1. Journal Club 亀田メディカルセンター 糖尿病内分泌内科 Diabetes and Endocrine Department, Kameda Medical Center 松田 昌文 Matsuda, Masafumi 2007 年７月５日 8:20-8:50 B 棟８階 カンファレンス室

3. Diabetes & Endocrine Division, Kawasaki Medical School 膵臓 肝臓 血 糖 脳 インスリン ↑ SU 薬の糖代謝への作用 200 g/ 日 120g/ 日 乳 酸 乳 酸 グリコーゲン ( 食事 ) 16g 筋肉 SU 薬SU 薬 速効型インス リン分泌促進 薬 速効型インス リン分泌促進 薬

4. 4 CONHCH 2 CH 2 SO 2 NHCO NH Cl OCH 3 H3CH3CSO 2 NHCO NH N スルホニルウレア（ SU ）骨 格 グリクラジ ド グリベンクラミド グリメピ リド ナテグリニ ド ミチグリニ ド CONHCH 2 CH 2 SO 2 NHCO NH CH 3 N H3CH3C H5C2H5C2 CONHCHCH 2 CO 2 H (CH 3 ) 2 CH NCOCH 2 CHCH 2 CO 2 H H3CH3CSO 2 NHCONHCH 2 CH 2 CH 2 CH 3 トルブタミ ド 主要なインスリン分泌促進薬の化学構造式 ベンズアミド（ BA ） 骨格 速効型イ ンスリン 分泌促進 薬

5. 膵臓 β 細胞 SU 受容体への結合

6. Ichikawa K. et al. : Arzneim. -Forsch. / Drug Res. : 52, 605, 2002 × ③ 細胞膜 脱分極 Ca 2+ K+K+ の増加 選択的結合 ④ ⑤ ⑤ 糖輸送担体 （ GLUT2 ） ブドウ糖 インスリン分泌 電位依存性 Ca チャネル SUR1 （膵タイプ SU 受容体） ② ① 糖代謝 ［ ATP ］ ［ ADP ］ 細胞内 Ca 2+ の増加 ATP 感受性 K チャネル SU 薬 速効型インスリン 分泌促進薬 SU 薬・速効型インスリン分泌促進薬の作用機序

7. To compare the pharmacokinetic and pharmacodynamic effects of glimepiride between once and twice-daily dosing in type 2 diabetic patients. AIM

8. Criteria for subjects inclusion criteria: treated with 2 mg glimepiride alone over 4 weeks duration, age 40 – 70 years, weighing less than 25 kg/m 2 of body mass index, HbA 1C less than 8.0%. All subjects were free of concomitant illness such as heart disease, hepatic (serum alanine aminotransferase more than the upper limit of normal) or renal (serum creatinine more than the upper limit of normal) dysfunction. None of the patients had a history of severe hypoglycemia, active proliferative retinopathy or clinically significant neuropathy. Concomitant medications without hypoglycemic agents were permitted if the dose was stabilized for one month and during the study.

9. PROTCOL Prior to the randomized 2-period crossover study, treated with once-daily 2 mg of glimepiride in order to stabilize metabolic control over 3 to 5 weeks as a screening period. Randomization: 2 mg of glimepiride before breakfast PO QD twice-daily with 1 mg before breakfast and dinner, PO BID treated for 4 weeks (the first-period of crossover). Then, the regimen was reversed from that used in the first-period. Patients were treated by the new regimen for 4 weeks (the second-period of crossover). During the study period, they were asked to maintain a fixed calorie diet, which was calculated individually based on the ideal body weight and physical activity of each patient. They were also asked to fix meal times at 8 am for breakfast, midday for lunch and 6 pm for dinner. Subjects were admitted one day before the final day of each period of the study. On the next day, 24-h profiles for serum glimepiride concentration, plasma glucose, serum insulin and C-peptide levels were analyzed. For the determination of HbA 1C and other biochemical parameters, blood was drawn before breakfast. For the pharmacokinetic experiment, serum glimepiride concentrations: 14 times over 24 hours. For pharmacodynamic experiment, plasma glucose levels: 19 times, serum insulin and C-peptide levels: 15 times. During experiments, each subject was fed an individually fixed-calorie diet three times, which they were asked to maintain before admission. Except for the fixed meals, no food or drink other than water was permitted until completion of studies.

10. Subjects QD BID 2mg QD screening randomize cross admission 4 weeks BID QD

12. A 24-hr profile of serum insulin(A) and C-peptide(B) at the last day of each crossover period. 2 mg QD (black circle) or 1 mg BID (white square) glimepiride. Results are shown as mean ± SEM (n = 8).

15. Conclusion In summary, this crossover study demonstrates that the pharmaco- dynamic and safety profiles in once-daily dose of glimepiride in type 2 diabetic patients are not different from those in twice-daily dosing. Once-daily dosing is more suitable for the type 2 diabetic patients treated with glimepiride.

18. Background Primary aldosteronism was previously believed to account for1% of hypertensive patients; however, recent studies applying the plasma aldosterone (PAC)-toplasma renin activity (PRA) ratio as a screening test have reported a much higher prevalence of this disease, accounting for 10–32% of the patients with essential hypertension and 50% of patients with nondiureticinduced hypokalemia

19. We aimed to determine the prevalence of primary aldosteronism in diabetic subjects with poorly controlled hypertension despite treatment with multiple antihypertensive agents. AIM

20. Screening Method Screening was performed while subjects continued their usual blood pressure medications. Three blood pressure measurements were taken 5 min apart, and the average of the last two measurements was used for data analysis. Subjects with serum potassium 3.5 mEq/l received KCl (40 mEq/day for 1 week). Once serum potassium was 3.5 mEq/l, subjects were rescreened (because hypokalemia suppresses PAC and lowers the PAC-to-PRA ratio). K>3.5 11 21 100

22. We observed a prevalence of 14% of primary aldosteronism in diabetic subjects with poorly controlled hypertension while taking 3 antihypertensive agents. Accordingly, diabetic patients with poorly controlled hypertension while taking ≧ 3 antihypertensive drugs should be screened for primary aldosteronism using the PAC-to- PRA ratio followed by salt suppression testing in those with a positive screening ratio. Conclusion

23. Renin ng/ml (0.3-2.9) Aldosteron pg/ml (35.7-240) Renin ng/ml/hr less than 1 Aldosteron ng/dl more than 12 Furosemide 2hrs Captril 50mg for diagnosis Standing 4hrs Ald(IHA → ↑, APA ↓ ） ACTH load Ald (IHA →, APA ↑ ） AgII load Ald (IHA ↑, APA → ） Dex supp for GRA Ald ↓