Volume 1 number 1 Summer 2003
Special issue for the abstracts of the 7th Pan Arab Conference on Diabetes
PACD7 , 25 – 28 March 2003 Cairo

Abstract Number : 80
"NEW INSIGHTS INTO THE SULFONYLUREAS: THE MYSTERY OF CARDIOVASCULAR SAFETY 
VERSUS TOXICITY”

Prof. DR. Nagwa Amr Lachine, 
Egypt

Type 2 diabetes mellitus (T2DM) is traditionally viewed as a predictor of cardiovascular (CV) morbidity & mortality. Despite recent studies demonstrating the likely benefit of good glycemic control in decreasing CV risk in T2DM, there have been doubtful concerns about the safety of Sulfonylureas (SUs). Much controversy were generated following the results of the University Group Diabetes Program (UGDP) study (1970) reporting that patients treated with tolbutamide sustained an unexplained increased CV mortality compared with diet treatment alone .The question of CV safety of SUs in T2DM patients has been re opened in face of new evidence based molecular data concerning the inhibitory effect of SUs on the SU receptors (SURs) &ATP sensitive K+ (K ATP) channels present in the pancreatic beta cells as well as the cardiomyocytes.SUs exert their stimulant effect on insulin secretion by binding to SURs which leads to blockage of the K ATP channels present on the surface of the plasma membrane of the beta cells. Two types of pancreatic SURs exist:
1-SUR1 (140 Kd): it has 2 binding sites, the SU binding site & the benzamido Binding site,for the binding of the 1st (consisting of SU moiety only) & 2nd (Consisting of SU moiety & benzamido side chain) generations of SUs. 2-SURx (65 Kd): for the binding of glimeperide (the 3rd generation SU) which explain its low affinity to the beta cell membrane. SURs2A, which have single benzamido binding sites, most probably are involved in the extrapancreatic glucose lowering effect of SUs, as they are highly expressed in skeletal muscle cells & adipocytes. Moreover, glimeperide appears to exert its pronounced insulin mimetic effect through interaction with the structures of the caveolae. The caveolae are invaginations in the plasma membranes in most of the cells of the body but highly abundant in adipocytes &skeletal muscle cells. SURs2A are also highly expressed in cardiomocytes, so SURs may inhibit the opening of K ATP channels in cardiac mucle cells & thereby abolish the endogenous cardioprotective ischemic preconditioning. However, the cardiomyocyte K ATP channels are thought to be closed under physiologic condition, & hence SUs are likely to be without effect in the diabetics without cardiac disease. During ischemic activation of these sarcolemmal membranes SURs2A & their K ATP channels in the cardiac muscle cells only the 2nd generation SUs possessing the benzamido side chain may lead to blockage of these channels. However this inhibition seems to be rapidly reversed as it is mediated through a single binding site (the benzamido-binding site). So recently the mitochondrial membrane K ATP channels have been postulated to be responsible of the mediation of the ischemic preconditioning & it has been demonstrated in both experimental as well as clinical human studies that glyburide, but not glimeperide, impaired ischemic preconditioning. Waiting for further confirmatory data demonstrating that ischemic preconditioning is a sure clinical phenomenon, it appears advisable to keep an eye on the possible cardiotoxic effect of some of the old SUs particularly in the diabetics suffering from CV disease. Never forget that only with proper control of hyperglycemia, hypertension, dyslipidemia &microalbuminuria that we can achieve the best possible outcomes in our T2DM patients.

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