Journal Club 2016年1月28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 Merovci A, Abdul-Ghani M, Mari A, Solis Herrera C, Xiong J, Daniele G, Tripathy D, DeFronzo R. Effect of Dapagliflozin With and Without Acipimox on Insulin Sensitivity and Insulin Secretion in T2DM Males. J Clin Endocrinol Metab. 2016 Jan 14:jc20152597. 2016年1月28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

DOI: http://dx.doi.org/10.1210/jc.2015-2597 - See more at: http://press.endocrine.org/doi/10.1210/jc.2015-2597?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed&#sthash.W6KD0y6I.dpuf J Clin Endocrinol Metab. 2016 Jan 14:jc20152597.

Aim: To investigate the effect of lowering the plasma glucose and free fatty acid concentrations with dapagliflozin and acipimox, respectively, on insulin sensitivity and insulin secretion in T2DM individuals.

METHODS: 14 male T2DM patients received an OGTT and euglycemic hyperinsulinemic clamp at baseline and were treated for three weeks with dapagliflozin (10 mg per day). During week 3, acipimox (250 mg four times per day) treatment was added to dapagliflozin. The OGTT and insulin clamp were repeated at the end of weeks 2 and 3.

Acipimox (trade name Olbetam in Europe) is a niacin derivative used as a hypolipidemic agent. It is used in low doses and may have less marked adverse effects, although it is unclear whether the recommended dose is as effective as are standard doses of nicotinic acid. Acipimox inhibits the production of triglycerides by the liver and the secretion of VLDL cholesterol, which leads indirectly to a modest reduction in LDL and increase in HDL cholesterol. Long-term administration is associated with reduced mortality, but unwanted effects limit its clinical use. Adverse effects include flushing (associated with prostaglandin D2), palpitations, and gastrointestinal disturbances. Flushing can be reduced by taking aspirin 20 to 30 minutes before taking acipimox. High doses can cause disorders of liver function, impair glucose tolerance and precipitate gout. https://en.wikipedia.org/wiki/Acipimox 深く煎ったコーヒーには、ニコチン酸（ビタミンB3）が入っています。 ●コーヒーの香りはビタミンB3と同じ効き目（詳しくは →こちら ）。 　これは筆者の現役最後の実験です。ネズミにコーヒーの香りを飲ませると、あっという間に血中遊離脂肪酸が下がるのです。やや遅れて血中トリグリセリドも下がります。こんなこと滅多にないことです（詳しくは →こちら ）。 　高脂血症治療薬アシピモックスは、コーヒーの香りとは無関係に、ニコチン酸をモデルにして開発されました（当時のファルマシア社、後にファイザー社に吸収合併）。終わってみるとその構造は、コーヒーの香りＤＭＰとそっくりだったのです。 ●アシピモックスが開発された理由・・・「副作用のないニコチン酸を作りたい」。 　ニコチン酸は世界でたった１つしかない「善玉コレステロール（ＨＤＬ）を高める貴重なくすり」。しかし使い方が未熟だと、リバウンド現象が起こって、逆に状態を悪化します。そこで、ニコチン酸のリバウンドを無くせれば、素晴らしい高脂血症薬になるはずです。 ●アシピモックスは確かに使いやすくなりました。 　リバウンドは完全になくなりました。ヨーロッパを中心に３０ヶ国で承認され、中性脂肪を下げてＨＤＬを高める新薬です。しかし、なぜか日本と北米では、一旦開始された臨床試験（治験）が中断されてしまったのです。 それは１９７９年のことでした。アシピモックスを日本に導入するため臨床試験が行われていました。ところがそこに大型新薬「コレステロール低下薬」が割り込んできたのです。アシピモックスにとって不幸だったのは、どちらの試験も同じ高脂血症患者を相手にしていたことです。そのため臨床現場で患者の取り合いが起こりました。 http://d.hatena.ne.jp/coffees_for_healthy_life/20100201 The recommended dosage is one 250mg capsule 2 or 3 times daily to be taken with or after meals.

Figure 1. Plasma glucose (left) and C-peptide (right) concentrations during the OGTT performed at baseline, following dapagliflozin treatment for two weeks, and following combined dapagliflozin/acipimox treatment for one week.

Insulin secretory rate (ISR) during the OGTT was calculated by deconvolution of the plasma C-peptide concentration curve (17), and the ratio between the incremental area under the plasma insulin secretory rate and incremental area under the plasma glucose concentration was calculated as previously described (18). -cell glucose sensitivity, rate sensitivity, and the potentiation factor were calculated with the Mari model (17, 19). This model expresses glucose-stimulated insulin secretion (in pmol min-1 m-2) as the sum of two components: (i) the first component represents the dependence of insulin secretion on the absolute plasma glucose concentration at any time point during the OGTT and is characterized by a doseresponse function relating the two variables, the dose response slope being -cell glucose sensitivity. The dose response is modulated by a potentiation factor that encompasses several glucose-dependent and glucose-independent potentiating mechanisms (eg, prolonged exposure to hyperglycemia, nonglucose substrates, gastrointestinal (GI) hormones, neural modulation, and molecular/biochemical/enzymatic changes within the -cell). The second component represents the dependence of insulin secretion on the rate of change of plasma glucose, ie, the first derivative of plasma glucose concentration against time, and this parameter represents rate sensitivity. Rate sensitivity accounts for the observation that rapid changes in glucose concentration enhance insulin secretion more than slower changes in glucose concentration.

Figure 3. Beta cell glucose sensitivity (top panel) during the OGTT performed at baseline, following dapagliflozin treatment for two weeks, and following combined dapagliflozin/acipimox treatment for one week. Correlation between beta cell glucose sensitivity and fasting plasma glucose concentration on the day of the OGTT at baseline and following dapagliflozin and combined dapagliflozin/acipimox treatment (bottom panel).

RESULTS: Dapagliflozin cause glucosuria and significantly lowered the plasma glucose concentration (by 35 mg/dl, P<0.01) while the fasting plasma FFA concentration was unaffected. Acipimox caused a further decrease in the fasting plasma glucose concentration (by 20 mg/dl, P<0.01) and a significant decrease in the fasting plasma FFA concentration. Compared to baseline, insulin-mediated glucose disposal increased significantly at week 2 (from 4.48±0.50 to 5.30±0.50 mg/kgmin, p<0.05). However, insulin-mediated glucose disposal at week 3 (after the addition of acipimox) did not differ significantly from that at week 2. Glucose-stimulated insulin secretion at week 2 increased significantly compared to baseline and it increased further and significantly at week 3 compared to week 2.

CONCLUSION: Lowering the plasma glucose concentration with dapagliflozin improves both insulin sensitivity and beta cell function, while lowering plasma FFA concentration by addition of acipimox to dapagliflozin improves beta cell function without significantly affecting insulin sensitivity.

Message EmapgliflozinでFerranniniらはインスリン分泌 改善はすぐに起こっていることを示しており、 その時点でFFA上昇と脂肪酸化増加あり。FFAが 分泌刺激を更に高めているのか？というのは違 うらしい。 Acipimox自体の血糖降下作用がこのような現象 の説明としてはもっともらしいようである。