Future directions in insulin therapy.

Insulin therapy has a long history at the cutting edge of technological development through purification, extended-action, molecular chemistry, and devices, and in support technologies including self-measurement and patient education. But unmet needs remain large. Today's therapy cannot deliver minute-to-minute control of glucose levels, and cannot imitate the reflex/incretin driven physiological insulin delivery at mealtimes. Further it depends on a raft of devices for administration several times a day, devices liked for their functionality, but disliked as an intrusive reminder of the condition, several times a day. Approaches to overcoming these barriers include closed-loop systems and further modification of insulin formulations, but are limited by fundamental underlying difficulties. While clinical studies of oral insulin are in progress, the barriers to success look daunting. Development of small-molecule approaches (insulin-mimetic tablets) appears to have stalled, while concepts for glucose-responsive insulin as yet fail to deliver the necessary insulin-to-glucose gradient. Gene therapy, feasible in animals in preliminary studies, is not capable of providing feedback control. Transplantation of cultured islets and islet B-cells from stem cells thus looks to the be the best long-term prospect for insulin delivery in terms of overcoming the above barriers, but is a true biotechnological tour-de-force which will take time to mature.