Smith S A
Scientific Affairs, Diabetes, GlaxoSmithKline R&D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.
Biochimie. 2003 Dec;85(12):1219-30. doi: 10.1016/j.biochi.2003.10.010.
Insulin resistance is a key metabolic defect in type 2 diabetes that is exacerbated by obesity, especially if the excess adiposity is located intra-abdominally/centrally. Insulin resistance underpins many metabolic abnormalities-collectively known as the insulin resistance syndrome-that accelerate the development of cardiovascular disease. Thiazolidinedione anti-diabetic agents improve glycaemic control by activating the nuclear receptor peroxisome proliferator activated receptor-gamma (PPARgamma). This receptor is highly expressed in adipose tissues. In insulin resistant fat depots, thiazolidinediones increase pre-adipocyte differentiation and oppose the actions of pro-inflammatory cytokines such as tumour necrosis factor-alpha. The metabolic consequences are enhanced insulin signalling, resulting in increased glucose uptake and lipid storage coupled with reduced release of free fatty acids (FFA) into the circulation. Metabolic effects of PPARgamma activation are depot specific-in people with type 2 diabetes central fat mass is reduced and subcutaneous depots are increased. Thiazolidinediones increase insulin sensitivity in liver and skeletal muscle as well as in fat, but they do not express high levels of PPARgamma, suggesting that improvement in insulin action is indirect. Reduced FFA availability from adipose tissues to liver and skeletal muscle is a pivotal component of the insulin-sensitising mechanism in these latter two tissues. Adipocytes secrete multiple proteins that may both regulate insulin signalling and impact on abnormalities of the insulin resistance syndrome--this may explain the link between central obesity and cardiovascular disease. Of these proteins, low plasma adiponectin is associated with insulin resistance and atherosclerosis--thiazolidinediones increase adipocyte adiponectin production. Like FFA, adiponectin is probably an important signalling molecule regulating insulin sensitivity in muscle and liver. Adipocyte production of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis, and angiotensin II secretion are partially corrected by PPARgamma activation. The favourable modification of adipocyte-derived cardiovascular risk factors by thiazolidinediones suggests that these agents may reduce cardiovascular disease as well as provide durable glycaemic control in type 2 diabetes.
胰岛素抵抗是2型糖尿病的关键代谢缺陷，肥胖会加剧这种缺陷，尤其是当过多的脂肪堆积在腹部/中心部位时。胰岛素抵抗是许多代谢异常的基础，这些异常统称为胰岛素抵抗综合征，会加速心血管疾病的发展。噻唑烷二酮类抗糖尿病药物通过激活核受体过氧化物酶体增殖物激活受体γ（PPARγ）来改善血糖控制。该受体在脂肪组织中高度表达。在胰岛素抵抗的脂肪储存部位，噻唑烷二酮类药物可增加前脂肪细胞分化，并对抗促炎细胞因子（如肿瘤坏死因子-α）的作用。其代谢后果是增强胰岛素信号传导，导致葡萄糖摄取增加和脂质储存增加，同时减少游离脂肪酸（FFA）释放到循环中。PPARγ激活的代谢作用具有储存部位特异性——在2型糖尿病患者中，中心脂肪量减少，皮下脂肪储存增加。噻唑烷二酮类药物可增加肝脏、骨骼肌以及脂肪中的胰岛素敏感性，但它们在这些组织中并不高表达PPARγ，这表明胰岛素作用的改善是间接的。从脂肪组织到肝脏和骨骼肌的FFA可用性降低是后两种组织中胰岛素增敏机制的关键组成部分。脂肪细胞分泌多种蛋白质，这些蛋白质可能既调节胰岛素信号传导，又影响胰岛素抵抗综合征的异常情况——这可能解释了中心性肥胖与心血管疾病之间的联系。在这些蛋白质中，低血浆脂联素与胰岛素抵抗和动脉粥样硬化有关——噻唑烷二酮类药物可增加脂肪细胞脂联素的产生。与FFA一样，脂联素可能是调节肌肉和肝脏中胰岛素敏感性的重要信号分子。纤溶酶原激活物抑制剂-1（PAI-1，一种纤维蛋白溶解抑制剂）的脂肪细胞产生以及血管紧张素II分泌可通过PPARγ激活得到部分纠正。噻唑烷二酮类药物对脂肪细胞衍生的心血管危险因素的有利改变表明，这些药物可能降低心血管疾病风险，并为2型糖尿病患者提供持久的血糖控制。
