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１月 11 日 8:20-8:50 B 棟８階 カンファレンス室

2. From the University of Texas Health Science Center at San Antonio (R. Belfort, K.B., J.F., J.H., B.B., A.G., F.T., R. Berria, J.Z.M., S.D., R.H., R.D., G.A.B., S.S., K.C.); Brooke Army Medical Center (S.A.H., J.P., C.F.); and Audie L. Murphy Division, South Texas Veterans Health Care System (C.D., J.F., F.T., R.D., S.S., K.C.) — all in San Antonio, TX; and the Institute of Clinical Physiology, National Research Council, Pisa, Italy (A.G.). Address reprint requests to Dr. Cusi at the University of Texas Health Science Center at San Antonio, Diabetes Division, Rm. 3.380S, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900, or at cusi@uthscsa.edu. N Engl J Med 2006;355:2297-307.

4. Ref.13 Miyazaki Y, Mahankali A, Matsuda M, et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2002;87:2784-91.

5. Triglyceride volume in the liver will be estimated from signal intensities of proton spectroscopy obtained both from water and fat. All signal intensities, S, will be corrected for relaxation losses according to the formula: So=S(RD,TE,TM)/(1–exp(–RD/T1))exp(–TE/T2)exp(–TM/T1), where TM is the delay between the second and third pulses of the STEAM sequence, and RD=TR–TM–TE/2. Concentration of triglyceride [M] will be expressed as: [M]=2So(M)/So(H2O)nc x [H2O] x 10–A/20. The triglyceride made from typical free fatty acids (C17.4H33.1O2 [71]) has a molecular weight of ~812, and specific gravity of fat tissue is 0.9 g/ml. 1 ml of triglyceride contains 0.115 (=104/812x0.9) x 6.02 x 1023 hydrogen atoms. Water has a molecular weight of 18. 1 ml of water contains 0.111 (=2/18x1.0) x 6.02 x 1023 hydrogen atoms. If the water content in the liver is assumed to be 75% of lean mass, fat volume in the liver is approximated by the equation: Fat volume in the liver (ml) = Liver volume (ml) x So(M)/(1.4xSo(H2O)+So(M)).

6. Effect of Pioglitazone （ Liver, Abdominal Fat, etc. ） (EASD2005, Athens) 投与前投与後 ＊ ＊ :p<0.05 vs before -150 -100 -50 0 平均 CT 値 Difference in HbA 1c (%) 投与前後の adiponectin の差 (  g/ml) r=0.08, p:N.S. HbA 1C (%) 投与前投与後 ● 女性 ■ 男性 7.6 ± 4.0 15.0 ± 6.9 p<0.01 vs before Adiponectin (  g/ml) p<0.001 vs before 投与前投与後 7.7 ± 1.1 6.9 ± 0.9 5 6 7 8 9 10 11 BeforeAfter ＊ 0 1 2 3 4 TNF-alpha (pg/ml) CT value of Visceral Fat

7. Mechanism of Organ Prevention by Pioglitazone FatMuscle Pioglitazone  Beta cell prevension Improved insulin secretion Pancreas Decline of TNF-  Reduced Oxidative Stress Lipo-gluco-Toxicity Improvement Liver

8. Background and Aim We conducted a randomized, doubleblind, placebo-controlled trial to determine whether pioglitazone plus a calorie-restricted diet as compared with placebo plus a calorie-restricted diet may reverse the metabolic and histologic abnormalities in patients with nonalcoholic steatohepatitis.

10. MRS

12. Liver Biopsy One subject in the pioglitazone group declined to undergo the end-of-study liver biopsy (for that subject, only metabolic data were included).

14. Although greater weight loss might have decreased hepatic steatosis in our patients, we did not encourage drastic weight reduction because of difficulty with compliance and reports that it may worsen inflammation and even fibrosis. Earlier, uncontrolled studies in patients with nonalcoholic steatohepatitis showed marginal histologic improvement with troglitazone but promising results with rosiglitazone and pioglitazone. Recently, pioglitazone has been reported to prevent, in a dose-dependent manner, the activation of hepatic stellate cells (mediators of fibrosis) in an animal model of hepatic fibrosis. Because fibrosis may progress in up to one third of patients with nonalcoholic steatohepatitis, with obese patients who have type 2 diabetes at the greatest risk for progression, larger clinical trials of longer duration are needed to determine the long-term efficacy and safety of pioglitazone for patients with nonalcoholic steatohepatitis and to gain a better understanding of the mechanisms involved during thiazolidinedione therapy. NOTE

15. The administration of pioglitazone led to metabolic and histologic improvement in subjects with nonalcoholic steatohepatitis. Larger controlled trials of longer duration are warranted to assess the long- term clinical benefit of pioglitazone. CONCLUSIONS

16. Elevated plasma free fatty acid (FFA) levels are responsible for much of the insulin resistance in obese patients with type 2 diabetes. To lower plasma FFA levels effectively and long term, we have treated eight obese patients with type 2 diabetes for 2 months with placebo followed by 2 months of treatment with a combination of rosiglitazone (RGZ) (8 mg/day) and fenofibrate (FFB) (160 mg/day) in a single-blind placebo-controlled study design. Compared with placebo, RGZ/FFB lowered mean 24-h plasma FFA levels 30% (P < 0.03) and mean 24-h glucose levels 23% (P < 0.03) and increased insulin-stimulated glucose uptake (glucose rate of disappearance [GRd], determined using euglycemic-hyperinsulinemic clamp) 442% (P < 0.01), oral glucose tolerance (area under the curve for 3-h oral glucose tolerance test) 28% (P < 0.05), and plasma adiponectin levels 218% (P < 0.01). These RGZ/FFB results were compared with results obtained in five patients treated with RGZ alone. RGZ/FFB prevented the fluid retention usually associated with RGZ (1.6 vs. 5.6%, P < 0.05), lowered fasting plasma FFA more effectively than RGZ alone (22 vs. 5%, P < 0.05), and tended to be more effective than RGZ alone in lowering A1C (0.9 vs. 0.4%) and triglyceride levels (38 vs. 5%) and increasing GRd (442 vs. 330%). We conclude that RGZ/FFB is a promising new therapy for type 2 diabetes that lowers plasma FFA more than RGZ alone and in contrast to RGZ does not cause water retention and weight gain. Diabetes 56:248–255, 2007

18. Thiazolidinediones

19. Fibrates

20. Aim To determine whether treating patients with type 2 diabetes with FFB plus RGZ (RGZ/FFB) lowered plasma FFA levels long term and improved insulin sensitivity more effectively than treatment with RGZ alone

21. Study Subjects

22. Methods Euglycemic-hyperinsulinemic clamping 7 pmol (1mU) ･ kg -1 ･ min -1 for 4 h. Indirect calorimetry Glucose turnover:6,6 2 H 2 glucose Glycerol turnover: 2 H 5 glycerol

23. A: Twenty four–hour plasma FFA profiles (left) and mean 24-h FFA levels (right) of eight obese patients with type 2 diabetes pre- and postplacebo and post- RGZ/FFB treatment. Shown are means ± SE. B, breakfast; D, dinner; L, lunch. B: Twenty four–hour plasma glucose profiles (left) and mean 24-h glucose levels (right) in the same patients pre- and postplacebo and post-RGZ /FFB.

24. A: Glucose infusion rates needed to maintain euglycemia (GIR) (left) and mean GIR values (right) during the last hour of 4-h euglycemic- hyperinsulinemic clamps (right) in eight patients with type 2 diabetes pre- and postplacebo and post- RGZ/FFB treatment. B: Glucose rates of disappearance (GRd) and last hour GRd values (right). C: Endogenous glucose production rates (EGP) and last- hour EGP values (right). Shown are means SE. *P < 0.02 postplacebo versus post-RGZ /FFB.

26. Plasma glucose and insulin levels during 3-h OGTT in eight patients with type 2 diabetes pre- and postplacebo and post-RGZ/FFB treatment. Left panels show serial glucose and insulin levels. Right panels show areas under the 3-h OGTT curves. Shown are means ± SE.

27. Comparison between RGZ/FFB and RGZ treatment. Eight patients with type 2 diabetes were treated for 2 months with placebo followed by 2 months of RGZ/FFB (R/F). Five patients with type 2 diabetes were treated for 2 months with placebo followed by 2 months with RGZ alone (R). Effects of RGZ/FFB and RGZ are expressed in relation to effects of placebo (placebo effect 100%). Shown are means ± SE.

29. We conclude that RGZ/FFB is a promising new therapy for type 2 diabetes that lowers plasma FFA more than RGZ alone and in contrast to RGZ does not cause water retention and weight gain. Conclusion