Insulin Glulisine
Summary
Several large-scale studies have demonstrated the need for tight blood sugar control in diabetic patients. Daily subcutaneous injections of human insulin are traditionally used to try to control blood sugar. While this method provides an improvement in glycemic regulation, it does not perfectly reproduce the normal profile of endogenous insulin concentrations during the day. Advances in protein engineering techniques, however, have resulted in the development of insulin analogues with better absorption capabilities from the subcutaneous depot, allowing improved insulin profiles in patients. At the same time, new strategies for administering insulin subcutaneously, but also by other routes of administration, have been developed.
Abstract
The importance of the intensive control of blood glucose in patients with diabetes has been well documented in several large scale studies. Attempts to attain strict glucose control when managing diabetes have traditionally utilized daily subcutaneous injections of human insulin. This strategy has offered improvements in glycaemic control but is unable to fully replicate the normal diurnal plasma profile of endogenous human insulin. Advances in protein engineering techniques have, however, resulted in the formulation of a number of insulin analogues that offer more desirable properties of absorption from the subcutaneous depot and hence improved insulin profiles in patients with diabetes. Concurrent to the development of insulin analogues, devices to deliver insulin either subcutaneously or by other routes have also advanced. These novel delivery strategies are also likely to contribute to improved glycaemic control for patients with diabetes in the future.
Injection of exogenous insulin was first used as a treatment for diabetes in 1922, by Fred Banting and Charles Best, in a patient with type 1 diabetes, resulting in a decrease in blood sugar of 4.40 at 3.20 g/l. This progress, clinically very significant in that it demonstrated that type 1 diabetes was not necessarily fatal, paved the way for what has been, for more than 75 years, the management of diabetes, the injection of insulin. As research progresses, insulin therapy has had a significant impact on diabetes-related mortality and morbidity, and improved the quality of life for millions of patients.
Initially, the most widely used preparations were based on bovine or porcine insulin, but the arrival of recombinant DNA techniques made it possible to produce, in quantity, an exogenous insulin identical to the molecule produced by the pancreas. More recently, protein engineering has led to the development of insulin analogues specifically designed for subcutaneous injection, which may further improve the treatment of diabetic patients.
The importance of normoglycemia
The glycemic profile of healthy individuals is characterized by a low plasma glucose concentration which increases slightly after meals. The pace of this profile is ensured by a continuous release of insulin, with peaks of secretion in response to food intake. This tight glycemic control, which keeps the plasma glucose concentration within a range of 3.5 to 7 mmol/l [1], suggests that higher blood glucose concentrations are potentially harmful.
The results of the large-scale DCCT (diabetes control and complications trial) [2] and UKPDS (UK prospective diabetes study) [3] studies support this hypothesis by demonstrating that a context of hyperglycaemia (identified on the basis of the percentage of glycated hemoglobin HbA1c) is a major risk factor for microvascular complications in type 1 diabetes (DCCT study) as in type 2 (UKPDS study). In the UKPDS study, for example, intensive treatment reduced diabetes-related microvascular parameters by 25%. Moreover, the two studies showed that any reduction in the concentration of HbA1c leads, apparently without a threshold effect, to a reduction in the incidence of microvascular complications. Although the studies both show that the association between lower blood sugar and lower cardiovascular risk is less strong, analysis of the UKPDS data indicates that there is a continuum between blood sugar and cardiovascular risk. For example, for every one point decrease in HbA1c, there is a 25% reduction in all-cause mortality and an 18% reduction in myocardial infarctions, whether fatal or not. The results of the DCCT and UKPDS studies led to the recommendation to use antidiabetic therapiesintensive ticks, with the primary objective of reducing any hyperglycaemia.
Since the DCCT and UKPDS studies were performed, it has become increasingly clear that postprandial glucose concentration is an independent risk factor for diabetes-associated vascular disease, hence the importance of its control in terms of clinics. For example, the DECODE study (diabetes epidemiology: collaborative analysis of diagnostic criteria in Europe), carried out on more than 25,000 patients, showed that blood sugar measured 2 hours after an oral glucose load is more closely associated than blood sugar with fasting has an increased risk of death [4]. Similarly, the Honolulu heart study found a strong correlation between post-load glucose concentration and cardiovascular mortality [5], while postprandial glycaemia was found to be an independent risk factor for cardiovascular mortality in the diabetes intervention study [6]. . Finally, postprandial glucose concentrations are more closely correlated with HbA1c than fasting glucose levels, suggesting that postprandial glucose regulation plays a particularly important role in overall glycemic maintenance [7].
Based on data from the DCCT and UKPDS studies, and more recent findings on the importance of postprandial glycemic control, conventional insulin therapy has become more intensive. In particular, it is a question of reproducing the daily insulin profiles of healthy subjects as well as possible, and not just of reducing the HbA1c values. To this end, insulin therapy according to a basal-bolus regimen has become the rule. In this scheme, the injection of long-acting insulin preparations (depot insulin) once or twice a day is supplemented by a preprandial injection of rapid-acting insulin (regular insulin). Several biotechnological advances have made it possible to optimize basal-bolus treatment, in particular the arrival of insulin analogues. The rest of this article is largely devoted to the development of these analogues. This article also reviews the new routes of administration of these analogues, essential to optimize their action, and other molecules likely to result in the reproduction of a normal glycemic profile.
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insulin alternatives