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Insulin analogues: a step forward in the care in diabetes

The isolation of insulin by Banting and Best in 1921 transformed diabetes from a fatal condition to one that could be managed, giving hope for the first time that people with type 1 diabetes could expect a reasonable quality of life. With time, however, the limitations of animal insulin became apparent. The lack of purity led to allergic reactions and disfiguring injection site reactions while people with long-standing diabetes developed the chronic microvascular complications of retinopathy, nephropathy and neuropathy that are now so familiar. Initially it was suspected that insulin itself may have been responsible for the microvascular complications and it was only later that it became apparent that hyperglycaemia and diabetes themselves were responsible. The advent of recombinant technology allowed the introduction of human insulin and improved purity [1]. It seemed logical that human subjects should require human insulin and the use of animal insulin began to decline; and yet, is this the case? Subcutaneous insulin administration is unphysiological and leads to several challenges for the clinician and person with diabetes. The aggregation of insulin molecules into hexamers in the subcutaneous tissue means that absorption from a subcutaneous site is often delayed and may be unpredictable [2]. Consequently, human soluble insulin may not reach the circulation in time to match a postprandial peak of glucose while remaining in the circulation between meals. The mismatch between supply and demand may lead to postprandial hyperglycaemia while rendering the person at risk of hypoglycaemia later between meals and limiting their ability to achieve optimal glycaemic control. Modifications to human and animal insulin prolonged their duration of action to allow control overnight and between meals [3]. The pharmacological profile of these long-acting insulins, however, was also unpredictable and associated with an unphysiological and unwanted insulin peak overnight, leaving the recipient at risk of nocturnal hypoglycaemia. A further disadvantage of the subcutaneous administration of insulin is the reversal of the normal portal-systemic insulin concentration [4]. In non-diabetic individuals, insulin is secreted into the portal circulation and is largely cleared by the liver. Consequently, insulin concentrations are significantly higher in the portal circulation than in systemic circulation. Hepatic insulinization controls the rate of hepatic glucose output and glycogen storage and this may be impaired with reduced portal insulin. In addition, insulin is a major regulator of hepatic insulin-like growth factor I (IGF-I) production. In type 1 diabetes, reduced hepatic IGF-I production leads to reduced negative feedback to the pituitary and growth hormone hypersecretion, which in turn may have a role in the development of microvascular complications. In an attempt to overcome the problems associated with subcutaneous administration of human insulin, both short-acting and long-acting analogues of insulin have been developed [5]. Small modifications to the insulin molecule have changed their pharmacokinetics and have resulted in short-acting insulin that is absorbed more rapidly than standard human insulin. The shortacting insulin analogues are associated with less hypoglycaemia, particularly at night, and offer improved flexibility and convenience compared with soluble human insulin. Long-acting analogues provide a more stable and predictable basal insulin concentration with a lower propensity to weight gain than traditional longacting insulin and additionally, insulin detemir appears to be cleared preferentially by the liver, thereby, overcoming at least in part, one of the physiological disadvantages of subcutaneous administration. Premixed biphasic insulin analogues may also confer additional flexibility over standard human mixes. While insulin alone will not achieve excellent glycaemic control, these insulin analogues are a major advance in the management of diabetes and provide patients with the tools they need to strive for excellent control. The use of insulin analogues has become firmly established in