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  • Review Article
  • Published:

New horizons — alternative routes for insulin therapy

Nature Reviews Drug Discovery volume 1, pages 529–540 (2002)Cite this article

Key Points

  • Despite the introduction of insulin therapy, the pharmacokinetics of conventional insulin preparations given subcutaneously makes it difficult to replicate the normal pattern of nutrient-related and basal insulin secretion.

  • Realizing the dream of administering insulin orally has met with little, if any, success, despite the use of many strategies to overcome the barriers to absorption that are presented by the gastrointestinal tract. Administering insulin through the mucosa of the mouth is a potentially attractive option. However, the buccal and sublingual mucosae present special problems for insulin delivery due to the combined effects of the relatively thick, multilayered buccal barrier and the constant flow of saliva. Although the skin is easily accessible and has a large surface area, it is relatively impermeable to large hydrophilic polypeptides, such as insulin. The nasal mucosa is another potentially attractive route, but local barriers to absorption exist in the form of an active mucociliary transport mechanism and an enzymatically active, low-permeability, low-pH nasal epithelium.

  • The respiratory tree offers the largest available surface area for drug delivery, and provides an attractive option for the systemic delivery of drugs and polypeptide hormones.

  • Modern inhaler devices produce a polydisperse aerosol, and include a wide variety of nebulizers, pressurized metered-dose inhalers (pMDIs) and dry-powder inhalers (DPIs). These devices are limited by their dependence on the inspiratory flow rate, and hence patient technique, and are subject to large inter- and intra-subject variability. DPI devices are further limited by powder hygroscopicity, which reduces the respirable fraction.

  • The development of the intrapulmonary route has benefited from an improved understanding of the importance of aerosol particle size, inspiratory flow rate and inhaled volume. More research is continuing to ensure intrapulmonary delivery becomes a clinical reality. Specifically, methods of estimating bioavailability, biopotency and safety need to be standardized, and precision of dosing, dose adjustment and reproducibility remain key features. Assessing cost benefit is an integral part of the evaluation process.

  • Several other treatment options might be possible, including pancreas transplantation and islet-cell allotransplantation, and on the far horizon are exciting opportunities afforded by advancements in cell biology and genetics, some or all of which might provide the final opportunity for insulin independence.

  • This new millennium promises a revolutionary change in the delivery of insulin, which cannot come too soon for the billions of sufferers who are reliant on subcutaneous administration. Cautious optimism based on scientific rigour is the only way forward.

Abstract

Since the introduction of insulin therapy 80 years ago, the lives of millions of patients with diabetes have been saved, prolonged and immeasurably improved. However, restoring normal glucose levels in diabetic patients through administering insulin by subcutaneous injection has proved virtually impossible. The consequences for patients are serious complications, including diabetic retinopathy and nephropathy, which tend to result from persistent hyperglycaemia. Maximizing glucose control in diabetic patients requires several daily injections. In an effort to reduce this burden, alternative and less-intrusive routes for the administration of insulin are being explored.

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Figure 1: There are many alternative routes for the delivery of insulin.
Figure 2: The pulmonary tree provides a large surface area for drug/peptide delivery.
Figure 3: Pulmonary insulin-delivery devices.
Figure 4: Modification of inhaled insulin particles.

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Acknowledgements

I would like to thank S. Griffiths and L. Edwards for their help in the preparation of this manuscript, A. Shaw for the illustrations and G. Dodson for the insulin R6 hexamer structure.

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  1. Diabetes Research Unit, Llandough Hospital, University of Wales College of Medicine, Cardiff, CF64 2XX, Wales, UK

    David R. Owens

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DATABASES

LocusLink

glucagon

insulin

Medscape DrugInfo

insulin glargine

insulin lispro

Lente insulin

NPH insulin

OMIM

asthma

type 1 diabetes

type 2 diabetes

Glossary

HYPERGLYCAEMIA

An abnormally high level of glucose in the blood. It occurs when the body does not have enough insulin (insulin deficiency) or cannot use the insulin it does have (insulin resistance) to metabolize glucose.

NEPHROPATHY

A degenerative kidney disease that is associated with long-standing diabetes. Diabetic nephropathy is caused by damage to the glomerular capillaries. Features of the disorder include proteinuria, hypertension and progressive impairment of kidney function, which could, ultimately, lead to kidney failure.

RETINOPATHY

A degenerative disorder of the retina that is associated with long-standing diabetes. Diabetic retinopathy is one of the main causes of blindness. In an initial phase of the disorder, damage to retinal blood vessels causes leakage of fluid into the eye. Subsequently, new retinal vessels might form that, due to their fragile nature, could cause haemorrhage and subsequent blindness.

PHARMACOKINETICS

The study of the absorption, distribution, metabolism, excretion and interactions of a drug.

IONTOPHORESIS

The movement of ions under the influence of an applied electric field. The technique can be used to improve the absorption of drugs across the skin.

SONOPHORESIS

A method that is applied to increase transdermal drug delivery by the use of a high-frequency ultrasound system.

AMPHIPHILIC

One end of the molecule is hydrophilic and the other is hydrophobic.

BIOAVAILABILITY

The fraction or percentage of an administered drug or other substance that becomes available to the target tissue after administration.

EXCIPIENT

A largely inert substance that is added to a drug formulation to improve administration or absorption.

TYPE 2 DIABETES

A late-onset form of diabetes in which the pancreas produces insufficient insulin (insulin deficiency) or cannot use insulin (insulin resistance). Various treatments are used to control the condition, including dietary restriction, exercise, oral hypoglycaemic agents or injected insulin.

TYPE 1 DIABETES

An early-onset form of diabetes in which the β-cells of the pancreas produce little or no insulin. The condition is controlled with daily subcutaneous insulin injections or insulin that is delivered by either an external pump into the subcutaneous tissue or intraperitoneally.

MUCOCILIARY

Human airways are lined with a ciliary membrane. These cilia are ∼5 μm in length, and as the cilia beat, they engage with, and propel, a thin overlying layer of mucus.

HYGROSCOPICITY

The tendency of a drug or other substance to absorb or discharge moisture according to environmental conditions.

NEBULIZER

A device that uses pressurized air to turn a liquid medication into a fine mist for inhalation.

HbA1C

A modified form of haemoglobin that contains covalently bound glucose molecules. HbA1c levels are used to monitor long-term glycaemic control in diabetic patients. The HbA1c level reflects the average blood-glucose level over the previous four months. The HbA1c level in normal subjects is less than 7%. In poorly controlled diabetic subjects, levels above 12% could be seen.

SCINTIGRAPHY

A diagnostic test in which a two-dimensional picture of the internal structure of an organ is obtained. Radiolabelled chemicals are injected into the blood and are taken up by specific tissues. X-rays are used to produce an image of the organ.

PHAGOCYTOSIS

The process of the engulfment and destruction of extracellular materials by phagocytic cells, such as macrophages and neutrophils.

ALLOTRANSPLANTATION

The transfer of cells, tissues and/or whole organs from one individual to another within the same species.

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Owens, D. New horizons — alternative routes for insulin therapy. Nat Rev Drug Discov 1, 529–540 (2002). https://doi.org/10.1038/nrd836

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