doi: 10.1111/j.1463-1326.2009.01119.x Beneficial effects of K-ATP channel openers in diabetes: an update on mechanisms and clinical experiences V. Grill, 1,2 M. Radtke, 1,2 E. Qvigstad, 1,2 M. Kollind 1,3 and A. Bj ¨ orklund 4 1 Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway 2 Department of Internal Medicine, St Olav Hospital, Trondheim, Norway 3 Department of Internal Medicine, Levanger Hospital, Levanger, Norway 4 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden Stresses associated with the diabetic state participate in the demise of β-cells and therapies that eliminate or reduce such stresses are much needed. K-ATP channel openers, of which diazoxide is the most studied, are potentially useful because experimental studies show that they can counteract chronic over-stimulation of β-cells and protect against toxic conditions, including relative hypoxia. Several mechanisms may underlie the beneficial effects of diazoxide; these may include both indirect (counteracting over-stimulation) and direct mitochondrial effects. Side effects of diazoxide have limited its use in human trials. We have tested lower doses than previously of diazoxide and thereby largely eliminated side effects. In this setting, we demonstrate positive effects on β-cell function in type 2 diabetic patients who were simultaneously treated with bedtime insulin. However, such effects were absent in insulin-na ¨ ıve patients. In newly diagnosed type 1 diabetic patients, a 6-month intervention with diazoxide failed to result in better preservation of β-cell function. K-ATP channel openers have a potential to improve β-cell function in subgroups of type 2 diabetes patients. Analogues of diazoxide with more potency in relation to side effects would heighten the possibilities for K-ATP channel openers to be of therapeutic use in type 1 diabetes. Keywords: diabetes, diazoxide, hypoxia, islets of Langerhans Received 26 March 2009; accepted 28 April 2009 Introduction The capacity of β-cells to secrete insulin decreases throughout life and this process is accelerated not only in type 1 but also in type 2 diabetes [1]. The causes are partly different but partly shared for the two forms of diabetes. Autoimmune activity is specific for type 1 diabetes and is certainly the major factor behind the demise of β-cells. Insulin resistance and constituents of the diabetes state are important factors for the demise in type 2 diabetes; however, these factors are also important in type 1 diabetes. Hence, it is well documented that normalization Correspondence: Valdemar Grill, Department of Internal Medicine, St Olav Hospital, 7006 Trondheim, Norway. E-mail: valdemar.grill@ntnu.no of hyperglycaemia improves β-cell function in the short term in both type 1 and type 2 diabetes, and there is strong evidence that such normalization also exerts long-lasting beneficial effects in both types of diabetes [2,3]. The causes of these beneficial effects are, however, disputed. Most reviews on this topic emphasize the effects of ‘glucotoxicity’ or ‘lipotoxicity’ or ‘glucolipotoxicity’ [4]. Our own studies have shown the influence of ‘glucotoxicity’ [5] and ‘lipotoxicity’ [6]; however, the bulk of our observations imply that the main non-genetic and non-autoimmune factor that drives the demise of the β-cell is linked to chronic over- stimulation.  2009 The Authors Journal compilation  2009 Blackwell Publishing Ltd Diabetes, Obesity and Metabolism, 11 (Suppl. 4), 2009, 143–148 143