永井 良三

Genome-wide scanning is a powerful tool to identify susceptible chromosome loci, however, individual chromosomal regions still have many candidate genes. Although cDNA microarray analysis provides valuable information for identifying genes involved in pathogenesis, expression levels of many genes are changed. A novel approach for identification of therapeutic targets is the combination of genome-wide scanning and the use of DNA chips, as shown in Fig. (1). Using DNA chips, we screened for secreted molecules, the expressions of which were changed in adipose tissues from mice rendered insulin resistance. Decreased expression of one of these molecules, adiponectin/Acrp30, correlates strongly with insulin resistance. Interestingly, recent genome-wide scans have mapped a susceptibility locus for type 2 diabetes and metabolic syndrome to chromosome 3q27, where adiponectin gene is located. Decreasing serum adiponectin levels are associated with increased risk for type 2 diabetes. Interestingly, adiponectin was decreased in insulin resistant rodent models both of obesity and lipoatrophy, and replenishment of adiponectin ameliorated their insulin resistance. Moreover, adiponectin transgenic mice ameliorated insulin resistance and diabetes Adiponectin knockout mice showed insulin resistance and glucose intolerance. In muscle and liver, adiponectin activated AMP kinase and PPARalpha pathways thereby increasing beta-oxidation of lipids, leading to decreased TG content, which ameliorated insulin resistance under a high-fat diet. Despite similar plasma glucose and lipid levels on an apoE deficient background, adiponectin transgenic apoE deficient mice showed amelioration of atherosclerosis, which was associated with decreased expressions of class A scavenger receptor and tumor necrosis factor alpha. Finally, cDNA encoding adiponectin receptors (AdipoR1 and R2) have been identified by expression cloning, which facilitates the understanding of molecular mechanisms of adiponectin actions and obesity-linked diseases such as diabetes and atherosclerosis and the designing of novel antidiabetic and anti-atherogenic drugs with AdipoR1 and R2 as molecular targets.

We previously demonstrated that Irs2-/- mice develop diabetes due to beta-cell growth failure and insulin resistance; however, glucose-induced insulin secretion was increased in islets isolated from Irs2-/- mice. Pdx-1, a transcription factor important for maintenance of the beta-cell function, was recently reported to be severely reduced in Irs2-/- murine beta-cells. We report herein that Pdx-1 expression, including the amount of Pdx-1 localized in the nucleus, is not down-regulated in our Irs2-/- murine beta-cells with a C57BL/6 background. We have also demonstrated the expression of upstream genes of Pdx-1, such as HNF3beta and HNF1alpha, as well as its downstream genes, including insulin, Glut2, and Nkx6.1, to be well preserved. We have further demonstrated Pdx-1 expression to also be preserved in beta-cells of 30-week-old diabetic Irs2-/- mice. In addition, surprisingly, even in Irs2-/- mice on a high fat diet with markedly elevated blood glucose, exceeding 400 mg/dl, Pdx-1 expression was not reduced. Furthermore, we found Pdx-1 to be markedly decreased in certain severely diabetic Irs2-/- mice with a mixed C57BL/6J x 129Sv background. We conclude that 1) Pdx-1 expression in Irs2-/- mice is regulated in a strain-dependent manner, 2) Irs2-/- mice develop diabetes associated with beta-cell growth failure even when Pdx1 expression is preserved, and 3) Pdx-1 expression is preserved in severely hyperglycemic Irs2-/- mice with a C57BL/6 background on a high fat diet.

三尖弁狭窄症(TS)を合併し,焼灼に難渋した房室結節回帰性頻拍の1例を経験した.解剖学的アプローチでコッホ三角部と考えられる部位の電位はすべていわゆるon the valve型であり,small A largeV型の電位はヒス東電位記録部位(HBE)から2mm以内でしか記録されず,スローポテンシャルは記録されなかった.3次元エレクトロアナトミカルマッピングシステム(CARTOTM)を用いて,HBEをマッピングし,解剖学的アプローチで冠静脈洞側から焼灼を開始したが,成功通電部位はHBEから3mmの点であり,この局所電位もon the valve型であった.右房右室間に拡張期に10mmHgの圧格差を認め,右房造影と経食道心エコーでTSを認めた.形態的に三尖弁輪の異常を伴い,ヒス束近傍での通電を要する症例ではCARTOTMは有用と考えられ報告した.