Elsevier

Archives of Medical Research

Volume 36, Issue 3, May–June 2005, Pages 258-272
Archives of Medical Research

Review article
Insulin Therapy: Current Alternatives

https://doi.org/10.1016/j.arcmed.2005.03.012Get rights and content

In normal humans, blood glucose and insulin are maintained within a narrow range despite wide variations in physical activity and dietary intake. At present, reproducing this pattern is an impossible task in type 1 diabetes and extremely difficult in type 2 DM. New approaches using novel insulin analogs and routes of administration, attempting to replicate physiological insulin secretion in diabetic patients, are improving the profiles of glucose levels and, thus, the quality of life. Ultra-short-acting insulin analogues and ultra-long-acting analogues are being used for prandial and basal effects with better results, lower prevalence of hypoglycemia, and, hopefully, fewer chronic complications. Non-invasive routes of administration are being developed. The most promising appears to be inhaled insulin according to studies demonstrating excellent control, apparently without significant side effects, although in relatively short-term trials. Longer-term studies to assure the safety are still necessary before recommending its extended use. This is an extensive, up-to-date review of recent advances in insulin therapy.

Introduction

The Diabetes Control and Complications Trial (DCCT) confirmed the relationship between diabetes control and the prevalence of chronic complications (1). Based on this trial, the main goal of diabetes treatment is to obtain plasma glucose levels as close to normal as is currently possible with the lowest number of severe hypoglycemic episodes (2). Results of a study (3) done in our institution in 18 normal subjects, in whom glucose and insulin concentrations were measured frequently before, during, and after meals, revealed an intimate relationship between the changes in glucose and insulin resulting from fine regulatory mechanisms that are lost or severely altered in patients with diabetes. The exact reproduction of this pattern by exogenous insulin is virtually impossible. The available insulins are far from replicating the observed physiologic changes.

Techniques of genetic engineering developed during the last 20 years have allowed the introduction of multiple molecules of modified insulins. These are obtained by changes of the native protein through the substitution or addition of amino acid residues or binding to other chemical molecules, to modify their speed and length of action, with more selective, organ-specific effects and, lately, with new possible routes of administration. These innovations have allowed us to reach much lower and closer to normal levels of glycemia with lower prevalence of hypoglycemia. The main barriers for use of these new procedures continue to be poor information, economic limitations, and fear of hypoglycemia.

This article intends to review extensively and update the current alternatives for insulin therapy. Only the advances will be reviewed. Other techniques such as air-powered injectors, continuous subcutaneous (SC) insulin infusion, implantable insulin infusion pumps, intraperitoneal (IP) insulin delivery systems, and islet cell encapsulation will not be examined.

Effective treatment of type 1 diabetes requires insulin therapy to cover separately the replacement of basal and prandial levels. This intensive insulin therapy demands the application of multiple injections. Different from the previous insulins, insulin analogues have the advantage to reproduce levels of insulin more closely to the physiological ones and to achieve target glycemia with a lower prevalence of hypoglycemia.

Section snippets

Ultra-Rapid Analogues

We think, like others, that these analogues should be classified as molecules of ultra-short/ultra-rapid action. This denomination will permit its distinction from regular insulin since these analogues have a faster and shorter action and reach peaks higher than those obtained with regular insulin. The available ultra-rapid-acting analogues, lispro and aspart, both produce elevations of insulin that resemble more closely the normal changes produced in response to feeding (4).

Insulin Lispro

The first analogue

Conclusions

At present, insulin substitution therapy is still considered imperfect. The administration of the hormone by non-physiologic routes makes it difficult to obtain normal levels of the hormone at the precise moment and at the right place during feeding, rest, exercise, etc. Novel insulin analogues and routes of administration have been developed (147) that allow better levels of control and safety and, hopefully, with less chronic complications.

The introduction of new analogues that simulate

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