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Journal Club

Journal Club. Abdul-Ghani MA, Abdul-Ghani T, Stern MP, Karavic J, Tuomi T, Bo I, Defronzo RA, Groop L. Two-Step Approach for the Prediction of Future Type 2 Diabetes Risk. Diabetes Care. 2011 Jul 25. [Epub ahead of print]

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Journal Club

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  1. Journal Club Abdul-Ghani MA, Abdul-Ghani T, Stern MP, Karavic J, Tuomi T, Bo I, Defronzo RA, Groop L. Two-Step Approach for the Prediction of Future Type 2 Diabetes Risk. Diabetes Care. 2011 Jul 25. [Epub ahead of print] Shimoda M, Kanda Y, Hamamoto S, Tawaramoto K, Hashiramoto M, Matsuki M, Kaku K. The human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells via regulation of cell kinetics and suppression of oxidative and endoplasmic reticulum stress in a mouse model of diabetes. Diabetologia. 2011 May;54(5):1098-108. Epub 2011 Feb 22. 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8月11日　8:30-8:55 ８階　医局

  2. Prevention of Diabetes Mellitus Matsuda M.;GEKKAN TOUNYOUBYOU;2,16-22,20102:16-22, 2010.

  3. Prevention of Diabetes Mellitus Matsuda M.; Endocrinology＆Diabetology;26,1,35-41,2008.

  4. the San Antonio Diabetes Prediction Model (SADPM) In this equation, p the probability of developing diabetes over the 7.5 year follow-up period; ageis in years; sex = 1 if female, 0 if male; MA =1 if Mexican American, 0 if non-Hispanic white; FG fasting glucose in mg/dL; SBP systolic blood pressure in mm Hg; HDL high-density lipoprotein cholesterol level in mg/dL; BMI body mass index in kg/m2; and family history =1 if at least one parent or sibling has diabetes or 0 if not. Ann Intern Med. 2002;136:575-581

  5. the 1Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, Texas; the 2Division of Clinical Epidemiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas; and the 3Department of Clinical Sciences, Diabetes, and Endocrinology, and Lund University Diabetes Center, Lund University, Malmo, Sweden. DIABETES CARE DOI: 10.2337/dc10-2201

  6. OBJECTIVE— To develop a model for the prediction of T2DM risk on the basis of a multivariate logistic model and 1-h plasma glucose concentration (1-h PG). The San Antonio Heart Study is a population-based study inMexican Americans and non-Hispanic whites. The baseline examination was conducted in 1984–93, with a 7-year follow-up in 1991–94 The Botnia project was instituted in 1990 in order to investigate and explain these connections at three care centers in Osthrobothnia; Närpes, Korsholm and Malax-Korsnäs. At a later state the project was expanded to also cover Jakobstad and Vasa, along with other areas in Finland and southern Sweden. Until today, approximately 11000 people from 1400 families have participated in the project.

  7. RESEARCH DESIGNANDMETHODS— The model was developed in a cohort of 1,562 nondiabetic subjects from the San Antonio Heart Study (SAHS) and validated in 2,395 nondiabetic subjects in the Botnia Study. A risk score on the basis of anthropometric parameters, plasma glucose and lipid profile, and blood pressure was computed for each subject. Subjects with a risk score above a certain cut point were considered to represent high-risk individuals, and their 1-h PG concentration during the oral glucose tolerance test was used to further refine their future T2DM risk.

  8. http://en.wikipedia.org/wiki/Positive_predictive_value

  9. Suppose the fecal occult blood (FOB) screen test is used in 2030 people to look for bowel cancer:

  10. RESULTS— We used the San Antonio Diabetes Prediction Model (SADPM) to generate the initial risk score. A risk-score value of 0.065 was found to be an optimal cut point for initial screening and selection of high-risk individuals. A 1-h PG concentration .140 mg/dL in highrisk individuals (whose risk score was .0.065) was the optimal cut point for identification of subjects at increased risk. The two cut points had 77.8, 77.4, and 44.8% (for the SAHS) and 75.8, 71.6, and 11.9% (for the Botnia Study) sensitivity, specificity, and positive predictive value, respectively, in the SAHS and Botnia Study.

  11. CONCLUSIONS— A two-step model, based on the combination of the SADPM and 1-h PG, is a useful tool for the identification of high-risk Mexican-American and Caucasian individuals.

  12. Message/Comments 糖尿病を予測できるか？　米国サンアントニオで作ったモデルをスェーデンやフィンランドであてはまるかをやった！　 一般的検査でハイリスクだとOGTTをやるという２ステップ。 日本人にあてはまるかは？ （OGTTをやっている健診センターは10年くらいデータがあればすぐ論文書けるでしょう）

  13. ヒトGLP-1アナログ製剤リラグルチド C-16 脂肪酸(パルミチン酸) His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Glu Ser Lys Ala Ala Gln Gly Glu Leu Tyr Glu 7 9 Phe Arg Ile Ala Trp Val Gly Arg Leu Gly 36 ヒトGLP-1 リラグルチド ヒトGLP-1と97%の相同性を保つ ヒトGLP-1アナログ （1日1回の皮下注射） DPP-4により切断され、不活化 7 9 His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Lys Ala Ala Gln Gly Glu Leu Tyr Glu Phe 36 Lys Ile Ala Trp Leu Val Gly Arg Gly T½=1.5–2.1 min • 皮下からゆっくりと吸収される • DPP-4に切断されにくい • 血中半減期の大幅な延長(T½=13 hrs) Knudsen et al. J Med Chem 2000;43:1664–9; Degn et al. Diabetes 2004;53:1187–94

  14. db/db mouse misty mouse C57BLKS/J m+/m+ C57BLKS/J +Leprdb/+Leprdb Diabetes Division, Kawasaki Medical School

  15. Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan Diabetologia (2011) 54:1098–1108

  16. Aims/hypothesis We investigated the molecular mechanism by which the human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells in diabetic db/db mice.

  17. Methods Male db/db and m/m mice aged 10 weeks received liraglutide or vehicle for 2 days or 2 weeks. In addition to morphological and biochemical analysis of pancreatic islets, gene expression profiles in the islet core area were investigated by laser capture microdissection and real-time RT-PCR.

  18. Abbreviations eIF2α Eukaryotic translation initiation factor 2 α ER Endoplasmic reticulum ERK Extracellular signal-regulated kinase GLP-1 Glucagon-like peptide-1 GSIS Glucose-stimulated insulin secretion HES1 Hairy and enhancer of split-1 4HNE 4-Hydroxy-2-noneal modified protein MAPK Mitogen-activated protein kinase PCNA Proliferative cell nuclear antigen PI3K Phosphoinositide3-kinase They received a subcutaneous injection ofliraglutide(200 μg/kg) or vehicle (PBS) twice daily (09:00 and 16:00 hours).

  19. 2 weeks db/db

  20. 2 days db/db

  21. the proportion of antibody-positive cells (to PCNA) was measured to evaluate the proliferative effect on pancreatic islets. Fig. 3 Islet morphology and function in db/db mice treated with vehicle (black bars) or liraglutide (white bars) for 2 days or 2 weeks. a Haematoxylin–eosin staining, followed by double immunohistochemical staining with antibodies against glucagon and somatostatin. Scale bars 100 μm. b Beta cell mass, measured as described; n=5 (a, b). c Immunohistochemical staining with antibodies against PCNA, quantified (d) as ratio. e, f 4-HNE and (g, h) TUNEL assays and quantification as indicated. c–h n=3 for each assay, scale bars 100 μm. The proportion of cells positive for PCNA (c, d) and 4-HNE (e, f) was measured in each islet and expressed as average proportion for a minimum of 50 islets from each experimental animal. *p<0.05, **p<0.01

  22. Fig. 3 Islet morphology and function in db/db mice treated with vehicle (black bars) or liraglutide (white bars) for 2 days or 2 weeks. e, f 4-HNE and (g, h) TUNEL assays and quantification as indicated. c–h n=3 for each assay, scale bars 100 μm. The proportion of cells positive for PCNA (c, d) and 4-HNE (e, f) was measured in each islet and expressed as average proportion for a minimum of 50 islets from each experimental animal. DNase-treated cells were used as a positive control in the TUNEL assay (g, h), with results of the TUNEL assay expressed as the average number of TUNEL-positive cells per islet by assessing a minimum of 50 islets from each experimental animal. *p<0.05, **p<0.01

  23. Fig. 3 Islet morphology and function in db/db mice treated with vehicle (black bars) or liraglutide (white bars) for 2 days or 2 weeks. iIslet insulin content and (j) islet triacylglycerol content; n=5. k GSIS was assessed by use of lower and higher glucose concentrations (3 mmol/l and 16.7 mmol/l); n=5. *p<0.05, **p<0.01

  24. The genes analysed in the present study were those associated with cell differentiation (Hlxb-9 [also known as Mnx1], Hes1, Neurod[also known as Neurod1] and Pdx1), cell proliferation (CycDand Erk-1 [also known as Mapk3]), endoplasmic reticulum (ER) stress (Xbp1), antioxidativestress (Cat and Gpx), lipid synthesis (Srebp-1c [also known as Srebf1] and Fas) and cell apoptosis (Bcl2, Casp8, Casp3 and Cad). To quantify gene expression, 2ΔCt was calculated using 18S rRNA as an internal control. Bcl-2 (B-cell lymphoma 2) : anti-apoptotic

  25. 2 weeks cell differentiation cell proliferation 2 days 2 weeks cell apoptosis Fig. 4 Gene expression in the core area of islets in db/db mice treated with vehicle (black bars) or liraglutide (white bars). a–f Expression of genes involved in cell differentiation and proliferation after 2 weeks and (g–l) 2 days of treatment. a, g Hlxb-9, (b, h) Hes1, (c, i) Neurod, (d, j) Pdx1, (e, k) Erk1, (f, l) CycD. m–t Expression of genes involved in pro-apoptosis and anti-apoptosis after 2 weeks (m–p) and 2 days (q–t) of treatment. m, q Bcl2, (n, r) Casp8, (o, s) Casp3, (p, t) Cad. n=4 for each group; *p<0.05, **p<0.01; †p<0.005; ‡p<0.0001; §p=0.08

  26. 2 days cell apoptosis 2 weeks antioxidative stress ER stress lipid synthesis 2 days Fig. 4 Gene expression in the core area of islets in db/db mice treated with vehicle (black bars) or liraglutide (white bars). Expression of genes involved in pro-apoptosis and anti-apoptosis after 2 weeks (m–p) and 2 days (q–t) of treatment. m, q Bcl2, (n, r) Casp8, (o, s) Casp3, (p, t) Cad. u–dd Expression of genes involved in anti-oxidative stress, ER stress and lipid synthesis after 2 weeks (u–y) and 2 days (z–dd) of treatment. u, z Gpx, (v, aa) Cat, (w, bb) Xbp1, (x, cc) Fas, (y, dd) Srebp-1c. n=4 for each group; *p<0.05, **p<0.01; †p<0.005; ‡p<0.0001; §p=0.08

  27. 2 weeks m/m

  28. 2 weeks m/m

  29. cell differentiation cell proliferation cell apoptosis antioxidative stress ER stress lipid synthesis

  30. Results Liraglutide treatment for 2 weeks improved metabolic variables and insulin sensitivity in db/db mice. Liraglutide also increased glucose-stimulated insulin secretion (GSIS) and islet insulin content in both mouse strains and reduced triacylglycerol content in db/db mice. Expression of genes involved in cell differentiation and proliferation in both mouse strains was regulated by liraglutide, which, in db/dbmice, downregulated genes involved in pro-apoptosis, endoplasmic reticulum (ER) stress and lipid synthesis, and upregulated genes related to anti-apoptosis and anti-oxidative stress. In the 2 day experiment, liraglutide slightly improved metabolic variables in db/dbmice, but GSIS, insulin and triacylglycerol content were not affected. In db/dbmice, liraglutide increased gene expression associated with cell differentiation, proliferation and anti-apoptosis, and suppressed gene expression involved in pro-apoptosis; it had no effect on genes related to oxidative stress or ER stress. Morphometric results for cell proliferation, cell apoptosis and oxidative stress in db/dbmice islets were consistent with the results of the gene expression analysis.

  31. Conclusions/interpretation Liraglutide increases beta cell mass not only by directly regulating cell kinetics, but also by suppressing oxidative and ER stress, secondary to amelioration of glucolipotoxicity.

  32. Message/Comments GLP-1アナログ製剤が膵臓β細胞にどのように影響するか興味があるところである。

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