EXTRAPANCREATIC EFFECTS OF SULFONYLUREAS - A COMPARISON BETWEEN GLIMEPIRIDE AND CONVENTIONAL SULFONYLUREAS

被引:88
作者
MULLER, G [1 ]
SATOH, Y [1 ]
GEISEN, K [1 ]
机构
[1] HOECHST JAPAN LTD,DIV PHARMA RES & DEV,KAWAGOE,SAITAMA 35011,JAPAN
关键词
GLIBENCLAMIDE; GLIMEPIRIDE; INSULIN ACTION; ADIPOCYTES; DIAPHRAGM; GLUCOSE TRANSPORT; METABOLISM; CAMP;
D O I
10.1016/0168-8227(95)01089-V
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The contribution of extrapancreatic effects of sulfonylureas to the blood glucose-decreasing activity was reevaluated in vivo and in vitro with several conventional sulfonylureas and with the new one glimepiride. In vivo, in dogs, after single approximately equipotent blood glucose-decreasing doses, the sulfonylureas were tested for a ranking in the ratios of mean plasma insulin-increasing and blood glucose-decreasing activity. Studies were also performed in hyperglycemic hyperinsulinemic KK-A(y) mice under once daily treatment for 8 weeks. In vitro, glimepiride and glibenclamide were tested for the ranking of their extrapancreatic activity with respect to the stimulation of glucose transport and glucose metabolizing processes in normal and insulin-resistant fat cells as well as in the isolated diaphragm. Furthermore, in vitro studies were performed, especially with glimepiride, in order to characterize the molecular mechanism for the extrapancreatic activity. The dog studies revealed a marked ranking in the ratios of plasma insulin-increasing and blood glucose-decreasing activity between the different sulfonylureas (glimepiride < glipizide < gliclazide < glibenclamide). In the hyperglycemic hyperinsulinemic KK-A(y) mice, glimepiride reduced blood glucose by 40%, plasma insulin by 50% and HBA(1c) by 33%, whereas glibenclamide and gliclazide had no effect on these parameters. In vitro, glimepiride and glibenclamide had extrapancreatic effects within the lower mu M range, with glimepiride exhibiting 2-3-fold lower ED(50) values than glibenclamide. In the absence of insulin, both stimulated glucose transport - up to 60% of the maximum insulin response in the rat diaphragm and up to 35% in 3T3 adipocytes. Glycogenesis was stimulated in the rat diaphragm - up to 55% of the maximum insulin effect; lipogenesis in 3T3 adipocytes - up to 40%. The studies on the molecular mechanism of extrapancreatic activity with rat adipocytes and diaphragm suggest that these direct insulin-mimetic effects rely on the induction of GLUT4 translocation from internal stores to the plasma membrane and on the activation of the key metabolic enzymes, glycogen synthase and glycerol-3-phosphate acyltransferase. These processes occur within the same drug concentration range and with the same ranking between glimepiride and glibenclamide as observed for glucose utilization and transport. The direct effects of sulfonylureas may ultimately be regulated by a glycosyl-phosphatidylinositol-specific phospholipase C, shown to be activated by glimepiride in rat adipocytes. Lipolytic cleavage products thereby generated from glycolipidic structures may in turn stimulate specific protein phosphatases which activate key regulatory proteins/enzymes of glucose and lipid metabolism. Conclusion: From the ranking of the sulfonylureas in the ratio of mean insulin-releasing and mean blood glucose decreasing-activity at single doses in vivo, it is deduced that sulfonylureas have a variable degree of blood glucose decreasing-acivity which is independent of their insulin secretion-stimulating activity. The different degree of this extrapancreatic activity in vivo is confirmed a corresponding ranking in stimulation of glucose utilization in vitro. Dephosphorylation and activation of key enzymes of glucose transport and metabolism induced by a glycosyl phosphatidylinositol-specific phospholipase C might be the molecular basis for the extrapancreatic activity of sulfonylureas.
引用
收藏
页码:S115 / S137
页数:23
相关论文
共 109 条
[11]   INSULIN-STIMULATED RELEASE OF LIPOPROTEIN-LIPASE BY METABOLISM OF ITS PHOSPHATIDYLINOSITOL ANCHOR [J].
CHAN, BL ;
LISANTI, MP ;
RODRIGUEZBOULAN, E ;
SALTIEL, AR .
SCIENCE, 1988, 241 (4873) :1670-1672
[12]   RISK-FACTORS FOR NIDDM IN WHITE-POPULATION - PARIS PROSPECTIVE-STUDY [J].
CHARLES, MA ;
FONTBONNE, A ;
THIBULT, N ;
WARNET, JM ;
ROSSELIN, GE ;
ESCHWEGE, E .
DIABETES, 1991, 40 (07) :796-799
[13]  
CHEN H, 1993, J PHARMACOL EXP THER, V264, P1293
[14]   SULFONYLUREA-STIMULATED GLUCOSE-TRANSPORT ASSOCIATION WITH DIACYLGLYCEROLLIKE ACTIVATION OF PROTEIN-KINASE-C IN BC3H1 MYOCYTES [J].
COOPER, DR ;
VILA, MC ;
WATSON, JE ;
NAIR, G ;
POLLET, RJ ;
STANDAERT, M ;
FARESE, RV .
DIABETES, 1990, 39 (11) :1399-1407
[15]  
CROOKS MJ, 1973, J PHARM PHARMACOL, V16, P304
[16]   GLYCOLIPID ANCHORING OF PLASMA-MEMBRANE PROTEINS [J].
CROSS, GAM .
ANNUAL REVIEW OF CELL BIOLOGY, 1990, 6 :1-39
[17]  
CUSHMAN SW, 1980, J BIOL CHEM, V255, P4758
[18]   METABOLIC CONSEQUENCES OF HYPERINSULINEMIA IMPOSED ON NORMAL RATS ON GLUCOSE HANDLING BY WHITE ADIPOSE-TISSUE, MUSCLES AND LIVER [J].
CUSIN, I ;
TERRETTAZ, J ;
ROHNERJEANRENAUD, F ;
JEANRENAUD, B .
BIOCHEMICAL JOURNAL, 1990, 267 (01) :99-103
[19]   GLYBURIDE-STIMULATED GLUCOSE-TRANSPORT IN CULTURED MUSCLE-CELLS VIA PROTEIN KINASE-C-MEDIATED PATHWAY REQUIRING NEW-PROTEIN SYNTHESIS [J].
DAVIDSON, MB ;
MOLNAR, IG ;
FURMAN, A ;
YAMAGUCHI, D .
DIABETES, 1991, 40 (11) :1531-1538
[20]  
DeFronzo R A, 1983, Am J Med, V74, P52, DOI 10.1016/0002-9343(83)90654-X