Obesity - April 2000 The potential pharmaceutical market for obesity and NIDDM is huge. There are recognised deficiencies in existing diabetes drugs, and novel drug development in this area is needed. The rapidly expanding knowledge of the cause of obesity and diabetes at the molecular level is helping the swift development of novel drugs in this area. Please find the Executive Summarie from New Therapeutic Approaches to NIDDM, presented by James G. McCormack, Ph.D., D.Sc., Director of Target Cell Biology, Novo Nordisk A/S, Denmark IBC Life Sciences, Obesity. New Therapeutic Approaches to NIDDM For further information and details of the comprehensive documentation available from this event, please visit: www.ibc-lifesci.com/ix187 1. New Therapeutic Approaches to NIDDM [top] James G. McCormack, Ph.D., D.Sc., Director of Target Cell Biology, Novo Nordisk A/S, Denmark The landmark UKPDS study of NIDDM led to the conclusion that intensive blood glucose control, by whatever means, leads to significantly fewer late complications. The study also led to the recommendations that treatment should be more aggressive and aim at HbA1C values of as low as possible, and include more combination therapy ("poly-pharmacy"), plus earlier and more frequent use of insulin. The UKPDS also indicated that current therapies are not sufficiently adequate, and that new approaches to combating NIDDM are required. This presentation will firstly examine two newer approaches based on existing therapies, and then describe some of the molecular targets being addressed in current drug discovery and clinical development programs for NIDDM. One way in which the earlier and more frequent use of insulin advocated by the UKPDS could be achieved would be by the development of a device and formulation whereby insulin could be delivered by the pulmonary route, and this approach is currently being evaluated in clinical trials. Key issues such as bio-availability and precision of dose and breath control need to be addressed, but the expected greater patient compliance and removal of the need for injections are obvious advantages. The new concept of Prandial Glucose Regulation using fast-acting, non-sulphonylurea, secretagogues which are taken just before meals such as repaglinide (Novonormâ/PrandinT) not only restores to the Type II diabetic patient a much more physiological insulin profile which in turn more efficiently clears the post-meal blood glucose surge, but also allows the ß-cell to rest and recover between meals, and additionally allows the patient more flexibility in meal planning. In this way better HbA1C lowering compared to more traditional sulphonylurea secretagogues can be achieved whilst at the same time the risk of hypoglycaemic episodes can be reduced. Further, and again in contrast to sulphonylureas, the action of repaglinide is not compromised in metabolically stressed cells and it also appears to better preserve insulin biosynthetic rates. Data will also be presented to show that repaglinide, in contrast to the other marketed rapid acting secretagogue nataglinide, is very ß-cell specific and does not affect exocytosis from a-cells or pituitary cells. Clinical studies on co-treatment with metformin or troglitazone or NPH insulin have also shown that repaglinide is ideally suited for combination therapy. In looking at some of the molecular targets being addressed in R & D programs directed towards NIDDM, it is evident that currently a "holistic" approach is being pursued, the elements of which are targeted towards alleviating the four major phenotypic expressions of NIDDM, namely (i) insulin resistance, (ii) hepatic glucose over-production, (iii) insulin deficiency, and (iv) obesity/dyslipidemia, and examples of targets in each of these areas will be presented as indicated below. In looking to the future genetics may play a larger role, eg in patient/therapy matching, and the UKPDS has certainly stimulated much more activity in the ß-cell regeneration and protection area. (i) In the context of enhancing insulin's effectiveness, many targets are being proposed and pursued, however, the recent data supporting the concept of inhibition of phosphotyrosine phosphatase 1B as a means of enhancing and prolonging insulin signaling events is of interest and note. (ii) Several targets are also being approached for inhibition of hepatic glucose over-production, and some experimental data using the examples of inhibition of glucagon action and of glycogen phosphorylase inhibition will be presented. (iii) Clinical studies on NIDDM patients with GLP-1 have led to the concept that it may be the ideal, entirely glucose-dependent, physiological insulin secretagogue, and recent studies wherein other desirable effects of the hormone have been described, and the notion that there may be an insufficiency of the hormone in the diabetic state, have re-enforced this. Recent advances whereby the problem of the too short half-life of GLP-1 may be overcome will be described. The concept of ??cell rest already mentioned in the context of repaglinide has been further explored using chronic treatment with the potassium channel opener diazoxide to reduce insulin secretion in models of NIDDM with hyperinsulinaemia. These show that this treatment can lead to an improvement in insulin sensitivity and protection of the ??cells. Diazoxide treatment has also been shown to increase weight loss in obese humans. (iv) Many anti-obesity targets are also being pursued, as described in the first day of this symposium, but it is noteworthy that elevated fluxes of fatty acids are seen early in the development of NIDDM and this is believed to be a major contributor to the insulin resistant state and the associated dyslipidaemia. Reduction in FFA levels is thus a valid target and can be achieved by anti-lipolytic agents such as acipimox, and studies in humans have shown that this can lead to an improvement in insulin sensitivity in NIDDM patients. However, the agents available at present have side-effect concerns, and their impact and effectiveness wears off over time. However, these problems are probably mechanism related and other targets within anti-lipolysis should be considered. In summary, there are many interesting new approaches to combat NIDDM currently under research and development, some of which should, in time, provide the novel treatment modalities whereby the desired outcomes advocated by the UKPDS may be achieved.