Glibenclamide Mimics Metabolic Effects of Metformin in H9c2 Cells

Abstract

Background: Sulfonylureas, such as glibenclamide, are antidiabetic drugs that stimulate beta-cell insulin secretion by binding to the sulfonylureas receptors (SURs) of adenosine triphosphate-sensitive potassium channels (K ATP ). Glibenclamide may be also cardiotoxic, this effect being ascribed to interference with the protective function of cardiac K ATP channels for which glibenclamide has high affinity. Prompted by recent evidence that glibenclamide impairs energy metabolism of renal cells, we investigated whether this drug also affects the metabolism of cardiac cells. Methods: The cardiomyoblast cell line H9c2 was treated for 24 h with glibenclamide or metformin, a known inhibitor of the mitochondrial respiratory chain. Cell viability was evaluated by sulforodhamine B assay. ATP and AMP were measured according to the enzyme coupling method and oxygen consumption by using an amperometric electrode, while Fo-F1 ATP synthase activity assay was evaluated by chemiluminescent method. Protein expression was measured by western blot. Results: Glibenclamide deregulated energy balance of H9c2 cardiomyoblasts in a way similar to that of metformin. It inhibited mitochondrial complexes I, II and III with ensuing impairment of oxygen consumption and ATP synthase activity, ATP depletion and increased AMPK phosphorylation. Furthermore, glibenclamide disrupted mitochondrial subcellular organization. The perturbation of mitochondrial energy balance was associated with enhanced anaerobic glycolysis, with increased activity of phosphofructo kinase, pyruvate kinase and lactic dehydrogenase. Interestingly, some additive effects of glibenclamide and metformin were observed. Conclusions: Glibenclamide deeply alters cell metabolism in cardiac cells by impairing mitochondrial organization and function. This may further explain the risk of cardiovascular events associated with the use of this drug, alone or in combination with metformin.

Inhibitory Action of Antidiabetic Drugs on the Free Radical Production by the Rod Outer Segment Ectopic Aerobic Metabolism

“…MTF can also be utilized in combination with sulfonylureas such as glibenclamide (GLB), also known as glyburide in the US. Interestingly, GLB also targets the mitochondrial respiratory complexes I, II, and III, but not IV, determining a reduction of oxygen consumption and ATP synthesis in H9c2 cardiomyoblast cells [27,28]. GLB also caused a dose-dependent increment of the AMP/ATP ratio, due to a deregulated energy balance similar to that obtained with MTF.…”

“…However, the in vivo effects of MTF remain not fully understood [53]. Nonetheless, GLB exerts an action on aerobic metabolism, by inhibiting the respiratory complexes I, II, and III [27].…”

“…The literature reports in vitro studies using high MTF concentrations to inhibit the OxPhos activity in several cell types, including tumors [25,35]. Since GLB shows a similar behavior on complex I activity but also affects the complex III activity [27], we evaluated whether a combination of these anti-diabetic drugs can exert additive effects on the aerobic metabolism of rod OS. Data show that the combination of MTF and GLB determines a significant additive inhibitory effect on complex I activity, in comparison to the single treatment with GLB.…”

Glibenclamide-Induced Autophagy Inhibits Its Insulin Secretion-Improving Function in β Cells

“…SUs bind to their receptors (sulfonylurea receptor 1, SUR1), which are the regulatory subunits of the ATP-dependent potassium (K ATP ) channel. Thus, SUs can close the K ATP channel in pancreatic β cells, followed by membrane depolarization and open the voltage-dependent Ca 2+ channels (VDCCs) to increase intracellular calcium (Ca 2+ ), resulting in insulin secretion and decreasing blood glucose [4–6]. Glibenclamide is a second-generation SU drug that inhibits SUR1 at nanomolar concentrations and targets K ATP (Sur1-Kir6.2) channels for the treatment of T2DM [7].…”

AMPK is associated with the beneficial effects of antidiabetic agents on cardiovascular diseases

“…Very little research can be retrieved on the relationship between sulfonylureas and AMPK nor meglitinides and AMPK. Glibenclamide induced a dose-dependent increase of the AMP/ATP ratio by inhibiting complexes I, II, III [31], resulting in an increased AMPK phosphorylation in H9C2 cells. However, it profoundly changes cell metabolism in cardiomyocytes by impairing mitochondrial structure and function and induces irreversible damage beyond the benefits of AMPK activation.…”