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 major problem of precision and bioavailability (2). Nevertheless, inhaled insulin will likely be approved in the next few years (3) since recent studies look promising. In type 1 diabetic patients, inhaled insulin was comparable to subcutanous insulin in reducing postprandial glucose levels (4). In a multicenter phase II trial with type 2 diabetic patients failing oral agents, adjunctive inhaled insulin was able to reduce hemoglobin A1c significantly compared to placebo (5). Chemical modification of the peptide insulin could potentially lead to better oral absorption and reduce its degradation after ingestion. In this connection, hexyl insulin seems to exhibit these characteristics in animal studies, and was able to increase serum insulin levels in a dose-dependent manner in healthy volunteers (6). However, the duration of this effect was limited to the first 30 min after ingestion, suggesting that there may still be a problem with stability and bioavailability. Studies in diabetic patients are planned and should determine whether these compounds will be clinically useful. The group of Nag at Calyx is currently working on a series of plant-derived substances that lower blood glucose levels when given orally to several different rodent models of diabetes including ob/ob and db/db mice as well as fa/fa rats and streptozotocin-induced diabetic rats (7, 8). While some of these compounds seem to mediate their effects via the insulin receptor, others show no competitive binding to the receptor. All of them share the ability to up-regulate the glucose transporters, GLUT 1 and 4. In addition, they were reported to reduce plasma levels of triglycerides, free fatty acids and cholesterol. Moller’s group at Merck screened over 50 000 natural and synthetic substances in a cell-based assay for insulin-like activity. They recently discovered a small non-peptidyl molecule (L-783,281) from a fungal (Pseudomassaria) extract (1). Surprisingly, purification of the active compound revealed that L-783,281 structurally is a quinone. No other currently known antidiabetic drugs belong to this substance class. L-783,281 seems to bind directly to the intracellular b-subunit of the insulin receptor containing the insulin receptor tyrosine kinase activity. Binding leads to a conformational change resulting in activation of the kinase and induction of the insulin signaling cascade downstream of the receptor at micromolar concentrations. L-783,281 leads to phosphorylation of a number of proteins of the insulin signaling pathway including European Journal of Endocrinology (1999) 141 561–562 ISSN 0804-4643 H IG H L IG H T