1. Journal Club 埼玉医科大学 総合医療センター 内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田 昌文 Matsuda, Masafumi 2010 年 8 月 26 日 8:30-8:55 ８階 医局 Zhang X, Saaddine JB, Chou CF, Cotch MF, Cheng YJ, Geiss LS, Gregg EW, Albright AL, Klein BE, Klein R. Prevalence of diabetic retinopathy in the United States, 2005-2008. JAMA. 2010 Aug 11;304(6):649-56. Ronald CW Ma, Claudia HT Tam, Ying Wang, Andrea O Luk, Cheng Hu, Xilin Yang, Vincent Lam, Alfred WH Chan, Janice SK Ho, Chun-Chung Chow, Peter CY Tong, Weiping Jia, Maggie CY Ng, Wing-Yee So, Juliana CN Chan Genetic variants of the protein kinase c-  1 gene and development of end-stage renal disease in patients with type 2 diabetes JAMA. 2010 Aug 25;304(8):881-889.

3. Division of Diabetes Translation, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia (Drs Zhang, Saaddine, Chou, Cheng, Geiss, Gregg, and Albright); Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, MD (Dr Cotch); Department of Ophthalmology and Visual Sciences, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin (Drs B. Klein and R. Klein) JAMA. 2010;304(6):649-656

4. DIABETIC RETINOPATHY IS THE leading cause of new cases of legal blindness among adults aged 20 to 74 years in the United States. Klein R, Klein B. Vision disorders in diabetes. In: National Diabetes Data Group, ed. Diabetes in America. 2nd ed. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 1995:293–337. 1988-1994 (National Health and Nutrition Examination Surveys III [NHANES III]).

5. Context The prevalence of diabetes in the United States has increased. People with diabetes are at risk for diabetic retinopathy. No recent national population-based estimate of the prevalence and severity of diabetic retinopathy exists. Objectives To describe the prevalence and risk factors of diabetic retinopathy among US adults with diabetes aged 40 years and older. Background

6. Design, Setting, and Participants Analysis of a cross- sectional, nationally representative sample of the National Health and Nutrition Examination Survey 2005-2008 (N=1006). Diabetes was defined as a self-report of a previous diagnosis of the disease (excluding gestational diabetes mellitus) or glycated hemoglobin A1c of 6.5% or greater. Two fundus photographs were taken of each eye with a digital nonmydriatic camera and were graded using the Airlie House classification scheme and the Early Treatment Diabetic Retinopathy Study severity scale. Prevalence estimates were weighted to represent the civilian, non institutionalized US population aged 40 years and older. Main Outcome Measurements Diabetic retinopathy and vision-threatening diabetic retinopathy. Methods

7. Vision-threatening diabetic retinopathy, a level that may soon result in vision loss if left untreated, was defined as the presence of severe non proliferative diabetic retinopathy, proliferative diabetic retinopathy, or clinically significant macular edema.

11. Results Results The estimated prevalence of diabetic retinopathy and vision- threatening diabetic retinopathy was 28.5% (95% confidence interval [CI], 24.9%-32.5%) and 4.4% (95% CI, 3.5%-5.7%) among US adults with diabetes, respectively. Diabetic retinopathy was slightly more prevalent among men than women with diabetes (31.6%; 95% CI, 26.8%-36.8%; vs 25.7%; 95% CI, 21.7%-30.1%; P=.04). Non- Hispanic black individuals had a higher crude prevalence than non-Hispanic white individuals of diabetic retinopathy (38.8%; 95% CI, 31.9%-46.1%; vs 26.4%; 95% CI, 21.4%-32.2%; P=.01) and vision-threatening diabetic retinopathy (9.3%; 95% CI, 5.9%-14.4%; vs 3.2%; 95% CI, 2.0%-5.1%; P=.01). Male sex was independently associated with the presence of diabetic retinopathy (odds ratio [OR], 2.07; 95% CI, 1.39- 3.10), as well as higher hemoglobin A1c level (OR, 1.45; 95% CI, 1.20- 1.75), longer duration of diabetes (OR, 1.06 per year duration; 95% CI, 1.03-1.10), insulin use (OR, 3.23; 95% CI, 1.99-5.26), and higher systolic blood pressure (OR, 1.03 per mm Hg; 95% CI, 1.02-1.03).

12. Conclusion Conclusion In a nationally representative sample of US adults with diabetes aged 40 years and older, the prevalence of diabetic retinopathy and vision-threatening diabetic retinopathy was high, especially among Non-Hispanic black individuals.

13. Message/Comments 米国で糖尿病性網膜症の疫学データはサン プリングだが眼底写真を撮っている。 失明がどのくらいか不明だが米国では糖尿 病患者の４～５％が失明の危険性のある網 膜症というのはかなりショックなデータ。

15. Activation of PKC in diabetic kidney by hyperglycemia leading to multiple pathological changes in diabetic nephropathy Fundamental & Clinical Pharmacology 22 (2008) 231–240 Ruboxistaurin: LY 333531

16. Protein kinase C, beta 1 A new drug application seeking approval from USA-FDA for ruboxistaurin for the treatment of moderate to severe non-proliferative diabetic retinopathy was submitted by Eli Lilly in February 2006. Lilly received an approval letter from the FDA in August, 2006. FDA requested additional 3-year, phase 3 clinical trial to provide additional efficacy data before approving the drug in moderate to severe non-proliferative retinopathy. 17 April 2007 The manufacturer of ruboxistaurin has advised us that they have withdrawn regulatory applications in relation to this product at this time. The Institute has therefore decided to remove this appraisal from its work programme. LY333531 administration in diabetic rats resulted in near normalization of GFR and filtration fraction. Use of PKC b inhibitor in a small patient population of type 2 DN showed a significant reduction in albuminuria, prevented loss of eGFR and improvement in renal function

17. Department of Medicine and Therapeutics (Drs Ma, Wang, Luk, Yang, Chow, Tong, Ng, So, and J. Chan; Mss Tam and Ho; and Messrs Lam and A. Chan), Hong Kong Institute of Diabetes and Obesity (Drs Ma and J. Chan), and Li Ka Shing Institute of Health Sciences (Dr J. Chan), Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China; and Department of Endocrinology and Metabolism, Shanghai Clinical Center of Diabetes, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China (Drs Hu and Jia). Dr Ng is now with Department of Pediatrics, Section on Medical Genetics, Centers for Diabetes Research and Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina. JAMA. 2010;304(8):881-889

18. Background Context Protein kinase C-β (PKC-β) is a cell-signaling intermediate implicated in development of diabetic complications. Objective To examine the risk association of PKC- β1 gene (PRKCB1) polymorphisms and end-stage renal disease (ESRD) in an 8-year prospective cohort of Chinese patients with type 2 diabetes.

19. Design, Setting, and Participants We genotyped 18 common tag single nucleotide polymorphisms (SNPs) that span the PRKCB1 gene (r 2 =0.80) in 1172 Chinese patients (recruited 1995-1998) without renal disease at baseline. A validation cohort included an additional 1049 patients with early-onset diabetes who were free of renal disease at baseline and were recruited after 1998. Main Outcome Measures Associations of PRKCB1 polymorphisms under additive, dominant, and recessive genetic models with new onset of ESRD (defined as estimated glomerular filtration rate<15 mL/min/1.73m 2 or dialysis or renal-related death) were assessed by Cox proportional hazard regression, adjusted for all conventional risk factors including use of medications Methods

23. Adjusted for mean values of sex, age, duration of diabetes, systolic and diastolic blood pressure, hemoglobin A1c, total cholesterol, natural logarithm of triglycerides, estimated glomerular filtration rate, natural logarithm of albumin excretion rate, retinopathy (present/absent),and use of medications (yes/no). Three significant and independent single-nucleotide polymorphisms with r 2 <0.80 (rs3760106 with the dominant model, rs7404928 with the recessive model, and rs4787733 with the additive model) were selected to calculate the number of risk alleles for end-stage renal disease (ESRD).

25. Results Results After a mean (SD) of 7.9 (1.9) years, 90 patients (7.7%) progressed to ESRD. Four common SNPs were associated with ESRD (P<.05). The closely linked T allele at rs3760106 and G allele rs2575390 (r 2 =0.98) showed the strongest association with ESRD (hazard ratio [HR], 2.25; 95% confidence interval [CI], 1.31-3.87; P=.003, and HR, 2.26; 95% CI, 1.31-3.88; P=.003, respectively). Four common variants predicted ESRD in separate models. The HR for ESRD increased with increasing number of risk alleles (P<.001) in the joint effect analysis. The adjusted risk for ESRD was 6.04 (95% CI, 2.00-18.31) for patients with 4 risk alleles compared with patients with 0 or 1 risk allele. Incidence was 4.4 per 1000 person-years (95% CI, 0.5-8.2) among individuals with 0 or 1 risk allele compared with 20.0 per 1000 person-years (95% CI, 8.8- 31.1) in those carrying 4 risk alleles (6.9% of the cohort). These results were validated in a separate prospective cohort of young-onset diabetic patients. Of 1049 patients in the validation cohort, 151 (14.3%) developed chronic kidney disease (CKD) during follow-up, and there were significant associations between both the T allele of rs3760106 and the G allele of rs2575390 and development of CKD (HR, 1.68; 95% CI, 1.10-2.57; P=.02, and HR, 1.62; 95% CI, 1.07-2.47; P=.02, respectively).

26. Conclusion Conclusion Genetic variants in the PRKCB1 gene were independently associated with development of ESRD in Chinese patients with type 2 diabetes.

27. Message PKC-  が網膜症や腎症に重要な役割をするこ とはよく知られている。 糖尿病性腎症進展のリスクとしてこの遺伝子多 型が関与することは意義があるが、 PKC-  阻 害薬の開発はどうなっているのだろうか？ 日本での同様な研究 Araki S, Haneda M, Sugimoto T, et al. Polymorphisms of the protein kinase C-beta gene (PRKCB1) accelerate kidney disease in type 2 diabetes without overt proteinuria. Diabetes Care. 2006;29(4):864-868. T allele at 1054 C/T and G allele at 546 C/G