Müller G, Wied S, Wetekam E M, Crecelius A, Unkelbach A, Pünter J
Hoechst Aktiengesellschaft Frankfurt a.M., SBU Metabolic Diseases H825, Frankfurt am Main, Germany.
Biochem Pharmacol. 1994 Aug 30;48(5):985-96. doi: 10.1016/0006-2952(94)90369-7.
The long-term hypoglycemic activity of sulphonylurea drugs has been attributed, in part at least, to the stimulation of glucose utilization in extra-pancreatic tissues. The novel sulphonylurea, glimepiride, gives rise to a longer lasting reduction in the blood sugar level in dogs and rabbits compared to glibenclamide (Geisen K, Drug Res 38: 1120-1130, 1988). This cannot be explained adequately by elevated plasma insulin levels. This study investigated whether this prolonged hypoglycemic phase was based on the drug's abilities to stimulate glucose utilization and affect the underlying regulatory mechanisms in insulin-sensitive cells in vitro. It was found that in the absence of added insulin, glimepiride and glibenclamide (1-50 microM) stimulated lipogenesis (3T3 adipocytes) and glycogenesis (isolated rat diaphragm) approximately 4.5- and 2.5-fold, respectively, and reduced the isoproterenol-stimulated lipolysis (rat adipocytes) up to 40-60%. The increased glucose utilization was correlated with a 3-4-fold higher 2-deoxyglucose transport rate and amount of GLUT4 at the plasma membrane, as well as with increased activities of key metabolic enzymes (glycerol-3-phosphate acyltransferase, glycogen synthase) within the same concentration range. Furthermore, the low Km cAMP-specific phosphodiesterase was activated 1.8-fold, whereas the cytosolic cAMP level and protein kinase A activity ratios were significantly lowered after incubation of isoproterenol-stimulated rat adipocytes with the sulphonylureas. In many of the aspects studied the novel sulphonylurea, glimepride, exhibited slightly lower ED50-values than glibenclamide. This study demonstrates correlations existing between drug-induced stimulation of glucose transport/metabolism and cAMP degradation/protein kinase A inhibition as well as between the relative efficiencies of glimepiride and glibenclamide in inducing these extra-pancreatic processes. Therefore, it is suggested that the stimulation of glucose utilization by sulphonylureas is mediated by a decrease of cAMP-dependent phosphorylation of GLUT4 and glucose metabolizing enzymes. The therapeutic relevance of extra-pancreatic effects of sulphonylureas, in general, and of the differences between glimepiride and glibenclamide as observed in vitro in this work, in particular, remain to be elucidated.
磺酰脲类药物的长期降血糖活性至少部分归因于其对胰腺外组织葡萄糖利用的刺激作用。与格列本脲相比，新型磺酰脲类药物格列美脲能使犬和兔的血糖水平降低持续更长时间（Geisen K，《药物研究》38：1120 - 1130，1988）。血浆胰岛素水平升高并不能充分解释这一现象。本研究调查了这种延长的降血糖阶段是否基于该药物在体外刺激葡萄糖利用以及影响胰岛素敏感细胞潜在调节机制的能力。结果发现，在未添加胰岛素的情况下，格列美脲和格列本脲（1 - 50微摩尔）分别刺激脂肪生成（3T3脂肪细胞）和糖原生成（分离的大鼠膈肌）约4.5倍和2.5倍，并使异丙肾上腺素刺激的脂肪分解（大鼠脂肪细胞）降低多达40% - 60%。在相同浓度范围内，葡萄糖利用增加与质膜上2 - 脱氧葡萄糖转运速率和GLUT4量提高3 - 4倍相关，也与关键代谢酶（甘油 - 3 - 磷酸酰基转移酶、糖原合酶）活性增加相关。此外，低Km的cAMP特异性磷酸二酯酶被激活1.8倍，而异丙肾上腺素刺激的大鼠脂肪细胞与磺酰脲类药物孵育后，胞质cAMP水平和蛋白激酶A活性比值显著降低。在许多研究方面，新型磺酰脲类药物格列美脲的ED50值略低于格列本脲。本研究证明了药物诱导的葡萄糖转运/代谢刺激与cAMP降解/蛋白激酶A抑制之间存在相关性，以及格列美脲和格列本脲在诱导这些胰腺外过程中的相对效率之间存在相关性。因此，提示磺酰脲类药物对葡萄糖利用的刺激作用是通过降低GLUT4和葡萄糖代谢酶的cAMP依赖性磷酸化介导的。一般而言，磺酰脲类药物胰腺外作用的治疗相关性以及本研究中体外观察到的格列美脲和格列本脲之间的差异的治疗相关性仍有待阐明。
