Federal Institute for Drugs and Medical Devices, Kurt-Georg-Kiesinger-Allee 3, Bonn, Germany.
Diabetes Obes Metab. 2011 Sep;13(9):791-9. doi: 10.1111/j.1463-1326.2011.01409.x.
Sulphonylureas (SUs) are among the most widely used oral hypoglycaemic drugs that stimulate insulin secretion. In addition, SUs have pleiotropic effects on other tissues. Conflicting findings have been reported regarding the effects of SUs on adipocytes. We have now investigated the actions of glimepiride and glibenclamide (=glyburide) in primary human adipocytes.
Primary cultured human white pre-adipocytes were differentiated in vitro according to a standard protocol. Lipid accumulation was assessed by Oil Red O staining and determination of triglyceride content; gene expression was measured by RT PCR and Western blotting.
Initially, we characterized the genes regulated during human pre-adipocyte differentiation by performing global microarray analysis. Treatment with glimepiride and glibenclamide caused an increased accumulation of lipid droplets and triglycerides. In addition, genes involved in lipid metabolism were induced and chemokine expression was decreased. Interestingly, the effects of SUs were generally qualitatively and quantitatively similar to those of pioglitazone. In direct comparison, glibenclamide was more potent than glimepiride with respect to the induction of fatty acid binding protein 4 (FABP4) (EC(50) 0.32 vs. 2.8 µM), an important adipocyte marker gene. SU-induced differentiation was virtually completely blocked by the peroxisome proliferator-activated receptor γ (PPARγ)-antagonist T0070907 but not affected by diazoxide, indicating PPARγ activation by SUs. Repaglinide had no effect on adipogenesis, although it causes insulin liberation like SUs.
In primary human pre-adipocytes, glibenclamide and glimepiride strongly induced differentiation, apparently by activating PPARγ. Thus, SUs but not repaglinide may be used to influence insulin resistance beyond their effect on insulin liberation.
磺酰脲类（SUs）是最广泛使用的刺激胰岛素分泌的口服降糖药之一。此外，SUs 对其他组织具有多种作用。关于 SUs 对脂肪细胞的影响，已有相互矛盾的研究结果报道。我们现在研究了格列美脲和格列本脲（= 格列吡嗪）在原代人脂肪细胞中的作用。
根据标准方案，在体外培养原代人白色前脂肪细胞进行分化。用油红 O 染色和甘油三酯含量测定评估脂质积累；通过 RT-PCR 和 Western blot 测定基因表达。
首先，我们通过进行全基因组微阵列分析来描述人前脂肪细胞分化过程中调节的基因。格列美脲和格列本脲处理导致脂滴和甘油三酯积累增加。此外，参与脂质代谢的基因被诱导，趋化因子表达减少。有趣的是，SUs 的作用在性质和数量上通常与吡格列酮相似。直接比较，格列本脲比格列美脲在诱导脂肪酸结合蛋白 4（FABP4）（EC(50) 0.32 对 2.8µM）方面更有效，FABP4 是一个重要的脂肪细胞标记基因。过氧化物酶体增殖物激活受体 γ（PPARγ）拮抗剂 T0070907 几乎完全阻断了 SU 诱导的分化，但不受 diazoxide 影响，表明 SUs 激活了 PPARγ。尽管格列美脲像 SUs 一样引起胰岛素释放，但它对脂肪生成没有影响。
在原代人前脂肪细胞中，格列本脲和格列美脲强烈诱导分化，显然是通过激活 PPARγ。因此，SUs 可能会影响胰岛素抵抗，而不仅仅是其对胰岛素释放的影响，但不包括格列美脲。
