Contemporary Metabolism

1 Disorders of Purine and Pyrimidine Metabolism.- 1.1. Introduction.- 1.2. Purine Metabolism.- 1.2.1. Hypoxanthine Reutilization as a Normal Regulator of Purine Synthesis de Novo.- 1.2.2. Drugs That Increase Purine Synthesis de Novo.- 1.2.3. Changes in Purine Metabolism with Cellular Proliferation.- 1.2.4. Role of the Purine Nucleotide Cycle.- 1.2.5. Role of the Purine Nucleotide Cycle in Transport Processes.- 1.2.6. Effect of Fructose.- 1.3. Adenosine Deaminase Deficiency Associated with Severe Combined Immunodeficiency Disease.- 1.3.1. Clinical Presentation.- 1.3.2. Frequency.- 1.3.3. Enzyme Abnormality.- 1.3.4. Screening Tests.- 1.3.5. Prenatal Diagnosis.- 1.3.6. Genetic Heterogeneity.- 1.3.7. Metabolic Studies.- 1.3.8. Model Systems of Adenosine Deaminase Deficiency.- 1.3.9. Treatment.- 1.4. Purine Nucleoside Phosphorylase Deficiency.- 1.4.1. Clinical Presentation.- 1.4.2. Enzyme Abnormalities.- 1.4.3. Purine Metabolites in Urine.- 1.4.4. Metabolic Studies.- 1.4.5. Treatment.- 1.4.6. Purine Nucleoside Phosphorylase Distribution in Human Tissues.- 1.5. Biochemical Basis of the Immunodeficiency in Adenosine Deaminase and Purkie Nucleoside Phosphorylase Deficiency.- 1.5.1. Ribonucleoside Accumulation.- 1.5.2. Pyrimidine Starvation.- 1.5.3. Possible Role of Cyclic AMP.- 1.5.4. Deoxyribonucleoside Accumulation.- 1.5.5. Implications for Therapy.- 1.6. Purine 5'-Nucleotidase Deficiency in Hypogammaglobulinemia.- 1.6.1. Clinical Categories with Low Purine 5'-Nucleotidase.- 1.6.2. Enzyme Characteristics.- 1.7. Adenine Phosphoribosyltransferase Deficiency.- 1.7.1. Clinical Presentation.- 1.7.2. Composition of Calculi.- 1.7.3. Purine Metabolites in the Urine and Plasma.- 1.7.4. Adenine Phosphoribosyltransferase Activity in Erythrocytes.- 1.7.5. Treatment.- 1.7.6. Metabolic Significance.- 1.7.7. Frequency.- 1.8. Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency.- 1.8.1. Genetic Heterogeneity.- 1.8.2. Enzyme Characteristics.- 1.8.3. Enzyme Assays.- 1.8.4. Genetic Transformation.- 1.8.5. Neurological Disorders.- 1.8.6. Attempts to Produce a Hypoxanthine-Guanine- Phosphoribosyltransferase-Deficient Mouse.- 1.8.7. Mechanism of Excessive Purine Synthesis.- 1.8.8. Other Metabolic Correlations.- 1.9. Increased Phosphoribosyl-1-Pyrophosphate Synthetase Activity.- 1.9.1. Enzyme Characteristics.- 1.9.2. Inheritance.- 1.9.3. Biochemical Studies.- 1.10. Xanthinuria.- 1.10.1. Conditions Associated with Hypouricemia.- 1.10.2. Clinical Presentation.- 1.11. Gouty Arthritis.- 1.11.1. Hyperuricemia.- 1.11.2. Diagnosis.- 1.11.3. Disorders Associated with Gout.- 1.11.4. The Kidney and Gout.- 1.11.5. Association of Hyperuricemia and Vascular Disease.- 1.11.6. Association of Hyperuricemia with Avascular Necrosis of the Femoral Head.- 1.11.7. Acute Attack of Gout.- 1.11.8. Treatment.- 1.11.9. Metabolic Factors That Contribute to Hyperuricemia.- 1.12. Decreased Adenylate Deaminase Activity.- 1.13. Abnormalities of Pyrimidine Metabolism.- 1.13.1. Ammonia and Pyrimidine Nucleotide Synthesis.- 1.13.2. Pyrimidine 5'-Nucleotidase Deficiency.- 1.13.3. Orotic Aciduria.- 1.14. Abnormalities of DNA Repair (Xeroderma Pigmentosum).- 1.15. Purine and Pyrimidine Compounds as Inhibitors of Viral and Cellular Proliferation.- 1.15.1. Effective Clinical Treatment of Herpes Encephalitis with Adenine Arabinoside.- 1.15.2. New Antiviral Agents.- References.- 2 Metabolic Actions of Ethanol.- 2.1. Effects of Ethanol on Protein Metabolism.- 2.1.1. Origin of the Increased Liver Protein.- 2.1.2. Type of Proteins That Accumulate after Chronic Alcohol Consumption.- 2.1.3. Mechanisms of the Alcohol-Induced Accumulation of Liver Protein.- 2.1.3.1. Effects of Ethanol on Protein Synthesis.- 2.1.3.2. Effects of Ethanol on Protein Secretion.- 2.1.3.3. Effects of Ethanol on Protein Catabolism.- 2.1.4. Summary of the Alcohol-Induced Alterations of Hepatic Protein Metabolism and Possible Consequences.- 2.2. Effects of Ethanol on Lipid Metabolism.- 2.2.1. Liver Upids.- 2.2.2. Alcohol-Induced Alterations in the Metabolism of Serum Lipoproteins.- 2.2.3. Alcohol, Coronary Heart Disease, and High-Density Lipoproteins.- 2.2.4. Conclusion.- References.- 3 Disorders of Lipid and Lipoprotein Metaboiism.- 3.1. Introduction.- 3.2. Lipoprotein Structure and Metabolism.- 3.2.1. General Review.- 3.2.2. Apolipoprotein C-II.- 3.2.3. High-Density Lipoproteins.- 3.2.4. The Lp(a) Lipoprotein.- 3.2.5. Lipoprotein-X and Liver Disease.- 3.3. Type III Hyperlipoproteinemia.- 3.3.1. Diagnosis.- 3.3.2. Apolipoprotein E.- 3.3.3. Pathophysiology; Treatment.- 3.4. Tangier Disease.- 3.5. High-Density Lipoprotein Levels and Coronary Heart Disease.- 3.5.1. Epidemiologic Studies.- 3.5.2. Alcohol, High-Density Lipoproteins, and Coronary Risk.- 3.5.3. Other Clinical Studies.- 3.5.4. Pathophysiology.- 3.5.5. Implications.- 3.6. Cholesterol Metabolism and Its Regulation.- 3.6.1. In Intact Humans.- 3.6.2. In Cultured Cells.- 3.7. Familial Hypercholesterolemia.- 3.7.1. Epidemiologic and Clinical Studies.- 3.7.2. Pathophysiology.- 3.7.3. Therapy.- 3.8. Chronic Renal Failure and Hyperlipidemia.- 3.8.1. Pathophysiology.- 3.8.2. Therapy.- 3.9. Hypertriglyceridemia.- 3.9.1. Pathophysiology.- 3.9.2. Diabetes Mellitus; Other Clinical Studies.- 3.9.3. Treatment Effects: Diet, Drugs, Exercise.- 3.10. Hyperlipidemia and Its Treatment.- 3.10.1. Epidemiologic Studies.- 3.10.2. Definition and Classification.- 3.10.3. Diet.- 3.10.4. Drugs.- 3.10.5. Prevention of Ischemic Heart Disease.- References.- 4 Nutrition and Cellular Growth of the Brain.- 4.1. Methods for Producing Early Malnutrition.- 4.2. Malnutrition and Brain Size.- 4.3. Malnutrition and Cellular Growth of the Brain.- 4.4. Malnutrition and Myelination.- 4.5. Other Effects of Malnutrition on the Growing Brain.- 4.6. Regional Changes Induced by Malnutrition.- 4.7. Malnutrition and Cellular Growth of the Peripheral Nerves.- 4.8. Malnutrition and Cellular Growth of the Human Brain.- References.- 5 Metabolic Aspects of Renal Stone Disease.- 5.1. Introduction.- 5.2. Renal Stone Disease Secondary to Increased Crystalloid Excretion.- 5.2.1. Hypercalciuria.- 5.2.2. Hyperuricosuria.- 5.2.3. Hyperoxaluria.- 5.3. Treatment of Renal Stone Disease.- References.- 6 Hormone Receptors, Cyclic Nucleotides, and Control of Cell Function.- 6.1. Introduction.- 6.2. Receptor Systems.- 6.2.1. Physiological Regulation of Receptors.- 6.2.2. Relationship of Receptors to Adenylate Cyclase.- 6.2.3. Opiate Receptors and Endorphins.- 6.2.4. Catecholamine Receptors.- 6.2.4.1. Adrenergic Receptors.- 6.2.4.2. a-Adrenergic Receptors.- 6.2.4.3. Dopamine.- 6.2.5. Hormone Receptors in the Kidney.- 6.2.6. Somatomedin Receptors, Multiplication- Stimulating Activity, and Other Growth Factors.- 6.2.7. Insulin Receptors.- 6.3. Regulation of Adenylate Cyclase.- 6.3.1. Guanine Nucleotide Control.- 6.3.2. Guanosine Triphosphatase.- 6.3.3. Guanine Nucleotides and Agonist Affinity.- 6.3.4. Cholera Toxin and Adenylate Cyclase.- 6.4. Protein Kinases.- 6.4.1. Cell Regulation by Occupied Cyclic AMP Receptors.- 6.5. Calcium Regulation of Cyclic Nucleotide Concentration.- 6.6. Cyclic Nucleotides in the Extracellular Fluids.- 6.6.1. Nephrogenous Cyclic AMP in Parathyroid and Related Disorders.- References.- 7 Diabetes Mellitus.- 7.1. Heterogeneity of Diabetes Mellitus.- 7.1.1. The Histocompatibility System (HLA) and Genetic Susceptibility to Diabetes Mellitus.- 7.1.2. Susceptibility to Viral Infection and Viral Infection in the Etiology of Diabetes Mellitus.- 7.1.5. Autoimmunity in Diabetes Mellitus.- 7.2. Insulin Secretion.- 7.2.1. Experimental Results in Animals: Hypothalamic Influences.- 7.2.2. Regulation in Man.- 7.2.2.1. Effects of Intraportal and Peripheral Infusions of Glucagon on Insulin Secretion.- 7.2.2.2. Effects of Secretin.- 7.2.2.3. Effects of Hypocalcemia and Theophylline.- 7.2.2.4. Plasma Insulin in Early Diabetes.- 7.2.2.5. Plasma Insulin in Diabetes.- 7.2.2.6. Measurement of Other Beta Cell Secretory Products: Proinsulin and C- Peptide.- 7.2.2.7. Effects of Control of Diabetes on Insulin Secretion.- 7.3. Insulin Resistance and Insulin Receptors.- 7.3.1. Insulin Resistance and Sensitivity.- 7.3.2. Insulin Receptors.- 7.3.2.1. Insulin Receptors and Insulin Resistance in Diabetes.- 7.3.2.2. Insulin-Binding in Other Clinical Conditions.- 7.3.3. Autoantibodies to Insulin Receptors.- 7.4. Diabetes and Exercise.- 7.4.1. Exercise and Diabetes Mellitus in Man.- 7.4.2. Effect of Exercise in Depancreatized Dogs.- 7.4.3. Effect of in Vitro Contracting Skeletal Muscle on Glucose Uptake.- 7.5. Diabetes and Pregnancy.- 7.5.1. Special Considerations.- 7.5.2. Management of Pregnancy in Diabetic Patients.- 7.6. Acidosis in Diabetes.- 7.6.1. Diabetic Ketoacidosis.- 7.6.1.1. Diabetic Ketoacidosis and Low-Dose Insulin Therapy.- 7.6.2. Lactic Acidosis.- 7.7. Long-Term Complications.- 7.7.1. Diabetic Neuropathy.- 7.7.1.1. Evidence of Genetic Heterogeneity.- 7.7.1.2. Radiculopathy.- 7.7.1.3. Peripheral Neuropathy.- 7.7.1.4. Diabetic Amyotrophy.- 7.7.1.5. Autonomic Neuropathy.- 7.7.1.6. Myoinositol Metabolism.- 7.7.1.7. Experimental Diabetes and Diabetic Neuropathy.- 7.7.2. Diabetic Microangiopathy.- 7.7.2.1. Muscle Capillary Basement Membrane Thickening.- 7.7.2.2. Diabetic Microangiopathy and Intravascular Factors.- 7.7.2.3. Diabetic Retinopathy.- 7.7.2.4. Renal Changes and Nephropathy.- 7.7.3. Bone Mass in Diabetes Mellitus.- 7.8. Treatment of Diabetes Mellitus.- 7.8.1. General Considerations.- 7.8.2. Glycosylated Hemoglobin and Diabetic Control.- 7.8.3. Diet.- 7.8.4. Insulin.- 7.8.4.1. Chronic Insulin Therapy.- 7.8.4.2. Insulin Antibodies.- 7.8.4.3. Lipoatrophy.- 7.8.4.4. Insulin Delivery Systems.- 7.8.5. Transplantation.- 7.8.6. Oral Hypoglycemic Agents.- References.- 8 Glucagon and Somatostatin.- 8.1. Anatomy of the Islets of Langerhans.- 8.1.1. Topographical Relationships of the Islet Cells.- 8.1.2. Vascular and Neural Relationships.- 8.1.3. "Paracrine" Relationships.- 8.1.4. Subcellular Specializations.- 8.1.4.1. Tight Junctions.- 8.1.4.2. Gap Junctions.- 8.2. Structure-Function Relationships of Glucagon.- 8.2.1. Biological Structure-Function Relationships.- 8.2.2. Immunologic Structure-Function Relationships.- 8.3. Pancreatic and Extrapancreatic Immunoreactive Glucagons.- 8.3.1. Immunoreactive Glucagon Fractions in Tissue Extracts.- 8.3.1.1. Pancreas.- 8.3.1.2. Stomach.- 8.3.1.3. Intestine.- 8.3.1.4. Salivary Gland.- 8.3.2. Biosynthesis of Pancreatic Glucagon.- 8.3.3. Extrapancreatic A Cells and Glucagon Secretion.- 8.3.3.1. A Cells.- 8.3.3.2. Glucagon.- 8.3.4. Immunoreactive Glucagon in Plasma.- 8.4. Glucagon Metabolism, Clearance, and Degradation.- 8.5. Actions of Glucagon.- 8.5.1. Mechanisms.- 8.5.1.1. Receptor Binding.- 8.5.1.2. Adenylate Cyclase Activation.- 8.5.1.3. Glycogenolysis.- 8.5.1.4. Gluconeogenesis.- 8.5.1.5. Ketogenesis.- 8.5.1.6. Effects on Lipids.- 8.5.2. Physiology.- 8.5.2.1. Glycogenolysis.- 8.5.2.2. Gluconeogenesis.- 8.6. Control of Glucagon Secretion.- 8.6.1. Control by Nutrients.- 8.6.1.1. Glucose.- 8.6.1.2. Amino Acids.- 8.6.1.3. Free Fatty Acids.- 8.6.2. Influence of Hormones.- 8.6.2.1. Gastrointestinal Hormones.- 8.6.2.2. Neurotensin and Substance P.- 8.6.2.3. Bombesin.- 8.6.2.4. Other Factors.- 8.6.3. Neural Control.- 8.6.3.1. Hypothalamic Influences.- 8.6.3.2. Adrenergic Stimulation-Stress and Exercise.- 8.6.3.3. Dopaminergic Influence.- 8.6.3.4. Serotonin.- 8.7. Glucagonlike Immunoreactivity (Enteroglucagon).- 8.8. Somatostatin.- 8.8.1. Distribution in Tissues.- 8.8.1.1. Central Nervous System.- 8.8.1.2. Gastrointestinal Tract.- 8.8.1.3. Pancreas.- 8.8.2. Pancreatic Somatostatin Release.- 8.8.3. Mechanism of Action.- 8.8.4. Abnormalities of Somatostatin.- 8.8.5. Somatostatin Degradation.- 8.8.6. Somatostatin Analogues.- 8.9. Glucagon in Clinical Medicine.- 8.9.1. Diabetes Mellitus.- 8.9.1.1. A-Cell Function in Diabetes.- 8.9.1.2. Effect of Insulin on A-Cell Function in Juvenile-Type Diabetes Mellitus.- 8.9.1.3. Effect of Insulin on Adult-Onset Diabetics.- 8.9.1.4. Pathophysiologic Importance of Glucagon in Insulin Deficiency.- 8.9.1.5. Controversy Concerning the Importance of Glucagon in Diabetes Mellitus.- 8.9.1.6. Controversy Concerning the Role of Glucagon in the Presence of Insulin.- 8.9.1.7. Mechanism of Somatostatin-Induced Amelioration of Diabetic Hyperglycemia.- 8.9.2. Glucagonoma.- 8.9.3. Nondiabetic Hyperglucagonemia.- 8.9.4. Glucagon Deficiency.- References.- 9 Recent Advances in Body Fuel Metabolism.- 9.1. Introduction.- 9.2. Glucose Metabolism.- 9.2.1. Is Glucagon Essential in Diabetes?.- 9.2.1.1. Somatostatin-Induced Hypoglucagonemia.- 9.2.1.2. Pancreatectomized Man.- 9.2.2. Effects of Hyperglucagonemia.- 9.2.2.1. Normal Man.- 9.2.2.2. Diabetes.- 9.2.2.3. Uremia.- 9.2.3. Glucose Production: Gluconeogenesis from Alanine.- 9.2.4. The Counterregulatory Response to Hypoglycemia.- 9.3. Ketone and Fatty Acid Metabolism.- 9.3.1. Hormonal Control of Ketogenesis.- 9.3.2. Role of Malonyl-Coenzyme A.- 9.3.3. Hypoketonemic Action of Alanine.- 9.4. Amino Acid Metabolism.- 9.4.1. Origin of Alanine Synthesized in Skeletal Muscle.- 9.4.2. Metabolic Fate of Glutamine Utilized by Intestine.- 9.5. Fuel Metabolism in Exercise.- 9.5.1. Influence of Glucose Ingestion before Exercise.- 9.5.2. Influence of Ethanol Ingestion.- 9.5.3. Glucose-Sparing Effect of Free Fatty Acids.- 9.5.4. Interaction of Exercise and Insulin in Diabetes 376.- References.- 10 What's New in Obesity: Current Understanding of Adipose Tissue Morphoiogy.- 10.1. Introduction.- 10.2. Techniques for Measuring Adipocyte Size and Number.- 10.2.1. Intact Tissue.- 10.2.2. Osmium-Fixed Tissue.- 10.2.3. Adipocyte Suspensions.- 10.2.4. Advantages and Disadvantages of Counting Techniques.- 10.3. Cellularity of Adipose Tissue in Man and Animals.- 10.3.1. Development of Adipose Cellularity in Man.- 10.3.2. Adipose Cellularity in Laboratory Rodents.- 10.3.3. Cellularity in Human Obesity.- 10.3.4. Cellularity in Animal Obesity.- 10.4. How Constant Is Adipocyte Number?.- 10.4.1. Stability of Cell Number.- 10.4.2. Changes in Cell Number.- 10.5. How Are New Adipocytes Formed?.- 10.6. Significance of Cell Size and Number in Energy Regulation.- References.- 11 Divalent Ion Metabolism.- 11.1. Introduction.- 11.2. Vitamin D.- 11.2.1. Introduction.- 11.2.2. Metabolism and Transport of 25-Hydroxy-Vitamin Dg.- 11.2.3. Regulation of 25-Hydroxy-Vitamin Dg-la- Hydroxylase and Generation of 1,25-Dihydroxy- Vitamin Dg.- 11.2.4. Measurement of Vitamin D Metabolites in Plasma.- 11.2.5. Actions of Vitamin D.- 11.2.5.1. Effects on Phosphate Homeostasis and Absorption.- 11.2.5.2. Actions of Vitamin D on the Kidney.- 11.2.5.3. Effect of Vitamin D on the Parathyroid Glands.- 11.2.6. Biological Actions of 24,25-Dihydroxy-Vitamin Dg..- 11.2.7. Metabolism and Degradation of Vitamin D.- 11.2.8. Intestinal Calcium Absorption and Mechanism of Adaptation to a Low-Calcium Diet.- 11.2.8.1. Methods of Assessing Calcium Absorption.- 11.3. Clinical Disorders That Involve Altered Vitamin D Metabolism.- 11.3.1. Abnormal Metabolism of 25-Hydroxy-Vitamin Dg.- 11.3.1.1. Liver Disease.- 11.3.1.2. Anticonvulsants.- 11.3.1.3. Nephrotic Syndrome.- 11.3.2. Defective Production of 1,25-Dihydroxy-Vitamin Dg.- 11.3.2.1. Renal Osteodystrophy.- 11.3.2.2. Diabetes MeUitus.- 11.3.2.3. Osteomalacia Related to Mesenchymal Tumor.- 11.3.2.4. Fanconi Syndrome.- 11.3.3. Other Disorders with Uncertain Relationship to Vitamin D.- 11.3.3.1. Neonatal Hypocalcemia.- 11.3.3.2. Familial Hypophosphatemic Vitamin-D- Resistant Rickets.- 11.3.3.3. "Itai-Itai" Disease.- 11.3.3.4. Metabolic Acidosis.- 11.3.3.5. Glucocorticoid Treatment.- 11.3.4. Endocrine Disorders with Altered Production of I, 25-Dihydroxy-Vitamin Dg.- 11. 3.4.1. Hypoparathyroidism.- 11.3.4.2. Pseudohypoparathyroidism.- 11.4. Phosphorus Metabolism.- 11.4.1. Regulation of Phosphorus by the Kidney.- 11.4.1.1. Effect of Restriction of Phosphorus Intake.- 11.4.1.2. Adaptation to High-Phosphorus Intake.- 11.4.1.3. Effect of Parathyroid Hormone.- 11.4.1.4. Effects of Estrogen on Phosphate Metabolism.- 11.4.1.5. Growth Hormone and Renal Phosphate Reabsorption.- 11.4.1.6. Other Factors That Affect Renal Handling of Phosphorus.- 11.4.2. Phosphate-Depletion Syndrome.- References.- 12 Metabolism of Amino Acids and Organic Acids.- 12.1. Pyruvate Metabolism and Its Disorders.- 12.2. Pyruvate Metabolism and Its Regulation.- 12.2.1. Pyruvate Kinase.- 12.2.2. The Pyruvate Dehydrogenase Complex.- 12.2.3. Pyruvate Carboxylase.- 12.2.4. Phosphoenolpyruvate Carboxykinase and the Malate Shutde.- 12.2.5. Metabolic Regulation of Pyruvate Metabolism.- 12.3. Specific Disorders of Pyruvate Metabolism.- 12.3.1. Erythrocyte Pyruvate Kinase Deficiency.- 12.3.2. Pyruvate Carboxylase Deficiency.- 12.3.3. Phosphoenolpyruvate Carboxykinase Deficiency.- 12.3.4. Pyruvate Dehydrogenase Complex Mutants.- 12.3.4.1. Pyruvate Decarboxylase Deficiency.- 12.3.4.2. Dihydrolipoyl Transacetylase Deficiency.- 12.3.4.3. Dihydrolipoyl Dehydrogenase Deficiency.- 12.3.5. Pyruvate Dehydrogenase Phosphatase Deficiency.- 12.3.6. Decreased Activity of Pyruvate Oxidation in Patients with Friedreich's Ataxia and OtherNeuromuscular Diseases.- References.