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！

●
●
●
●
●
●
●
●
Amylin
Hydroxychloroquine
The 53 rd Annual Meeting of the Japan
Diabetes Society 27 May, 2010 Okayama
Inhaled insulin
SGLT-2 (sodium glucose transportor-2) inhibitors
– Prof. Ferrannini E
Glucokinase activators
– Dr. Eiki J
PPARx
– Prof. McGuill JB
GPR 40 (G-protein coupled receptor 40) agonists
– 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 Bristol-
Myers 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.

Research design.
At baseline, all subjects received a 4-hour hyperinsulinemic euglycemic clamp with 33 H-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 33 H-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 33 H-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.

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。

●
●
●
●
●
●
●
●
Amylin
Hydroxychloroquine
The 53 rd Annual Meeting of the Japan
Diabetes Society 27 May, 2010 Okayama
Inhaled insulin
SGLT-2 (sodium glucose transportor-2) inhibitors
– Prof. Ferrannini E
Glucokinase activators
– Dr. Eiki J
PPARx
– Prof. McGuill JB
GPR 40 (G-protein coupled receptor 40) agonists
– 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

1 National Institue for Health Research, Exeter Clinical Research Facility, Exeter
Medical School, University of Exeter, Exeter, United Kingdom
2 Department 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).

Editorial | January 15, 2014
Insights From Monogenic Diabetes and Glycemic Treatment Goals for Common
Types of Diabetes
Jose C. Florez, MD, PhD 1,2,3,4
1 Center for Human Genetic Research, Massachusetts General Hospital, Boston
2 Diabetes Research Center, Diabetes Unit, Massachusetts General Hospital, Boston
3 Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
4 Department 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.

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？