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Journal Club
Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, Xiong
J, Perez Z, Norton L, Abdul-Ghani MA, Defronzo RA.
Dapagliflozin improves muscle insulin sensitivity but enhances endogenous
glucose production.
J Clin Invest. 2014 Feb 3;124(2):509-14.
Steele AM1, Shields BM1, Wensley KJ1, Colclough K2, Ellard S3, Hattersley AT1.
Prevalence of vascular complications among patients with glucokinase mutations
and prolonged, mild hyperglycemia.
JAMA. 2014 Jan 15;311(3):279-86.
2014年2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
SGLT2阻害薬による研究は糖毒性のコンセプト解明に重要な役割を果たした！
J. Clin. Invest. 79：1510-1515, 1987
糖毒性の概念形成にフロリジンは重要な役割を果たした！
New hypoglycemic drugs
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●
●
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Amylin
The 53rd Annual Meeting of the Japan
Diabetes Society 27 May, 2010 Okayama
Hydroxychloroquine
Inhaled insulin
SGLT-2 (sodium glucose transportor-2) inhibitors
–
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Glucokinase activators
–
●
Prof. McGuill JB
GPR 40 (G-protein coupled receptor 40) agonists
–
●
Dr. Eiki J
PPARx
–
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Prof. Ferrannini E
Dr. Takeuchi K
Bromocriptine
–
Prof. Matsuda
approved
Luseogliflozin
FIG. 1. SGLT2 inhibitors in late-stage clinical trials.
Based upon their PK/PD relationship, we postulate that their mechanism of action is
related to secretion and/or active reabsorption in the proximal tubule and slow off rate
from the SGLT2 target.
Liu JJ, Lee T, DeFronzo RA.: Why Do SGLT2 inhibitors inhibit only 30-50% of renal
glucose reabsorption in humans? Diabetes. 2012 Sep;61(9):2199-204.
2012年11月1日 Journal Club
Diamant M, Morsink LM.: SGLT2 inhibitors for diabetes: turning symptoms into therapy.
Lancet. 2013 Jul 11. doi:pii: S0140-6736(13)60902-2. 10.1016/S0140-6736(13)60902-2.
[Epub ahead of print] (reviewed on 2013/10/24)
LX4211: Lexicon Pharmaceuticals, Princeton, NJ
Clinical Pharmacology & Therapeutics (2012); 92 2, 158–169.
Diabetes 62:3324–3328, 2013 reviewed on 2013/10/24
Diabetes Care. 2013 Sep;36(9):2508-15. (reviewed on 2013/7/11)
Dapagliflozin
Dapagliflozin (rINN/USAN) is an experimental drug being studied by BristolMyers Squibb in partnership with AstraZeneca as a potential treatment for type 1
and 2 diabetes. Although dapagliflozin's method of action would operate on
either type of diabetes or other conditions resulting in hyperglycemia, the
current clinical trials specifically exclude participants with Type 1 diabetes.
In July 2011 an FDA committee recommended against approval until more data
was available. The Prescription Drug User Fee Act (PDUFA) date for dapagliflozin
for the treatment of Type 2 diabetes was extended three months by the FDA to
January 28, 2012. (Dapagliflozin Declined by FDA)
SGLT2 inhibitors: Canagliflozin Dapagliflozin Remogliflozin Sergliflozin
http://en.wikipedia.org/wiki/Dapagliflozin
Appendix Figure 4. Change in mean HbA1c level over time
calculated by using the placebo group to impute missing data
in the safety analysis set and analyzed by treatment group
and discontinuation status.
DAPA = dapagliflozin; INS = insulin; PLA = placebo.
Ann Intern Med. 2012 Mar 20;156(6):405-415.(rev.2012/4/5)
Figure 3. Adjusted mean changes in total body weight over.
Ann Intern Med. 2012 Mar 20;156(6):405-415.(rev.2012/4/5)
J Clin Invest. doi:10.1172/JCI70704.
Chronic hyperglycemia impairs insulin
action, resulting in glucotoxicity, which
can be ameliorated in animal models by
inducing glucosuria with renal glucose
transport inhibitors. Here, we examined
whether reduction of plasma glucose
with a sodium-glucose cotransporter 2
(SGLT2) inhibitor could improve insulinmediated tissue glucose disposal in
patients with type 2 diabetes.
Eighteen diabetic men were randomized
to receive either dapagliflozin (n = 12) or
placebo (n = 6) for 2 weeks. We
measured insulin-mediated whole body
glucose uptake and endogenous
glucose production (EGP) at baseline
and 2 weeks after treatment using the
euglycemic hyperinsulinemic clamp
technique.
Research design.
At baseline, all subjects received a 4-hour hyperinsulinemic euglycemic clamp
with 3-3H-glucose to quantitate whole body insulin-mediated glucose disposal and
EGP following a 10-hour overnight fast (see below). Within 7 to 14 days after
completing the insulin clamp, subjects were admitted to the Clinical Research
Center for 3 days.
Starting at 6:00 AM on day 1, basal EGP was measured with 3-3H-glucose, which
was administered as a prime (25 μCi × FPG/100) continuous (0.25 μCi/min)
infusion for 3 hours (6:00–9:00 AM). Blood samples for determination of plasma
glucose, insulin, glucagon, and tritiated glucose radioactivity were obtained every
5 to 10 minutes during the last 30 minutes.
At 6:00 AM on day 2, subjects received a 3-3H-glucose infusion as per day 1, and
the tritiated glucose infusion was continued for 7 hours. After a 3-hour
equilibration period (9:00 AM) on day 2, subjects received dapagliflozin (10 mg) or
placebo in randomized double-blind fashion, and blood samples were drawn
every 20 minutes for 4 hours after drug administration.
At 6:00 AM on day 3, following a 10-hour overnight fast, subjects received a repeat
tritiated glucose infusion as per day 2 and dapagliflozin (10 mg) or placebo was
ingested 3 hours after starting the tritiated glucose infusion, which was given for
a total of 7 hours. 24-hour urinary collections for measurement of urinary glucose
excretion were obtained on days 0, 1, 2, and 3.
After day 3, subjects continued to take dapagliflozin (10 mg/d) or placebo for an
additional 12 days, and, on day 14, the euglycemic hyperinsulinemic clamp was
repeated.
important clinical implications.
The increase in EGP (0.36 mg/kg/min) on day 3 compared with that at
day 1 in dapagliflozin-treated subjects resulted in the addition of
approximately 47 grams of glucose per day to the systemic circulation.
This amount of glucose (∼47 grams) approximates half of the amount
of glucose (∼91 grams) excreted in the urine secondary to SGLT2
inhibition by dapagliflozin on day 3. Thus, the increase in EGP in
response to glucosuria offsets approximately half of the amount of
glucosuria produced by inhibiting SGLT2. If the increase in EGP would
have been prevented, the decrease in FPG caused by dapagliflozin
would have been approximately double. It would be of great interest to
examine combination therapy with SGLT2 inhibitor plus an incretin
mimetic agent that inhibits glucagon and stimulates insulin secretion
(26). These incretin-mediated actions would be anticipated to block the
increase in EGP produced by the SGLT2 inhibitor and augment its
glucose lowering ability. Based on these considerations, we postulate
that combination therapy with SGLT2 inhibitor plus DPP-4 inhibitor or
GLP-1 analog would exert an additive or even synergistic effect to
lower plasma glucose concentration and HbA1c in individuals with
T2DM.
The decrease in plasma glucose concentration during day 2 of
the study (Figure 3) in subjects receiving placebo can be
explained by the prolonged fasting period (∼20 hours).
Consistent with this, the rate of EGP decreased significantly in
subjects receiving placebo from 2.10 ± 0.11 mg/kg/min at
baseline to 1.40 ± 0.07 mg/kg/min at study’s end (P < 0.001).
The mean difference in EGP between dapagliflozin-treated and
placebo-treated subjects (0.70 ± 0.10 mg/kg/min) is virtually
identical to the amount of glucose excreted in the urine during the
study in dapagliflozin-treated subjects (∼15 grams). Thus, the
decrease in FPG in placebo-treated subjects was entirely
accounted for by a decline in EGP, while the decline in FPG in
dapagliflozin-treated subjects was entirely accounted for by renal
glucose excretion.
Dapagliflozin treatment induced glucosuria and
markedly lowered fasting plasma glucose. Insulinmediated tissue glucose disposal increased by
approximately 18% after 2 weeks of dapagliflozin
treatment, while placebo-treated subjects had no
change in insulin sensitivity. Surprisingly, following
dapagliflozin treatment, EGP increased substantially
and was accompanied by an increase in fasting
plasma glucagon concentration. Together, our data
indicate that reduction of plasma glucose with an
agent that works specifically on the kidney to induce
glucosuria improves muscle insulin sensitivity.
However, glucosuria induction following SGLT2
inhibition is associated with a paradoxical increase
in EGP.
These results provide support for the
glucotoxicity hypothesis, which
suggests that chronic hyperglycemia
impairs insulin action in individuals with
type 2 diabetes.
Message
Dapagliflozinで糖毒性が改善されインスリン感
受性が改善した。
それはともかく、腎臓からブドウ糖が排泄され
た半分くらいは肝臓からのブドウ糖産生でキャ
ンセルされてしまったという。
さらに、肝臓からのブドウ糖産生はグルカゴン
の上昇によっている。
ということは、SGLT-2阻害薬とインクレチン薬
の併用は血糖降下には有用と思われるそうであ
る。
New hypoglycemic drugs
●
●
●
●
Amylin
The 53rd Annual Meeting of the Japan
Diabetes Society 27 May, 2010 Okayama
Hydroxychloroquine
Inhaled insulin
SGLT-2 (sodium glucose transportor-2) inhibitors
–
●
Glucokinase activators
–
●
Prof. McGuill JB
GPR 40 (G-protein coupled receptor 40) agonists
–
●
Dr. Eiki J
PPARx
–
●
Prof. Ferrannini E
Dr. Takeuchi K
Bromocriptine
–
Prof. Matsuda
MODY:
メンデル遺伝様式（常染色体優性）で発症する若年糖尿病であり（通常 25歳以下の発症）
http://www.nanbyou.or.jp/entry/907
糖尿病全体の1-3％程度と
推定されていますが、確か
な調査報告は無く、日本人
における頻度は不明です。
６種類の病型の頻度は日本
人MODY全体の約20％を
占めると推定されています
が、大半の80％程度の原
因遺伝子は依然として未知
です。
Maturity-onset diabetes
of the young (MODY)
type 2 results from
inactivating or loss of
function mutations in
GCK, the gene that
encodes glucokinase.
東京女子医科大学岩崎Dr
http://en.wikipedia.org/wiki/Maturity_onset_diabetes_of_the_young
1National
Institue for Health Research, Exeter Clinical Research Facility, Exeter
Medical School, University of Exeter, Exeter, United Kingdom
2Department of Molecular Genetics, Royal Devon and Exeter National Health
Service Foundation Trust, Exeter, United Kingdom
JAMA. 2014;311(3):279-286.
Importance Glycemic targets in diabetes have
been developed to minimize complication risk.
Patients with heterozygous, inactivating
glucokinase (GCK) mutations have mild fasting
hyperglycemia from birth, resulting in an elevated
glycated hemoglobin (HbA1c) level that mimics
recommended levels for type 1 and type 2
diabetes.
Objective To assess the association between
chronic, mild hyperglycemia and complication
prevalence and severity in patients with GCK
mutations.
Design, Setting, and Participants Cross-sectional
study in the United Kingdom between August 2008 and
December 2010. Assessment of microvascular and
macrovascular complications in participants 35 years or
older was conducted in 99 GCK mutation carriers
(median age, 48.6 years), 91 nondiabetic, familial,
nonmutation carriers (control) (median age, 52.2 years),
and 83 individuals with young-onset type 2 diabetes
(YT2D), diagnosed at age 45 years or younger (median
age, 54.7 years).
Main Outcomes and Measures Prevalence and
severity of nephropathy, retinopathy, peripheral
neuropathy, peripheral vascular disease, and
cardiovascular disease.
Our study is limited by the relatively small number of patients known to have GCK
mutations, which necessitates a cross-sectional study rather than a longitudinal study and
limits power.
Although the prevalence of complications was low for both the GCK mutation and control
groups, we are unable to prove equivalence with our sample size. We would need a control
group more than 10 times larger to detect statistical significance between the groups at the
prevalences we observed. However, with the exception of mild background retinopathy, the
prevalence of all complications was very low in the patients with a GCK mutation, with
similar CIs to the control participants and significantly lower than those seen in the YT2D
group. Even if proved to be statistically different, it is unlikely that differences in the low
prevalence rates seen would be of clinical significance.
Our definition of the YT2D cohort’s duration of hyperglycemia is not precise because
individuals may have been unaware that they had type 2 diabetes and complications can
occur in up to 50% of people before a medical diagnosis for symptoms is sought.31 Even
with this likely underestimation of duration of hyperglycemia in the patients in the YT2D
cohort, their duration should not be as long as the patients with a GCK mutation whose
hyperglycemia is present from birth. Because the researchers who conducted clinical
assessments of macrovascular disease were aware of the clinical category of many of the
patients, not all clinical assessments were collected in a blinded fashion.
Finally, there were more women recruited in our GCK group. This is unlikely to affect
microvascular disease rates but could affect macrovascular disease rates. With so few
cases in the GCK group, it is not possible to adjust for this difference statistically. However,
the prevalence of coronary heart disease in the GCK mutation group for both men and
women is similar to that reported in England for a similar age range (45-54 years)32: 5% for
the GCK group vs 3.6% for England in men and 1.2% for the GCK group vs 1.3% for England
in women. Although these results are similar to those of the general population, our CIs
were wide and larger numbers would be required to investigate this further.
Results Median HbA1c was 6.9% in patients with the GCK mutation, 5.8% in
controls, and 7.8% in patients with YT2D. Patients with GCK had a low
prevalence of clinically significant microvascular complications (1% [95% CI,
0%-5%]) that was not significantly different from controls (2% [95% CI, 0.3%8%], P=.52) and lower than in patients with YT2D (36% [95% CI, 25%-47%],
P<.001). Thirty percent of patients with GCK had retinopathy (95% CI, 21%41%) compared with 14% of controls (95% CI, 7%-23%, P=.007) and 63% of
patients with YT2D (95% CI, 51%-73%, P<.001). Neither patients with GCK nor
controls required laser therapy for retinopathy compared with 28% (95% CI,
18%-39%) of patients with YT2D (P<.001). Neither patients with GCK patients
nor controls had proteinuria and microalbuminuria was rare (GCK, 1% [95% CI,
0.2%-6%]; controls, 2% [95% CI, 0.2%-8%]), whereas 10% (95% CI, 4%-19%)
of YT2D patients had proteinuria (P<.001 vs GCK) and 21% (95% CI, 13%32%) had microalbuminuria (P<.001). Neuropathy was rare in patients with
GCK (2% [95% CI, 0.3%-8%]) and controls (95% CI, 0% [0%-4%]) but present
in 29% (95% CI, 20%-50%) of YT2D patients (P<.001). Patients with GCK had
a low prevalence of clinically significant macrovascular complications (4% [95%
CI, 1%-10%]) that was not significantly different from controls (11% [95% CI,
5%-19%]; P=.09), and lower in prevalence than patients with YT2D (30% [95%
CI, 21%-41%], P<.001).
Conclusions and Relevance
Despite a median duration of 48.6
years of hyperglycemia, patients
with a GCK mutation had low
prevalence of microvascular and
macrovascular complications.
These findings may provide insights
into the risks associated with
isolated, mild hyperglycemia.
Editorial | January 15, 2014
Insights From Monogenic Diabetes and Glycemic Treatment Goals for Common
Types of Diabetes
Jose C. Florez, MD, PhD1,2,3,4
1Center
for Human Genetic Research, Massachusetts General Hospital, Boston
2Diabetes Research Center, Diabetes Unit, Massachusetts General Hospital, Boston
3Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
4Department of Medicine, Harvard Medical School, Boston, Massachusetts
Overall, it is clear that despite the low frequency of
glucokinase MODY, knowledge of its natural course
has implications for the management of common
forms of diabetes, and it illustrates how clinical
insights gained from the study of monogenic
syndromes can improve understanding of complex
diseases.
JAMA. 2014;311(3):249-251.
Message
35歳以上の被験者273人を対象に、グルコキナー
ゼ（GCK）変異に伴う軽度の慢性高血糖と血管合
併症有病率の関連を横断研究で検討。臨床的に
重大な細小血管合併症の有病率は、GCK変異保有
者1％、対照2％（非有意）、若年性糖尿病患者
36％だった。大血管合併症有病率は、それぞれ
4％、11％（非有意）、30％だった。
GCK変異で細胞内でブドウ糖が代謝経路に入らな
い場合は合併症が起こりにくい？
⇒GCK活性化で血糖を下げても合併症が起こるの
ではないか？

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