Mechanism of insulin resistance and strategy of treatment

为了探讨2型糖尿病胰岛素抵抗的分子机制，我们研究了胰岛素受体底物(IRS)-2缺陷小鼠的胰岛素抵抗机制。我们澄清了IRS-2^&lt；-/-&gt；小鼠通过腺病毒基因转移恢复肝脏中IRS-2的联合治疗和通过持续注射瘦素icv改善肥胖完全改善了IRS-2^&lt；-/-&gt；小鼠的胰岛素抵抗(Suzuki等人，J.Biol.Chem.279、25039、2004年)。我们还通过将IRS2lox小鼠与β-Cre小鼠杂交，产生了下丘脑特异的IRS2^&gt；小鼠。βHT-IR-2^&lt；-/-&gt；小鼠表现出肥胖诱导的胰岛素抵抗以及β细胞增殖缺陷(Kubota等，J.Crin.Invest，114,917,2004)，支持这样的观点，即下丘脑中的IR-2参与瘦素信号，因此下丘脑中缺少IR-2导致与胰岛素抵抗相关的肥胖。我们先前已经证明，血清脂联素水平的下降会导致…更多的LS是高脂饮食诱导胰岛素抵抗的重要原因之一。我们通过表达克隆的方法克隆了两种脂联素受体AdipoR1和AdipoR2。在加入脂联素后，它们能够传递激活AMP激酶和PPARα的信号。此外，在高脂饮食诱导的肥胖和胰岛素抵抗小鼠中，肝脏和骨骼肌中表达的脂联素受体被发现下调(Tuchida等人，J.Biol.Chem.279、30817、2004年)。我们先前假设较大的脂肪细胞与全身性胰岛素抵抗有关，而较小的脂肪细胞与胰岛素敏感性有关。我们证明DGAT-2参与了瘦素抵抗引起的脂肪细胞肥大的过程(Suzuki等人，J Biol Chem。280、3331、2005)。关于胰岛素信号缺陷导致胰岛素抵抗和血管损伤的机制，我们证明了胰岛素抵抗的IRS-1和IRS-2缺陷小鼠都表现出代谢综合征，并进一步表明IRS-2对血管损伤具有保护作用(Kubota等人，循环107,3073,2003)。较少

To dissect the molecular mechanism of insulin resistance in Type 2 diabetes, we investigated the mechanism of insulin resistance in insulin receptor substrate (IRS)-2 deficient mice. We clarified that combined treatment of IRS-2^<-/-> mice with restoration of IRS-2 in liver through adenoviral gene transfer and amelioration of obesity by continuous leptin icv injection completely improved insulin resistance in IRS-2^<-/-> mice (Suzuki et al., J.Biol.Chem. 279, 25039, 2004). We also generated β cell, hypothalamus-specific IRS-2^<-/-> mice by crossing IRS-2 lox mice with RIP-Cre mice. The β HT-IRS-2^<-/-> mice showed obesity-induced insulin resistance as well as defects in β cell proliferation (Kubota et al., J.Crin.Invest., 114, 917, 2004), supporting the notion that, IRS-2 in the hypothalamus is involved in leptin signaling, thus lack of IRS-2 in the hypothalamus resulting in obesity associated with insulin resistance. We previously demonstrated that a decrease in serum adiponectin leve … More ls is one of the crucial causes of high fat diet-induced insulin resistance. We cloned two types of adiponectin receptors adipoR1 and adipoR2 by expression cloning. They are able to transmit signals which activate AMP kinase and PPAR α after the addition of adiponectin. In addition, adiponectin receptors expressed in liver and skeletal muscles are found to be down-regulated in high fat diet-induced obese and insulin resistant mice (Tsuchida et al., J.Biol.Chem. 279, 30817, 2004). We previously hypothesized that larger adipocytes are associated with systemic insulin resistance while smaller adipocytes are associated with insulin sensitivity. We demonstrated that DGAT-2 is involved in the process of adipocyte hypertrophy caused by leptin resistance (Suzuki et al., J Biol Chem. 280, 3331, 2005). On the mechanism how insulin signaling defects cause insulin resistance and vascular damage, we demonstrated that both IRS-1 and IRS-2 deficient mice which are insulin resistant showed metabolic syndromes and further showed that particularly IRS-2 has protective effect against vascular injury (Kubota et al., Circulation 107, 3073, 2003). Less