Beneficial effects of K-ATP channel openers in diabetes: an update on mechanisms and clinical experiences.
Stresses associated with the diabetic state participate in the demise of beta-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 beta-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 beta-cell function in type 2 diabetic patients who were simultaneously treated with bedtime insulin. However, such effects were absent in insulin-naïve patients. In newly diagnosed type 1 diabetic patients, a 6-month intervention with diazoxide failed to result in better preservation of beta-cell function. K-ATP channel openers have a potential to improve beta-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.
Grill
V
V
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. valdemar.grill@ntnu.no
Radtke
M
M
Qvigstad
E
E
Kollind
M
M
Björklund
A
A
D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D003981:Diazoxide / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D054086:KATP Channels / Q000187:drug effects* / Q000378:metabolism
D007004:Hypoglycemic Agents; D007328:Insulin; D054086:KATP Channels; D003981:Diazoxide