| Co-Investigator(Kenkyū-buntansha) |
KADOWAKI Takashi The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (30185889)
TERAUCHI Yasuo Yokohama City University, Faculty of Medicine, Professor, 大学院・医学系研究科, 教授 (40359609)
YAMAUCHI Toshimasa The University of Tokyo, Faculty of Medicine, Visiting Assistant Professor, 医学部附属病院, 寄附講座教員(客員助教授) (40372370)
SUZUKI Ryo The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手
|
|---|
| Budget Amount *help |
¥14,800,000 (Direct Cost: ¥14,800,000)
Fiscal Year 2004: ¥5,600,000 (Direct Cost: ¥5,600,000)
Fiscal Year 2003: ¥9,200,000 (Direct Cost: ¥9,200,000)
|
|---|
| Research Abstract |
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
|
