Insulin: Part 2 by A. HasselblattInsulin: Part 2 by A. Hasselblatt

Insulin: Part 2

EditorA. Hasselblatt, F.v. Bruchhausen

Paperback | November 23, 2011

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The present subvolume was assigned to other editors than those of the first part, which may also serve to explain the delay in publication. The compilation of a volume on insulin for the Handbook of Experimental Pharmacology appeared to us an enticing task, for two reasons in particular. Insulin has now been in use for 50 years and can be classified among the old­ established and almost sacrosanct drugs; for this very reason the knowledge of this hormone, its mode of action, and quality of effect demands special attention. No limitation on its use can yet be foreseen. Recent work on the formation, secretion and probable activity in the organism of a hormone like insulin, which is produced within the body, opens up prospects of penetrating the mysteries of both the work and the regulatory possibilities of this small "drug factory" within the organism, the pancreatic islet. It may be more than just coincidence that this peptide hormone was called after its place of fabrication. Furthermore, the work done on insulin has stimulated other studies for the assessment and elucidation of other hormonal systems. It was not the intention of the editors to compile all known effects of insulin in the present volume, as it was felt that such an attempt would result merely in a list of facts that would be of questionable value and certainly incomplete.
Title:Insulin: Part 2Format:PaperbackPublished:November 23, 2011Publisher:Springer Berlin HeidelbergLanguage:English

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ISBN - 10:3642660045

ISBN - 13:9783642660047

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Table of Contents

Secretion of Insulin.- A. The Kinetics of Insulin Release.- I. Introduction.- II. Dissociation of Different Phases of Insulin Secretion.- III. Influence of Non-glucose Stimulators.- IV. Role of Insulinogenesis.- V. Kinetic Characteristics of Insulin Response to Glucose.- VI. Theoretical Models for Insulin Secretion.- VII. Application in Man.- References.- B. Insulin Synthesis in ?-Cells.- I. Role of Proinsulin in Insulin Biosynthesis.- 1. Introduction.- 2. Chemical Structure and Properties of Proinsulin and Related Compounds.- 3. Secretory Cycle of the ?-Cell.- 4. Localization of the Converting Process.- 5. The Nature of the Proinsulin Converting Enzymes.- 6. The Products of Conversion and Their Intracellular Fate.- 7. Significance of Proinsulin for the Biosynthesis of Insulin.- II. Secretion of Proinsulin and C-Peptide and their Significance.- 1. Secretion of Proinsulin and C-Peptide In Vitro.- 2. Immunological Methods for the Determination of Circulating Proinsulin and Related Peptides.- 3. Secretion of Proinsulin and C-Peptide In Vivo.- a) Proinsulin.- ?) Normal subjects and animals.- ?) Pathological states.- b) Intermediate Forms.- c) C-Peptide.- 4. Peripheral Degradation of Proinsulin.- 5. Biological Activity.- a) In-Vivo Studies.- b) In-Vitro Studies.- 6. Prospects and Conclusions.- References.- C. Biochemistry and Biophysics of Insulin Secretion.- I. Energy Metabolism of the B-Cell.- 1. Introduction.- 2. Methodological Problems in the Study of Islet Metabolism.- a) Preparation of Islet Samples.- b) Microchemical Assay.- 3. Enzymatic Equipment and Nucleotide Levels of the B-Cells.- a) Phosphorylation of Glucose.- b) Glycolysis.- c) Pentose Phosphate Shunt.- d) Citric Acid Cycle and Respiratory Chain.- e) Amino Acids.- f) Lipids and Fatty Acids.- g) Glycogen Metabolism.- h) The Level of Nucleotides in the B-Cells.- 4. Substrate Utilization and Metabolism in the B-Cell.- a) Metabolism of Glucose.- b) Metabolism of Non-Carbohydrate Substrates.- 5. Energy Metabolism of the B-Cell In Relation To Insulin Biosynthesis and Secretion.- References.- II. Hexoses and Insulin Secretion.- 1. Introduction.- 2. Insulin Secretion Due to Hexoses and Pentoses as Well as Their Derivatives and Analogues.- a) Effects of Hexoses, Hexose Derivatives, and of Mannoheptulose.- ?) Stimulation of release.- ?) Inhibition of release by hexoses and mannoheptulose.- ?) Modulation of release by 2-deoxyglucose and mannoheptulose.- ?) Insulin release due to phlorizin.- ?) Effects of fasting and feeding on glucose-induced insulin release.- ?) The kinetics of release and of inhibition of release due to hexoses and mannoheptulose.- b) Effects of Polyols and Pentoses.- 3. The Permissive Action of Glucose Allowing Insulin Release Due to Calorigenic Molecules of Low Molecular Weight.- a) Glucose Dependency of Release Due to Various Stimuli.- b) Experimental Alterations of Chemosensitivity of Islets.- 4. Metabolic Function of Hexoses in the Islets of Langerhans.- a) Stimulation of Glycolysis and Respiration in Islets by Various Hexoses.- b) Dissociations of Metabolic and Insulin-Releasing Actions of Hexoses.- c) Dissociation of Metabolic and Permissive Functions of Glucose.- d) The Significance of Metabolite and Cofactor Levels in Islets Exposed to Glucose and Other Substrates.- 5. Interactions of Hexoses and Alloxan in Islets.- 6. Electrophysiological Effects of Hexoses on Islet Cells.- 7. A Possible Model Explaining the Multiple Actions of Glucose on the ?-Cells.- References.- III. Amino Acids and Insulin Secretion.- 1. Introduction.- 2. Transport and Metabolism of Amino Acids by Islet Cells.- a) Transport of Amino Acids.- b) Synthesis and Degradation of Amino Acids.- c) Protein Degradation.- d) Amino Acid Levels.- 3. Amino Acid-Induced Insulin Secretion.- a) L-Arginine and Related Substances.- b) L-Leucine and Related Substances.- c) Other Amino Acids.- 4. Conclusions.- References.- IV. Participation of the Adenylate Cyclase System.- 1. Introduction.- 2. The Regulation of cAMP Metabolism in the B-cell.- a) Membrane Receptors in the B-cell.- b) Insular Adenylate Cyclase.- c) Insular Phosphodiesterase.- d) The Level of cAMP in the B-cell.- ?) Immediate Regulation of cAMP Concentration in the B-cell.- ?) Long-term Regulation of cAMP Concentration in the B-cell.- e) Conclusion.- 3. The Effect of cAMP Upon Insulin Release.- a) The Insulinotropic Action of cAMP.- b) Combined Effects of cAMP and Other Insulino tropic Agents.- c) Combined Effects of cAMP and Inhibitory Agents.- 4. The Mode of Action of cAMP in the B-cell.- a) Effects of cAMP on Glucose Metabolism in the B-cell.- b) Effects of cAMP on Insulin Biosynthesis.- c) Effects of cAMP on Islet-cell Protein Phosphokinase.- d) Effects of cAMP on Tubulin Metabolism in the B-cell.- e) Effects of cAMP on Calcium Handling by the B-cell.- 5. Physiological Significance of the B-cell Adenylate Cyclase System.- a) Insulinotropic Action of Hormonal Polypeptides and the Entero-Insular Axis.- b) Inhibition of Insulin Release by Catecholamines During Stress and Exercise.- 6. Concluding Remark.- References.- V. Role of Cations.- 1. Introduction.- 2. Calcium.- a) Effect of Calcium Upon Insulin Release.- b) The Handling of Calcium by the B-cell.- c) The mode of Action of Calcium in the B-cell.- 3. Barium.- 4. Magnesium.- 5. Sodium.- a) Effect of Sodium on Islet Function.- b) Insular Handling of Sodium.- 6. Potassium.- a) Effect of Potassium on Islet Function.- b) Insular Handling of Potassium.- 7. pH.- a) Effect of pH on Islet Function.- b) Intracellular pH of Insular Tissue.- 8. Cations and Secretory Granules.- 9. Conclusion.- References.- VI. The Bioelectrical Activity of the Islet Cell Membrane.- 1. Introduction.- 2. Measurement of Electrical Properties of Islet Cells.- 3. Electrical Activity Induced by Islet Stimulants.- 4. Relationship Between Electrical Activity and Insulin Release.- 5. Effect of Ions on Glucose-Induced Electrical Activity.- a) Monovalent Ions.- b) Divalent Cations.- 6. Effects of Inhibitors and Anoxia on Electrical Activity.- 7. Effect of Diabetogenic Agents.- 8. Discussion.- References.- D. Effects of Sulfonylurea Derivatives on Pancreatic ?-Cells.- I. Introduction.- II. Descriptive Aspects of Insulin Release, Insulin Biosynthesis, and ?-Cell Morphology.- 1. Acute Effects on Insulin Release.- 2. Insulin Biosynthesis and Long-term Effects on Insulin Secretion.- 3. ?-Cell Morphology.- III. Explanatory Hypotheses Concerning the Insulin-Releasing Action of Sulfonylureas.- 1. Enhanced Glucose Recognition.- 2. Enhanced Recognition of Amino Acids.- 3. Increase of Cyclic AMP.- 4. Redistribution of Metal Ions.- 5. Binding to Plasma Membrane.- 6. Direct Effects on Insulin Storage.- IV. Concluding Remarks.- References.- Pharmacokinetics of Insulin.- A. Distribution in the Organism.- I. Introduction.- 1. Early Distribution Studies.- 2. Specificity of Distribution Pattern of 131I-labelled Insulin.- 3. Limitations of Early Distribution Studies.- 4. Reinvestigation of Distribution of 131I-labelled Insulin in the Rat.- 5. Role of the Liver and Kidneys in the Distribution and Degradation of Insulin.- 6. Intracellular Distribution of Insulin.- II. Dynamics of Insulin Distribution.- III. Kinetics of Insulin Distribution.- 1. Rate of Plasma Insulin Disappearance (Half-Life Concept).- 2. Limitations of Plasma Half-Life Estimates.- 3. Alternative Methods of Analysis of Plasma Insulin Disappearance.- 4. Limitations of Estimation of Metabolic Clearance Rates or Fractional Loss Rates of Insulin from Plasma.- IV. Summary and Conclusions.- References.- B. Degradation of Insulin.- I. Qualitative Aspects of Inactivation of Insulin.- 1. Inactivation of Insulin by Tissue Brei and Extracts.- 2. 131I-Insulin Degradation by Tissue Extracts, Slices and Homogenates.- 3. Specificity of 131I-Insulin Degradation by Tissue Extracts and Homogenates.- 4. Further Studies on the Nature, Specificity, and Localization of Enzymatic Degradation Processes for Insulin.- a) Evidence for Reductive Cleavage of S-S Bonds in Insulin.- b) Evidence for Proteolytic Degradation of Insulin.- II. Subcellular Localization of Insulin Degradation.- III. Regulation of Insulin-Degrading Activity.- IV. Quantitative and Kinetic Aspects of Proteolytic Degradation of 131I-Insulin.- V. Comments.- VI. Summary and Conclusions.- References.- Effects of Insulin and Proinsulin.- A. Insulin Receptor Interactions and the Action of Insulin.- I. Introduction.- II. Insulin Receptors.- 1. Binding of Iodoinsulin to Receptors.- 2. Localization of Receptors.- a) Localization of Receptors to Cell Surfaces.- b) Assymetric Positioning of the Insulin Receptor in the Membrane.- 3. Insulin Receptor Interaction.- a) Properties of the Insulin Receptor Interaction.- b) Effect of Enzymatic Digestions.- ?) Neuraminidase.- ?) Proteases.- ?) Galactosidases.- ?) Phospholipases.- c) Effects of Insulin-Agarose Derivatives.- d) Insulin Receptors and Plant Lectins.- e) Insulin-Resistant States.- 4. Solubilization and Isolation of the Insulin Receptor.- III. Mechanism of Insulin Action.- References.- B. Effects of Insulin on Cellular Protein Synthesis.- I. Introduction.- II. Insulin and Amino Acid Transport in Muscle Reconsidered.- 1. Relation of Insulin Action on Protein Synthesis to the Action of the Hormone on Amino Acid Transport.- 2. Insulin and Amino Acid Transport in Muscle.- a) Accumulation of Individual Natural Amino Acids.- b) Amino Acid Transport in the Absence of Protein Synthesis.- 3. The Nature of the Effect of Insulin on Amino Acid Transport.- 4. Does Availability of Amino Acids Limit Protein Synthesis in Muscle ?.- 5. The Dilemma of the Functional Heterogeneity of the Intracellular Amino Acid Pool.- a) Evidence for Compartmentalization.- b) Possible Organization of Amino Acid Pools.- c) Amino Acid Pools and the Measurement of Protein Synthesis.- III. Insulin, Diabetes and the Function of Muscle Ribosomes.- 1. Muscle Ribosomes from Diabetic Animals Catalyze Protein Synthesis Less Effectively than Do Ribosomes from Normal Animals.- 2. Small Amounts of Insulin Administered to Diabetic Animals Rapidly Increase the Synthesis of Protein by Ribosomes.- 3. Insulin Increases the Synthesis of all Muscle Proteins.- 4. Diabetes Reduces the Number of Active Ribosomes in Muscle.- 5. Preparations of Ribosomes from the Muscle of Diabetic Animals Contain Fewer Polysomes and More Monomers than Normal.- 6. Insulin-Induced Formation of Polysomes and Increase in Protein Synthesis Do not Require the Synthesis of RNA.- 7. The Reduced Ability of Diabetic Ribosomes to Translate Messenger RNA is not Related to the Binding of the Template.- 8. Diabetic Ribosomes Are Less Effective than Normal in the Translation of Poly- uridylic Acid at Lower Concentrations of Magnesium and More Effective at Higher Concentrations of the Cation.- 9. When Hybrid Ribosomes Containing a Normal and Diabetic Subunit Are Constructed, the Defect in Protein Synthesis Appears to Be Carried by the 60S Subunit.- 10. Diabetes Does not Alter the Peptidyl Transferase Activity of Ribosomes.- 11. The Elongation Factor-2 Catalyzed Hydrolysis of GTP by Muscle Ribosomes is not Changed in Diabetes.- 12. Diabetic Ribosomes Bind Less Phe-tRNA than Normal at Low Concentrations of Magnesium and More at High Concentrations.- 13. Diabetic Ribosomes Are Less Effective than Normal in the Translation of Polyuridylic Acid and RNA Extracted from Encephalomyocarditis Virus (EMCV RNA).- 14. Formation of an Initiation Complex by Normal and Diabetic Ribosomes.- IV. Insulin, Diabetes, and the Structure of Ribosomes.- 1. No Difference Has Been Found in the Proteins of Normal and Diabetic Ribosomes.- 2. No Difference Has Been Found in the RNA of Normal and Diabetic Ribosomes, although Diabetes Does Decrease the Number of Ribosomes to Be Found in Muscle.- 3. Diabetes Decreases the Melting Temperature of Ribosomes.- 4. The Pleotypic Program and the Intracellular Mediator of Insulin Action.- V. Coda.- References.- C. Effects of Insulin on Nucleic Acids, Nucleotides and Cyclic AMP.- I. Introduction.- II. Preliminary Considerations.- 1. Insulin as an Inductor or Depressor.- 2. Insulin as a Ligand Interacting with the Cell Membrane.- III Action of Insulin on Nucleic Acids.- 1. In Rat Diaphragm.- 2. In Liver.- 3. Discussion.- IV. Action of Insulin on the Incorporation of 32P-Labelled Inorganic Phosphate into Mononucleotides in Rat Diaphragm and Adipose Tissue.- 1. Experimental Approach.- 2. Phosphate Turnover in the Diaphragm of the Normal Rat.- 3. Phosphate Turnover in the Diaphragm of the Hypophysectomized Rat Treated with or without Growth Hormone.- 4. Phosphate Turnover in Isolated Adipose Tissue Cells.- 5. Effects of Insulin on Phosphate Turnover.- a) Discussion.- b) Significance.- V. Interaction of Insulin with the Cyclic AMP System.- 1. The Action of Insulin upon the cAMP Level.- 2. Mechanisms of the Effect of Insulin upon the cAMP Level.- a) Decrease in the Activity of Adenylate Cyclase.- b) Increase in the Activity of Cyclic AMP-Phosphodiesterase.- c) Is Insulin Acting at the Kinase Level ?.- 3. Conclusion: The Search for "Another" Transducer Specific for Insulin.- VI. General Conclusions.- References.- D. Metabolic Effects on Muscular Tissue.- I. Introduction.- II. Muscular Tissues Used for the Study of Insulin Action.- III. Effects of Insulin on Transport Processes.- 1. Glucose and Other Sugars.- a) Use of Sugars and Analogues.- b) Methodical Problems.- c) Insulin Membrane Action and Degradation.- d) Kinetics.- e) Inhibition of Insulin-Stimulated Sugar Transport.- 2. Electrolytes and Water.- a) Monovalent Cations.- ?) Potassium.- ?) Sodium.- b) Divalent Cations.- c) Anions.- d) Membrane Potential.- e) Water.- 3. Relationship Between the Transport of Glucose and Electrolytes.- a) Extracellular Ionic Milieu.- b) Intracellular Ionic Milieu.- c) Ionic Permeability of the Plasma Membrane.- IV. Effects of Insulin on Metabolic Processes.- 1. Sugar Phosphorylation.- 2. Glycogen Metabolism.- a) Amount and Labelling Studies.- b) Glycogen Synthetase.- 3. Glycolysis.- 4. Oxidation of Glucose and Other Substrates.- 5. Lipid Metabolism.- 6. Electrolytes and Glucose Metabolism.- V. "Insulin-Like" Effects.- 1. Contractile Activity.- 2. Anoxia and Metabolic Poisons.- 3. Hyperosmolarity.- 4. Enzymes.- 5. Compounds Structurally Related to Insulin.- References.- E. Metabolic Effects on Adipose Tissue in vitro.- I. Introduction and Early Studies.- II. Description of the Effects of Insulin.- 1. Membrane Transport of D-glucose and Related Sugars.- a) Recognition of Sugar Transport as a Major Locus of Insulin Action.- b) Evidence that the Transport of D-glucose is Accelerated by Insulin.- c) Transport Studies in Ghosts.- d) Characteristics of the Effect of Insulin on D-glucose Uptake.- e) Effect of Insulin on the Transport of Other Sugars.- f) Role of Monovalent Cations in Sugar Uptake.- 2. Glycogen Metabolism.- 3. Fatty Acid Synthesis.- a) Conversion of Intracellular Glucose to Pyruvate.- b) Conversion of Pyruvate to Intramitochondrial Citrate.- c) Conversion of Intramitochondrial Citrate to Fatty Acids.- 4. Triglyceride Metabolism.- a) Esterification of Fatty Acids.- b) Hydrolysis of Triglycerides.- c) Uptake of Triglycerides.- 5. Tissue Respiration and ATP Production.- 6. Amino Acid Metabolism and Protein Synthesis.- III. Analysis of the Mechanism of Action of Insulin.- 1. The Insulin Receptor.- 2. Correlation with Tissue cyclic-AMP Concentration.- 3. Role of Adenylate Cyclase.- 4. Role of Phosphodiesterase.- 5. Reflections.- References.- F. Direct In Vitro Effects of Insulin on Liver Metabolism.- I. Effects of Insulin on the Net Glucose Balance and on Glycogen Metabolism.- II. In Vitro Effects of Insulin on Gluconeogenesis in Liver.- III. The Mode of Action of Insulin on 3?,5?-cAMP-Mediated Processes in Vitro.- IV. Effects of Insulin on Electrolyte Metabolism.- V. Effects of Insulin on Hepatic Lipid Metabolism.- VI. Effects of Insulin on the Metabolism of Amino Acids and Proteins.- References.- G. Action of Insulin on Some Other Organs and on Differentiation.- I. Action on Stomach Function and Exocrine Pancreas.- 1. Action on Stomach Function.- a) Stimulation of Gastric Secretion by Insulin Hypoglycemia.- b) Inhibitory Actions of Insulin.- c) Direct Mucosal Stimulation of Acid Secretion.- d) Participation of Intracellular Mediation in Oxyntic Cells.- References.- 2. Action on the Exocrine Pancreas.- a) Influence of Insulin on Exocrine Pancreas Secretion.- b) Influence of Insulin on Synthesis of Pancreatic Juice Components.- c) Trophic Effects of Insulin on Exocrine Pancreas Tissue.- References.- II. Action on the Mammary Gland.- 1. General Metabolic Alterations.- 2. Specific Functional Alterations.- References.- III. Action on the Crystalline Lens.- 1. Diabetic and Sugar Cataract.- 2. Hexose Transport in Lens.- 3. Lens Differentiation.- References.- IV. Action on Some Mesenchymal Tissues and Single Cells.- 1. Action on Fibrocytes and Mesenchymal Tissues.- a) Action of Insulin on Fibroblasts in Culture.- b) Action of Insulin on Skin and Wound Tissue.- c) Action of Insulin on Cartilage and Bone.- References.- 2. Action on Tumor Cells.- References.- 3. Action on Blood Cells.- a) Erythrocytes.- b) Granulocytes and Lymphocytes.- References.- H. Metabolie Alterations in the Body by Insulin.- I. Effect of Insulin on the Fate of Glucose.- 1. Introduction.- 2. Isotope Dilution Techniques.- a) Definitions and Problems Arising from Incomplete Intermixing.- b) Recycling of Label.- c) Data from Studies Applying Isotope Dilution Techniques.- ?) Changes in the fate of body glucose induced by a deficient supply of insulin or by the diabetic state.- ß) Changes in the fate of glucose induced by insulin.- ?) Effect of glucose loading on the fate of body glucose as measured by isotope dilution.- 3. Effect of Insulin on the Fate of Body Glucose as Measured by Catheterization Techniques.- a) Measurements of the Net Balance of Glucose across the Liver.- b) Effect of Insulin on Net Splanchnic Glucose Output.- 4. Effect of Insulin on Glucose Utilization by the Extrahepatic Tissues.- 5. Conclusions.- References.- II. Alterations in Fat Metabolism.- 1. Introduction.- 2. Normal Metabolism of Lipids.- a) Postprandial State.- b) The Postabsorptive State (12-18 h after the Last Meal).- 3. Effects of Severe Insulinopenia.- a) Short-Term Insulin Deficiency (up to 6 h).- b) Long-Term Insulin Deficiency (One Day or More).- 4. Glycogenesis Type I.- 5. The Primary Lipodystrophies.- 6. Excess Insulin and Endogenous Hypertriglyceridemia.- 7. Endogenous Hyperlipemia and Insulin Resitance.- 8. Conclusions.- References.- I. Modification of the Effects of Insulin by Hormonal Factors.- I. Introduction.- II. Insulin.- 1. Effect on Blood Glucose Concentration.- 2. Effect on Hepatic Glucose Output.- 3. Effect on Perfused Liver.- 4. Effect of Endogenous Insulin on Hepatic Glucose Output.- 5. Effect on Glycogen Concentration.- 6. Effect on Hepatic Gluconeogenesis.- 7. Effect on Glucose Uptake.- 8. Comments.- III. Growth Hormone.- 1. Hypophysectomy - Effect on Glucose Production, Uptake, and Sensitivity to Insulin.- 2. Growth Hormone Administration in the Hypophysectomized Animal.- 3. Growth Hormone Administration in the Normal Animal.- 4. Growth Hormone-Induced Diabetes.- 5. Comments.- IV. Adrenal Glucocorticosteroids.- 1. Adrenalectomy - Effect on Glucose Production, Uptake, and Sensitivity to Insulin.- 2. Glucocorticoid Administration in Hypophysectomized and Adrenalectomized Animals.- 3. Glucocorticoid Administration in the Normal Animal.- 4. Comments.- V. Epinephrine.- 1. Effect on Hepatic Glucose Output.- 2. Effect on Glucose Uptake.- 3. Comments.- VI. Glucagon.- 1. Effect on Hepatic Glucose Output.- 2. Effect on Glucose Uptake.- 3. Comments.- VII. Prolactin and Human Placental Lactogen (HPL).- VIII. Thyroid Hormones.- IX. Concluding Remarks.- References.- Immunopathology of Insulin.- A. Insulin Allergy, "Cellular" Antibodies and Insulitis.- I. Insulin Allergy.- 1. Introduction.- 2. Clinical Symptoms.- a) Local Delayed Reaction.- b) Immediate Local or Generalized Reactions.- c) Other Types.- 3. Frequency.- 4. Diagnostic Procedures.- a) Skin Tests.- b) Laboratory Findings (Cytological and Serological Studies).- ?) Delayed allergic reaction.- ?) Immediate type allergy.- c) Histological Examinations.- 5. Pathogenesis and Classification.- 6. Concepts of Etiology.- a) Immunogenicity of Insulin and the Role of Proinsulin and Insulin-Related Proteins.- b) Antigenic Determinants of the Insulin Molecule.- 7. Relationship to Insulin Resistance.- 8. Relationship to Lipodystrophy.- 9. Treatment.- a) Delayed Allergic Reaction.- b) Immediate Allergic Reactions.- ?) Hypoglycemic agents.- ?) Change of insulin.- ?) Desensitization.- ?) Other measures.- II. "Cellular" Antibodies and Insulitis.- References.- B. Insulin-Binding Antibodies of Serum and Insulin Resistance.- I. Methods for the Determination of Insulin Antibodies.- 1. Determination by Inhibition of Insulin Effects.- a) Inhibition of Insulin Effects in Animals.- b) Inhibition of Insulin Effects in Isolated Tissue.- c) Inhibition of Insulin Degradation and Elimination.- 2. Determination of Insulin-Binding Antibodies by Immunological Tests.- a) Serologic Methods.- b) Passive Antibody Transfer.- 3. Detection of Insulin Antibodies by Direct Measurement of Insulin Antibody Binding.- a) Electrophoresis.- b) Ultracentrifugation.- c) Precipitation of Insulin-Protein Complexes.- d) Adsorption Techniques.- 4. Calculation of Quantitative Parameters of Insulin-Antibody Binding at Equilibrium.- II. Chemical-Physical Properties of Insulin Antibodies.- 1. Classification in Regard to Serum Protein Fractions.- 2. Two Main Components of Insulin Antibodies of IgG Class.- III. Influence of the Insulin Molecule on its Binding to Insulin Antibodies of Serum.- 1. Effect of Species Differences on Insulin Immunology.- 2. Effects of Chemical Modifications on the Antibody Binding of Insulin.- a) Insulin Chains and Chain Fragments.- b) Insulin Modifications with Intact Spatial Configuration.- ?) Analogs of insulin with shortened chains.- ?) Insulin analogs with prolonged chains.- ?) Insulin analogs with varied primary structure.- ?) Insulin derivatives.- ?) Cross-linked insulins.- ?) Insulin with partially cleaved disulfide bridges.- IV. Insulin Antibodies in Man.- 1. Without Previous Insulin Treatment.- 2. After Insulin Treatment.- a) Insulin-Binding Antibodies and Insulin Requirement.- b) Insulin-Binding Antibodies and the Quality of Metabolic Control in Diabetics.- c) Acute Effects of Insulin Antibodies on Metabolic Processes.- d) Chronic Effects of Insulin-Binding Antibodies on Metabolic Processes.- V. Antibody-Dependent Insulin Resistance.- 1. Pathogenesis.- 2. Frequency of Occurrence.- 3. Clinical Picture.- 4. Therapy.- References.- Determination and Preparations of Insulin.- A. Radioimmunoassay of Insulin.- I. Introduction.- II. Principles of the Radioimmunological Method.- III. Methods of Radioimmunoassay of Insulin.- 1. Materials.- 2. Insulin Labeling.- a) Principles.- b) Method of Labeling Insulin.- c) Purification of Iodine-Labeled Insulin.- 3. Separation of Free Insulin from Antibody-Bound Labeled Insulin by Means of Amberlite.- 4. Sensitivity and Accuracy of the Radioimmunoassay of Insulin.- a) Serum Dilution and Antiserum Used.- b) Concentration of Radioactively Labeled Insulin.- 5. Serum Insulin Assays.- 6. Other Methods of Separation.- a) General Survey.- b) Double-Antibody Method.- c) Separation with Charcoal and Dextran.- d) Cellulose Powder.- 7. Use of Insulin Receptors for Assay Purposes.- IV. Assay of Proinsulin and C-Peptide.- 1. Proinsulin Assay.- 2. C-Peptide.- References.- B. The Biological Assay of Insulin-Like Serum Activity (ILA).- I. Introduction.- II. Principle and Survey of Insulin Bioassays.- 1. In- Vivo Methods.- 2. In- Vitro Methods.- a) Rat-Diaphragm Method.- b) Rat-Adipose-Tissue Method.- c) Rat-Fat-Cell Method.- III. Practical Execution of Insulin Bioassays.- 1. In-Vivo Methods (Glycogen Synthesis of the Rat Diaphragm in Situ).- a) Experimental Animals.- b) Method.- c) Analytic Methods.- d) Calculation.- e) Norms.- f) Interference.- 2. In- Vitro Methods.- a) Determination of Insulin Activity from Glycogen Synthesis of the Isolated Rat Diaphragm.- ?) Experimental animals.- ß) Materials.- ?) Method.- ?) Analytic methods.- ?) Calculation.- b) Determination of the Insulin Activity from 14CO2 Production of Isolated Rat Epididymal Adipose Tissue.- ?) Experimental animals.- ß) Materials.- ?) Method.- ?) Analytic methods.- ?) Calculation.- ?) Norm.- IV. Forms of ILA in the Blood and their Significance: Conclusions.- 1. Immunologic and Biologic ILA.- 2. Nonsuppressible Insulin-like Activity (NSILA).- 3. Bound Insulin.- 4. Synalbumin.- References.- C. Methods for the Standardization of Insulin and the Determination of Blood Glucose Concentration.- I. Standardization of Insulin.- 1. Synopsis and Introduction.- 2. Methods of Standardization.- a) Mouse Convulsion Test.- b) Hypoglycemic Effect in Rabbits.- c) Standardization of Insulin Preparations with Prolonged Action.- d) Statistics.- II. Methods of Determining Blood Glucose Concentration.- 1. Chemical Methods of Measuring Blood Glucose Concentration.- a) Methods Based on Reduction.- b) Formation of Osazone.- c) Furfural-Reaction.- 2. Enzymic Methods of Determining Glucose.- a) Digestion by Microorganisms.- b) Reaction with Pure Enzymes.- ?) Glucose oxidase plus peroxidase.- ß) Glucose oxidase without peroxidase.- ?) Hexokinase plus glucose-6-phosphate-dehydrogenase.- References.- D. The Isolation of Insulin from the Pancreas.- I. General Aspects of Insulin Isolation.- 1. The Need for Insulin and How It Is Satisfied.- 2. Properties of the Pancreas Influencing Isolation.- 3. Properties of Insulin Influencing Isolation.- 4. Methods of Detecting Impurities.- II. Methods of Insulin Isolation.- 1. Extraction and Precipitation.- 2. Adsorption to Ion Exchangers.- 3. Table: Yield of Insulin Obtained Using Different Methods.- III. Insulin Purification Using Chromatographic Methods.- 1. Paper Chromatography.- 2. Gel Chromatography.- 3. Ion Exchange Chromatography.- a) Cation Exchangers.- b) Anion Exchangers.- IV. Special Purification Processes.- 1. Countercurrent Distribution and Partition Chromatography.- 2. Electrophoresis.- V. Table: Isolation of Insulin from Different Species.- VI. Isolation of Insulin Analogs and the C-Peptide.- References.- E. Insulin Preparations with Prolonged Effect.- I. Introduction.- 1. History.- 2. Pharmaceutical Chemistry.- 3. Absorption.- 4. Timing.- 5. Mixtures.- 6. Stability.- 7. Immunological Side Effects.- II. Insulin Preparations.- 1. PZI and NPH.- a) Protamine Insulin.- b) PZI.- c) NPH.- d) Pharmaceutical Composition.- 2. Surfen Insulins.- 3. The Lente Insulins.- a) Introduction.- b) Chemistry.- c) Crystallization of Insulin.- ?) The role of metal ions.- ?) The shape and size.- d) Composition.- e) Timing of Action.- f) Clinical Results.- 4. Insulin Rapitard.- III. Monocomponent Insulin.- 1. Introduction.- 2. Immunogenicity of Components of Crystalline Insulin in Rabbits.- 3. Preparation and Stability of MC Insulin Preparations.- 4. Clinical Results.- a) Insulin Antibodies.- b) Antibodies Against Proinsulin and a-Component.- References.- Author Index.