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 松田 昌文 Matsuda, Masafumi 2013 年 7 月 4 日 8:30-8:55 ８階 医局 Bergenstal RM, Klonoff DC, Garg SK, Bode BW, Meredith M, Slover RH, Ahmann AJ, Welsh JB, Lee SW, Kaufman FR; the ASPIRE In-Home Study Group. Threshold-Based Insulin-Pump Interruption for Reduction of Hypoglycemia. N Engl J Med. 2013 Jun 22. [Epub ahead of print] Ziegler AG, Rewers M, Simell O, Simell T, Lempainen J, Steck A, Winkler C, Ilonen J, Veijola R, Knip M, Bonifacio E, Eisenbarth GS. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA. 2013 Jun 19;309(23):2473-9. doi: 10.1001/jama.2013.6285.

2. From the International Diabetes Center at Park Nicollet, Minneapolis (R.M.B.); the Diabetes Research Institute, Mills–Peninsula Health Services, San Mateo (D.C.K.), and Medtronic, Northridge (J.B.W., S.W.L., F.R.K.) — both in California; the Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora (S.K.G., R.H.S.); Atlanta Diabetes Associates, Atlanta (B.W.B.); Department of Medicine, University of Wisconsin, Madison (M.M.); and the Harold Schnitzer Diabetes Health Center, Oregon Health and Science University, Portland (A.J.A.). N Engl J Med 2013. DOI: 10.1056/NEJMoa1303576

3. Background The threshold-suspend feature of sensor-augmented insulin pumps is designed to minimize the risk of hypoglycemia by interrupting insulin delivery at a preset sensor glucose value. We evaluated sensor- augmented insulin-pump therapy with and without the threshold-suspend feature in patients with nocturnal hypoglycemia.

4. Methods We randomly assigned patients with type 1 diabetes and documented nocturnal hypoglycemia to receive sensor-augmented insulin-pump therapy with or without the threshold-suspend feature for 3 months. The primary safety outcome was the change in the glycated hemoglobin level. The primary efficacy outcome was the area under the curve (AUC) for nocturnal hypoglycemic events. Two-hour threshold- suspend events were analyzed with respect to subsequent sensor glucose values.

5. MiniMed Paradigm Veo http://www.diabetes-support.org.uk/info/?page_id=729

8. http://www.medtronic-diabetes.co.uk/product-information/paradigm-veo/index.html

9. Figure 2. Primary and Key Secondary End Points. As shown in Panel A, the mean (±SD) changes in glycated hemoglobin concentrations during the study phase (the primary safety end point) were similar in the threshold-suspend and control groups (0.00±0.44% vs. −0.04±0.42%; difference, 0.05 percentage points; 95% confidence interval [CI], −0.05 to 0.15). As shown in Panel B, the mean area under the curve (AUC) for nocturnal hypoglycemic events during the study phase (the primary efficacy end point) was 37.5% lower in the threshold-suspend group than in the control group (P<0.001). As shown in Panel C, the percentage of sensor glucose values that were less than 70 mg per deciliter was lower in the thresholdsuspend group than in the control group, whether during nighttime hours (6.0% vs. 10.0%) or during daytime and nighttime hours combined (5.3% vs. 8.1%). The P value was less than 0.001 for each range in the panel. (See Table S2 in the Supplementary Appendix for the percentages of sensor glucose values in all ranges.) To convert values for glucose to mmol per liter, multiply by 0.05551.

11. * The four reported serious adverse events in the run-in phase were radiculopathy resulting in laminectomy in one patient, coronary ischemia and stent placement in one patient, coronary artery disease in one patient, and atypical chest pain in one patient. † The two reported serious adverse events in the study phase were severe hypoglycemia in one patient and pneumonia in one patient.

12. Results A total of 247 patients were randomly assigned to receive sensor- augmented insulin pump therapy with the threshold-suspend feature (threshold-suspend group, 121 patients) or standard sensor-augmented insulin-pump therapy (control group, 126 patients). The changes in glycated hemoglobin values were similar in the two groups. The mean AUC for nocturnal hypoglycemic events was 37.5% lower in the threshold suspend group than in the control group (980±1200 mg per deciliter [54.4±66.6 mmol per liter] × minutes vs. 1568±1995 mg per deciliter [87.0±110.7 mmol per liter] × minutes, P<0.001). Nocturnal hypoglycemic events occurred 31.8% less frequently in the threshold-suspend group than in the control group (1.5±1.0 vs. 2.2±1.3 per patient week, P<0.001). The percentages of nocturnal sensor glucose values of less than 50 mg per deciliter (2.8 mmol per liter), 50 to less than 60 mg per deciliter (3.3 mmol per liter), and 60 to less than 70 mg per deciliter (3.9 mmol per liter) were significantly reduced in the threshold-suspend group (P<0.001 for each range). After 1438 instances at night in which the pump was stopped for 2 hours, the mean sensor glucose value was 92.6±40.7 mg per deciliter (5.1±2.3 mmol per liter). Four patients (all in the control group) had a severe hypoglycemic event; no patients had diabetic ketoacidosis.

13. Conclusions This study showed that over a 3-month period the use of sensor-augmented insulinpump therapy with the threshold- suspend feature reduced nocturnal hypoglycemia, without increasing glycated hemoglobin values. (Funded by Medtronic MiniMed; ASPIRE ClinicalTrials.gov number, NCT01497938.)

14. Message 1 型糖尿病患者 247 人を対象に、設定血糖値での 注入停止機能付きインスリンポンプの効果を無作 為化比較試験で評価（ ASPIRE 試験）。 HbA1c 値の変化は、機能付き・機能なしの両ポンプ群で 同等だった。夜間低血糖イベントの平均曲線下面 積（ AUC ）は、機能なし群に比べ機能付きポン プ群で 37.5 ％小さかった（ P ＜ 0.001 ）。

16. Institute of Diabetes Research, Helmholtz Zentrum Mu¨nchen, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universita¨tMu¨nchen, Neuherberg, Germany (Drs Ziegler and Winkler); Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora (Drs Rewers, Steck, and Eisenbarth); Department of Pediatrics (Drs O. Simell, T. Simell, and Lempainen) and Immunogenetics Laboratory (Dr Lempainen and Ilonen), University of Turku, and Department of Pediatrics, Turku University Hospital (Drs O. Simell, T. Simell, and Lempainen), Turku, Finland; Department of ClinicalMicrobiology, University of Eastern Finland, Kuopio, Finland (Dr Ilonen); Department of Pediatrics, Institute of Clinical Medicine, University of Oulu, Oulu, Finland (Dr Veijola); Children’s Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, and Department of Pediatrics, Tampere University Hospital, Tampere, Finland (Dr Knip); Center for Regenerative Therapies Dresden, and Paul Langerhans Institute Dresden, German Center for Diabetes Research, Dresden University of Technology, Dresden, Germany (Dr Bonifacio). JAMA. 2013;309(23):2473-2479

17. Importance Type 1 diabetes usually has a preclinical phase identified by circulating islet autoantibodies, but the rate of progression to diabetes after seroconversion to islet autoantibodies is uncertain. Objective To determine the rate of progression to diabetes after islet autoantibody seroconversion.

18. Design, Setting, and Participants Data were pooled from prospective cohort studies performed in Colorado (recruitment, 1993-2006), Finland (recruitment, 1994- 2009), and Germany (recruitment, 1989-2006) examining children genetically at risk for type 1 diabetes for the development of insulin autoantibodies, glutamic acid decarboxylase 65 (GAD65) autoantibodies, insulinoma antigen 2 (IA2) autoantibodies, and diabetes. Participants were all children recruited and followed up in the 3 studies (Colorado, 1962; Finland, 8597; Germany, 2818). Follow-up assessment in each study was concluded by July 2012. Main Outcomes and Measures The primary analysis was the diagnosis of type 1 diabetes in children with 2 or more autoantibodies. The secondary analysis was the diagnosis of type 1 diabetes in children with 1 autoantibody or no autoantibodies.

20. Progression to type 1 diabetes at 10-year follow-up after islet autoantibody seroconversion in 585 children with multiple islet autoantibodies was 69.7% (95% CI, 65.1%-74.3%), and in 474 children with a single islet autoantibody was 14.5% (95% CI, 10.3%-18.7%). Risk of diabetes in children who had no islet autoantibodies was 0.4% (95% CI, 0.2%-0.6%) by the age of 15 years.

24. Results Progression to type 1 diabetes at 10-year follow-up after islet autoantibody seroconversion in 585 children with multiple islet autoantibodies was 69.7% (95% CI, 65.1%-74.3%), and in 474 children with a single islet autoantibody was 14.5% (95% CI, 10.3%-18.7%). Risk of diabetes in children who had no islet autoantibodies was 0.4% (95% CI, 0.2%-0.6%) by the age of 15 years. Progression to type 1 diabetes in the children with multiple islet autoantibodies was faster for children who had islet autoantibody seroconversion younger than age 3 years (hazard ratio [HR], 1.65 [95% CI, 1.30-2.09; P ＜.001]; 10-year risk, 74.9% [95% CI, 69.7%-80.1%]) vs children 3 years or older (60.9% [95% CI, 51.5%-70.3%]); for children with the human leukocyte antigen (HLA) genotype DR3/DR4-DQ8 (HR, 1.35 [95% CI, 1.09-1.68; P=.007]; 10-year risk, 76.6% [95% CI, 69.2%-84%]) vs other HLA genotypes (66.2% [95% CI, 60.2%-72.2%]); and for girls (HR, 1.28 [95% CI, 1.04-1.58; P=.02];10- year risk, 74.8% [95% CI, 68.0%-81.6%]) vs boys (65.7% [95% CI, 59.3%- 72.1%]).

25. Conclusions and Relevance The majority of children at risk of type 1 diabetes who had multiple islet autoantibody seroconversion progressed to diabetes over the next 15 years. Future prevention studies should focus on this high-risk population.

26. Message 前向きコホート研究 3 件（対象者 1 万 3777 人）のデータを対象に、遺伝的な 1 型糖尿 病（ DM ）高リスク小児における膵島自己 抗体（ ICA ）へのセロコンバージョン後の DM への進行速度を検討。追跡調査 10 年間 での発症率は、複数 ICA 保有者で 69.7 ％、 単一保有者で 14.5 ％、非保有者の 15 歳ま での DM 発症リスクは 0.4 ％だった。 ICA 保有小児、 15 歳までに DM 発症