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６月 14 日 8:20-8:50 B 棟８階 カンファレンス室

2. Petteri Hovi, M.D., Sture Andersson, M.D., Ph.D., Johan G. Eriksson, M.D., Ph.D., Anna-Liisa Järvenpää, M.D., Ph.D., Sonja Strang-Karlsson, M.D., Outi Mäkitie, M.D., Ph.D., and Eero Kajantie, M.D., Ph.D. N Engl J Med Volume 356(20):2053-2063 May 17, 2007

3. Study Overview The authors of this study report that young adults with very low birth weights have higher levels of insulin resistance, glucose intolerance, and blood pressure as compared with young adults who were born at term Since lifestyle interventions may help in preventing type 2 diabetes and hypertension, recognizing that formerly low-birth-weight babies are at apparent increased risk might provide opportunities for intervention

4. Study Subjects

6. Anthropometry and Body Composition We measured blood pressure and serum lipid levels, and in 150 very-low-birth- weight subjects and 136 subjects born at term, we also measured body composition by means of dual-energy x-ray absorptiometry.

7. Glucose and Insulin Concentrations and the Insulin-Resistance Index (HOMA-IR) As compared with the subjects born at term, the very-low-birth-weight subjects had a 6.7% increase in the 2-hour glucose concentration (95% confidence interval [CI], 0.8 to 12.9), a 16.7% increase in the fasting insulin concentration (95% CI, 4.6 to 30.2), a 40.0% increase in the 2-hour insulin concentration (95% CI, 17.5 to 66.8), an 18.9% increase in the insulin- resistance index determined by homeostatic model assessment (95% CI, 5.7 to 33.7), and an increase of 4.8 mm Hg in systolic blood pressure (95% CI, 2.1 to 7.4).

8. Indexes of Glucose Regulation and Blood Pressure in a Multiple Regression Analysis

9. Conclusion Young adults with a very low birth weight have higher indexes of insulin resistance and glucose intolerance and higher blood pressure than those born at term

12. a reduction in plasma NEFA levels and NEFA turnover a shift in fat distribution from visceral and hepatic to subcutaneous depots improved hepatic and peripheral (muscle) insulin sensitivity enhanced insulin signalling a threefold increase in plasma AD concentration, which is closely related to the decrease in hepatic fat content and enhanced hepatic and peripheral insulin sensitivity

13. AIM To determine the effect of PPAR-α treatment on hepatic fat content, plasma AD concentration and muscle AMPK activity in humans with type 2 diabetes

14. Subjects and Methods Fifteen patients with type 2 diabetes participated age52 ± 3 years, BMI31.5 ± 1.3 kg/m 2 HbA 1c 9.0 ± 0.7% [mean ± SEMs] subjects were assigned randomly (using a table of random numbers) to receive FENO, 200 mg/day (n = 8), or PIO, 45 mg/day (n = 7), for 3 months and this was followed by addition of the other agent for an additional 3 months in an open-label study

15. BaselineFENOFENO+PIO Body weight (kg) 89.2 ± 4.089.4 ± 4.292.6 ± 3.0 a,c HbA 1c (%) 9.0 ± 0.68.9 ± 0.57.4 ± 0.5 a,c FPG (mmol/l)x18 10.60 ± 1.0010.49 ± 1.337.43 ± 0.50 a,c Fasting plasma insulin (pmol/l) / 7.18 83 ± 1377 ± 1249 ± 6 a,c Fasting plasma NEFA (μmol/l) 623 ± 55621 ± 52393 ± 30 b,d Total cholesterol (mmol/l) / 0.0259 5.59 ± 0.474.40 ± 0.26 c 4.35 ± 0.26 c LDL-cholesterol (mmol/l) 3.63 ± 0.412.79 ± 0.26 c 2.81 ± 0.20 c HDL-cholesterol (mmol/l) 0.89 ± 0.021.02 ± 0.04 c 1.14 ± 0.04 a,c Triacylglycerol (mmol/l) / 0.0113 2.20 ± 0.141.59 ± 0.13 d 0.96 ± 0.09 b,d Table 1 Anthropometric and metabolic parameters in eight type 2 diabetic patients at baseline, after 3 months of FENO monotherapy, and after 3 months of FENO plus PIO combination therapy (FENO+PIO)

16. BaselinePIOFENO+PIO Body weight (kg) 88.3 ± 2.692.4 ± 4.2 d 92.8 ± 3.0 d HbA 1c (%) 9.0 ± 0.67.8 ± 0.4 d 8.0 ± 0.5 d FPG (mmol/l) x18 11.48 ± 1.277.66 ± 0.50 c 8.21 ± 0.66 c Fasting plasma insulin (pmol/l) / 7.18 77 ± 1342 ± 6 c 49 ± 13 c Fasting plasma NEFA (μmol/l) 784 ± 53546 ± 43 c 553 ± 51 c Total cholesterol (mmol/l) / 0.0259 5.65 ± 0.465.28 ± 0.344.57 ± 0.33 a,c LDL-cholesterol (mmol/l) 3.60 ± 0.283.44 ± 0.263.00 ± 0.20 a,c HDL-cholesterol (mmol/l) 1.00 ± 0.021.12 ± 0.02 c 1.23 ± 0.04 a,c Triacylglycerol (mmol/l) / 0.0113 2.12 ± 0.281.61 ± 0.22 c 1.00 ± 0.15 a,c Table 2 Anthropometric and metabolic parameters in seven type 2 diabetic patients at baseline, after 3 months of PIO monotherapy, and after 3 months of FENO plus PIO combination therapy (FENO+PIO)

17. Fig. 1 a Effect of FENO (Feno) monotherapy and PIO (Pio) monotherapy for 3 months on hepatic fat content (a), R d (d) and plasma adiponectin levels (g). Effect of FENO added for 3 months to PIO therapy on hepatic fat content (b), R d (e) and plasma adiponectin levels (h). Effect of PIO for 3 months added to FENO therapy on hepatic fat content (c), R d (f) and plasma adiponectin levels (i). *p < 0.05; **p < 0.005. Means ± SEM

18. Fig. 2 Effect of FENO (Feno) alone for 3 months and addition of PIO (Pio) to FENO for 3 months on skeletal muscle AMPK activity expressed as the phosphorylated AMPK (P- AMPK):total AMPK ratio in six type 2 diabetic patients. *p < 0.01. Means ± SEM

19. Treatment of type 2 diabetic patients with a PPAR-α agonist (FENO) has no effect on plasma glucose/NEFA/AD concentrations, hepatic fat content, muscle AMPK activity, or hepatic, adipocyte and peripheral (muscle) tissue insulin sensitivity despite a reduction in plasma triacylglycerol levels and an increase in HDL-cholesterol. Addition of FENO to PIO-treated patients causes a further reduction in plasma triacylglycerol levels and a further increase in HDL-cholesterol, but has no effect on glycaemic control, peripheral tissue (muscle), hepatic or adipocyte insulin sensitivity, hepatic fat content or plasma AD levels beyond that observed with PIO monotherapy. Summary