Differential interaction of glimepiride and glibenclamide with the β-cell sulfonylurea receptor I. Binding characteristics

Abstract

Glimepiride is a novel sulfonylurea drug for treatment of non-insulin-dependent diabetes mellitus with higher blood sugar lowering efficacy in diabetic patients than glibenclamide raising the question whether this characteristics is in line with different binding of glimepiride and glibenclamide to the 0-cell sulfonylurea receptor. Scatchard plot analysis of [3H]sulfonylurea binding to membranes isolated from rat 0-cell tumors and (RINm5F) insulinoma cells and to RINm5F cells demonstrated that glimepiride has a 2.5-3-fold lower affinity than glibenclamide. This corresponded well to the 8-9-fold higher kof f and 2.5-3-fold higher kon rates of glimepiride compared to glibenclamide as revealed by the dissociation and association kinetics of [3H]sulfonylurea binding and the K d values calculated thereof. In agreement, the concentrations required for half-maximal displacement of [3H]sulfonylurea bound to 0-cell membranes were significantly higher for glimepiride compared to glibenclamide. However, the binding affinity of glimepiride measured by both equilibrium binding and kinetic binding studies upon solubilization of 0-cell tumor membranes and RINm5F cell membranes increased up to the value for glibenclamide. This was primarily based on a drastic decrease of the dissociation rate constant of glimepiride whereas the kinetics of glibenclamide binding remained largely unaffected upon solubilization. These data suggest that the K d value alone is not sufficient for characterization of a suifonylurea drug, since the kinetic binding parameters may also determine its acute blood sugar lowering efficacy.

Differential interaction of glimepiride and glibenclamide with the β-cell sulfonylurea receptor II. Photoaffinity labeling of a 65 kDa protein by [3H]glimepiride

“…Molecular mass marker proteins for electrophoresis were obtained from Sigma, Deisenhofen, Germany. All other reagents and materials were purchased as described in the accompanying report [11]. Rats of the strain NEDH (New and protein was precipitated as published [12].…”

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AbstractGlimepiride is a novel sulfonylurea for the treatment of type II-diabetic patients exhibiting different receptor binding kinetics to B-cell membranes with 8-9-fold higher kof f rate and 2.5-3-fold higher kon rate compared to glibenclamide (see accompanying paper (Miiller, G. et al (1994) Biochim. Biophys.

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Stimulation of glucose utilization in 3T3 adipocytes and rat diaphragm in vitro by the sulphonylureas, glimepiride and glibenclamide, is correlated with modulations of the cAMP regulatory cascade

“…All the other materials and chemicals were obtained as described previously [11, 121. Cell culture and incubation of 3 T3 adipocytes. This was done according to published methods [11] with modifications: cells were grown (150 or 35 mm culture plates per condition) in DMEM (25 or 2 mL per condition) containing 25 mM glucose, 10% FCS and antibiotics. Confluent and differentiated cells (80-90% of the cells expressed the adipocyte phenotype) were washed twice with Krebs-Ringerphosphate buffer and then incubated in the same buffer (10 or 1 mL) with sulphonylurea or insulin as indicated.…”

Change in patients’ body weight after 12 months of treatment with glimepiride or glibenclamide in Type 2 diabetes: a multicentre retrolective cohort study

“…The mechanism behind the weight loss associated with glimepiride has not been established. However, it is likely that the lower insulin secretion stimulated by glimepiride relative to other SUs is involved [6,7,19,20]. Acute post-challenge hyperinsulinaemia predicts weight gain [21], and an intervention study in normoglycaemic, morbidly obese adolescents showed that metformin treatment led to greater weight loss than placebo [22].…”

“…Acute post-challenge hyperinsulinaemia predicts weight gain [21], and an intervention study in normoglycaemic, morbidly obese adolescents showed that metformin treatment led to greater weight loss than placebo [22]. Moreover, glimepiride also exerts a number of extrapancreatic, insulin-independent, glucose-lowering effects [6,7,20], and improved peripheral glucose uptake and decreased endogenous glucose production have both been observed after treatment with glimepiride [10]. These insulin-sparing effects of glimepiride could, therefore, explain the weight neutrality or weight loss associated with its use.…”