Transcript P - 埼玉医科大学総合医療センター 内分泌・糖尿病内科

Journal Club
Mozaffarian D, Cao H, King IB, Lemaitre RN, Song X, Siscovick DS,
Hotamisligil GS.
Trans-palmitoleic Acid, metabolic risk factors, and new-onset diabetes in U.S.
Adults: a cohort study.
Ann Intern Med. 2010 Dec 21;153(12):790-9.
Bolk N, Visser TJ, Nijman J, Jongste IJ, Tijssen JG, Berghout A.
Effects of evening vs morning levothyroxine intake: a randomized doubleblind crossover trial.
Arch Intern Med. 2010 Dec 13;170(22):1996-2003.
2011年1月6日 8:30-8:55
８階 医局
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
N Engl J Med 2010;363:2540-6.
N Engl J Med 2010;363:2540-6.
CONCLUSION
The patient described in the vignette has elevated glucose levels in the
context of acute illness. With ongoing use of glucocorticoids and the institution
of nutritional support, further elevations in his plasma glucose level can be
expected. He has a glycated hemoglobin level of 5.3%, which indicates that
he does not have preexisting diabetes. Although the results of randomized
trials of intensive insulin therapy in ICU patients have been inconsistent, most
of the data do not support the hypothesis of a survival benefit, and some data
have suggested increased mortality. All the trials in which the targeted
glucose concentration was 80 to 110 mg per deciliter showed increased rates
of hypoglycemia. Moreover, marked hyperglycemia itself is associated with
increased risks of adverse outcomes. Thus, pending more data to guide the
development of optimal glucose levels, we recommend a target of 140 to 180
mg per deciliter (which is in accordance with the most recent guidelines), with
the use of an established, preferably computerized insulin-infusion algorithm
and close monitoring of glucose levels. In consideration of these moderate
target levels, we recommend that nutritional support be introduced gradually,
preferably by the enteral route, and that infusion of substantial quantities of
intravenous dextrose be avoided.
N Engl J Med 2010;363:2540-6.
Quite possibly. Even in the
absence of overt diabetes,
insulin resistance confers an
increased risk of cardiovascular
disease, cancer, and shortened
life span, and the vast majority
of obese persons have insulin
resistance and hence are at risk
for these consequences. Safe
insulin sensitizers could
conceivably be used to prevent
the development of diabetes
and cardiovascular disease in
persons with insulin resistance.
N Engl J Med 2010;363:2667-9.
炭素数が18でひとつの不飽和結合が9位にシス型
配置する場合には、その構造は、C18:1(9-cis)と表
します。飽和脂肪酸としては、カプリン酸C10:0、ラ
ウリン酸C12:0、ミリスチン酸C14:0、パルミチン酸
C16:0、ステアリン酸C18:0などがあります。不飽和
脂肪酸としては、オレイン酸C18:1(9-cis)、リノール
酸C18:2(9,12-cis)、リノレン酸C18:3(9,12,15-cis)、
エイコサペンタエン酸(EPA) C20:5(5,8,11,14,17cis)、ドコサヘキサエン酸(DHA)
C22:6(4,7,10,13,16,19-cis)などが知られています。
「食品に含まれるトランス脂肪酸」
ヒトを含めた大部分の生物（一部例外については、後述）に含まれている不飽和脂肪酸は、
ほとんどシス型です。トランス脂肪酸は、主として以下の食材に由来します。
１） 硬化油
２） 肉類や乳製品
３） 精製油
1999年の報告では計算上、日本人のトランス脂肪酸摂取は、約60％を硬化油から、約
25％を肉類、乳製品から、約15％を精製油から摂取している。一方、1999年の米国の報
告では、米国人は、トランス脂肪酸の75-80%を硬化油から、残り20-25%を肉類、乳製品
から摂取していた。
「硬化油とは」
現在、加工技術のひとつに「水素添加による硬化油の製造」法が挙げられます。油脂の
水素添加というのは、油脂を構成する脂肪酸の不飽和結合部分に水素を付加させることを
いいます。その結果、油脂の不飽和度が減少し、融点の上昇、流動性の低下、可塑性の変
化、固化などの油脂の物性が変化します。このとき、副反応として、不飽和脂肪酸の二重
結合の位置が移動、共役化、シス-トランスの異性化が起こります。この油脂の水素添加反
応（hydrogenation）を硬化反応（hardening）といい、水素添加された油脂を硬化油と呼ぶ
ことがあります。
「硬化油の製造」
油脂の水素添加反応は、液状の油脂中にニッケルなどの金属触媒を懸濁し、よく撹拌し
ながら、気体の水素ガスを接触させて、不飽和結合に水素分子を付加させます。触媒に吸
着、活性化された不飽和結合が、水素原子と結合することなく、再び触媒表面から脱着す
る際に、不飽和結合の位置移動や共役化、シス-トランスの異性化反応が進行します。油脂
の水素添加反応において、水素分圧、反応温度等の設定条件に依存して、油脂の水素添
加反応と異性化反応の割合が変化します。
「硬化油製造の目的」
硬化油を製造する目的は、使用目的に適合する物性を持つ食用油脂を製造することです。
例えば、油脂に水素添加反応を施すことにより、魚油や綿実油のような液状油を材料にし
て、動物性油脂に近い物性を持つ固形油をつくり出したり、酸化安定性の高い液状油を創
出したりすることができます。また、動物性油脂と比較すると、硬化油はより安価です。食用
に供する硬化油は、硬化の程度により以下のような目的で製造されています。
１） 高度硬化油：牛脂、綿実油などを極度に硬化し、フレーク状の融点の高い製品をつくる。
マーガリンやショートニングに少量添加して可塑性を改良する。
２） 中程度硬化油：大豆油、綿実油、ナタネ油、魚油を原料として中程度に硬化する。マー
ガリンなどに配合し、口どけのよい、安定性に富む製品をつくる。
３） 軽度硬化油：植物油脂を軽度に硬化して、自動酸化や加熱による劣化を受けにくい、酸
化安定性の高い液状油をつくる。
「肉類や乳製品のトランス脂肪酸」
牛などの反芻動物の胃内に共生するバクテリアは、シス型の不飽和脂肪酸をトランス型
に変換する特殊な酵素を持っています。このバクテリアが産生するトランス脂肪酸は主にバ
クセン酸C18:1(11-trans)（図５左）です。一方、硬化油等には、エライジン酸C18:1(9-trans)
（図５右）など、多種類のトランス脂肪酸が含まれています。牛肉や乳製品には、2-5%程度
のトランス脂肪酸が含まれていますが、その大部分はバクセン酸です。バクセン酸は、エラ
イジン酸とは不飽和結合の位置が異なる位置異性体です。
http://www.nfri.affrc.go.jp/yakudachi/transwg/kagaku.html#top
Dr. Mozaffarian: Harvard School of Public
Health, 665 Huntington Avenue, Building 2-319, Boston, MA 02115.
Dr. Cao: National Institutes of Health, 10 Center Drive, Building 10,
8N105A, Bethesda, MD 20892.
Dr. King: University of New Mexico, 2703 Frontier Avenue Northeast,
Suite 190, Albuquerque, NM 87131.
Drs. Lemaitre and Siscovick: Cardiovascular Health Research Unit, 1730
Minor Avenue, Suite 1360, Seattle, WA 98101.
Dr. Song: Fred Hutchinson Cancer Research Center, M5 A864, 1100
Fairview Avenue North, Seattle, WA 98109.
Dr. Hotamisligil: Harvard School of Public Health, 665 Huntington
Avenue, Building 1-605, Boston, MA 02115.
パルミトレイン酸（パルミトレインさん、
palmitoleic acid）は、タラ肝油、イワシ油、
ニシン油に含まれる炭素数16のcis-9-モノ
不飽和脂肪酸である。C15H29CO2H、
IUPAC組織名 (Z)-hexadec-9-enoic acid,
n-7、数値表現 16:1、分子量254.41、融点
5℃、比重0.894。CAS登録番号 373-49-9。
Ann Intern Med. 2010;153:790-799.
Background: Palmitoleic acid (cis-16:1n-7),
which is produced by endogenous fat synthesis,
has been linked to both beneficial and
deleterious metabolic effects, potentially
confounded by diverse determinants and tissue
sources of endogenous production.
Transpalmitoleate (trans-16:1n-7) represents a
distinctly exogenous source of 16:1n-7,
unconfounded by endogenous synthesis or its
determinants, that may be uniquely informative.
Objective: To investigate whether circulating
trans-palmitoleate is independently related to
lower metabolic risk and incident type 2 diabetes.
Design: Prospective cohort study from 1992 to 2006.
Setting: Four U.S. communities.
Patients: 3736 adults in the Cardiovascular Health
Study.
Measurements: Anthropometric characteristics and
levels of plasma phospholipid fatty acids, blood lipids,
inflammatory markers, and glucose–insulin measured
at baseline in 1992 and dietary habits measured 3
years earlier. Multivariate-adjusted models were used
to investigate how demographic, clinical, and lifestyle
factors independently related to plasma phospholipid
trans-palmitoleate; how trans-palmitoleate related to
major metabolic risk factors; and how transpalmitoleate related to new-onset diabetes (304
incident cases). Findings were validated for metabolic
risk factors in an independent cohort of 327 women.
In our separate validation cohort, higher erythrocyte trans-palmitoleate levels
were associated with lower levels of interleukin-6 (multivariate-adjusted levels
across quartiles, 2.3 vs. 1.8 ng/L; P for trend = 0.020) and CRP (31.4 vs. 20.0
nmol/L; P for trend = 0.020) and trends toward lower total cholesterol–HDL
cholesterol ratios (4.21 vs. 3.87; P for trend = 0.099) and hemoglobin A1c (5.92%
vs. 5.66%; P for trend = 0.056). In similar analyses, higher plasma
transpalmitoleate levels were associated with higher levels of HDL cholesterol
(1.46 vs. 1.60 mmol/L [56.5 vs. 61.7 mg/dL]; P for trend = 0.033) and lower total
cholesterol–HDL cholesterol ratios (4.28 vs. 3.63; P for trend < 0.001) and
hemoglobin A1c (5.88% vs. 5.64%; P for trend = 0.028).
Results: In multivariate analyses, whole-fat dairy
consumption was most strongly associated with higher
trans-palmitoleate levels. Higher trans-palmitoleate levels
were associated with slightly lower adiposity and,
independently, with higher high-density lipoprotein
cholesterol levels (1.9% across quintiles; P < 0.040), lower
triglyceride levels (－19.0%; P < 0.001), a lower total
cholesterol–HDL cholesterol ratio (－4.7%; P < 0.001), lower
C-reactive protein levels (－13.8%; P < 0.05), and lower
insulin resistance (－16.7%, P < 0.001). Trans-palmitoleate
was also associated with a substantially lower incidence of
diabetes, with multivariate hazard ratios of 0.41 (95% CI,
0.27 to 0.64) and 0.38 (CI, 0.24 to 0.62) in quintiles 4 and 5
versus quintile 1 (P for trend < 0.001). Findings were
independent of estimated dairy consumption or other fatty
acid dairy biomarkers. Protective associations with
metabolic risk factors were confirmed in the validation cohort.
Conclusion: Circulating trans-palmitoleate is
associated with lower insulin resistance,
presence of atherogenic dyslipidemia, and
incident diabetes. Our findings may explain
previously observed metabolic benefits of dairy
consumption and support the need for detailed
further experimental and clinical investigation.
Primary Funding Source: National Heart, Lung,
and Blood Institute and National Institute of
Diabetes and Digestive and Kidney Diseases of
the National Institutes of Health.
Limitation: Results could be affected by measurement error
or residual confounding.
Message/Comments
食べたものはともあれ、血中トランス-パ
ルミチン酸の量でインスリン感受性が決
まってくるらしい。
【用法・用量】
レボチロキシンナトリウムとして通常，成人25～400μgを1 日
1 回経口投与する．
一般に，投与開始量には25～100μg，維持量には100～400μgを
投与することが多い．
なお，年齢，症状により適宜増減する．
Department of Internal Medicine, Maasstad Hospital Rotterdam, Rotterdam (Drs
Bolk and Berghout and Mss Nijman and Jongste), Department of Endocrinology,
Erasmus Medical Center Rotterdam, Rotterdam (Dr Visser), and Department of
Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam (Dr
Tijssen), the Netherlands.
Arch Intern Med. 2010;170(22):1996-2003
Background: Levothyroxine sodium is widely
prescribed to treat primary hypothyroidism.
There is consensus that levothyroxine should be
taken in the morning on an empty stomach. A
pilot study showed that levothyroxine intake at
bedtime significantly decreased thyrotropin
levels and increased free thyroxine and total
triiodothyronine levels. To date, no large
randomized trial investigating the best time of
levothyroxine intake, including quality-of-life
evaluation, has been performed.
Methods: To ascertain if levothyroxine intake at
bedtime instead of in the morning improves
thyroid hormone levels, a randomized doubleblind crossover trial was performed between April
1, 2007, and November 30, 2008, among 105
consecutive patients with primary hypothyroidism
at Maasstad Hospital Rotterdam in the
Netherlands. Patients were instructed during 6
months to take 1 capsule in the morning and 1
capsule at bedtime (one containing levothyroxine
and the other a placebo), with a switch after 3
months. Primary outcome measures were thyroid
hormone levels; secondary outcome measures
were creatinine and lipid levels, body mass index,
heart rate, and quality of life.
Figure 2. Thyroid hormone levels after
6 and 12 weeks of morning or bedtime
intake of levothyroxine sodium. To
convert thyrotropin level to micrograms
per liter, multiply by 1.0; free thyroxine
level to picomoles per liter, multiply by
12.871; and total triiodothyronine level
to nanomoles per liter, multiply by
0.0154.
Results: Ninety patients completed the trial and were
available for analysis. Compared with morning intake, direct
treatment effects when levothyroxine was taken at bedtime
were a decrease in thyrotropin level of 1.25 mIU/L (95%
confidence interval [CI], 0.60-1.89 mIU/L; P<.001), an
increase in free thyroxine level of 0.07 ng/dL (0.02-0.13
ng/dL; P=.01), and an increase in total triiodothyronine level
of 6.5 ng/dL (0.9-12.1 ng/dL; P=.02) (to convert thyrotropin
level to micrograms per liter, multiply by 1.0; free thyroxine
level to picomoles per liter, multiply by 12.871; and total
triiodothyronine level to nanomoles per liter, multiply by
0.0154). Secondary outcomes, including quality-of-life
questionnaires (36- Item Short Form Health Survey, Hospital
Anxiety and Depression Scale, 20-Item Multidimensional
Fatigue Inventory, and a symptoms questionnaire), showed
no significant changes between morning vs bedtime intake of
levothyroxine.
Conclusions: Levothyroxine taken at
bedtime significantly improved thyroid
hormone levels. Quality-of-life variables
and plasma lipid levels showed no
significant changes with bedtime vs
morning intake. Clinicians should consider
prescribing levothyroxine intake at bedtime.
Trial Registration: isrctn.org Identifier:
ISRCTN17436693 (NTR959).
Message/Comments
チラーヂンSの投与が朝食後でうまくゆか
なければ朝食前、また眠前というのがよい
であろう。
が、飲まないとダメなので実際は？