1. Journal Club 亀田メディカルセンター 糖尿病内分泌内科 Diabetes and Endocrine Department, Kameda Medical Center 松田 昌文 Matsuda, Masafumi 2008 年７月３日 8:20-8:50 B 棟８階 カンファレンス室 Sobngwi E, Choukem SP, Agbalika F, Blondeau B, Fetita LS, Lebbe C, Thiam D, Cattan P, Larghero J, Foufelle F, Ferre P, Vexiau P, Calvo F, Gautier JF.: Ketosis-prone type 2 diabetes mellitus and human herpesvirus 8 infection in sub-saharan Africans. JAMA. 2008 Jun 18;299(23):2770-6. Ishigaki Y, Katagiri H, Gao J, Yamada T, Imai J, Uno K, Hasegawa Y, Kaneko K, Ogihara T, Ishihara H, Sato Y, Takikawa K, Nishimichi N, Matsuda H, Sawamura T, Oka Y.: Impact of Plasma Oxidized Low-Density Lipoprotein Removal on Atherosclerosis. Circulation. 2008 Jun 16. [Epub ahead of print]

2. JAMA. 2008;299(23):2770-2776

3. Background and Aim An atypical form of type 2 diabetes mellitus (DM-2) is revealed by ketosis (ketosis-prone type 2 diabetes mellitus), frequently occurring in individuals who are black and of African origin, and characterized by an acute onset requiring transient insulin therapy. Its sudden onset suggests precipitating factors. To investigate the putative role of human herpesvirus 8 (HHV-8) in the pathogenesis of ketosis-prone DM-2.

4. Methods A cross-sectional study in which antibodies were searched against latent and lytic HHV-8 antigens using immunofluorescence. The presence of HHV-8 in genomic DNA was investigated in 22 of the participants at clinical onset of diabetes. We also tested whether HHV-8 was able to infect human pancreatic β cells in culture in vitro. The study was conducted at Saint-Louis University Hospital, Paris, France, from January 2004 to July 2005. All participants were black and of African origin: 187 were consecutive diabetic patients of whom 81 had ketosis-prone DM-2 and 106 had nonketotic DM-2, and 90 individuals were nondiabetic control participants who were matched for age and sex.

9. Results HHV-8 antibodies were found in 71 patients (87.7%) with ketosis-prone DM-2 vs 16 patients (15.1%) with nonketotic DM-2 (odds ratio, 39.9; 95% confidence interval, 17.1-93.4; P<.001) and 36 of the control participants (40.0%) (odds ratio, 10.7; 95% confidence interval, 4.9-23.4; P<.001). HHV-8 in genomic DNA was present in 6 of 13 patients with ketosis-prone DM-2 tested at acute onset and in 0 of 9 patients with nonketotic DM-2. HHV-8 proteins were present in human islet cells that were cultured for 4 days in the presence of HHV-8.

10. Conclusion In this preliminary cross-sectional study, the presence of HHV-8 antibodies was associated with ketosis-prone DM-2 in patients of sub-Saharan African origin. Longitudinal studies are required to understand the clinical significance of these findings.

11. DM-1 coxsackievirus B DM-2 hepatitis C virus human herpesvirus 1 hepatitis B virus infection, diabetes has been attributed to interferon therapy Fulminant diabetes in Japanese patients, a disease that resembles ketosis-prone diabetes, may be precipitated by viruses. Other Viruses Associated With Diabetes

12. HHV-8 in Japan Prevalence 0.2% among HIV-1 negative populations 11.6% among HIV-1 positive patients (J Med Virol 57:159-162, 1999)

15. Background Several clinical studies of statin therapy have demonstrated that lowering low- density lipoprotein (LDL) cholesterol prevents atherosclerotic progression and decreases cardiovascular mortality. In addition, oxidized LDL (oxLDL) is suggested to play roles in the formation and progression of atherosclerosis. However, whether lowering oxLDL alone, rather than total LDL, affects atherogenesis remains unclear.

16. Methods To clarify the atherogenic impact of oxLDL, lectin-like oxLDL receptor 1 (LOX-1), an oxLDL receptor, was expressed ectopically in the liver with adenovirus administration in apolipoprotein E–deficient mice at 46 weeks of age. Hepatic LOX-1 expression enhanced hepatic oxLDL uptake, indicating functional expression of LOX- 1 in the liver. Although plasma total cholesterol, triglyceride, and LDL cholesterol levels were unaffected, plasma oxLDL was markedly and transiently decreased in LOX-1 mice.

20. Figure 4. Hepatic LOX-1 expression completely inhibited atherosclerosis progression. A, Aortic atherosclerosis was evaluated as the Oil Red O–positive area. B, The Oil Red O– positive areas were quantified and expressed as percentages of the total aortic area in baseline (46-week- old) mice (gray bars; n=9), 50-week-old LacZ mice (white bars; n=13), and 50-week-old LOX-1 mice (black bars; n=13). Representative histological findings of the whole aorta are shown in A. Data are presented as mean±SE. **P<0.01.

24. Results In controls, atherosclerotic lesions, detected by Oil Red O staining, were markedly increased (by 38%) during the 4- week period after adenoviral administration. In contrast, atherosclerotic progression was almost completely inhibited by hepatic LOX-1 expression. In addition, plasma monocyte chemotactic protein-1 and lipid peroxide levels were decreased, whereas adiponectin was increased, suggesting decreased systemic oxidative stress. Thus, LOX1 expressed in the livers of apolipoprotein E–deficient mice transiently removes oxLDL from circulating blood and possibly decreases systemic oxidative stress, resulting in complete prevention of atherosclerotic progression despite the persistence of severe LDL hypercholesterolemia and hypertriglyceridemia.

25. Conclusion OxLDL has a major atherogenic impact, and oxLDL removal is a promising therapeutic strategy against atherosclerosis.