Department of Pathology, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Biol Pharm Bull. 2011;34(5):644-54. doi: 10.1248/bpb.34.644.
The diabetic "lipotoxicity" hypothesis presents that fat-induced visceral white adipose tissue insulin resistance plays a central role in the pathogenesis of type 2 diabetes. Berberine, a hypolipidemic agent, has been reported to have antidiabetic activities. The molecular mechanisms for this property are, however, not well clarified. Therefore in this study type 2 diabetic hamsters were induced by high-fat diet with low-dose streptozotocin. Then, we investigated the gene expression alterations and explored the molecular mechanisms underlying the therapeutic effect of berberine on fat-induced visceral white adipose tissue insulin resistance in diabetic hamsters by microarray analysis followed by real-time reverse transcription-polymerase chain reaction (RT-PCR) confirmation. Type 2 diabetic hamsters exhibited hyperglycemia and relative hyperinsulinemia, glucose intolerance, insulin resistance, intra-adipocyte lipid accumulation, significant increase in body weight and visceral white adipose tissue weight, abnormal serum adipokines levels, and deleterious dyslipidemia. Furthermore, they had increased sterol regulatory element-binding proteins (SREBPs) expression and decreased liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) expression in visceral white adipose tissue. After 9-week berberine treatment, fat-induced insulin resistance and diabetic phenotype in type 2 diabetic hamsters were significantly improved. Compared with diabetic hamsters, expression of LXRs and PPARs significantly increased and SREBPs significantly decreased in visceral white adipose tissue from berberine-treated diabetic hamsters. These results suggest that altered visceral white adipose tissue LXRs, PPARs, and SREBPs transcriptional programs are involved in the therapeutic mechanisms of berberine on fat-induced visceral white adipose tissue insulin resistance in type 2 diabetic hamsters.
糖尿病“脂毒性”假说提出，脂肪诱导的内脏白色脂肪组织胰岛素抵抗在 2 型糖尿病的发病机制中起核心作用。小檗碱是一种降脂药物，据报道具有抗糖尿病作用。然而，这种特性的分子机制尚不清楚。因此，本研究采用高脂肪饮食联合小剂量链脲佐菌素诱导 2 型糖尿病仓鼠。然后，我们通过微阵列分析和实时逆转录聚合酶链反应（RT-PCR）验证，研究了小檗碱对糖尿病仓鼠脂肪诱导的内脏白色脂肪组织胰岛素抵抗的治疗作用的基因表达变化，并探讨了其分子机制。2 型糖尿病仓鼠表现为高血糖和相对高胰岛素血症、葡萄糖耐量受损、胰岛素抵抗、脂肪细胞内脂质堆积、体重和内脏白色脂肪组织重量显著增加、血清脂联素水平异常以及脂代谢紊乱。此外，它们在内脏白色脂肪组织中表现出固醇调节元件结合蛋白（SREBPs）表达增加，肝 X 受体（LXRs）和过氧化物酶体增殖物激活受体（PPARs）表达减少。经过 9 周的小檗碱治疗，2 型糖尿病仓鼠的脂肪诱导胰岛素抵抗和糖尿病表型得到显著改善。与糖尿病仓鼠相比，小檗碱治疗的糖尿病仓鼠内脏白色脂肪组织中 LXRs 和 PPARs 的表达显著增加，SREBPs 的表达显著降低。这些结果表明，内脏白色脂肪组织中 LXRs、PPARs 和 SREBPs 转录程序的改变可能参与了小檗碱治疗 2 型糖尿病仓鼠脂肪诱导的内脏白色脂肪组织胰岛素抵抗的机制。
