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Hope for insulin mimetic oral antidiabetic drugs.

The discovery of insulin at the beginning of this century was a major breakthrough in medicine, and initiated a new era in our understanding and treatment of diabetes. Nonetheless, diabetic patients who require insulin are still confronted with the discomfort of multiple subcutaneous injections or continuous insulin infusions. Recently, Moller’s group (1) has discovered a small molecule that binds to the intracellular b-subunit of the insulin receptor and mimics the effects of insulin. This compound is a non-peptidyl fungal metabolite which can be given orally, and exerts antidiabetic effects in mice. These findings, even though preliminary, raise the hope for new insulin-like oral drugs. During the past 77 years over which insulin has been given to diabetic patients, there have been many improvements in the preparation and the mode of administration. Molecular biology made the production of recombinant human insulin possible, and modern chemistry enabled the development of long-acting, and recently of very short-acting insulin formulations. These advances proved to be very useful in order to achieve tight glycemic control. Additionally, insulin pens provide patients with convenient injection devices and external insulin infusion pumps help control type 1 diabetic patients more easily and reduce the number of injections. Over the last few years, an increasing number of patients have undergone pancreas transplantation for a definitive cure of their type 1 diabetes. However, significant risks due to surgery and to lifelong immunosuppression are associated with this major invasive procedure. For type 2 diabetic patients, several different classes of oral antidiabetic drugs have been developed including the new class of insulin sensitizer, thiazolidinediones. These drugs have provided glycemic control for many non-insulin-dependent diabetic patients. But once type 2 diabetic patients progress to a more advanced stage of the disease and require insulin, they are left with the same limited options of insulin administration as type 1 diabetic patients. There have been a number of efforts to find novel routes for insulin administration in order to provide more comfort to the patient and to ensure higher compliance. At this year’s American Diabetes Association meeting in San Diego, California, major approaches such as the development of inhaled insulin and of oral insulin by chemical modification and the screening for insulin mimetic substances were presented. A variety of inhaled insulin systems have been tested with the