Synthetic insulin – a matter of life and death
Nicholas Field
Diabetes was first described around 1500 BC by ancient Egyptian doctors who noted ‘ too great emptying of the urine ’ (1). However, it is only within the last hundred years that the principal causes of diabetes mellitus have been understood, and the critical hormone, insulin, has been identified. Since the first purification from canine pancreatic extract, the science of pharmaceutical insulin has developed rapidly, leading to the award of two Nobel prizes and a fascinating story of Chemistry. Before discussing this narrative, it is necessary to outline the physiology of the body and pathophysiology of diabetes. The human body must control blood glucose concentration within a tight range in order to function correctly. When the glucose concentration falls below the lower limit of this physiological range, a situation known as hypoglycaemia, the body responds by secreting hormones, including glucagon and adrenaline, to restore blood glucose to normal (2). The other effects of these hormones on the body include hunger, tremor, sweating and an increased heart rate. If the blood glucose concentration falls too low, impaired cognitive function, reduced conscious level, seizures, coma or even death may occur (2). Insulin, a peptide hormone secreted by beta-cells of the pancreatic islets of Langerhans, acts to lower blood glucose concentration (3, 4). The release of insulin is stimulated directly, at the level of a glucose-sensing mechanism within each beta-cell, and by neural stimulation through the autonomic nervous system, controlled by glucose-sensitive neurones in the brainstem and the ventromedial nucleus of the hypothalamus (5). Under the influence of insulin, the liver and muscle cells take up glucose and convert it to glycogen, an insoluble branched polysaccharide storage molecule. Insulin also facilitates lipogenesis (the formation of fat) in adipose tissue and inhibits gluconeogenesis (the synthesis of glucose from non-carbohydrate molecules, such as fatty acids and amino acids) (6). The disease (more properly nowadays considered as a group of diseases) in which insulin activity is deficient, is termed diabetes mellitus. Type 1 diabetes, which is the most common form in children and slim young adults, is caused by an immunologically mediated destruction (auto-immune; self- destruction) of the pancreatic beta-cells. This results in absolute insulin deficiency which can be rapidly fatal if left untreated. Type 2 diabetes is more prevalent in middle-aged and older people. On a background of genetic predisposition, a high body mass index associated with excess eating results in the body becoming insensitive to insulin; initial compensation, through increased stimulation of the pancreatic beta cells, is followed eventually by progressive loss of insulin secreting capacity (7). In the two major types of diabetes and in other rarer forms, normal glucose homeostasis is impaired by relative or complete lack of insulin. If not correctly managed, this results in prolonged excessive blood glucose concentration (7). In the short term, very high glucose concentration causes dehydration because glucose is excreted in the urine, taking water with it in a process known as osmotic diuresis. In type 1 diabetes, the complete absence of insulin and the associated extreme physiological stress can cause ketoacidosis, a rapidly developing and life-threatening situation arising from the breakdown of fatty acids to ketones (by oxidation) and the associated acidification of the blood. Persisting or
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