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Insulin stimulus‐secretion coupling is triggered by a novel thiazolidinedione/sulfonylurea hybrid in rat pancreatic islets
Author(s) -
Mendes Camila P.,
Postal Bárbara G.,
Oliveira Geisel T. C.,
Castro Allisson J. G.,
Frederico Marisa J. S.,
Moraes Ana L. L.,
Neuenfeldt Patrícia D.,
Nunes Ricardo J.,
Menegaz Danusa,
Silva Fátima R. M. B.
Publication year - 2019
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.26746
Subject(s) - sulfonylurea , pancreatic islets , thiazolidinedione , insulin , endocrinology , secretion , medicine , chemistry , islet , diabetes mellitus , type 2 diabetes
New compounds with promising antidiabetic activity were synthesized. For the first time, a portion of the glibenclamide molecule was bound to a part of the core structure of thiazolidinedione to evaluate insulin secretagogue activity. Following studies in our laboratory, 4‐{2‐[2‐(3,4‐dichlorophenyl)‐4‐oxo‐1,3‐thiazolidin‐3‐yl]ethyl}benzene‐1‐sulfonamide (DTEBS) was selected to evaluate glycemia using the glucose tolerance test and insulin secretagogue activity by E.L.I.S.A. The mechanism of action of this compound was studied by 45 Ca 2+ influx and whole‐cell patch‐clamp in rat pancreatic isolated islets. Furthermore, AGE formation in vitro was investigated. We herein show that this novel hybrid compound (DTEBS) exhibits an insulinogenic index and a profile of serum insulin secretion able to maintain glucose homeostasis. Its mechanism of action is mediated by ATP‐sensitive potassium channels (KATP) and L‐type voltage‐dependent calcium channels (VDCC) and by activating protein kinase C and A (PKC and PKA). In addition, the stimulatory action of the compound on calcium influx and insulin secretion indicates that the potentiation of voltage‐sensitive K+ currents (Kv) is due to the repolarization phase of the action potential after secretagogue excitation‐secretion in pancreatic islets. Furthermore, under these experimental conditions, the compound did not induce toxicity and the in vitro late response of the compound to protein glycation reinforces its use to prevent complications of diabetes. DTEBS exerts an insulin secretagogue effect by triggering KATP, VDCC, and Kv ionic currents, possibly via PKC and PKA pathway signal transduction, in beta‐cells. Furthermore, DTEBS may hold potential for delaying the late complications of diabetes.