Main description:

Since insulin became available for the treatment of diabetes in 1922 a number of major advances have been made, which include the modification of insulin to vary its timing of action, its purification, and latterly, the production of human insulin. Human insulin in quantities sufficiently large for therapy has been made available by two techniques developed in parallel during the late 1970s. These involve either (i) formulation in E. coli bacteria suitably encoded by DNA recombinant methods of the A- and B-chains of human insulin followed by a chain combination reaction ('biosynthetic' human insulin) or (ii) enzymatic conversion (transpeptidation) of porcine insulin brought to react with a threonine ester by porcine trypsin in a mixture of water and organic solvents, yielding human insulin ('semi-synthetic' human insulin). This book includes the first clinical-pharmacological studies of each of the highly purified 'semi-synthetic' human insulin preparations: Actrapid (R) HM; Monotard (R) HM; Protaphane (R) HM; Actraphane (R) HM; and Ultratard (R) HM (Novo Industri A/S, Copenhagen). The preliminary studies established their safety and efficacy relative to their porcine and bovine counterparts emphasising the relevance of species and formulation on the pharmacokinetics and biological responses to insulin. Additional investigations with human insulin demonstrated the influence of insulin concentration, site of administration, the addition of aprotinin to insulin and the mixing of 'short-' and 'intermediate-acting' formulations on insulin 'bioavailability'. Examination of the 'within' and 'between' subject day-to-day variation in absorption and the effect of subcutaneous insulin also demonstrates the dominating influence of insulin responsiveness.

Contents:

1 Introduction.- 1.1 Historical introduction to diabetes and its treatment.- 1.1.1 The clinical syndrome of diabetes mellitus.- 1.1.2 The discovery of insulin.- 1.1.3 Summary.- 1.2 The evolution of insulin.- 1.2.1 Production of insulin.- 1.2.2 Purity and immunogenicity of insulin.- 1.2.2.1 Insulin purity.- 1.2.2.2 Clinical implications of the quest for insulin purity.- 1.2.2.3 Other considerations insulin species, etc.- 1.2.3 Human insulin.- 1.2.3.1 Human cadaveric pancreas.- 1.2.3.2 Total peptide synthesis.- 1.2.3.3 Enzymatic conversion of porcine to human insulin.- 1.2.3.4 Recombinant DNA technology.- 1.2.4 Summary.- 2 Objectives of investigations.- 3 Investigational procedures.- 3.1 Clinical: Subjects, Materials, Methods.- 3.2 Laboratory methods.- 4 Clinical-pharmacological studies.- 4.1 'Short-acting' insulin preprations.- 4.1.1 Study of safety and efficacy of human insulin in normal man.- 4.1.2 Comparison of subcutaneous human, porcine and bovine insulin in man.- 4.1.3 Comparative study of subcutaneous human and porcine insulin in man, without the concomitant use of somatostatin.- 4.1.4 The influence of somatostatin on the metabolic and hormonal responses to subcutaneous human and porcine insulin.- 4.1.5 Dose-response study of human, porcine and bovine insulin.- 4.1.6 Comparative study of intravenous and intramuscular administration of human insulin.- 4.1.7 A study of intravenous (human, porcine, bovine) and intramuscular (human) insulin in normal man.- 4.1.8 A study of the hormonal counterregulatory responses to subcutaneous and intravenous human ('semi-synthetic', 'biosynthetic') and porcine insulins.- 4.2 Insulin preparations with prolonged effect.- 4.2.1 'Intermediate-acting' insulin preparations.- 4.2.1.1 A study of human ('semi-synthetic') and porcine Lente (Monotard) insulins (U-40).- 4.2.1.2 A study of human ('semi-synthetic' and 'biosynthetic') and porcine NPH ('isophane') insulins (U-40).- 4.2.1.3 Comparative study of Lente (Monotard) and NPH insulins ('semisynthetic' human insulin: U-100, U-40; porcine insulin: U-40).- 4.2.2 'Long-acting' insulin preparations.- 4.2.2.1 A study of human ('semi-synthetic') porcine and bovine Ultralente insulins (U-100).- 4.3 Factors influencing subcutaneous absorption of human insulin.- 4.3.1 Site of administration and influence of a protease inhibitor, aprotinin (Trasylol).- 4.3.2 Insulin concentration: U-40 vs U-100 'short-' and 'intermediate-acting' insulin preparations.- 4.3.2.1 U-40 versus U-100: 'short-acting insulins.- 4.3.2.2 U-40 versus U-100: 'intermediate-acting' insulin study.- 4.3.2.3 General discussion and summary.- 4.3.3 Insulin mixtures.- 4.3.3.1 Soluble and NPH mixtures.- 4.3.3.2 Soluble and Lente mixtures.- 4.3.3.3 Discussion.- 4.3.4 'Within' and 'between' subject variation.- 4.3.4.1 Soluble insulin (U-100).- 4.3.4.2 Lente insulin (U-100).- 4.3.4.3 General discussion.- 5 Summary.- Acknowledgements.