Interaction Of Sulfonylureas Research Articles

Facilitation of β-cell KATP channel sulfonylurea sensitivity by a cAMP analog selective for the cAMP-regulated guanine nucleotide exchange factor Epac

Clinical studies demonstrate that combined administration of sulfonylureas with exenatide can induce hypoglycemia in type 2 diabetic subjects. Whereas sulfonylureas inhibit β-cell KATP channels by binding to the sulfonylurea receptor-1 (SUR1), exenatide binds to the GLP-1 receptor, stimulates β-cell cAMP production, and activates both PKA and Epac. In this study, we hypothesized that the adverse in vivo interaction of sulfonylureas and exenatide to produce hypoglycemia might be explained by Epac-mediated facilitation of KATP channel sulfonylurea sensitivity. We now report that the inhibitory action of a sulfonylurea (tolbutamide) at KATP channels was facilitated by 2’-O-Me-cAMP, a selective activator of Epac. Thus, under conditions of excised patch recording, the dose-response relationship describing the inhibitory action of tolbutamide at human beta cell or rat INS-1 cell KATP channels was left-shifted in the presence of 2’-O-Me-cAMP, and this effect was abolished in INS-1 cells expressing a dominant-negative Epac2. Using an acetoxymethyl ester prodrug of an Epac-selective cAMP analog (8-pCPT-2'-O-Me-cAMP-AM), the synergistic interaction of an Epac activator and tolbutamide to depolarize INS-1 cells and to raise [Ca2+]i was also measured. This effect of 8-pCPT-2'-O-Me-cAMP-AM correlated with its ability to stimulate phosphatidylinositol 4,5-bisphosphate hydrolysis that might contribute to the changes in KATP channel sulfonylurea-sensitivity reported here. On the basis of such findings, we propose that the adverse interaction of sulfonylureas and exenatide to induce hypoglycemia involves at least in part, a functional interaction of these two compounds to close KATP channels, to depolarize β-cells, and to promote insulin secretion.

Inhibition of ATP-sensitive K +-channels by a sulfonylurea analogue with a phosphate group

Hypoglycaemic sulfonylureas initiate insulin secretion by direct inhibition of ATP-sensitive K +-channels in the pancreatic β-cells. These channels are composed of two proteins, a pore-forming subunit (K IR6.2 in the case of β-cells) and a regulatory subunit, the sulfonylurea receptor (SUR). In the present study we characterised the interaction with SURs of the new sulfonylurea analogues 5-chloro- N-[2-(4-hydroxyphenyl)ethyl]-2-methoxybenzamide (compound I) and {4-[2-(5-chloro-2-methoxybenzamido)ethyl]phenyl}phosphate (compound II). Compounds I and II differ from the sulfonylurea analogue meglitinide only in so far as the carboxylic group of meglitinide is replaced by a hydroxyl group or a phosphate group, respectively. The binding affinities of compound II for the SUR subtypes SUR1 (identified in β-cells) and SUR2A (identified in heart and skeletal muscle) were higher by 55 or 21-fold, respectively, than the corresponding affinities for compound I. In inside-out patch–clamp experiments compound II inhibited ATP-sensitive K +-channels of the SUR1/K IR6.2-type (characteristic of β-cells) with an ic 50 value of 0.16 μM which is 6-fold lower than the corresponding value for meglitinide. These findings strongly support the conclusion that the interaction of sulfonylureas and acidic analogues with SURs is favoured by the anionic group of these drugs and that a phosphate group allows more efficient ligand interaction with SUR1 than a carboxylic group.

Interaction of sulfonylureas and exercise on glucose homeostasis in type 2 diabetic patients.

To determine whether the plasma glucose-lowering effects of sulfonylureas and acute submaximal exercise are additive and, accordingly, to determine whether they may increase the risk of hypoglycemia when combined in fasting patients. Eight postabsorptive type 2 diabetic patients were examined at three occasions: after oral sulfonylurea (7 mg glibenclamide), during 60 min of ergometer cycle exercise at 57 +/- 3% of VO2max, and during exercise after glibenclamide. Heart rate, VO2, and lactate responses to exercise were comparable (P > 0.05) on days with and without glibenclamide. Plasma insulin concentrations were always increased by glibenclamide, and they were lowered identically by exercise with and without glibenclamide. However, throughout exercise, absolute concentrations of insulin were lower on days without glibenclamide compared with days with glibenclamide (34.5 +/- 4.7 vs. 47.4 +/- 5.5 pmol/l; P < 0.05). At the start of exercise, glucose concentrations were similar between experiments (P > 0.05). The rate of decrease in glucose during exercise was higher (P < 0.05) on days with both glibenclamide and exercise, compared with days with glibenclamide alone and days with exercise alone (-0.035 +/- 0.009 vs. -0.016 +/- 0.002 and -0.022 +/- 0.005 mmol.l-1.min-1, respectively). Consequently, the glucose nadir was lower on days with glibenclamide and exercise than on days with glibenclamide or exercise alone (6.7 +/- 1.1 vs. 8.1 +/- 0.9 and 7.6 +/- 1.0 mmol/l, respectively; P < 0.05). During exercise, the rate of appearance of plasma glucose determined by 3-[3H]glucose infusion was lower on days with glibenclamide than on days without glibenclamide (2.3 +/- 0.1 vs. 2.9 +/- 0.1 mg.min-1.kg-1; P < 0.05). In contrast, glucose clearance was identical (P > 0.05). In postabsorptive type 2 diabetic patients, the hypoglycemic action of glibenclamide and exercise is enhanced when the treatments are combined. The interaction reflects an increased inhibition by glibenclamide-enhanced insulin levels of hepatic glucose production when hepatic glucose production is accelerated by exercise.

Intracellular targets for antidiabetic sulfonylureas and potassium channel openers

Antidiabetic sulfonylureas and potassium channel openers affect the activity of the ATP-regulated potassium channel (K ATP channel) present in the plasma membrane of various cells. This causes a broad spectrum of physiological responses, including the modulation of insulin release from pancreatic B-cells and the relaxation of smooth muscle. Recently, new targets for antidiabetic sulfonylureas and potassium channel openers were found in membranes of organelles, such as mitochondria and zymogen- and insulin-containing granules. By acting on these targets, the drugs modulate, independently of K ATP channel activity, insulin release from pancreatic B-cells, and they regulate K + transport in mitochondria and zymogen granules. The interaction of sulfonylureas and potassium channel openers with intracellular targets gives additional basic information about their properties. Additionally, these studies could be important because of the medical applications of sulfonylureas and potassium channel openers.

Interaction of sulfonylureas with the transport of bile acids into hepatocytes

The sulfonylurea compounds glisoxepide and glibenclamide inhibit the uptake of bile acids into isolated rat hepatocytes. The K i values for the inhibition of cholate uptake was 9 μM with glibenclamide and 200 μM with glisoxepide. The inhibition of cholate uptake by both sulfonylureas was noncompetitive. Uptake of the conjugated bile acid taurocholate was inhibited by glibenclamide, K i = 75 μM. Again the inhibition was noncompetitive. Glisoxepide inhibited taurocholate uptake only in the absence of sodium ions. Under sodium-free conditions glisoxepide also strongly inhibited cholate uptake. The inhibition was competitive, K i = 42 μM. Both bile acids interfered with the hepatocellular uptake of [ 3H]glisoxepide, with IC 50 values of 375 and 467 μM for cholate and taurocholate, respectively. The uptake of [ 3H]glibenclamide was inhibited by cholate, IC 50 = 328 μM, but not by taurocholate. Glisoxepide uptake was further inhibited by blockers of the hepatocellular monocarboxylate transporter, by the loop diuretic bumetanide, by 4,4′-diisothiocyano-2,2′-stilbenedisulfonate (DIDS) and by sulfate. Glibenclamide uptake was weakly inhibited by DIDS and by anthracene-9-carboxylic acid (A-9-C) but not by bumetanide and sulfate. Neither bromosulfophthalein nor the fatty acid oleate inhibited glisoxepide or glibenclamide uptake. These results are consistent with the transport of glisoxepide via the transport system for the unconjugated bile acid cholate. Glibenclamide uptake is mediated by a still unknown hepatocellular transport system.

Interaction of sulfonylureas with pancreatic beta-cells. A study with glyburide

Interaction of sulfonylureas with pancreatic beta-cells. A study with glyburide

Circular dichroism studies on the interaction of sulfonylureas with insulin.

The interaction of 5 sulfonylurea derivatives with insuline was investigated by means of circular dichroism measurements. It was found that all sulfonylureas investigated decrease the ellipticity band of insulin at 208 nm, whereas the band at 222 nm remains unaffected. It is suggested that these observations are due to a change of the insulin conformation, provoked by the interaction of the drugs with insulin. It is assumed that such an effect on the insulin conformation can influence the binding properties of insulin, e.g. in respect to the insulin aggregation, to the binding to insulin antibodies and to a bound, inactive form of insulin in the plasma. Some other drugs have similar, but mostly smaller effects on the CD spectrum of insulin. Therefore, the importance of these observations for the hypoglycaemic action of the sulfonylureas is not yet clear.