 Subunit composition.- 5.1.3 The insulin receptor precursor and its gene.- 5.1.4 Relationship to other receptors.- 5.2 The insulin receptor tyrosine kinase.- 5.2.1 Phosphorylation of the insulin receptor.- 5.2.2 Substrates for the insulin receptor tyrosine kinase.- 5.2.3 Physiological role of insulin receptor tyrosine kinase phosphorylation.- 5.3 Insulin receptor internalization.- 6 Molecular Mechanisms of Insulin Signal Transduction.- 6.1 The cAMP system.- 6.1.1 Effects of insulin on the cAMP system.- 6.2 The inositoltrisphosphate-diacylglycerol system.- 6.2.1 Inositol lipid metabolism.- 6.2.2 Mechanism of second-messenger action.- 6.2.3 Summary of the hypothesis.- 6.2.4 Insulin action and the Insl,4,5P3/DG system.- 6.3 The involvement of glycosylphosphatidylinositol (GPI) in insulin action.- 6.3.1 Anchoring of membrane proteins by GPIs.- 6.3.2 GPI in insulin action.- 7 Summary and Perspectives.- 7.1 Summary.- 7.2 Perspectives.