Journal Club

1. Journal Club NauckMA1, Meier JJ. Diagnostic accuracy of an "amended" insulin-glucose ratio for the biochemical diagnosis of insulinomas. Ann Intern Med. 2012 Dec 4;157(11):767-75. doi: 10.7326/0003-4819-157-11-201212040-00004. Hooper L1, Abdelhamid A, Moore HJ, Douthwaite W, Skeaff CM, Summerbell CD. Effect of reducing total fat intake on body weight: systematic review and meta-analysis of randomised controlled trials and cohort studies. MJ. 2012 Dec 6;345:e7666. doi: 10.1136/bmj.e7666. 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 2012年12月20日8:30-8:55 ８階　医局

2. インスリン分泌指標（見た目） HOMA-b CPI 空腹時　C-peptide(ng/ml) 100 × 空腹時　insulin(μU/ml)×360 空腹時血糖　(mg/dl) 空腹時血糖　(mmol/L)　－　3.5 SUIT 空腹時　insulin(μU/ml) 空腹時　C-peptide(ng/ml)×1485 空腹時血糖　(mg/dl)　－　63.0 空腹時血糖　(mg/dl) －　61.8

3. インスリノーマ評価の指標 Fajansの指標(インスリン値/血糖値＞0.3) Turnerの指数(インスリン値×100/(血糖値－30)＞50) (Turner RC, Oakley NW, Nabarro JD. Control of basal insulin secretion, with special reference to the diagnosis of insulinomas. Br Med J. 1971;2:132-5.) (CryerPE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, et al; Endocrine Society. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J ClinEndocrinol Metab. 2009;94:709-28.) An occasional patient with an insulinoma may not fulfill these criteria even during a 72-h fast, and a few have plasma insulin levels below 3 μU/ml (18 pmol/liter) during fasting hypoglycemia, but plasma C-peptide levels are usually 0.6 ng/ml (0.2 mmol/liter) or greater and plasma proinsulin levels are usually 5.0 pmol/liter or greater in the latter patients.

4. 糖尿病学会地方会抄録 原因不明の意識消失を伴う低血糖にジアゾキシドが有効であった一例 【症例】18歳の男性。17歳にて深夜痙攣発作を起こし救急搬送され低血糖と判明しブドウ糖静注にて改善。18歳になり早朝痙攣発作。スナックにて改善した。身長167cm、体重62kg、BMI 22.2kg/m2。75g経口ブドウ糖負荷試験にて負荷前血糖71mg/dl、インスリン値2μU/ml、180分値それぞれ51mg/dl、6μU/mlであった。入院にて絶食試験施行。48時間後血糖値とCペプチド値は54mg/dl、0.29ng/ml、56時間後67mg/dl、0.37ng/mlでインスリンノーマの可能性は低く中止。終了時ACTH 9.3pg/ml、コルチゾール5.3μg/dl、GH 0.69ng/ml、グルカゴン 126pg/ml、総ケトン体4.3mmol/Lであった。退院後CGMを一度施行し低血糖はなかったが、SMBGで低血糖があったためジアゾキシド(25mg)を処方したところ朝夕食後各１錠にて低血糖を起こすことはなかった。インスリン感受性は良くインスリン分泌が更に相対的に上昇した症例と思われた。

5. 【主訴】意識消失（低血糖）【現病歴】2011年12月、夜2時頃就寝した後3時頃痩箪発作を起こし、南古谷病院に救急搬送、血糖測定不能（Low）でブドウ糖静注して改善。2012年2月17日夕食を18時頃摂取、チョコレートを食べながら勉強して夜1時頃就寝、2月18日朝5時55分頃けいれん（強直性）で叫んだのを家族が気付いた。直ちにチョコレートやジュースを摂取させたところ5～10分程度でけいれんは改善し、当院救急搬送時は血糖98mg/dlで意識清明。頭部CT異常なく、低血糖発作の疑いで2月18日当科紹介受診。3月17日75gOGTT：血糖(mg/dl）＊インスリン（μU/ml）前71＊2 30値103＊32 60値102＊34 120値80＊26 180値51＊6 insulinogenicindex：0.94 HOMA-IR:0.35特発性低血糖の診断で甘い物単独で食べず食物繊維を多く摂取するよう指示。5月11日22:30就寝後叫び声がして四肢を伸展し指を開き強直し歯を食いしばり白目をむいている状態を両親が確認し救急搬送。3分で意職改善（血糖84mg/dl）。5月12日当科受診。食物繊維多めに1日3食食べること、炭水化物・甘味飲料は控えるよう指示。以後発作無く経過。5月24日脳波異常なし。5月24日CGM装着するもデータ採取できず。7月28日インスリノーマの除外のため絶食試験目的で当科入院。 【既往歴】特になし【生活歴】最初の発作は大学受験の真っ最中で、チョコなどの摂取が増えていた。秋頃よりサッカー（部活）やめ（高校時代は56kgだったが）＋7kg増え受験期は63kｇ（2012/2/17受診時167.2ｃｍ62．2kg）炭水化物あまり食べないように指示受け最近は54kg程度。喫煙：－飲酒：一アレルギー 【家族歴】ＤＭ(-)，甲状腺(-）【常用薬】なし 【入院時身体所見】特記することなし 【入院後経過】 朝8:30頃朝食を済ませて7/319:50に入院。 72時間絶食試験について説明しながら7/3110：20にルート確保。10:25に1回目の採血施行。(BG:104mg/dI)以降6時間ごとに採血開始(ルーチン:血糖、インスリン、Cペプチド)。 12時間後のインスリン1μＵ/m1未満に抑制。24時間後の8/110:25に血糖54mg/dI(＜60mg/dl)まで低下したので以降2時間ごとの採血に変更。8回目の16:25の採血まで　血糖54mg/dl　インスリン1μＵ/ml未満の状態続きインスリノーマの可能性は低いと判断。本人と相談して17:55絶食試験中止とした。 18:10終了時採血施行。血糖67mg/dI低血糖症状なし気分不快なし。試験終了後グルカゴン1ｍｇ静注。18:40のBG81ｍｇ/dlその後19:００前から1800kcalの普通食を摂取。翌6:00の採血で血糖65mg/dlまで血糖低下認められた。反応性低血糖の疑いで退院時にCGMを装着し、8/311:00退院。 ＜その他の入院検査データ＞ 絶食試験開始時(7/3110：25)コルチゾール　9.9μg/dlGH0.06ng/ml　グルカゴン　75pg/ml 終了時(8/218:10）コルチゾール　5.3μg/dlGH0.69ng/ml　グルカゴン　126pg/ml ソマトメジンC143ng/ml　副腎皮質刺激ホルモン　9.3pg/mlHbA1c5.2％　インスリン抗体125nU/ml未満　結合率0.4％未満　静脈血総ケトン体4289μmol/L　アセト酢酸　702μmol/L3-H酪酸　3587μmol/L 8/219:00　通常食摂取後採血:PG 65mg/dl インスリン 2 C-ペプチド0.51 (その他 乳酸 9mg/dl ピルビン酸 0.3mg/dl アドレナリン18pg/ml ノルアドレナリン 171pg/ml ド-パミン　5pg/ml以下）

6. Dr. Nauck: Diabeteszentrum Bad Lauterberg, Kirchberg 21, D-37431 Bad Lauterbergim Harz, Germany. Dr. Meier: MedizinischeKlinik I, Abteilungfu¨rDiabetologie und GasrointestinaleEndokrinologie, St. Josef-Hospital, Klinikum der Ruhr- Universita¨t, Gudrunstraße 56, 44891 Bochum, Germany. Ann Intern Med. 2012;157:767-775.

7. Background: Recent biochemical diagnostic guidelines for insulinomas require demonstration of hypoglycemia with inappropriately elevated (nonsuppressed) insulin, C-peptide, or proinsulin, but these criteria may overlap with those in patients without insulinomas. Use of an “amended” insulin–glucose ratio that accounts for the normal variation in insulin secretion according to prevailing glycemia may improve diagnostic accuracy. Objective: To compare the diagnostic accuracy of current diagnostic guideline criteria with the amended insulin–glucose ratio in patients with a suspected insulinoma.

8. Design: Retrospective cohort study. Setting: 2 specialized university departments in Germany. Patients: 114 patients with suspected hypoglycemia over 10 years having diagnostic prolonged fasts. Measurements: Glucose, insulin, C-peptide, and the amended insulin–glucose ratio were measured during and at discontinuation of prolonged fasts.

9. Figure 1. Study flow diagram All diagnosed insulinomas were confirmed by surgery and histologic evaluation. Amended insulin– glucose ratios of at least 53.6 (pmol/L)/(mmol/L) were considered abnormally high (12). Insulin1U = 6nmol (Insulin 1U = 7.18nmol) Glucose 180g=1mol Insulin 1μU/ml = 6 pmol/L Glucose 100mg/dl=18mmol/L I/Ga = 53.6 pmol/L / mmol/L = 1.608 μU/ml / mg/dl

10. Details of Prolonged Fasts in the Patient With Insulinoma and the Control PatientMisclassified on the Basis of the Amended Insulin–Glucose Ratio at the Time of Discontinuation The patient with insulinoma who was misclassified because of a falsely low (that is, normal) amended insulin– glucose ratio showed a secretory burst with a peak insulin increment to 101 pmol/L at 11 hours of fasting, followed by hypoglycemia (1.8 mmol/L [32 mg/dL]) at 12 hours. The fast was terminated at 14 hours, when plasma glucose had already recovered to 4.2 mmol/L (75 mg/dL). The control patient who was misclassified because of an abnormally high (that is, diagnostic) amended insulin– glucose ratio had a plasma glucose level of 1.7 mmol/L (30 mg/dL) and an insulin concentration of 51 pmol/L at the time of discontinuation. Insulin had increased above the previous level of 23 pmol/L without an accompanying increment in C-peptide (details not shown). Retrospective evaluation of the 2 misclassified patients (Figure 2) shows that the evaluation of previous time points (before discontinuation of the prolonged fasts) would have helped to interpret these results correctly, or at least to suggest additional diagnostic studies (13, 28, 29) in these patients. Accordingly, an “amended” insulin– glucose ratio has been proposed that is derived from the simple insulin– glucose ratio by subtracting 1.7 mmol/L (30 mg/dL) from the measured glucose concentrations (12), based on the assumption that human cells secrete negligible amounts of insulin at a glucose concentration less than 1.7 mmol/L (30 mg/dL).

19. Patients with insulinoma are shown in the prev. panel and control patients are shown in the middle panel separated by sex (mean [95% CI]). The proportion of female and male control patients with a glucose concentration less than 3.1 mmol/L (<55 mg/dL) is shown in the bottom panel. In the top panel, individual glucose concentrations over time are shown, highlighting the first glucose concentration less than 3.1 mmol/L (<55 mg/dL) (open circles) and the glucose concentration at the time of discontinuation of prolonged fasts (solid circles). In the middle panel, solid lines are means, and dotted lines are 95% CIs; statistical analysis was performed using repeated-measures analysis of variance, and asterisks indicate significant differences (by analysis of variance) between female and male control patients at single time points. To convert glucose values from mmol/L to mg/dL, divide by 0.0555. A = female vs. male control patients; B = changes over time; AB = interaction.

20. Results: Of 114 patients who were evaluated, 49 had surgical resection of histologically confirmed insulinomas. Insulinoma was excluded in 65 patients; follow-up for a mean of 10 years (range, 0 to 16 years) showed no progressively severe hypoglycemic events or diagnoses of insulinoma. Patients with insulinoma had lower glucose levels and higher insulin and C-peptide levels overall than did control patients at the end of prolonged fasts, but there was considerable overlap. The amended insulin–glucose ratio correctly identified 48 of 49 patients with insulinoma and excluded the diagnosis in 64 of 65 control patients, resulting in positive and negative predictive values of 0.98 (95% CI, 0.89 to 1.00) and 0.99 (CI, 0.92 to 1.00), respectively, compared with 0.75 (CI, 0.63 to 0.85) and 0.98 (CI, 0.89 to 1.00), respectively, for glucose, insulin, and C-peptide concentration criteria.

21. Limitation: The study had a retrospective design, no proinsulin concentrations were available, and a nonspecific insulin immunoassay (crossreactive with proinsulin) was used. Conclusion: The amended insulin–glucose ratio showed improved diagnostic accuracy over established criteria that use glucose, insulin, and C-peptide concentrations.

22. Message 低血糖症疑い患者114人を対象に、修正インスリン・グルコース比のインスリノーマ診断精度を後ろ向きコホート研究で検討。インスリノーマ患者49人中48人、除外患者65人中64人を同定した。陽性的中率は0.98、陰性的中率は0.99で、グルコース、インスリン、Cペプチド濃度を用いる現行基準（同0.75、0.98）を上回った。 著者はインクレチンやβ細胞枯渇で超有名だが、インスリノーマの診断の論文まで書いている！ Turner指標は有名だが案外エビデンスが少なかったようだがこれで使われる！

25. Objective To investigate the relation between total fat intake and body weight in adults and children.

26. Design Systematic review and meta-analysis of randomised controlled trials and cohort studies. Data sources Medline, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials to June 2010. Inclusion criteriaRandomised controlled trials and cohort studies of adults or children that compared lower versus usual total fat intake and assessed the effects on measures of body fatness (body weight, body mass index, or waist circumference) after at least six months (randomised controlled trials) or one year (in cohorts). Randomised controlled trials with any intention to reduce weight in participants or confounded by additional medical or lifestyle interventions were excluded. Data extraction Data were extracted and validity was assessed independently and in duplicate. Random effects meta-analyses, subgroups, sensitivity analyses, and metaregression were done.

35. Results 33 randomised controlled trials (73 589 participants) and 10 cohort studies were included, all from developed countries. Meta-analysis of data from the trials suggested that diets lower in total fat were associated with lower relative body weight (by 1.6 kg, 95% confidence interval −2.0 to −1.2 kg, I2=75%, 57 735 participants). Lower weight gain in the low fat arm compared with the control arm was consistent across trials, but the size of the effect varied. Metaregression suggested that greater reduction in total fat intake and lower baseline fat intake were associated with greater relative weight loss, explaining most of the heterogeneity. The significant effect of a low fat diet on weight was not lost in sensitivity analyses (including removing trials that expended greater time and attention on low fat groups). Lower total fat intake also led to lower body mass index (−0.51 kg/m2, 95% confidence interval −0.76 to −0.26, nine trials, I2=77%) and waist circumference (by 0.3 cm, 95% confidence interval −0.58 to −0.02, 15 671 women, one trial). There was no suggestion of negative effects on other cardiovascular risk factors (lipid levels or blood pressure). GRADE assessment suggested high quality evidence for the relation between total fat intake and body weight in adults. Only one randomised controlled trial and three cohort studies were found in children and young people, but these confirmed a positive relation between total fat intake and weight gain.

36. Conclusions There is high quality, consistent evidence that reduction of total fat intake has been achieved in large numbers of both healthy and at risk trial participants over many years. Lower total fat intake leads to small but statistically significant and clinically meaningful, sustained reductions in body weight in adults in studies with baseline fat intakes of 28-43% of energy intake and durations from six months to over eight years. Evidence supports a similar effect in children and young people.

37. Message 33の無作為化比較試験および10のコホート研究から、脂肪摂取量の体重への影響をシステマティックレビューとメタ解析で検討。エネルギー摂取量の28-43％を脂肪摂取とする成人では、6カ月から8年の観察試験において、脂肪摂取が少ないほど、わずかだが、統計学的有意で臨床的意味のある、持続的な体重減少を示すと示唆された。 脂肪を減らすと、同じカロリーだと糖とタンパクが増えるのだが．．．