Journal Club

1. Journal Club Furmli S, Elmasry R, Ramos M, Fung J. Therapeutic use of intermittent fasting for people with type 2 diabetes as an alternative to insulin. BMJ Case Rep. 2018 Oct 9;2018. pii: bcr-2017-221854. doi: 10.1136/bcr-2017-221854. Lowe WL Jr, Scholtens DM, Lowe LP, Kuang A, Nodzenski M, Talbot O, Catalano PM, Linder B, Brickman WJ, Clayton P, Deerochanawong C, Hamilton J, Josefson JL, Lashley M, Lawrence JM, Lebenthal Y, Ma R, Maresh M, McCance D, Tam WH, Sacks DA, Dyer AR, Metzger BE; HAPO Follow-up Study Cooperative Research Group. Association of Gestational Diabetes With Maternal Disorders of Glucose Metabolism and Childhood Adiposity. JAMA. 2018 Sep 11;320(10):1005-1016. doi: 10.1001/jama.2018.11628. 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 2018年11月1日　8:30-8:55 ２階　医局

2. 1 Family Medicine, University of Toronto Faculty of Medicine, Toronto, Ontario, Canada 2 Saint James School of Medicine, Arnos Vale, Saint Vincent and the Grenadines 3 Canadian Memorial Chiropractic College, Toronto, Ontario, Canada 4 Corporate Medical Centre, Scarborough, Ontario, Canada 5 Department of Medicine, Scarborough Hospital, Scarborough, Ontario, Canada BMJ Case Rep. 2018 Oct 9;2018. pii: bcr-2017-221854. doi: 10.1136/bcr-2017-221854.

3. Summary This case series documents three patients referred to the Intensive Dietary Management clinic in Toronto, Canada, for insulin-dependent type 2 diabetes. It demonstrates the effectiveness of therapeutic fasting to reverse their insulin resistance, resulting in cessation of insulin therapy while maintaining control of their blood sugars. In addition, these patients were also able to lose significant amounts of body weight, reduce their waist circumference and also reduce their glycated haemoglobin level.

4. Background Therapeutic fasting may reduce insulin requirements in T2D. Given the rising cost of insulin, patients may potentially save significant money. Further, the reduced need for syringes and blood glucose monitoring may reduce patient discomfort. Therapeutic fasting has the potential to fill this gap in diabetes care by providing similar intensive caloric restriction and hormonal benefits as bariatric surgery without the invasive surgery. Therapeutic fasting is defined as the controlled and voluntary abstinence from all calorie-containing food and drinks from a specified period of time. This differs from starvation, which is neither deliberate nor controlled.

6. Treatment All patients were seen in the IDM clinic after the initial educational seminar and dietary and insulin adjustments were made. Patients were followed in the clinic biweekly in the first few weeks until the insulin was discontinued. The primary intervention used in this case series was dietary education and medically supervised therapeutic fasting. All patients were given detailed instructions on monitoring blood glucose, and insulin dosage was reduced prior to starting their fasting regimen in anticipation of the reduced dietary intake. Patients were closely monitored medically and instructed to stop fasting immediately if unwell for any reason. All three patients participated in a 6-hour long nutritional training seminar which outlined many topics including the pathophysiology of diabetes, insulin resistance, education on macronutrients, and the principles of dietary management of diabetes including therapeutic fasting as well as safety. After completing the educational training, the patients were instructed to follow a scheduled 24-hour fasts three times per week over a period of several months. Over the time period they were evaluated for glycaemic control and other diabetes-related health measures.

7. Treatment All patients followed similar dietary regimen. Patients 1 and 3 followed alternating-day 24-hour fasts, and patient 2 followed the triweekly 24-hour fasts schedule. On fasting days, the patients only consumed dinner, whereas on non-fasting days the patients consumed lunch and dinner. Low-carbohydrate meals were recommended when eating meals. Patients were examined on average twice a month and labs were recorded. At each visit, patients’ daily blood sugar diaries were reviewed and further dietary and medication adjustments made if needed. Blood sugars were measured by patients at least four times daily during the insulin-weaning period. Target daily blood sugars were <10 during the initial insulin-weaning phase and <7 thereafter. In addition, patients’ weight, waist circumference and blood pressures were measured and recorded at each visit.

12. Results: Despite its complete novelty of fasting for all three patients, it was well tolerated. No patient stopped fasting at any point out of choice. In general, our feedback from the patients in this programme was very positive, and a number of patients commented on enjoying being actively involved in the process of managing their diabetes.

13. Learning points • Medically supervised, therapeutic fasting regimens can help reverse type 2 diabetes (T2D) and minimise the use of pharmacological and possibly surgical interventions in patients with T2D. • Therapeutic fasting is an underutilised dietary intervention that can provide superior blood glucose reduction compared with standard pharmacological agents. • Fasting is a practical dietary strategy. • With proper education and support, we found compliance to be good.

14. Message 2型糖尿病患者は間欠的な絶食によって良好な血糖コントロールが得られ、インスリン治療や一部の血糖降下薬の服用を中止できる可能性があることが、スカーバロー病院（カナダ）のJason Fung氏らが実施した小規模な研究から示された。詳細は「BMJ Case Reports」10月9日オンライン版に発表された。 　この研究は、40～67歳の3人の男性2型糖尿病患者を対象としたもの。参加した患者の糖尿病罹病期間は10～25年で、複数の経口血糖降下薬を服用し、インスリン治療を行っていた。また、3人とも高血圧や高コレステロール血症を合併していた。 　参加した患者には、まず、絶食療法の管理法や安全性などに関するトレーニングセミナーを6時間受けてもらった。その後、3人のうち2人は1日置きに24時間絶食させ、残る1人には1週間のうち3日間絶食してもらい、7～11カ月にわたり継続してもらった。 　絶食日には、お茶やコーヒー、水、スープなどほとんどカロリーがない飲み物と超低カロリーの夕食のみを取ってもらい、その他の日には昼食と夕食を取ってもらった。なお、食事を取る際には低炭水化物のメニューが推奨された。また、平均で月2回の診察を行い、血液検査で血糖コントロール状況を評価したほか、体重や腹囲、血圧を測定した。また、必要に応じて薬剤の調整を行った。 　その結果、絶食を始めてから1カ月以内に、3人ともインスリン注射を中止できたことが分かった。うち1人については、開始からわずか5日でインスリン注射を中止していた。また、3人のうち2人はその他の糖尿病治療薬の服用も中止でき、残る1人は4種類のうち3種類の服用を中止できた。さらに、3人とも体重は10～18％減り、腹囲は10～22％減少したほか、HbA1c値は6.8～11％から6～7％に改善した。低血糖エピソードは3人とも認められなかった。 　これらの結果を踏まえ、Fung氏らは「24時間の間欠的な絶食により、2型糖尿病患者のインスリン抵抗性が改善したり、糖尿病治療薬の使用を中止できることが分かった」と述べている。また、間欠的な絶食によって体重や腹囲が減少し、良好な血糖コントロールが得られたことで、「将来の糖尿病合併症のリスク低減につながる可能性がある」と同氏は指摘している。 　一方で、Fung氏らは「今回の研究は小規模な観察研究であるため、絶食療法は2型糖尿病治療として確実に有用だと結論付けることはできない」と強調している。しかし、「米国やカナダの成人の10人に1人が糖尿病である現状を踏まえると、今回の研究結果は注目に値するものだ」と話している。 https://www.m3.com/clinical/news/635912?portalId=mailmag&mmp=EZ181025&mc.l=342374813&eml=a7513070f503c2bc1035eb325eed04d6http://casereports.bmj.com/content/2018/bcr-2017-221854.abstractFurmli

16. 妊娠糖尿病 とは？ 血糖が上昇する病気です 空腹時 92mg/dl以上， 負荷後１時間 180mg/dl以上， 負荷後２時間 153mg/dl以上 放置すると_____________

17. 妊娠糖尿病 とは？ 血糖が上昇する病気です 空腹時 92mg/dl以上， 負荷後１時間 180mg/dl以上， 負荷後２時間 153mg/dl以上 (どれか１つ) 放置すると合併症（巨大児など） （糖尿病の診断基準の血糖値は合併症発症で決めている！）

18. The group developed diagnosticcut points for the fasting, 1-h, and 2-h plasma glucose measurements that conveyed an odds ratio for adverse outcomes of at least 1.75 compared with women with the mean glucose levels in the HAPO study(23316 pregnant women). 平均血糖 (FPG 80.9mg/dl, 1-h PG 134.1mg/dl, 2-h PG 111.0mg/dl) の女性に比較し1.75倍以上のリスクとなる血糖が閾値

19. 1Northwestern University Feinberg School of Medicine, Chicago, Illinois 2MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio 3National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 4Ann and Robert H. Lurie Children’s Hospital, Chicago, Illinois 5Royal Manchester Children’s Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, School of Medical Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester, England 6Rajavithi Hospital, Bangkok, Thailand 7Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada 8Queen Elizabeth Hospital, School of Clinical Medicine and Research, University of the West Indies, Barbados 9Kaiser Permanente of Southern California, Pasadena 10Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children’s Medical Center of Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 11Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China 12St Mary’s Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, England 13Royal Victoria Hospital, Belfast, Ireland JAMA. 2018 Sep 11;320(10):1005-1016. doi: 10.1001/jama.2018.11628.

20. Importance The sequelae of gestational diabetes (GD) by contemporary criteria that diagnose approximately twice as many women as previously used criteria are unclear. Objective To examine associations of GD with maternal glucose metabolism and childhood adiposity 10 to 14 years’ postpartum.

21. Setting, and Participants The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study established associations of glucose levels during pregnancy with perinatal outcomes and the follow-up study evaluated the long-term outcomes (4697 mothers and 4832 children; study visits occurred between February 13, 2013, and December 13, 2016). Exposures Gestational diabetes was defined post hoc using criteria from the International Association of Diabetes and Pregnancy Study Groups consisting of 1 or more of the following 75-g oral glucose tolerance test results (fasting plasma glucose ≥92 mg/dL; 1-hour plasma glucose level ≥180 mg/dL; 2-hour plasma glucose level ≥153 mg/dL). Main Outcomes and Measures Primary maternal outcome: a disorder of glucose metabolism (composite of type 2 diabetes or prediabetes). Primary outcome for children: being overweight or obese; secondary outcomes: obesity, body fat percentage, waist circumference, and sum of skinfolds (>85th percentile for latter 3 outcomes).

28. Results The analytic cohort included 4697 mothers (mean [SD] age, 41.7 [5.7] years) and 4832 children (mean [SD] age, 11.4 [1.2] years; 51.0% male). The median duration of follow-up was 11.4 years. The criteria for GD were met by 14.3% (672/4697) of mothers overall and by 14.1% (683/4832) of mothers of participating children. Among mothers with GD, 52.2% (346/663) developed a disorder of glucose metabolism vs 20.1% (791/3946) of mothers without GD (odds ratio [OR], 3.44 [95% CI, 2.85 to 4.14]; risk difference [RD], 25.7% [95% CI, 21.7% to 29.7%]). Among children of mothers with GD, 39.5% (269/681) were overweight or obese and 19.1% (130/681) were obese vs 28.6% (1172/4094) and 9.9% (405/4094), respectively, for children of mothers without GD. Adjusted for maternal body mass index during pregnancy, the OR was 1.21 (95% CI, 1.00 to 1.46) for children who were overweight or obese and the RD was 3.7% (95% CI, −0.16% to 7.5%); the OR was 1.58 (95% CI, 1.24 to 2.01) for children who were obese and the RD was 5.0% (95% CI, 2.0% to 8.0%); the OR was 1.35 (95% CI, 1.08 to 1.68) for body fat percentage and the RD was 4.2% (95% CI, 0.9% to 7.4%); the OR was 1.34 (95% CI, 1.08 to 1.67) for waist circumference and the RD was 4.1% (95% CI, 0.8% to 7.3%); and the OR was 1.57 (95% CI, 1.27 to 1.95) for sum of skinfolds and the RD was 6.5% (95% CI, 3.1% to 9.9%).

29. Conclusions and Relevance Among women with GD identified by contemporary criteria compared with those without it, GD was significantly associated with a higher maternal risk for a disorder of glucose metabolism during long-term follow-up after pregnancy. Among children of mothers with GD vs those without it, the difference in childhood overweight or obesity defined by body mass index cutoffs was not statistically significant; however, additional measures of childhood adiposity may be relevant in interpreting the study findings.

30. Message 　妊娠中の高血糖と有害妊娠転帰を検討したHAPO試験およびその長期追跡試験に参加した母親4697例および小児4832例を対象に、妊娠糖尿病（GDM）と分娩後10-14年時の母親の糖代謝疾患および児の肥満との関連を検討。国際糖尿病・妊娠学会（IADPSG）基準に基づいた事後評価では、母親全体の14.3％、試験に参加した小児の母親14.1％がGDMだった。 　その結果、追跡期間中央値11.4年での母親の糖代謝異常（2型糖尿病および前糖尿病状態の複合）発生率はGDM群52.2％、非GDM群20.1％で（オッズ比3.44、リスク差25.7％）だった。小児の過体重または肥満発生率は母親がGDMの小児群39.5％、非GDMの小児群28.6％、肥満発生率はそれぞれ19.1％、9.9％で、有意差は示されなかった(?)。 母親の代謝異常発生率や小児の肥満や過体重などは有意差ありなのでは？ https://www.m3.com/clinical/journal/19565