20150910FTO&Metformin

Journal Club
Claussnitzer M, Dankel SN, Kim KH, Quon G, Meuleman W, Haugen C, Glunk V,
Sousa IS, Beaudry JL, Puviindran V, Abdennur NA, Liu J, Svensson PA, Hsu YH,
Drucker DJ, Mellgren G, Hui CC, Hauner H, Kellis M.
FTO Obesity Variant Circuitry and Adipocyte Browning in Humans.
N Engl J Med. 2015 Sep 3;373(10):895-907. doi: 10.1056/NEJMoa1502214.
Buse JB, DeFronzo RA, Rosenstock J, Kim T, Burns C, Skare S, Baron A, Fineman
M.
The Primary Glucose-Lowering Effect of Metformin Resides in the Gut, Not the
Circulation. Results From Short-term Pharmacokinetic and 12-Week Dose-Ranging
Studies.
Diabetes Care. 2015 Aug 18. pii: dc150488.
2015年9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
Matsuda, Masafumi
Fat mass and obesity-associated protein also known as alpha-ketoglutaratedependent dioxygenase FTO is an enzyme that in humans is encoded by the FTO
gene located on chromosome 16. As one homolog in the AlkB family proteins, it is
the first mRNA demethylase that has been identified. Certain variants of the FTO
gene appear to be correlated with obesity in humans.
1 Function
2 FTO demethylates m6A in mRNA
3 Tissue distribution
The FTO gene is widely expressed in both fetal and adult tissues.
4 Clinical significance
4.1 Association with obesity
4.2 Association with Alzheimer's disease
4.3 Association with other diseases
Origin of name
By exon trapping, Peters et al. (1999) cloned a novel gene from a region of several
hundred kb deleted by the mouse 'fused toes' (FT) mutation. They named the gene
'fatso' (Fto) due to its large size.
Chr 16 in humans
https://en.wikipedia.org/wiki/FTO_gene
Iroquois-class homeodomain protein IRX-3, also known as Iroquois homeobox
protein 3, is a protein that in humans is encoded by the IRX3 gene.
Function
IRX3 is a member of the Iroquois homeobox gene family and plays a role in an early step of
neural development. Members of this family appear to play multiple roles during pattern
formation of vertebrate embryos. Specifically, IRX3 contributes to pattern formation in the
spinal cord where it tranlates a morphogen gradient into transcriptional events, and is
directly regulated by NKX2-2.
Clinical significance
Association with obesity
Obesity-associated noncoding sequences
within FTO interact with the promoter of IRX3
and FTO in human, mouse, and zebrafish.
Obesity-associated single nucleotide
polymorphisms are related to the expression
of IRX3 (not FTO) in the human brain. A direct
connection between the expression of IRX3
and body mass and composition was shown
through the decrease in body weight of 2530% in IRX3-deficient mice. This suggests
that IRX3 influences obesity. Manipulation of
IRX3 and IRX5 pathways has also been shown
to decrease obesity markers in human cell
cultures.
Chr 16 in humans
https://en.wikipedia.org/wiki/IRX3
N Engl J Med. 2015 Sep 3;373(10):895-907.
Beth Israel Deaconess Medical Center and Hebrew SeniorLife, Gerontology Division, Harvard Medical
School, Boston (M.C., Y.-H.H.); Massachusetts Institute of Technology (MIT) Computer Science and Artificial
Intelligence Laboratory (M.C., G.Q., W.M., N.A.A., M.K.), and Broad Institute of MIT and Harvard, Cambridge
(M.C., G.Q., W.M., M.K.); Clinical Cooperation Group “Nutrigenomics and Type 2 Diabetes,” Helmholtz
Center Munich (M.C., H.H.), and Else Kröner-Fresenius Center for Nutritional Medicine, Klinikum rechts der
Isar, ZIEL–Institute for Food and Health, Technische Universität München (M.C., V.G., I.S.S., H.H.), Munich,
Germany; KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen,
and Hormone Laboratory, Haukeland University Hospital, Bergen, Norway (S.N.D., C.H., G.M.); Program in
Developmental and Stem Cell Biology, Hospital for Sick Children, and Department of Molecular Genetics,
University of Toronto (K.-H.K., V.P., J.L., C.-C.H.), and Department of Medicine, Lunenfeld-Tanenbaum
Research Institute, Mt. Sinai Hospital (J.L.B., D.J.D.), Toronto; and the Department of Molecular and Clinical
Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden (P.-A.S.).
Background
Genomewide association studies can be
used to identify disease-relevant genomic
regions, but interpretation of the data is
challenging. The FTO region harbors the
strongest genetic association with obesity,
yet the mechanistic basis of this association
remains elusive.
Methods
We examined epigenomic data, allelic activity,
motif conservation, regulator expression, and
gene coexpression patterns, with the aim of
dissecting the regulatory circuitry and mechanistic
basis of the association between the FTO region
and obesity. We validated our predictions with the
use of directed perturbations in samples from
patients and from mice and with endogenous
CRISPR–Cas9 genome editing in samples from
patients.
Regulators of mitochondrial thermogenesis (including IRF4,
PGC1α, PRDM16, and TBX15) control the expression of the
gene encoding uncoupling protein 1 (UCP1),
conflicting target genes and tissues, including FTO itself in a
whole-body knockout,17 IRX3 in pancreas20 or brain,19 RBL2
in lymphocytes,21 and RPGRIP1L in brain.18
連鎖不平衡（れんさふへいこう、英: Linkage disequilibrium、略称LD）とは生物の集団におい
て、複数の遺伝子座の対立遺伝子または遺伝的マーカー（多型）の間にランダムでない相関
が見られる、すなわちそれらの特定の組合せ（ハプロタイプ）の頻度が有意に高くなる集団遺
伝学的な現象をいう。それらは一般には同じ染色体上にあって遺伝的連鎖をしているが、連鎖
していても連鎖不平衡が見られない場合もあり、また例外的に別の染色体上で見られる場合
もある。つまり遺伝的連鎖とは別の（連鎖している場合も含む）現象である。
2つの遺伝子座に関する連鎖不平衡を考え、各対立遺伝子を変数I1 とI2 で表す。連鎖不平衡
パラメータδ を次のように定義する：
ここでp1 とp2 は2つの遺伝子座における単独の対立遺伝子の頻度を表し、h12 は両対立遺伝
子を合わせたハプロタイプの頻度を表す。この他にも様々なパラメータが用いられている。これ
が0でない場合に2つの対立遺伝子は連鎖不平衡にあるといい、それに対し δ = 0 の場合を連
鎖平衡という。
連鎖不平衡の原因は多くの場合、基本的には遺伝的連鎖にあり、対象とする集団の祖先が
持っていた特定のハプロタイプがまだ保存されている場合に連鎖不平衡が見られる。
また集団が複数の遺伝的集団からなる（見かけの単一集団で、まだあまり交雑していない）場
合、あるいは特定のハプロタイプが生物の生存や繁殖に有利である場合も原因となり、この場
合には異なる染色体上の対立遺伝子が（見かけ上）連鎖不平衡にあることもある。
International HapMap Project により人類集団の連鎖不平衡をオンラインで知ることができる。
これらの情報は特に、疾病に及ぼす遺伝的要因の解析に役立つことが期待されている。
https://ja.wikipedia.org/wiki/%E9%80%A3%E9%8E%96%E4%B8%8D%E5%B9%B3%E8%A1%A1
Figure 1. Activation of a Superenhancer in Human Adipocyte Progenitors by the FTO Obesity Risk
Haplotype.
Panel A shows the genetic association with body-mass index (BMI) for all common FTO locus
variants,14 including the reported single-nucleotide variant (SNV) rs1558902 (red diamond) and the
predicted causal SNV rs1421085 (red square). Gray shading delineates consecutive 10-kb
segments. CEU denotes a population of Utah residents with northern and western European
ancestry, and LD linkage disequilibrium.
An unusually long enhancer (12.8 kb) in mesenchymal
adipocyte progenitors indicated a major regulatory locus
Figure 1. Activation of a Superenhancer in Human Adipocyte Progenitors by the FTO Obesity Risk
Haplotype.
Panel B shows chromatin state annotations for the locus across 127 reference epigenomes (rows)
for cell and tissue types profiled by the Roadmap Epigenomics Project.15,16 For information on the
colors used to denote chromatin states, see Figure S1A in the Supplementary Appendix. Vertical
lines delineate the consecutive 10-kb segments shown in Panel A. ESC denotes embryonic stem
cell, HSC hematopoietic stem cell, and iPSC induced pluripotent stem cell.
Figure 1. Activation of a Superenhancer in Human Adipocyte Progenitors by the FTO
Obesity Risk Haplotype.
Panel C shows human SGBS adipocyte enhancer activity, for 10-kb tiles, of the risk and
nonrisk haplotypes with the use of relative luciferase expression. The boxes indicate
means from seven triplicate experiments, and T bars indicate standard deviations.
Haplotype-specific enhancer assays showed activity in association with the
risk haplotype that was 2.4 times as high as that associated with the nonrisk
haplotype in human SGBS adipocytes (i.e., adipocytes derived from a patient
with the Simpson–Golabi–Behmel syndrome), which indicated genetic control
of enhancer activity.
Impson–Golabi–Behmel syndrome (SGBS), also called Bulldog syndrome, Sara Agers
syndrome, Golabi–Rosen syndrome, Simpson dysmorphia syndrome (SDYS) or Xlinked dysplasia gigantism syndrome (DGSX), is a rare inherited congenital disorder that
can cause craniofacial, skeletal, cardiac, and renal abnormalities. The syndrome is
inherited in an X-linked recessive fashion, where males express the phenotype and
females usually do not. Females that possess one copy of the mutation are considered
to be carriers of the syndrome and may express varying degrees of the phenotype.
https://en.wikipedia.org/wiki/Simpson%E2%80%93Golabi%E2%80%93Behmel_syndrome
Figure 2. Activation of IRX3 and IRX5 Expression in Human Adipocyte Progenitors by
the FTO Obesity Risk Genotype.
Panel A shows gene annotations and LD with array tag variant rs9930506 in a 2.5-Mb
window; LD is expressed as r2 values in the CEU population. Arrows indicate the
direction of transcription of annotated genes in the locus.
CEU denotes a population of Utah residents with northern and
western European ancestry, and LD linkage disequilibrium.
Figure 2. Activation of IRX3 and IRX5 Expression in Human Adipocyte Progenitors by
the FTO Obesity Risk Genotype.
Panel B shows chromosome conformation capture (Hi-C) interactions contact
probabilities in human IMR90 myofibroblasts, 22 revealing a 2-Mb topologically
associating domain, and LD mean r2 statistics for all SNV pairs at 40-kb resolution.
topology associating domain (TAD)
最近、遺伝子の組織や発生時期特異的な発
現調節の基本構造単位としてtopology
associating domain(TAD)と呼ばれる領域に
注目が集まっている。ヒトゲノムには約２０００
のTADが存在すると考えられているが、TAD
の存在が広く認められるようになったのはつ
い最近のことだ。TAD概念の確立には、核内
で位相的に接して存在しているゲノム領域を
特定するchromosome conformation capture
と呼ばれる方法の開発が大きく寄与している。
一つのTADは平均５００kb—1Mb程度の大き
さで、その中に１個から複数の細胞特異的、あ
るいは発生時期特異的に働くcoding遺伝子と、
その発現調節（エンハンサー）領域を含む長い
DNA単位が大きな塊を作って核内に存在して
いると考えられる。図１はPopeらの論文
（Nature, 515:402, 2014）から拝借したTADの
イメージ図だが、それぞれのTAD単位を構成
するDNAが、分離した毛糸玉のようにまとまっ
て核内に存在していることが表現されている。
なぜこのような構造化が必要なのか？これに
ついては、遺伝子発現の時期や場所を決めて
いる調節ユニットを一つの塊として構造化する
必要に答えたのがTADではないかと考えられ
ている。
実際、HiCと呼ばれるChromosome conformation capture法を用
いて、どの領域がどの領域と隣接していかを調べると、遺伝子や
エンハンサーの相互作用がTAD内に制限されていることがわかる。
図１のヒートマップはHiCの結果をマッピングしたもので、各領域
がコンタクトしている確率が高いほど赤くなるよう示されている。核
という狭い３次元空間では、原理的に各領域はどの領域とも近接
することは可能だが、実際にはTAD内にある領域は同じTAD内の
領域と相互作用する確率が高い。TAD内部の塩基配列は特に保
存されているわけではないが、各TADの間には、種間でよく保存さ
れた、CTCF分子の結合配列、house keeping遺伝子、tRNA遺伝
子、そしてSINEトランスポゾンなどが集まった境界領域が存在し
ている。最近の研究から、この境界が、一つのTAD 内のエンハン
サーの効果が、隣接したTADに影響を及ぼさないよう制限するイ
ンシュレーターの働きをしているのではと考えられるようになって
きた。私たちの体は何百種類もの細胞から出来ており、それぞれ
の細胞ごとに働いている遺伝子は違っている。とはいえ、それぞ
れの細胞分化に必要な遺伝子群を、分化ステージや細胞系列に
合わせて狭い領域にまとめることは難しい。このため全く異なる細
胞で発現する遺伝子が隣接して存在することはゲノムでは普通に
見られる。従って、一つのTADの発現が、隣のTADにある遺伝子
の発現に影響を及ぼさないよう構造化されていることは重要だ
Figure 2. Activation of IRX3 and IRX5 Expression in Human Adipocyte Progenitors by
the FTO Obesity Risk Genotype.
Panel C shows box plots for expression levels, after 2 days of differentiation, in human
adipose progenitors isolated from 20 risk-allele carriers and 18 nonrisk-allele carriers,
evaluated by means of a quantitative polymerasechain-reaction analysis for all genes in
the 2.5-Mb locus. The horizontal line within each box represents the median, the top and
bottom of each box indicate the 75th and 25th percentile, and I bars indicate the range.
Figure 3. Regulation of Obesity-Associated Cellular Phenotypes in Human Adipocytes
by IRX3 and IRX5.
Panel A shows the mitochondrial and FXR and RXR activation genes with strongest
positive (in red) or negative (in green) correlation with IRX3 and IRX5 in human perirenal
adipose tissue from 10 participants..
Figure 3. Regulation of Obesity-Associated Cellular Phenotypes in Human Adipocytes
by IRX3 and IRX5.
Panels B and C show box plots of the increased adipocyte diameter and decreased
mitochondrial DNA content in isolated differentiated adipocytes from risk-allele carriers
(16 and 8 participants, respectively) relative to nonriskallele carriers (26 and 8,
respectively). The vertical line within each box represents the median, the left and right
margins of each box indicate the interquartile range, and I bars indicate the range.
Figure 3. Regulation of Obesity-Associated Cellular Phenotypes in Human Adipocytes
by IRX3 and IRX5.
Panel D shows box plots of the altered basal and isoproterenol-stimulated oxygen
consumption rate (OCR) on small interfering RNA (siRNA) knockdown and doxycycline
(DOX)–mediated overexpression of IRX3 and IRX5 in 8 risk-allele carriers and 10
nonrisk-allele carriers. The siRNA efficiency was 62% for IRX3 and 71% for IRX5. The
horizontal line within each box represents the median, the top and bottom of each box
indicate the interquartile range, and I bars indicate the range.
Figure 5. Rescue of Metabolic Effects on Adipocyte Thermogenesis through Editing of
SNV rs1421085 in a Risk-Allele Carrier.
Panel A shows increased mean expression of IRX3 and IRX5 during early adipocyte
differentiation specifically for the risk allele; increased expression levels are rescued by
C-to-T genome editing. I bars indicate standard deviations.
Figure 5. Rescue of Metabolic Effects on Adipocyte Thermogenesis through Editing of
SNV rs1421085 in a Risk-Allele Carrier.
Panel B shows increased expression of thermogenic and mitochondrial genes on C-to-T
endogenous single-nucleotide editing of rs1421085 in adipocyte progenitors from a
patient with the risk allele.
Panel C shows increased basal and isoproterenol-stimulated OCR on C-to-T singlenucleotide endogenous rescue of rs1421085 in adipocytes from a risk-allele carrier.
Figure 5. Rescue of Metabolic Effects on Adipocyte Thermogenesis through Editing of
SNV rs1421085 in a Risk-Allele Carrier.
Panel D shows a summary of our mechanistic model of the FTO locus association with
obesity, implicating a developmental shift favoring lipid-storing white adipocytes over
energyburning beige adipocytes. At its core lies a single-nucleotide T-to-C variant,
rs1421085, which disrupts a conserved ARID5B repressor motif and activates a
mesenchymal superenhancer and its targets (IRX3 and IRX5), leading to reduced heat
dissipation by mitochondrial thermogenesis (a process that is regulated by UCP1,
PGC1α, and PRDM16) and to increased lipid storage in white adipocytes.
Results
Our data indicate that the FTO allele associated with obesity represses
mitochondrial thermogenesis in adipocyte precursor cells in a tissueautonomous manner. The rs1421085 T-to-C single-nucleotide variant
disrupts a conserved motif for the ARID5B repressor, which leads to
derepression of a potent preadipocyte enhancer and a doubling of IRX3
and IRX5 expression during early adipocyte differentiation. This results
in a cell-autonomous developmental shift from energy-dissipating beige
(brite) adipocytes to energy-storing white adipocytes, with a reduction in
mitochondrial thermogenesis by a factor of 5, as well as an increase in
lipid storage. Inhibition of Irx3 in adipose tissue in mice reduced body
weight and increased energy dissipation without a change in physical
activity or appetite. Knockdown of IRX3 or IRX5 in primary adipocytes
from participants with the risk allele restored thermogenesis, increasing
it by a factor of 7, and overexpression of these genes had the opposite
effect in adipocytes from nonrisk-allele carriers. Repair of the ARID5B
motif by CRISPR–Cas9 editing of rs1421085 in primary adipocytes from
a patient with the risk allele restored IRX3 and IRX5 repression,
activated browning expression programs, and restored thermogenesis,
increasing it by a factor of 7.
Conclusions
Our results point to a pathway for adipocyte
thermogenesis regulation involving ARID5B,
rs1421085, IRX3, and IRX5, which, when
manipulated, had pronounced pro-obesity and
anti-obesity effects.
(Funded by the German Research Center for
Environmental Health and others.)
Message
FTOアレルは直接に肥満に関与するのでなく、脂肪前駆細胞ミト
コンドリアにおける熱生成に関与している。FTOのrs1421085 Tto-CバリアントはIRX3・IRX5遺伝子活性を増幅し、これがミトコ
ンドリア熱生成抑制と脂質貯蔵をもたらす。マウスモデルにおけ
る脂肪細胞内Irx3阻害は身体活動・食欲の変化を伴わず体重を
減少させてエネルギー消費を増加させた。また、IRX3・IRX5抑制
患者からのプライマリ脂肪細胞rs1421085のCRISPR-Cas9編集によ
るARID5Bモチーフの修復により、熱発生能を回復させることがで
きた。
FTOに関するランドマーク研究であり、焦点をIRX遺伝子群にシフ
トさせた。
http://www.medicalonline.jp/news.php?t=review&m=lifestyle&date=201508&file=20
150824-NEJM-xx-L.csv
ヒトにおける FTO 肥満遺伝子多様体経路と脂肪細胞の褐色化
M. Claussnitzer and Others
ゲノムワイド関連解析は，疾患に関連するゲノム領域の同定に使用できるが，データの解釈が困難である．FTO 領域は肥満ともっ
とも強く関連することが示されているが，その基本的機序はまだほとんどわかっていない．
FTO 領域と肥満の関連について，その調節経路と基本的機序を詳しく調査するために，エピゲノムデータ，アレルの活性，モチー
フの保存，調節因子の発現，遺伝子共発現パターンを調査した．それに基づき遺伝子多様体が作用する可能性のある細胞の種類を
予測し，患者とマウスから採取したサンプルに対して直接的摂動実験を行い，患者から採取したサンプルに対して CRISPR–Cas9
による内在性遺伝子のゲノム編集を行って，予測を検証した．
今回のデータから，肥満に関連する FTO 遺伝子アレルは，前駆脂肪細胞におけるミトコンドリア熱産生を組織自律的に抑制するこ
とが示された．FTO の多様体 rs1421085 の T から C への一塩基多様体は ARID5B 抑制因子の保存されたモチーフを破壊するため
，前駆脂肪細胞の強力なエンハンサーの抑制が解除され，脂肪細胞分化早期の IRX3 と IRX5 の発現が倍増する．その結果，細胞
自律的な発生はエネルギーを散逸するベージュ（ブライト）脂肪細胞からエネルギーを蓄積する白色脂肪細胞へと移行し，ミトコ
ンドリア熱産生が 1/5 に減少し，脂質の蓄積が増加する．マウスの脂肪組織で Irx3 を阻害すると，身体活動や食欲の変化を伴わず
に，体重が減少し，エネルギー散逸が増大した．リスクアレル保有者の初代脂肪細胞で IRX3 または IRX5 をノックダウンさせる
と，熱産生が回復して 7 倍に増加し，リスクアレル非保有者の脂肪細胞でこれらの遺伝子を過剰発現させると逆の作用がみられた
．リスクアレル保有者の初代脂肪細胞の rs1421085 の ARID5B モチーフを CRISPR–Cas9 により編集して修復すると，IRX3 と
IRX5 の抑制が回復し，褐色化発現プログラムが活性化し，熱産生が回復し 7 倍に増加した．
今回の結果から，ARID5B，rs1421085，IRX3，IRX5 が関与する脂肪細胞の熱産生調節の経路の存在が示され，遺伝子操作によっ
て顕著な肥満促進作用，抗肥満作用がみられた．（ドイツ環境健康研究センターほかから研究助成を受けた．）
エピジェネティクス，アレルの活性，モチーフの保存，その他の手法を用いて，FTO 領
域と肥満との関連における，調整経路と基本的機序を詳細に調査した．重要であると思
われる脂肪細胞の熱産生経路が見つかった．
http://www.nejm.jp/abstract/vol373.p895
1University
of North Carolina School of Medicine, Chapel Hill, NC
2University of Texas Health Science Center, San Antonio, TX
3Dallas Diabetes and Endocrine Center, Dallas, TX
4Elcelyx Therapeutics, San Diego, CA
OBJECTIVE
Delayed-release metformin (Met DR) is
formulated to deliver drug to the lower bowel to
leverage the gut-based mechanisms of metformin
action with lower plasma exposure. Met DR was
assessed in two studies. Study 1 compared the
bioavailability of single daily doses of Met DR to
currently available immediate release metformin
(Met IR) and extended-release metformin (Met
XR) in otherwise healthy volunteers. Study 2
assessed glycemic control in subjects with type 2
diabetes (T2DM) over 12 weeks.
RESEARCH DESIGN AND METHODS
Study 1 was a Phase 1, randomized, four-period
crossover study in 20 subjects. Study 2 was a 12week, Phase 2, multicenter, placebo-controlled,
dose-ranging study in 240 subjects with T2DM
randomized to receive Met DR 600, 800, or 1,000
mg administered once daily; blinded placebo; or
unblended Met XR 1,000 or 2,000 mg (reference)
Met DR tablets were produced according to current good
manufacturing practices and comprise a Met IR
hydrochloride (HCl) core overlaid with a proprietary
enteric coat. The enteric coat, which includes Eudragit
polymers and other commonly used excipients, delays
disintegration and dissolution of the tablet until it reaches
a pH of 6.5 in the distal small intestine and beyond.
Tablet strengths used included 300 and 500 mg
metformin HCl.
Placebo tablets were visually identical but contained no
active ingredient.
Met IR and Met XR tablets used as comparator
treatments were commercially available products
(Glucophage; Bristol- Myers Squibb, New York, NY).
Figure 1—Plasma metformin concentrations and bioavailability after administration of a single daily dose (study 1).
A: Mean (SD) plasma metformin concentrations by treatment and time point. Evaluable population (N = 19).
Treatments were administered at t = 0 h (8:00 P.M.) and at t = 12 h (8:00 A.M.) except for Met XR, which was
administered as a single dose at t = 0 (black arrows). Meals were administered at t =20.42, 2.08, 11.5, 18.08, and
24.08 h relative to the first dose (dotted vertical lines).
Figure 1—Plasma metformin concentrations and bioavailability after administration of a single daily dose (study 1).
B: Relative bioavailability and exposure of single daily doses of Met DR bid vs. Met IR bid and Met XR qd.
Evaluable population (N = 19). Data are expressed as the percentage geometric LS mean ratio and the
corresponding 90% upper confidence limit.
***P＜0.0001 vs. Met IR or Met XR. t, last quantifiable concentration following dose administration.
Figure 2—Change in FPG and fasting metformin
concentrations in the 12-week study (study 2).
A: Median change in FPG level at week 4. Week 4
evaluable population (N = 215). P value from KruskalWallis test; 95% CI based on Hodges-Lehmann
estimation of the median difference vs. placebo;
baseline is defined as the median measurement at day 1.
B: Median change in and FPG AUC4–12wk (mg/dL *
week). Week 12 evaluable population (N = 196). *P ＜
0.05 vs. placebo for pairwise comparison without
adjustment.
C: Median fasting plasma metformin concentrations.
Week 12 evaluable population (N = 196).
Safety and Tolerability Consistent with the Glucophage/Glucophage XR prescribing
information (15), the most common treatment-emergent AEs (TEAEs) were
gastrointestinal in nature.
In study 1, the most commonly reported TEAEs in any treatment group included diarrhea,
nausea, vomiting, and headache. Most TEAEs were assessed as being unrelated to
study treatment and were mild in intensity; there were no deaths.
In study 2, all active treatments were well tolerated, and TEAEs were consistent with
Glucophage/Glucophage XR prescribing information (15). However, the incidence of
gastrointestinal TEAEs was relatively low (compared with prescribing information) in all
active treatment groups, with gastrointestinal TEAEs reported by 7.3%, 12.8%, 17.5%,
15.0%, 17.5%, and 12.5% of subjects, respectively, receiving placebo, 600 mgMet DR,
800 mg Met DR, 1,000 mg Met DR, 1,000 mg Met XR, and 2,000 mg Met XR. This
suggests that the population was tolerant to metformin, which is consistent with 88%of
subjects having receivedmetformin prior to study enrollment and washout.
As metformin accumulation can result in increased lactate production, which, in turn,
increases the risk of the rare but serious metabolic complication of lactic acidosis, the
effects of Met DR on plasma lactate levels were also evaluated in study 2. Mean lactic
acid values were within normal ranges throughout the study, but were elevated from
baseline by 0.31–0.33 mmol/L (median 0.19–0.29 mmol/L) for Met XR compared with
0.09–0.12 mmol/L (median 20.22 to 0.22 mmol/L) for Met DR and 0.16 mmol/L (median
0.17 mmol/L) for placebo (Fig. 3). The lack of change from baseline in lactate levels for
the Met DR groups most likely reflects lower metformin exposure. One subject treated
with 2,000 mg Met XR experienced moderate blood lactate increases for 16 days (up to
5.9 mmol/L) without other AEs or changes to the treatment regimen.
RESULTS
The bioavailability of 1,000 mg Met DR bid was ∼50%
that of Met IR and Met XR (study 1). In study 2, 600, 800,
and 1,000 mg Met DR qd produced statistically
significant, clinically relevant, and sustained reductions
in fasting plasma glucose (FPG) levels over 12 weeks
compared with placebo, with an ∼40% increase in
potency compared with Met XR. The placebo-subtracted
changes from baseline in HbA1c level at 12 weeks were
consistent with changes in FPG levels. All treatments
were generally well tolerated, and adverse events were
consistent with Glucophage/ Glucophage XR prescribing
information.
CONCLUSIONS
Dissociation of the glycemic effect from
plasma exposure with gut-restricted Met DR
provides strong evidence for a
predominantly lower bowel-mediated
mechanism of metformin action.
Message
日本にはXR製剤は存在しないが、Metforminの高
用量の作用機序は腸管を介するという説明は納
得できる。
DR製剤、メトホルミン腸溶錠というものが今後
出るのだろうか？乳酸値があまり上昇せず安
全そうである。

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