Transcript 20131010SweetTasteRec&GestDMEuro

Journal Club
Young RL, Chia B, Isaacs NJ, Ma J, Khoo J, Wu T, Horowitz M, Rayner CK.
Disordered control of intestinal sweet taste receptor expression and glucose
absorption in type 2 diabetes.
Diabetes. 2013 Oct;62(10):3532-41. doi: 10.2337/db13-0581.
Avalos GE, Owens LA, Dunne F; ATLANTIC DIP Collaborators.
Applying current screening tools for gestational diabetes mellitus to a
European population: is it time for change?
Diabetes Care. 2013 Oct;36(10):3040-4. doi: 10.2337/dc12-2669.
2013年10月10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 坂下 杏奈
Matsuda, Masafumi, Sakashita, Anna
Type 1, sweet, first
characterized in 2001:
TAS1R1 (TAS1R2)– TAS1R3
Type 2, bitter, first
characterized in 2000:
TAS2R1 – TAS2R50, and
TAS2R60
Sweet! receptors
The TAS1R2+TAS1R3
heterodimer receptor
functions as the sweet
receptor by binding to a
wide variety of sugars and
sugar substitutes.
These cells are shown to synapse upon the chorda
tympani and glossopharyngeal nerves to send their TAS1R2+3 expressing cells
are found in circumvallate
signals to the brain. The TAS1R3 homodimer also
functions as a sweet receptor in much the same way papillae and foliate papillae
as TAS1R2+3 but has decreased sensitivity to sweet near the back of the tongue
and palate taste receptor
substances. Natural sugars are more easily
cells in the roof of the
detected by the TAS1R3 receptor than sugar
mouth.
substitutes. This may help explain why sugar and
artificial sweeteners have different tastes.
the 1Nerve-Gut Research Laboratory, University of Adelaide, Adelaide, South
Australia, Australia; the 2Discipline of Medicine, University of Adelaide, Adelaide,
South Australia, Australia; the 3Centre of Research Excellence in Translating
Nutritional Science to Good Health, University of Adelaide, Adelaide, South
Australia, Australia; the 4Department of Gastroenterology and Hepatology, Royal
Adelaide Hospital, Adelaide, South Australia, Australia; the 5Department of
Endocrinology and Metabolism, Shanghai Renji Hospital, Shanghai Jiaotong
University, Shanghai, China; and the 6Department of Endocrinology, Changi
General Hospital, Singapore.
Diabetes 62:3532–3541, 2013
We previously established that the intestinal
sweet taste receptors (STRs), T1R2 and
T1R3, were expressed in distinct epithelial
cells in the human proximal intestine and
that their transcript levels varied with
glycemic status in patients with type 2
diabetes. Here we determined whether STR
expression was 1) acutely regulated by
changes in luminal and systemic glucose
levels, 2) disordered in type 2 diabetes, and
3) linked to glucose absorption.
Fourteen healthy subjects and 13 patients
with type 2 diabetes were studied twice, at
euglycemia (5.2 ± 0.2 mmol/L) or
hyperglycemia (12.3 ± 0.2 mmol/L).
Endoscopic biopsy specimens were
collected from the duodenum at baseline
and after a 30-min intraduodenal glucose
infusion of 30 g/150 mL water plus 3 g 3-Omethylglucose (3-OMG). STR transcripts
were quantified by RT-PCR, and plasma
was assayed for 3-OMG concentration.
the a-subunit of the G-protein gustducin (agustducin), leading to intracellular Ca2+ release,
gating of a taste-specific transient receptor
potential ion channel TRPM5
Plasma 3-OMG concentrations were significantly higher in type 2 diabetic patients than
in healthy control subjects during acute hyperglycemia.
Intestinal STR transcript levels decreased in healthy subjects during hyperglycemia
T1R2 levels increased significantly in type 2 diabetic patients under the same conditions
Intestinal STR transcript levels at baseline were
unaffected by acute variations in glycemia in
healthy subjects and in type 2 diabetic patients.
T1R2 transcript levels increased after luminal
glucose infusion in both groups during
euglycemia (+5.8 × 104 and +5.8 × 104 copies,
respectively) but decreased in healthy subjects
during hyperglycemia (21.4 × 104 copies). T1R2
levels increased significantly in type 2 diabetic
patients under the same conditions (+6.9 × 105
copies). Plasma 3-OMG concentrations were
significantly higher in type 2 diabetic patients than
in healthy control subjects during acute
hyperglycemia.
Intestinal T1R2 expression is
reciprocally regulated by luminal
glucose in health according to
glycemic status but is disordered in
type 2 diabetes during acute
hyperglycemia. This defect may
enhance glucose absorption in type
2 diabetic patients and exacerbate
postprandial hyperglycemia.
Greenfield JR, Chisholm
DJ.: How sweet it is:
intestinal sweet taste
receptors in type 2
diabetes. Diabetes. 2013
Oct;62(10):3336-7.
1 They are consistent with, but do not absolutely prove, an influence of intestinal STRs
on incretin hormones in humans, thereby suggesting another possible route for
pharmacological enhancement of the incretin response.
2 These findings suggest an unfavorable impact of disturbed STR regulation in type 2
diabetes—enhancement of glucose absorption during hyperglycemia, which could
accentuate postprandial hyperglycemia and lessen the benefit of energy reduction from
nonnutritive sweeteners. This raises the question as to whether these disturbances
might occur in the prediabetic state. Could the nonnutritive sweeteners in these drinks
be accentuating postprandial glycemia via effects on STRs, thereby contributing to the
progression of glucose intolerance?
Message
舌の味の受容体はともかく、昔から、もしかし
たら膵臓の味受容体が糖尿病と関係していると
いうのがあったが、現在は腸管ホルモン隆盛で
あり、腸管の味の受容体について研究が進んで
いるようである。糖尿病の病態進展にも関連し
ている可能性もある。
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！）
The group developed diagnostic cut 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
妊娠糖尿病、 2010年 糖尿病合併妊娠 妊娠糖尿病診断基準
定義：妊娠糖尿病gestational diabetes mellitus（GDM）は妊娠中にはじめて発見、ま
たは発症した糖代謝異常。しかし、overt diabetes in pregnancy（妊娠時に診断された
明らかな糖尿病）はGDMに含めない。
診断基準：
１．妊娠糖尿病（GDM） 75gOGTTにおいて次の基準の1点以上を満たした場合に診断
する。
① 空腹時血糖値≧92mg/dL（5.1mmol/L）
② 1時間値≧180mg/dL（10.0mmol/L）
③ 2時間値≧153mg/dL（8.5mmol/L）
２．妊娠時に診断された明らかな糖尿病 （overt diabetes in pregnancy） 以下のいず
れかを満たした場合に診断する。
① 空腹時血糖値≧126mg/dL
② HbA1C≧6.5％
③ 確実な糖尿病網膜症が存在する場合
④ 随時血糖値≧200mg/dL、あるいは75gOGTTで2時間値≧200mg/dLで
上記①～③のいずれかがある場合
註 HbA1C＜6.5％で75gOGTT 2時間値≧200mg/dLの場合は、妊娠時に診断された明
らかな糖尿病とは判定し難いので、High risk GDMとし、妊娠中は糖尿病に準じた管理
を行い、出産後は糖尿病に移行する可能性が高いので厳重なフォローアップが必要
＊＊＊＊＊＊ 産婦人科診療ガイドライン 産科編 2011
妊娠糖尿病、妊娠時に診断された明らかな糖尿病、 ならびに糖尿病合併妊婦の管理・
分娩
1. 早朝空腹時血糖値≦95mg/dL、食前血糖値≦100mg/dL、食後2時間血糖値
≦120mg/dLを目標に血糖を調節する。（C）
2. 耐糖能異常妊婦ではまず食事療法を行い、血糖管理できない場合はインスリン療法
を行う。（B）
3. 妊娠32週以降は胎児well-beingを適宜NST、BPS（biophysical profile score）な
どで評価し、問題がある場合は入院管理を行う。（C）
4. 血糖コントロール良好かつ胎児発育や胎児well-beingに問題ない場合、以下のいず
れかを行う。（B）
1) 40週6日まで自然陣痛発来待機（待機的管理）と41週0日以降の分娩誘発
2) 頸管熟化を考慮した37週0日以降の分娩誘発（積極的管理）
5. 遷延分娩時、陣痛促進時、あるいは吸引分娩時には肩甲難産に注意する。（C）
6. 血糖コントロール不良例、糖尿病合併症悪化例や巨大児疑い合併例では分娩時期、
分娩法を個別に検討する。（B）
7. 39週未満の選択的帝王切開例、血糖コントロール不良例、あるいは予定日不詳例の
帝王切開時には新生児呼吸窮迫症候群に注意する。（B）
8. 糖尿病合併妊婦分娩時においては連続的胎児心拍数モニタリングを行う。（B）
9. 分娩時は母体血糖値70～120mg/dLの正常範囲にコントロールする。（C）
10. 分娩後はインスリン需要量が著明に減少する。インスリン使用例では低血糖に注意
し、血糖値をモニターしながらインスリンを減量もしくは中止する。（B）
＊＊＊＊＊＊ 産婦人科診療ガイドライン 産科編 2011
1. 妊娠糖尿病（GDM、gestational diabetes mellitus）のスクリー
ニングを全妊婦に行う。（B）
2. スクリーニングは以下に示すような二段階法を用いて行う。（B）
妊娠初期に随時血糖測定。 95mg/dl以上は75gOGTT ただし
随時血糖値≧200mg/dL時には、75gOGTTは行わず、GDM(high
risk) か DM か について検討する。
妊娠中期（24～28週）に50gGCT（≧140mg/dLを陽性）、あるいは随
時血糖測定（≧100mg/dLを陽性）。
その対象は妊娠初期随時血糖法で陰性であった妊婦、ならびに同検
査陽性であったが75gOGTTで非GDMとされた妊婦。
GDM妊婦には分娩後6～12週の75gOGTTを勧める。“妊娠時に診
断された明らかな糖尿病”妊婦では耐糖能について再評価する。
カットオフ値
妊娠初期は随時血糖値
95mg/dl
妊娠中期はGCT (glucose challenge test) 140mg/dl
the Department of Medicine, National University of Ireland, Galway, Ireland.
From the ATLANTIC DIP study
Diabetes Care 36:3040–3044, 2013
OBJECTIVE
The optimal screening regimen for
gestational diabetes mellitus (GDM)
remains controversial. Risk factors
used in selective screening guidelines
vary. Given that universal screening is
not currently adopted in our European
population, we aimed to evaluate which
selective screening strategies were
most applicable.
RESEARCH DESIGN AND METHODS
Between 2007 and 2009, 5,500 women
were universally screened for GDM,
and a GDM prevalence of 12.4% using
International Association of Diabetes in
Pregnancy Study Groups (IADPSG)
criteria was established. We
retrospectively applied selective
screening guidelines to this cohort.
RESULTS
When we applied National Institute for Health and Clinical
Excellence (NICE), Irish, and American Diabetes
Association (ADA) guidelines, 54%(2,576), 58%(2,801),
and 76% (3,656) of women, respectively, had at least one
risk factor for GDM and would have undergone testing.
However, when NICE, Irish, and ADA guidelines were
applied, 20% (120), 16% (101), and 5% (31) of women,
respectively, had no risk factor and would have gone
undiagnosed. Using a BMI ≧ 30 kg/m2 for screening has a
specificity of 81% with moderate sensitivity at 48%.
Reducing the BMI to ≧ 25 kg/m2 (ADA) increases the
sensitivity to 80% with a specificity of 44%. Women with no
risk factors diagnosed with GDM on universal screening
had more adverse pregnancy outcomes than those with
normal glucose tolerance.
CONCLUSIONS
This analysis provides a strong
argument for universal screening.
However, if selective screening were
adopted, the ADA guidelines would
result in the highest rate of diagnosis
and the lowest number of missed cases.
HAROLD DAVID MCINTYRE, MD From the Mater Clinical School, University of
Queensland and Mater Health Services, South Brisbane, Queensland, Australia.
No diagnostic process or set of OGTT criteria will ever be able to
perfectly identify all women at risk for adverse pregnancy outcomes.
However, synthesis of available epidemiologic and clinical trial data
suggests that the IADPSG- and ADArecommended criteria represent
a reasonable and responsible approach to identifying women with
hyperglycemia in pregnancy who are likely to benefit from treatment.
DO SCREENING
DAVID SIMMONS, MD1,2 ROBERT G. MOSES, MD3 From the 1Institute of
Metabolic Science, Cambridge University Hospitals NHS Foundation Trust,
Cambridge, England; the 2Department of Rural Health, University of Melbourne,
Shepparton, Victoria, Australia; and the 3Illawarra Shoalhaven Local Health
District, Wollongong, New South Wales, Australia.
GDM is seen as one part of the cost of a totality of obstetric and perinatal
services, screening based on risks and/or a GCT cannot be endorsed for
either health or economic reasons.
EXAMINE ALL?!
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海外での5500人の妊婦のデータ解析であ
る。
米国ではA1Cを用いているが、それでも見逃
すし、リスクファクターのみだとかなり見
逃すようである。
日本でも一応 スクリーニングしてから
OGTTをする。日本では血糖測定したりブド
ウ糖負荷してしまうのでほぼ全例チェック
できていると思われるが．．．