1. Journal Club 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 2015 年 1 月 29 日 8:30-8:55 ８階 医局 Tripathy D1, Cobb JE, Gall W, Adam KP, George T, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, Henry RR, Kitabchi AE, Mudaliar S, Ratner RE, Stentz FB, Reaven PD, Musi N, Ferrannini E, DeFronzo RA. A Novel Insulin Resistance Index to Monitor Changes in Insulin Sensitivity and Glucose Tolerance: the ACT NOW Study. J Clin Endocrinol Metab. 2015 Jan 20:jc20143824.

2. Matsuda M.;GEKKAN TOUNYOUBYOU;2,16-22,2010 2:16-22, 2010. Prevention of Diabetes Mellitus Trialpublication follow-up, year drug No. of new on-set of DM No.(total) event per 1000 person-years control No. of new on-set of DM No.(total) event per 1000 person-years Thiazolidine *DPP20050.9Troglitazone1038728.7 Placebo Metformin ILS 37 21 16 391 397 393 105.1 58.8 45.2 TRIPOD20022.5Troglitazone1711459.6Placebo37122121.3 PIPOD20063.0Pioglitazone118642.6- *DREAM20063.0Rosiglitazone306236543.1Placebo686263486.8 *ACTNOW20084.0Pioglitazone103038.3Placebo4529937.6 *CANOE20103.9Met+Rosi1410334.9Placebo41104101.1 Other (α-GI, statin, fibrate, glinide) WOSCOP20015Pravastation5729993.8Placebo8239755.5 *STOP- NIDDM20023.3Acarbose22168298.2Placebo285686125.9 BIP20046.2Bezafibrate6615668.2Placebo8014787.8 *VICTORY20094Voglibose5089713.9Placebo10688130.0 *NAVIGATOR20106.5Nateglinide1674372669.1Placebo1580374764.9

3. EFFECT OF PIOGLITAZONE AND PLACEBO ON MATSUDA INDEX OF INSULIN SENSITIVITY 4 6 8 10 2 0 PlaceboPioglitazone PrePostPrePost Matsuda Index P<0.001 Insulin sensitivity as measured with the Matsuda index increased more with pioglitazone than with placebo (4.31±0.24 to 7.65±0.34 vs. 4.31±0.30 to 5.23±0.31, P<0.001).

4. N Engl J Med 2011;364:1104-15. 72 ％ reduction!

5. 1 Texas Diabetes Institute, San Antonio, Texas 2 University of Texas Health Science Center, San Antonio, Texas 3 Phoenix VA Health Care System, Phoenix, Arizona 4 College of Nursing and Health Innovation, Arizona State University, Phoenix, Arizona 5 SUNY Health Science Center at Brooklyn, Brooklyn, New York 6 Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 7 University of Southern California Keck School of Medicine, Los Angeles, California 8 Division of Endocrinology and Metabolism, Georgetown University, Washington, D.C. 9 VA San Diego Healthcare System, San Diego, California 10 University of California at San Diego, San Diego, California 11 Division of Endocrinology, Diabetes, and Metabolism, University of Tennessee, Memphis, Tennessee 12 Medstar Research Institute, Hyattsville, Maryland 13 Cardiometabolic Risk Unit, Institute of Clinical Physiology, Pisa, Italy Diabetes Care 36:3607–3612, 2013 In a stepwise multiple-variable analysis, only HbA 1c and β-cell function (ln[log] insulin secretion/insulin resistance index) predicted the development of diabetes (r = 0.49; P < 0.0001).

6. 1 Texas Diabetes Institute, University of Texas Health Science Center and S Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX; 2 Metabolon, Inc. 617 Davis Dr, Ste. 400, Durham, NC 27713 3 Phoenix VA Health Care System, Phoenix, AZ, 4 College of Nursing and Health Care Innovation., AZ State University, Phoenix, AZ; 5 Suny Health Science Center at Brooklyn, Brooklyn, NY; 6 Pennington Biomedical Research Center/LSU, Baton Rouge, LA; 7 University of Southern California Keck School of Medicine, Los Angeles, CA, 8 VA San Diego Healthcare System and University of California at San Diego; 9 University of Tennessee, Division of Endocrinology, Diabetes and Metabolism, Memphis, TN; 10 Inova Fairfax Hospital, Falls Church, VA; 11 Medstar Research Institute; 12 Department of Clinical & Experimental Medicine, University of Pisa School of Medicine, Pisa, Italy J Clin Endocrinol Metab. 2015 Jan 20:jc20143824.

7. Objective: To test the clinical utility of Quantose M Q to monitor changes in insulin sensitivity following pioglitazone therapy in prediabetic subjects. M Q is derived from fasting measurements of insulin, α- hydroxybutyrate, linoleoyl-glycerophosphocholine, and oleate, three non-glucose metabolites shown to correlate with insulin-stimulated glucose disposal.

8. Research design and methods: Participants were 428 of the total of 602 ACT NOW IGT subjects randomized to pioglitazone (45 mg/day) or placebo and followed for, 2.4 years. At baseline and study end fasting plasma metabolites required for determination of Quantose, HbA1c, and OGTT with frequent plasma insulin and glucose measurements to calculate, Matsuda Index of insulin sensitivity were obtained.

9. The Quantose M index (M Q ) is derived from a multiple linear regression based on fasting measurements (logarithmically transformed) of plasma  -HB, L-GPC, oleic acid, and insulin, as previously described (20). We chose the metabolites which had the highest correlation with insulin sensitivity obtained from hyperinsulinemic euglcyemic clamp studies  -HB –0.36, LGPC 0.33, and oleate – 0.22 (20). M Q is designed to estimate the clamp-derived M value. Cobb J, Gall WE,AdamKP, Nakhle P, Button E, Hathorn J, Lawton K, Milburn M, Perichon R, Mitchell M, Natali A, Ferrannini E. A novel fasting blood test for insulin resistance and prediabetes. J Diab Sci Tech. 2013;7:100–110.

10. Figure 1. Baseline (left panels) and change at close-out (right panels) values for Matsuda Index (top panels) and Quantose M Q (bottom panels) according to glucose tolerance status at close-out (NGTnormal glucose tolerance, IGTimpaired glucose tolerance, T2Dtype 2 diabetes) in subjects randomized to pioglitazone or placebo. Plots are mean 95% confidence intervals. #P =.008 for the difference between NGT and IGT/T2D; * P =.01 for the difference between NGT and IGT/T2D and § P =.01 for the difference between pioglitazone and placebo by 2-way ANOVA.

12. During a median follow-up of 2.4 years, 42 individuals in the placebo group and 12 in the pioglitazone group developed diabetes (HR = 0.25, 95%CI = 0.13– 0.50, P<.0001). Of the other 374 subjects, 181 regressed to NGT (110 with pioglitazone vs 71 with placebo, P <.02).

13. Figure 2. Relationship between close-out changes in Quantose MQ and Matsuda Index in subjects randomized to pioglitazone or placebo. The best fit is linear in both groups (r=0.69, P <.0001 for pioglitazone, and r=0.77, P<.0001 for placebo); the fitted line for the pioglitazone group is significantly (P<.01) different from that of the placebo group.

15. Supplemental Figure 1 - Change at close-out for Quantose MQ components according to glucose tolerance status at close-out (NGT=normal glucose tolerance, IGT=impaired glucose tolerance, T2D=type 2 diabetes) in subjects randomized to pioglitazone. Plots are mean + 95% confidence intervals. # p<0.0005 and * p<0.005 for the difference between NGT and IGT/T2D by 2-way ANOVA.

16. Results: Pioglitazone treatment lowered IGT conversion to diabetes (HR=0.25, 95%CI = 0.13–0.50, p<0.0001). While HbA1c did not track with insulin sensitivity, M Q increased in pioglitazone- treated subjects (by 1.45[3.45] mg.min −1.kg wbm −1 (median[interquartile range]), (p<0.001 vs placebo) as did, Matsuda Index (by 3.05[4.77] units, p<0.0001). M Q correlated with Matsuda Index at baseline and change in Matsuda Index from baseline (rho's of 0.85 and 0.79, respectively, p<0.0001) and was progressively higher across close-out glucose tolerance status (diabetes, IGT, NGT). In logistic models including only anthropometric and fasting measurements, M Q outperformed both Matsuda and fasting insulin in predicting incident diabetes.

17. Conclusions: In IGT subjects, Quantose M Q parallels changes in insulin sensitivity and glucose tolerance with pioglitazone therapy. Due to its strong correlation with improved insulin sensitivity and its ease of use, Quantose M Q may serve as a useful clinical test to identify and monitor therapy in insulin resistant patients.

18. Message インスリン感受性指標か、血糖上昇のリスク因子か 位置づけは今一つはっきりとはしないが、血糖以外 から血糖について予言するというおもしろい指標が 提唱された。 いろいろ測定しておくのは面倒かもしれない。（が 糖負荷をしなくていのが面白い！） Matsuda index との対比があるが、インスリン分 泌能がインスリン抵抗性よりも大切なはずで、本来 は disposition index を計算するところと思うが。 一番重要なのは、空腹時のインスリン感受性改善が インスリン分泌を回復させそう！リンクに Q M 計算に 用いた物質が関係しそう。