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 2011 年 6 月 9 日 8:30-8:55 ８階 医局 Kanat M, Norton L, Winnier D, Jenkinson C, Defronzo RA, Abdul-Ghani MA. Impaired early- but not late-phase insulin secretion in subjects with impaired fasting glucose. Acta Diabetol. 2011 May 8. DOI 10.1007/s00592-011-0285-x [Epub ahead of print] Schwartz AV, Vittinghoff E, Bauer DC, Hillier TA, Strotmeyer ES, Ensrud KE, Donaldson MG, Cauley JA, Harris TB, Koster A, Womack CR, Palermo L, Black DM; Study of Osteoporotic Fractures (SOF) Research Group; Osteoporotic Fractures in Men (MrOS) Research Group; Health, Aging, and Body Composition (Health ABC) Research Group. Association of BMD and FRAX score with risk of fracture in older adults with type 2 diabetes. JAMA. 2011 Jun 1;305(21):2184-92.

2. 筋肉 0 0 50 100 150 200 250 10.0 7.5 5.0 2.5 0 0 糖注入量 (mg/kg per min) 凸 凸 0 0 20 40 60 80 100 0 0 40 80 120 (  U/ml) (  インスリン ( 動脈側） （一定にするように注入 ) （一定にするように注入 ) インスリンクランプ法 0 0 40 80 120 血糖 ( 動脈側 ) (mg/dl) 分 分 グルコースクランプ法の一つ インスリン注入 アルゴリズム 内因性インスリン分泌は無 視できるレベルとなる 糖代謝 Rd (rate of disappearance) あるい は MCR (metabolic clearance rate) を測定 している。 [ 補正は FFM やインスリン値 ( 注 入率 )]

3. MCR (metabolic clearance rate) Dose of glucose AUC of PG conc. (non- steady state) = Glucose Dose PG 0 ~180min mean MCR ブドウ糖負荷後の糖代謝 (MCR)

4. Insulin Sensitivity during OGTT MCR of glucose Average Insulin conc. Dose of glucose PG × Insulin = can be estimated by ブドウ糖負荷後のインスリン感受 性

5. Induction of Composite Index ISI(comp) Inverse of Geometric Mean

6. DOI 10.1007/s00592-011-0285-x Diabetes Division, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA

7. Background and Aim Subjects with impaired fasting glucose (IFG) are at increased risk for type 2 diabetes. We recently demonstrated that IFG subjects have increased hepatic insulin resistance with normal insulin sensitivity in skeletal muscle. In this study, we quantitated the insulin secretion rate from deconvolution analysis of the plasma C-peptide concentration during an oral glucose tolerance test (OGTT) and compared the results in IFG subjects with those in subjects with impaired glucose tolerance (IGT) and normal glucose tolerance (NGT).

8. Methods One hundred and one NGT subjects, 64 subjects with isolated IGT, 24 subjects with isolated IFG, and 48 subjects with combined (IFG + IGT) glucose intolerance (CGI) received an OGTT. Plasma glucose, insulin, and C-peptide concentrations were measured before and every 15 min after glucose ingestion. Insulin secretion rate (ISR) was determined by deconvolution of plasma C-peptide concentration. Inverse of the Matsuda index of whole body insulin sensitivity was used as a measure of insulin resistance; 56 subjects also received a euglycemic hyperinsulinemic clamp. The insulin secretion/ insulin resistance (disposition) index was calculated as the ratio between incremental area under the ISR curve (DISR[AUC]) to incremental area under the glucose curve (DG[AUC]) factored by the severity of insulin resistance (measured by Matsuda index during OGTT or glucose disposal during insulin clamp).

9. Insulin secretion rate (ISR) was calculated by deconvolution of the plasma C- peptide concentration curve as previously described The insulin secretion/insulin resistance (disposition) index was determined by dividing DISR/DG by the severity of insulin resistance (DISR[AUC]/DG[AUC] 7 IR), as measured by TGD in the subgroup who received an insulin clamp or by the inverse of Matsuda index The Matsuda index incorporates both hepatic and muscle components of insulin resistance, correlates well with euglycemic insulin clamp and was calculated as follows: Matsuda Index = Matsuda, M., DeFronzo, R.A.: Insulin sensitivity indices obtained from oral glucose tolerance testing: Comparison with the euglycemic insulin clamp Diabetes Care Volume 22, Issue 9, September 1999, Pages 1462-1470

13. Fig. 3 Relationship between basal insulin secretion rate (ISR) and fasting plasma glucose (FPG) concentration. Figure 3a depicts the absolute ISR and Fig. 2b represents the ratio of the ISR to the fasting plasma glucose concentration. Subjects were divided into five equal quintiles based upon their fasting plasma glucose concentration. Each point represents the mean ± SE of each quintile (quintiles 1–4 contain 47 subjects; quintile 5 contains 49 subjects). The ISR rose progressively with the increase in FPG (r = 0.17, P\0.01). This correlation was abolished when the ISR was factored by the FPG for each group

14. Fig. 4 Insulin secretion/insulin instance index (calculated as explained in ‘‘Materials and methods’’ Section) during the OGTT in subjects with normal glucose tolerance (NGT) (n = 101), impaired glucose tolerance (IGT) (n = 64), impaired fasting glucose (IFG) (n = 24), and combined glucose intolerance (CGI) (n = 48). The upper panel (a) shows the early (0–30 min) insulin response during the OGTT and the lower panel (b) depicts the late (60–120 min) insulin response

15. Results Compared to NGT, the insulin secretion/insulin resistance index during first 30 min of OGTT was reduced by 47, 49, and 74% in IFG, IGT, and CGI, respectively (all<0.0001). The insulin secretion/insulin resistance index during the second hour (60–120 min) of the OGTT in subjects with IFG was similar to that in NGT (0.79 ± 0.6 vs. 0.72 ± 0.5, respectively, P = NS), but was profoundly reduced in subjects with IGT and CGI (0.31 ± 0.2 and 0.19 ± 0.11, respectively; P<0.0001 vs. both NGT and IFG).

16. Conclusions Earlyphase insulin secretion is impaired in both IFG and IGT, while the late-phase insulin secretion is impaired only in subjects with IGT.

17. Message/Comments 基本的にインスリン初期分泌の低下が糖尿病の 初期の膵 β 細胞の変化を反映されていると既に決 まっているように考えているのだが。 IFG と IGT について初期分泌低下だが、 IGT だけ が遅延分泌も低下しているとしている。 IFG で は遅延分泌が低下していないというのは新しい かもしれない。

19. JAMA. 2011;305(21):2184-2192 Departments of Medicine (Dr Bauer) and Epidemiology and Biostatistics (Drs Schwartz, Vittinghoff, Bauer, and Black and Ms Palermo), University of California, San Francisco; Kaiser Permanente Center for Health Research, Portland, Oregon (Dr Hillier); Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania (Drs Strotmeyer and Cauley); VA Medical Center and Division of Epidemiology and Community Health, University of Minnesota, Minneapolis (Dr Ensrud); Research Institute, California Pacific Medical Center, San Francisco (Dr Donaldson); Intramural Research Program, National Institute on Aging, Bethesda, Maryland (Drs Harris and Koster); Department of Health Care Studies, Maastricht University, Maastricht, the Netherlands (Dr Koster); and Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis (Dr Womack).

20. Context Type 2 diabetes mellitus (DM) is associated with higher bone mineral density (BMD) and paradoxically with increased fracture risk. It is not known if low BMD, central to fracture prediction in older adults, identifies fracture risk in patients with DM. Objective To determine if femoral neck BMD T score and the World Health Organization Fracture Risk Algorithm (FRAX) score are associated with hip and nonspine fracture risk in older adults with type 2 DM.

21. Design, Setting, and Participants Data from 3 prospective observational studies with adjudicated fracture outcomes (Study of Osteoporotic Fractures [December 1998- July 2008]; Osteoporotic Fractures in Men Study [March 2000-March 2009]; and Health, Aging, and Body Composition study [April 1997-June 2007]) were analyzed in older community- dwelling adults (9449 women and 7436 men) in the United States. Main Outcome Measure Self-reported incident fractures, which were verified by radiology reports.

22. Femoral Neck BMD T Score Femoral neck BMD T scores included in our models were calculated using sex- and race-specific young adult reference values from the third National Health and Nutrition Examination Survey (NHANES III), the method currently used in the output from clinical densitometers. T scores included in the WHO FRAX score were calculated using reference values for white women as required for this algorithm. BMD （ Bone Mineral Density ） ：骨密度 ＝ 骨量 ÷ 面積（単位 g/cm 2 ） BMC （ Bone Mineral Content ） ：骨塩量 （単位 g ） Area ：面積 （単位 cm 2 ） 世界の指標用語（ WHO （世界保健機関）から） T スコア： 若年齢の平均 BMD 値（基準値）を 0 として、標準偏差を 1SD として指 標を規定した値をいう。骨粗鬆症診断基準に用いられる。 Z スコア：同年齢の平均 BMD 値を 0 として、標準偏差を 1SD して指標を規定した 値をいう。骨粗鬆症診断には用いられない。（年齢とともに平均値が下がるた め） 診断基準 正常 T スコアが－ 1SD 以上 骨減少症 T スコアが－ 1 ～ － 2.5SD 骨粗鬆症 T スコアが－ 2.5 以下 ＊ 標準偏差： SD （ standard deviation ）

23. WHO FRAX Scores In the SOF and MrOS studies, the WHO 10-year absolute risks of hip and osteoporotic fracture (FRAX scores) were calculated by the WHO Collaborating Center for Metabolic Bone Disease, using the FRAX algorithm (version 3). The FRAX algorithm includes femoral neck BMD T score, age, sex, body mass index, previous history of fracture, parental history of hip fracture, current smoking, recent use of corticosteroids, presence of rheumatoid arthritis, and at least 3 alcoholic beverages per day. The FRAX scores have not been calculated for Health ABC study participants. The FRAX ® tool has been developed by WHO to evaluate fracture risk of patients. It is based on individual patient models that integrate the risks associated with clinical risk factors as well as bone mineral density (BMD) at the femoral neck.

30. Results Of 770 women with DM, 84 experienced a hip fracture and 262 a nonspine fracture during a mean (SD) follow-up of 12.6 (5.3) years. Of 1199 men with DM, 32 experienced a hip fracture and 133 a nonspine fracture during a mean (SD) follow-up of 7.5 (2.0) years. Age-adjusted hazard ratios (HRs) for 1-unit decrease in femoral neck BMD T score in women with DM were 1.88 (95% confidence interval [CI], 1.43-2.48) for hip fracture and 1.52 (95% CI, 1.31-1.75) for nonspine fracture, and in men with DM were 5.71 (95% CI, 3.42-9.53) for hip fracture and 2.17 (95% CI, 1.75-2.69) for nonspine fracture. The FRAX score was also associated with fracture risk in participants with DM (HRs for 1-unit increase in FRAX hip fracture score, 1.05; 95% CI, 1.03-1.07, for women with DM and 1.16;95%CI, 1.07-1.27, for men with DM; HRs for 1-unit increase in FRAX osteoporotic fracture score, 1.04; 95% CI, 1.02- 1.05, for women with DM and 1.09; 95% CI, 1.04-1.14, for men with DM). However, for a given T score and age or for a given FRAX score, participants with DM had a higher fracture risk than those without DM. For a similar fracture risk, participants with DM had a higher T score than participants without DM. For hip fracture, the estimated mean difference in T score for women was 0.59 (95% CI, 0.31-0.87) and for men was 0.38 (95% CI, 0.09-0.66).

31. Conclusions Among older adults with type 2 DM, femoral neck BMD T score and FRAX score were associated with hip and nonspine fracture risk; however, in these patients compared with participants without DM, the fracture risk was higher for a given T score and age or for a given FRAX score.

32. Message/Comments 骨の指標はともかく骨折リスクを反映するが、 ２型糖尿病患者は骨折しやすいようである。 前向き観察研究 3 件のデータから、大腿骨頸部の 骨密度測定値 BMD T スコアと WHO 骨折リスク評 価ツール（ FRAX ）と高齢 2 型糖尿病患者におけ る骨折リスクとの関連を調査。 BMD T スコアや FRAX と、股関節や非脊椎骨折リスクとの間に 関連が見られた。また、ある一定のスコアでは、 非糖尿病者よりも糖尿病患者の骨折リスクが高 かった。