Insulin production

Traditionally, commercial insulin preparations were produced by direct extraction from pancreatic tissue of slaughterhouse pigs and cattle, followed by multistep chromatographic purification. However, the use of animal-derived product had a number of potential disadvantages, including:

Figure 11.2 Structure of the insulin receptor (a). Binding of insulin promotes autophosphorylation of the p-subunits, where each p-subunit phosphorylates the other p-subunit. Phosphate groups are attached to three specific tyrosine residues (tyrosines 1158, 1162 and 1163), as indicated in (b). Activation of the p-subunit's tyrosine kinase activity in turn results in the phosphorylation of various intracellular (protein) substrates which trigger the mitogen-activated protein kinase and/or the phosphoinositide (PI-3) kinase pathway responsible for inducing insulin's mitogenic and metabolic effects. The underlying molecular events occurring in these pathways are complex (e.g. refer to Combettes-Souverain, M. and Issad, T. 1998. Molecular basis of insulin action. Diabetes and Metabolism, 24, 477-489)

Figure 11.2 Structure of the insulin receptor (a). Binding of insulin promotes autophosphorylation of the p-subunits, where each p-subunit phosphorylates the other p-subunit. Phosphate groups are attached to three specific tyrosine residues (tyrosines 1158, 1162 and 1163), as indicated in (b). Activation of the p-subunit's tyrosine kinase activity in turn results in the phosphorylation of various intracellular (protein) substrates which trigger the mitogen-activated protein kinase and/or the phosphoinositide (PI-3) kinase pathway responsible for inducing insulin's mitogenic and metabolic effects. The underlying molecular events occurring in these pathways are complex (e.g. refer to Combettes-Souverain, M. and Issad, T. 1998. Molecular basis of insulin action. Diabetes and Metabolism, 24, 477-489)

Table 11.2 Selected genes whose rate of transcription is altered by binding of insulin to its receptor. In virtually all instances, the ultimate effect is to promote anabolic events characteristic of insulin action. Two-dimensional gel electrophoresis has also pinpointed dozens of proteins of unknown function whose cellular level is altered by insulin

Protein class Gene product in transcription rate)

Integral membrane Insulin receptor n proteins GH receptor

Glucose transporters

Enzymes Fatty acid synthetase

Glutamine synthetase n

Pyruvate kinase

Fructose 1,6-bis-phosphatase ^

Phosphoenolpyruvate ^

carboxykinase Glucokinase

Hormones IGF-1

Glucagon ^

GH I

Transcription factors C-Myc

C-Fos egr-1

• Immunogenicity. Bovine insulin differs from human insulin by three amino acids and it elicits an immunological response in humans. This can trigger long-term complications, including insulin resistance (as anti-insulin antibodies neutralize some of the administered products). The presence of these antibodies can also affect the pharmacokinetic profile of the drug, as antibody-bound insulin molecules are largely resistant to the normal insulin degradative process. Porcine insulin, differs from human insulin by only a single amino acid (residue 30 of the B-chain; threonine in humans, alanine in pigs) and is essentially non-immunogenic in humans. However, many of the porcine insulin contaminants (including porcine proinsulin) are immu-nogenic in humans.

• Availability. Some 170 million people suffer from diabetes worldwide, a figure projected to double by 2030. Insulin administration is essential to the survival of those with type-1 (insulin-dependent) diabetes, and is required to control the progression of a minority of those with (the more common) insulin-independent type-2 diabetes. The annual insulin requirement has surpassed 5000 kg and continues to grow, prompting concern of an insulin shortfall from slaughterhouse sources.

Such issues and concerns underpinned the development of recombinant human insulin products, now routinely used in the management of diabetes.

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