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５月 20 日 8:30-8:55 ８階 医局 White NH, Sun W, Cleary PA, Tamborlane WV, Danis RP, Hainsworth DP, Davis MD; DCCT-EDIC Research Group. Effect of prior intensive therapy in type 1 diabetes on 10-year progression of retinopathy in the DCCT/EDIC: comparison of adults and adolescents. Diabetes. 2010 May;59(5):1244-53. Epub 2010 Feb 11. Bosco D, Armanet M, Morel P, Niclauss N, Sgroi A, Muller YD, Giovannoni L, Parnaud G, Berney T. Unique arrangement of alpha- and beta-cells in human islets of Langerhans. Diabetes. 2010 May;59(5):1202-10. Epub 2010 Feb 25.

2. (n=730) (n=711)

3. 76% 54%

4. 1 Washington University, St. Louis, Missouri; 2 The George Washington University, The Biostatistics Center, Rockville, Maryland; the 3 the School of Medicine, Yale University, New Haven, Connecticut; the 4University of Wisconsin–Madison, Madison, Wisconsin; and the 5University of Missouri, Columbia, Missouri. Diabetes 59: 1244–1253, 2010DIABETES, VOL. 59, MAY 2010

5. Background The aim of this study was to examine differences between adolescents and adults in persistence of the benefits of intensive therapy 10 years after completion of the Diabetes Control and Complications Trial (DCCT).

6. During the Epidemiology of Diabetes Interventions and Complications (EDIC) study, progression of retinopathy from DCCT closeout to EDIC year 10 was evaluated in 1,055 adults and 156 adolescents. Methods

17. Results During 10 years of follow-up, HbA1c (A1C) was similar between original intensive (INT) and conventional (CON) groups and between former adolescents and adults. At EDIC year 10, adults in the former INT group continued to show slower progression of diabetic retinopathy than those in the CON group (adjusted hazard reduction 56%, P < 0.0001), whereas in adolescents this beneficial effect had disappeared (32%, P < 0.13). Seventy-nine percent of observed differences in the prolonged treatment effect between adults and adolescents at year 10 were explained by differences in mean A1C during DCCT between adolescents and adults (8.9 vs. 8.1%), particularly between INT adolescents and adults (8.1 vs. 7.2%).

18. Conclusion Prior glycemic control during DCCT is vital for the persistence of the beneficial effects of INT therapy 10 years later. Lowering A1C to as close to normal as safely possible without severe hypoglycemia and starting as early as possible should be attempted for all subjects with type 1 diabetes. These results underscore the importance of maintaining A1C at target values for as long as possible because the benefits of former INT treatment wane over time if A1C levels rise.

19. Message 網膜症の予防には血糖管理は重要。 発症後すぐに血糖管理を開始し，継続すること が特に若年者では重要。

21. Butler et al, Diabetes 52:102-110,2003 空腹時血糖 FPG (mg/dl) 膵臓 β 細胞量 ß-cell Volume (%) 4 3 2 1 0 250 200 150 100 50 正常血糖血糖上昇 p<0.01 糖尿病 p<0.001 血糖がちょっと高めの段階から膵 β 細胞量は低下してい る 剖検例の解析 124 autopsies 正常血糖血糖上昇糖尿病

22. Meier JJ et al: Diabetes 58:1595–1603, 2009 2 1 0 p:NS p<0.001 糖尿病で膵 β 細胞量が著減 (Europe) 手術例の解析 33 patients with chronic pancreatitis (n = 17), benign pancreatic adenomas (n = 13), and tumors of the ampulla of Vater (n = 3) 正常血糖血糖上昇糖尿病 膵臓 β 細胞量 ß-cell Volume (%)

23. Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type 2 diabetic patients. Sakuraba H, Mizukami H, Yagihashi N, Wada R, Hanyu C, Yagihashi S. Diabetologia. 2002 Jan;45(1):85-96. 日本人２型糖尿病患者の膵 β 細胞

24. Copyright ©2003 The Endocrine Society Yoon, K. H. et al. J Clin Endocrinol Metab 2003;88:2300-2308 韓国人２型糖尿病患者の膵 β 細胞 (n=9)(n=10)(n=25)

25. 韓国人２型糖尿病患者 の膵 α 細胞 Copyright ©2003 The Endocrine Society Yoon, K. H. et al. J Clin Endocrinol Metab 2003;88:2300-2308 Normal pancreas donors (control group 1, n = 9). Whole pancreases were obtained from organ donors (six men and three women) between 19 and 64 yr of age (average, 41.3 ± 14.2 yr). The main causes of death were cerebral hemorrhage, traffic accident, and myocardial infarction. Patients with a pancreatic neoplasm but without diabetes (control group 2, n = 10). Patients with type 2 DM. The 25 type 2 diabetic patients (15 men and 10 women) were of mean age 60.0 ± 8.5 yr (range, 40–70 yr) and had a mean diabetes duration of 4.9 yr, ranging from newly detected patients to those who had been suffering from the disease for 20 yr (Table 3 ). Their mean BMI was 22.2 ± 3.8 kg/m 2 (17.8– 29.1 kg/m 2 ), and their general health was compatible with Whipple’s operation or pancreatectomy. In these patients, the mean value of hemoglobin A1c was 7.3 ± 2.8% Control 1 Control 2 DM (n=9)(n=10) (n=25)

26. Diabetes 59: 1202–1210, 2010DIABETES, VOL. 59, MAY 2010 the Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland. mouse human

27. Background It is generally admitted that the endocrine cell organization in human islets is different from that of rodent islets. However, a clear description of human islet architecture has not yet been reported. The aim of this work was to describe our observations on the arrangement of human islet cells.

28. Human pancreas specimens and isolated islets were processed for histology. Sections were analyzed by fluorescence microscopy after immunostaining for islet hormones and endothelial cells. Methods

29. insulin (red) and glucagon (green)

30. insulin (blue), glucagon (red), and CD34 (green) CD34: vessels

31. Supplemental Figure : A-D: confocal views of pancreatic islets labeled for insulin (blue), glucagon (red) and actin (green). Arrows show cytoplasmic extension intercalated between alpha- cells and labeled for actin. Scale bar, 20 mm. E and F: confocal views of pancreatic islets labelled for insulin (red) and glucagon (green). F: higher magnification of insert in E. Arrows show the granular staining in a cytoplamic extension. Scale bars, 10 mm in E, 3 mm in F. insulin actin glucagon

32. 16. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52:102–110 17. Klo¨ ppel G, Lo¨hr M, Habich K, Oberholzer M, Heitz PU. Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv Synth Pathol Res 1985;4:110–125 18. Saito K, Yaginuma N, Takahashi T. Differential volumetry of A, B and D cells in the pancreatic islets of diabetic and nondiabetic subjects. Tohoku J Exp Med 1979;129:273–283 19. Sakuraba H, Mizukami H, Yagihashi N, Wada R, Hanyu C, Yagihashi S. Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese type 2 diabetic patients. Diabetologia 2002;45:85–96 Reduced beta-cell mass in type 2 diabetic patients mantle core vessle Whole=core + mantle + vessle

33. T2DM mouse human Cultured human islets

34. mantle part core part

37. ASSOCIATION

38. CULTURE

40. Results In small human islets (40–60 μm in diameter), β-cells had a core position, α-cells had a mantle position, and vessels laid at their periphery. In bigger islets, α-cells had a similar mantle position but were found also along vessels that penetrate and branch inside the islets. As a consequence of this organization, the ratio of β-cells to α-cells was constantly higher in the core than in the mantle part of the islets, and decreased with increasing islet diameter. This core-mantle segregation of islet cells was also observed in type 2 diabetic donors but not in cultured isolated islets. Three-dimensional analysis revealed that islet cells were in fact organized into trilaminar epithelial plates, folded with different degrees of complexity and bordered by vessels on both sides. In epithelial plates, most β-cells were located in a central position but frequently showed cytoplasmic extensions between outlying non–β-cells.

41. Conclusion Human islets have a unique architecture allowing all endocrine cells to be adjacent to blood vessels and favoring heterologous contacts between β- and α-cells, while permitting homologous contacts between β-cells.

42. Message 人の膵ランゲルハンス氏島の構造は マウスや ラットのものと異なる。 血管を中心に織り込まれたような構造で血管の 側に α 細胞があり中央に β 細胞がある。 培養条件では β 細胞が α 細胞を包み込むような形 態となる。 ２型糖尿病患者では相対的にも β 細胞が減り α 細 胞が増えている。