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Journal Club

Journal Club.

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Journal Club

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  1. Journal Club Berrington de Gonzalez A, Hartge P, Cerhan JR, Flint AJ, Hannan L, MacInnis RJ, Moore SC, Tobias GS, Anton-Culver H, Freeman LB, Beeson WL, Clipp SL, English DR, Folsom AR, Freedman DM, Giles G, Hakansson N, Henderson KD, Hoffman-Bolton J, Hoppin JA, Koenig KL, Lee IM, Linet MS, Park Y, Pocobelli G, Schatzkin A, Sesso HD, Weiderpass E, Willcox BJ, Wolk A, Zeleniuch-Jacquotte A, Willett WC, Thun MJ. Body-mass index and mortality among 1.46 million white adults. N Engl J Med. 2010 Dec 2;363(23):2211-9. Kaneko K, Ueki K, Takahashi N, Hashimoto S, Okamoto M, Awazawa M, Okazaki Y, Ohsugi M, Inabe K, Umehara T, Yoshida M, Kakei M, Kitamura T, Luo J, Kulkarni RN, Kahn CR, Kasai H, Cantley LC, Kadowaki T. Class IA Phosphatidylinositol 3-Kinase in Pancreatic β Cells Controls Insulin Secretion by Multiple Mechanisms. Cell Metab. 2010 Dec 1;12(6):619-32. 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 2010年12月9日8:30-8:55 ８階　医局

  2. 男女別BMIと疾病合併率の関係 男性 女性 男性 女性 2.5 2.5 3.5 3.5 ● ● ● ● ● ● 2.0 ● 2.0 ● 疾 疾 ● 疾 ● 疾 3.0 3.0 ● ● 病 病 病 病 1.5 ● 1.5 ● ● 合 ● 合 合 ● 合 ● 2.5 2.5 ● ● ● ● ● ● ● 併 ● 併 ● 併 ● ● 併 ● ● ● 1.0 ● 1.0 ● ● ● ● ● ● ● ● ● 率 率 率 率 ● ● ● ● ● ● ● 2.0 ● ● 2.0 ● ● ● 0.5 0.5 22.2 22.2 21.9 21.9 1.5 1.5 0 0 30 25 30 30 25 20 25 30 20 25 20 20 BMI (kg/m ) BMI (kg/m ) 2 BMI (kg/m ) 2 BMI (kg/m ) 2 2 地方公務員3500名(20-60歳)の検診結果で疾患合併率を調査 肥満症診断基準検討委員会：肥満研究2000;6(1):18-28

  3. 日本人のまとめ 厚生労働省多目的コホート研究コホートIの10年間追跡結果 • 中年期男女の生命予後の観点から、 • 肥満は、健康上問題である事が日本人でも確認された。 • 痩せも、健康上問題であり、特に、日本人男性では肥満よりも、痩せ・痩せ傾向の方が公衆衛生上インパクトの大きな問題であった。 • 最も死亡リスクの低い • BMIは • 男性では23～27辺り、 • 女性では19～25辺り • 　であった。 International Journal of Obesity 2002;26:529-537

  4. BMIと死亡危険率の関連 米国において約100万人を14年間追跡した統計成績 (癌研究の疫学調査) 1982年(平均57歳，30歳以上)～1996年:男　457,785人，女　588,369人 男　23.5-24.9，女　22.0-23.4 kg/m2が最低値 From the Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, 1599 Clifton Rd. NE, Atlanta, GA 30329. EUGENIAE. CALLEN et al: N Engl J Med 341:1097-105, 1999

  5. Body mass index and mortality: results of a cohort of 184,697 adults in Austria Association between BMI and all-cause mortality in men and women in the VHM&PP cohort 1985–2006, stratified by age at enrolement. Hazard Rate Ratios adjusted for smoking status. The reference category is BMI 22.5–24.9 kg/m2. Error bars indicate 95% confidence intervals Eur J Epidemiol (2009) 24:83–91

  6. Body Weight and MortalityAmong Men and Women in China 169 871 Chinese men and women aged 40 years or older Gu, D. et al. JAMA 2006;295:776-783

  7. the Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (A.B.G., P.H., S.C.M., G.S.T., L.B.F., D.M.F., M.S.L., Y.P., A.S.); the Division of Epidemiology, College of Medicine, Mayo Clinic, Rochester, MN (J.R.C.); the Department of Nutrition, Harvard School of Public Health, (A.J.F., W.C.W.), Brigham and Women’s Hospital and Harvard Medical School (I-M.L.), and the Divisions of Preventive Medicine and Aging, Brigham and Women’s Hospital (H.D.S.) — all in Boston; the Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta (L.H., M.J.T.); the Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, University of Melbourne (R.J.M., D.R.E.), and the Cancer Epidemiology Center, Cancer Council Victoria (G.G.) — both in Melbourne, Australia; Cancer Research UK Genetic Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom (R.J.M.); the Department of Epidemiology, School of Medicine, University of California, Irvine, Irvine (H.A.-C.), Loma Linda University School of Public Health, Loma Linda (W.L.B.), and City of Hope National Medical Center, Department of Population Sciences, Duarte (K.D.H.) — all in California; the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore (S.L.C., J.H.-B.); the University of Minnesota School of Public Health, Minneapolis (A.R.F.); the Division of Nutritional Epidemiology, National Institute of Environmental Medicine (N.H., A.W.), and the Department of Medical Epidemiology and Biostatistics (E.W.), KarolinskaInstitutet, Stockholm; the Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC (J.A.H.); the Department of Environmental Medicine, New York University School of Medicine, New York (K.L.K., A.Z.-J.); the Department of Epidemiology, School of Public Health, University of Washington, and the Cancer Prevention Program, Fred Hutchinson Cancer Research Center — both in Seattle (G.P.); the Cancer Registry of Norway, Oslo, and the Department of Community Medicine, Tromso— both in Norway (E.W.); SamfundetFolkhalsan, Helsinki (E.W.); and Pacific Health Research Institute and Queen’s Medical Center, Honolulu (B.J.W.). N Engl J Med 2010;363:2211-9.

  8. BACKGROUND A high body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) is associated with increased mortality from cardiovascular disease and certain cancers, but the precise relationship between BMI and all-cause mortality remains uncertain.

  9. METHODS We used Cox regression to estimate hazard ratios and 95% confidence intervals for an association between BMI and all-cause mortality, adjusting for age, study, physical activity, alcohol consumption, education, and marital status in pooled data from 19 prospective studies encompassing 1.46 million white adults, 19 to 84 years of age (median, 58).

  10. WhiteWomen

  11. WhiteMen

  12. RESULTS The median baseline BMI was 26.2. During a median follow-up period of 10 years (range, 5 to 28), 160,087 deaths were identified. Among healthy participants who never smoked, there was a J-shaped relationship between BMI and all-cause mortality. With a BMI of 22.5 to 24.9 as the reference category, hazard ratios among women were 1.47 (95 percent confidence interval [CI], 1.33 to 1.62) for a BMI of 15.0 to 18.4; 1.14 (95% CI, 1.07 to 1.22) for a BMI of 18.5 to 19.9; 1.00 (95% CI, 0.96 to 1.04) for a BMI of 20.0 to 22.4; 1.13 (95% CI, 1.09 to 1.17) for a BMI of 25.0 to 29.9; 1.44 (95% CI, 1.38 to 1.50) for a BMI of 30.0 to 34.9; 1.88 (95% CI, 1.77 to 2.00) for a BMI of 35.0 to 39.9; and 2.51 (95% CI, 2.30 to 2.73) for a BMI of 40.0 to 49.9. In general, the hazard ratios for the men were similar. Hazard ratios for a BMI below 20.0 were attenuated with longer-term follow-up.

  13. CONCLUSIONS In white adults, overweight and obesity (and possibly underweight) are associated with increased all-cause mortality. All-cause mortality is generally lowest with a BMI of 20.0 to 24.9.

  14. Message/Comments 痩せすぎと太りすぎは死亡率が増える．．．．

  15. 転写因子であるFOXO1は、通常核内に存在して標的遺伝子の転写を活性化しています。ところがインスリンやIGF-Iといったホルモンのシグナルが受容体を介して細胞内に伝達されると、リン酸化酵素であるPKB/Aktが活性化されて核内に移行し、FOXO1の３ヶ所のセリン/スレオニン残基がリン酸化されます。このとき、おそらくFOXO1の核内移行シグナル配列に構造的変化が生じ、その結果、FOXO1は転写の場である核から細胞質へと局在が変化して転写が抑制されると考えられています。このメカニズムはFOXO1がリン酸化という化学修飾によりその活性を厳密に制御されていること、またインスリンによって発現量が抑制される遺伝子の転写調節にFOXO1が関与していることを示唆しています。転写因子であるFOXO1は、通常核内に存在して標的遺伝子の転写を活性化しています。ところがインスリンやIGF-Iといったホルモンのシグナルが受容体を介して細胞内に伝達されると、リン酸化酵素であるPKB/Aktが活性化されて核内に移行し、FOXO1の３ヶ所のセリン/スレオニン残基がリン酸化されます。このとき、おそらくFOXO1の核内移行シグナル配列に構造的変化が生じ、その結果、FOXO1は転写の場である核から細胞質へと局在が変化して転写が抑制されると考えられています。このメカニズムはFOXO1がリン酸化という化学修飾によりその活性を厳密に制御されていること、またインスリンによって発現量が抑制される遺伝子の転写調節にFOXO1が関与していることを示唆しています。

  16. Cell Metabolism 12, 619–632, December 1, 2010

  17. Type 2 diabetes is characterized by insulin resistance and pancreatic bcell dysfunction, the latter possibly caused by a defect in insulin signaling in b cells. Inhibition of class IA phosphatidylinositol 3-kinase (PI3K), using a mouse model lacking the pik3r1 gene specifically in bcells and the pik3r2 gene systemically (bDKOmouse), results in glucose intolerance and reduced insulin secretion in response to glucose. bcells of bDKOmice had defective exocytosis machinery due to decreased expression of soluble N-ethylmaleimide attachment protein receptor (SNARE) complex proteins and loss of cell-cell synchronization in terms of Ca2+ influx. These defects were normalized by expression of a constitutively active form of Akt in the islets of bDKOmice, preserving insulin secretion in response to glucose.

  18. Figure 1. Decreased Expressions of Insulin Signaling Molecules in db/db Mice in Accordance with Age-Dependent Attenuated Insulin Secretion (A–C) Profiles of body weight (A), blood glucose levels (B), and plasma insulin concentrations (C) in db/db and +/+ mice at 6, 10, and 14 weeks of age (n = 5–6). (D) mRNA levels of insulin signaling molecules. Expressions of the indicated genes were determined by quantitative RT-PCR of total RNA isolated from islets of db/db and +/+ mice at 6, 10, 14, and 18 weeks of age (n = 4–6). Data are presented as the means ± SEM.

  19. クラスI PI3Kはヘテロ二量体であり、シグナル伝達において重要な役割を果たす。これらはアミノ酸配列の相同性からクラスIAとクラスIBにさらに分けられる。クラスIAは p110α、β およびδからなり、調節サブユニットであるp85α、p55α、p50α、p85βおよびp55γと結合している。これらの調節サブユニットのうちp85αの発現が最も高い。p85α、p55α、p50αは同一遺伝子（Pik3r1）のスプライシングバリアントであり、p85βとp55γはそれぞれPik3r2およびPik3r3遺伝子に由来する。クラスIAはPKBの活性化に関与している。 Figure 1. Decreased Expressions of Insulin Signaling Molecules in db/db Mice in Accordance with Age-Dependent Attenuated Insulin Secretion (A–C) Profiles of body weight (A), blood glucose levels (B), and plasma insulin concentrations (C) in db/db and +/+ mice at 6, 10, and 14 weeks of age (n = 5–6). (D) mRNA levels of insulin signaling molecules. Expressions of the indicated genes were determined by quantitative RT-PCR of total RNA isolated from islets of db/db and +/+ mice at 6, 10, 14, and 18 weeks of age (n = 4–6). Data are presented as the means ± SEM.

  20. Figure 2. Pancreatic bCell-Specific Deletion of the pik3r1 Gene and Inhibition of PI3K Signaling in bCells in bPik3r1KO and bDKOMice bPik3r1KO p85α、p55α、p50α bDKO p85βおよびp55γ loss of the pik3r2 gene alone in other tissues (bDKO mice) using the systemic pik3r2 knockout mice (Pik3r2KO mice) and bPik3r1KO mice

  21. Forkhead box O1 (FoxO1) in b cells by immunostaining. Glucose stimulation resulted in marked impairment of PIP3 production Figure 2. Pancreatic b Cell-Specific Deletion of the pik3r1 Gene and Inhibition of PI3K Signaling in b Cells in bPik3r1KO and bDKO Mice (A and B) Immunohistochemical analysis using pancreas sections from 8-week-old male indicated genotypes of mice. Staining by p85a-specific antibody using pancreas sections of RIP-Cre and bPik3r1KO mice is shown in (A) (scale bar = 100 mm). Staining by pan-p85 (p85a and p85b) antibody using DAB substrate on pancreas sections of Flox, bPik3r1KO, Pik3r2KO, and bDKO mice is shown in (B) (scale bar = 100 mm). (C) Protein expression of p85 regulatory subunits in islets, liver, skeletal muscle, and hypothalami in 8-week-old male mice assessed by western blotting. (D) Decreased PI3K activity detected by accumulation of PIP3 in response to glucose stimulation. Staining for PIP3 using pancreatic sections of Flox, RIP-Cre, and bPik3r1KO mice is shown (scale bar = 100 mm). (E and F) Subcellular localization of FoxO1 in pancreatic b cell. Immunofluorescence staining for FoxO1 is shown (E) (scale bar = 50 mm). Quantified analysis FoxO1 intensity in the nucleus of pancreatic b cells of Flox, bPik3r1KO, Pik3r2KO, and bDKO mice is also shown (F). FoxO1 intensity in nuclei was normalized by FoxO1 intensity in total islet. Data are presented as the means ± SEM.

  22. Figure 3. Metabolic Features of bPik3r1KO and bDKO Mice (A) Profiles of body weight in male bPik3r1KO and bDKO mice with their controls at the indicated ages (n = 9–11). (B and C) Blood glucose levels after an i.p. injection of glucose (1.5 g/kg BW) in 8-week-old male RIP-Cre, Flox, bPik3r1KO (B) (n = 9–11), Pik3r2KO, and bDKO (C) (n = 10) mice with their controls. (D) Insulin tolerance test (0.75 U/kg BW) in 8-week-old male Flox, bPik3r1KO, Pik3r2KO, and bDKO mice with their controls (n = 9–11). (E) Serum insulin concentrations after i.p. injection of glucose (3 g/kg BW) in 12-week-old male Flox, bPik3r1KO, Pik3r2KO, and bDKO mice (n = 5–8). (F) Static incubation study of islets from 8-week-old Flox, bPik3r1KO, Pik3r2KO, and bDKO mice. Results are shown as an insulin secretion ratio to total insulin content (n = 5–10). Data are presented as the means ± SEM.

  23. Figure 3. Metabolic Features of bPik3r1KO and bDKO Mice (A) Profiles of body weight in male bPik3r1KO and bDKO mice with their controls at the indicated ages (n = 9–11). (B and C) Blood glucose levels after an i.p. injection of glucose (1.5 g/kg BW) in 8-week-old male RIP-Cre, Flox, bPik3r1KO (B) (n = 9–11), Pik3r2KO, and bDKO (C) (n = 10) mice with their controls. (D) Insulin tolerance test (0.75 U/kg BW) in 8-week-old male Flox, bPik3r1KO, Pik3r2KO, and bDKO mice with their controls (n = 9–11). (E) Serum insulin concentrations after i.p. injection of glucose (3 g/kg BW) in 12-week-old male Flox, bPik3r1KO, Pik3r2KO, and bDKO mice (n = 5–8). (F) Static incubation study of islets from 8-week-old Flox, bPik3r1KO, Pik3r2KO, and bDKO mice. Results are shown as an insulin secretion ratio to total insulin content (n = 5–10). Data are presented as the means ± SEM.

  24. Figure 4. Alterations in b Cell Mass, Apoptosis, and Cell Proliferation in Pancreas with Upregulated Phosphorylation of Erk1/2 in bPik3r1KO and bDKO Islets (A) Staining with antibodies to insulin (green) and glucagon (red) and nuclear stain DAPI using pancreatic sections from 8-week-old male mice of indicated genotypes (magnification: 203). (B) Histological analysis of pancreatic b cell area in Flox, bPik3r1KO, Pik3r2KO, and bDKO mice at 8 weeks of age. (C) Histological analysis of pancreatic b cell area in Flox, bPik3r1KO, Pik3r2KO, and bDKO mice at 32 weeks of age. (D) TUNEL staining of pancreatic sections at 8 weeks of age.

  25. b cell mass can be maintained by enhanced Erk signaling induced by decreased PI3K activity as long as input of the insulin signal to activate IRS/Erk pathway is preserved Figure 4. Alterations in b Cell Mass, Apoptosis, and Cell Proliferation in Pancreas with Upregulated Phosphorylation of Erk1/2 in bPik3r1KO and bDKO Islets (A) Staining with antibodies to insulin (green) and glucagon (red) and nuclear stain DAPI using pancreatic sections from 8-week-old male mice of indicated genotypes (magnification: 203). (B) Histological analysis of pancreatic b cell area in Flox, bPik3r1KO, Pik3r2KO, and bDKO mice at 8 weeks of age. (C) Histological analysis of pancreatic b cell area in Flox, bPik3r1KO, Pik3r2KO, and bDKO mice at 32 weeks of age. (D) TUNEL staining of pancreatic sections at 8 weeks of age.

  26. Figure 5. Glucose-Stimulated Exocytotic Events Estimated by Two-Photon Microscopy Imaging (A) Left: Glucose-stimulated exocytotic events averaged for 5–6 islets in each genotype, normalized by an arbitrary area (800 mm2) of islets. Right: Glucose-stimulated exocytotic events in 10 min. (B) Glucose-stimulated Ca2+ influx in single b cell measured by Ca2+ indicator fura-2. Fura-2 fluorescence (F) was normalized by the resting fluorescence (F0). F0 and F stand for resting and poststimulation fluorescence, respectively. (C and D) Defect of cell-cell synchronization in bDKO islets (n = 5–6) estimated by two-photon microscopy imaging. Data were acquired from islets from 8-weekold male Flox, Pik3r2KO, and bDKO mice. SEM of the Ca2+ influx latencies of all cells in an islet were measured in Flox, Pik3r2KO, and bDKO mice Each trace showed the alteration of the cytosolic Ca2+ concentrations recorded from single b cell in one islet.

  27. Figure 5. Glucose-Stimulated Exocytotic Events Estimated by Two-Photon Microscopy Imaging (C and D) Defect of cell-cell synchronization in bDKO islets (n = 5–6) estimated by two-photon microscopy imaging. Data were acquired from islets from 8-weekold male Flox, Pik3r2KO, and bDKO mice. SEM of the Ca2+ influx latencies of all cells in an islet were measured in Flox, Pik3r2KO, and bDKO mice (C). Each trace showed the alterations of the Ca2+ concentrations in a whole islet of indicated genotype (D, upper). The alterations of the cytosolic Ca2+ concentrations of single b cell from one islet of Flox, Pik3r2KO, and bDKO mice are shown in the lower panel of (D). Each trace showed the alteration of the cytosolic Ca2+ concentrations recorded from single b cell in one islet. (E and F) Exocytotic events triggered by photolysis of a caged-Ca2+ compound. Alteration of cytosolic Ca2+ concentrations provoked by caged-Ca2+ stimulation is shown in (E). Each trace showed the cytosolic Ca2+ concentration recorded from a single islet. Exocytotic events upon caged-Ca2+ stimulation, normalized by an arbitrary area (800 mm2) of islets, are shown in (F). Data are presented as the means ± SEM.

  28. Exocytosis from the insulin granules of b cells is largely dependent on soluble N-ethylmaleimide attachment protein receptor (SNARE) complex proteins, including SNAP25, VAMP2, Syntaxin 1a, and Rab27a Figure 6. Analysis of Gene Expressions in the Islets of 8-Week-Old Male Pik3r2KO and bDKO Mice and Effects of Constitutively Active FoxO1 (FoxO1-3A) or Akt (GagAkt) on the Gene Expression and Insulin Secretion (A) The expression levels of gck, kcnj11, abcc8, and slc2l2 in Pik3r2KO and bDKO islets (n = 5–6). (B) The expression levels of mature onset diabetes of the young (MODY) genes in Pik3r2KO and bDKO islets. (C) The expression levels of SNARE complex genes, snap25, vamp2, stx1a, rab27a, and gjd2. (D) Protein expression of SNARE complex and Connexin36 in Pik3r2KO and bDKO islets assessed by western blotting (n = 4). Data are presented as the means ± SEM.

  29. Figure 6. Analysis of Gene Expressions in the Islets of 8-Week-Old Male Pik3r2KO and bDKO Mice and Effects of Constitutively Active FoxO1 (FoxO1-3A) or Akt (GagAkt) on the Gene Expression and Insulin Secretion (E) Effects of constitutively active FoxO1 (FoxO1-3A) in the islet isolated from 8-week-old male Pik3r2KO mice on the mRNA levels of the indicated genes. (F) Effects of constitutively active Akt (GagAkt) in the islet isolated from 8-week-old male bDKO mice on the mRNA levels of the indicated genes. (G) Effects of constitutively active Akt (GagAkt) in the islets isolated from 8-week-old male bDKO mice on glucose-stimulated insulin secretion estimated by the static incubation. Data are presented as the means ± SEM.

  30. Figure 7. Analyses of Exocytotic Events of the Islets of db/db Mice by the Two-Photon Microscopy Imaging and Gene Expressions (A) Left: analysis of glucose-stimulated exocytotic events averaged for five islets, normalized by an arbitrary area (800 mm2) of islets. Right: measurements of exocytotic events in 10 min. (B) Exocytotic events upon caged-Ca2+ stimulation, normalized by an arbitrary area (800 mm2) of islets. (C) SEM of the Ca2+ influx latencies upon glucose stimulation (n = 5). (D) Upper: Each trace showed the alterations of the Ca2+ concentrations in a whole islet. Lower: Representative recordings from two-photon microscopy imaging show defects of cell-cell synchronization in db/db islets (n = 5–7). Each trace showed the changes of the cytosolic Ca2+ concentration of a single cell from one islet of +/+ mice and db/db mice. Data are presented as the means ± SEM.

  31. Exocytosis from the insulin granules of b cells is largely dependent on soluble N-ethylmaleimide attachment protein receptor (SNARE) complex proteins, including SNAP25, VAMP2, Syntaxin 1a, and Rab27a Figure 7. Analyses of Exocytotic Events of the Islets of db/db Mice by the Two-Photon Microscopy Imaging and Gene Expressions (E) mRNA expressions of gjd2 and SNARE complex genes estimated by quantitative real-time PCR in the islets of db/db and +/+ mice at 6, 10, and 14 weeks of age (n = 5–6). (F) Immunohistochemical analysis of pancreas sections from 10-week-old db/db and +/+ mice; staining for phosphorylation of Akt in the db/db islets. Data are presented as the means ± SEM.

  32. Conclusion The class IA PI3K pathway in b cells in vivo is important in the regulation of insulin secretion and may be a therapeutic target for type 2 diabetes

  33. Message/Comments PI3Kはインスリンのシグナル伝達で重要である。分泌調節にもかかわっている。

  34. 2010年12月02日 糖尿病におけるインスリン分泌低下のメカニズムを解明 ―2 型糖尿病治療の新規治療法に直結する発見― 現在、我が国で890万人の患者がいるといわれている2型糖尿病は、膵臓のβ細胞から分泌されるインスリンの量が減少して、全身でインスリン作用が低下し、血糖値が上昇する病気です。今回、東京大学医学部附属病院 糖尿病・代謝内科の植木浩二郎准教授らは、インスリンの作用はβ細胞自身においても重要であり、インスリンによって活性化されるPI3Kがインスリンの分泌を調節する鍵分子であることを解明しました。 β細胞だけでPI3Kを働かなくしたマウスでは、インスリンの分泌を調節する様々な蛋白の量が低下し、ブドウ糖に反応して分泌されるインスリンの量が低下しました。一方、PI3Kの働きを回復させると、インスリンの分泌も回復しました。また、肥満糖尿病（メタボ型）のマウスでもPI3Kの量や働きが低下しており、インスリンの分泌が減少していました。これらのことから、PI3Kの働きを強める作用があるインスリンの分泌が低下するとβ細胞でのインスリンの作用が弱くなり、PI3Kの働きが悪くなって、ますますインスリンの分泌が低下するという悪循環に陥っていることが分かりました。β細胞でのPI3Kの働きを高める薬物が、この悪循環を断ち切る糖尿病治療薬として期待されます。

  35. 　糖尿病はインスリンの分泌低下と、インスリンの分泌を活性化させる酵素の働きの低下が連鎖し、悪循環におちいり悪化していく。この酵素の働きを高める治療法を開発できれば、膵β細胞の機能や量の低下を防ぎ悪循環を断ち、糖尿病を改善できる可能性がある。 “インスリンの分泌を調節するカギ”となる酵素を解明 　糖尿病の多くを占める2型糖尿病は、肥満などがもたらすインスリン抵抗性と、膵臓のβ細胞からのインスリン分泌低下によって引き起こされる。2型糖尿病を発症する人では、β細胞の機能や量が加齢にともない低下することが知られている。 　研究者らは以前から、インスリンを分泌するβ細胞の量を維持するために、インスリンが必要となることに注目していた。糖尿病の人で、β細胞の自然死が増加し細胞量が減少することが知られているが、インスリンの作用不足との関連はよく分かっていなかった。さらに、β細胞の量が低下する以前から、インスリン分泌の低下がみられることが多く、そのメカニズムも不明だった。 　研究グループが着目したのは「PI3K」というβ細胞の中で作られる酵素。PI3Kはインスリンなどによって活性化され、骨格筋でのブドウ糖の取り込みやグリコーゲンの合成、肝臓での糖・脂質代謝、種々の臓器での細胞の自然死（アポトーシス）の抑制や細胞増殖に必要となる。 　肥満糖尿病マウスを使い実験を行い、インスリンの分泌が低下するより前に、PI3Kの働きが低下し、それが徐々に進行してインスリンの分泌量が減ることで、糖尿病も悪化することを発見した。 　また、PI3Kが制御する別の酵素を人為的に働かせると、それらの分子の発現が回復し、インスリン分泌も改善することも解明した。インスリン分泌を促すカギが「PI3K」にあり、糖尿病ではβ細胞でのインスリン作用低下によりPI3K活性が低下し、それがβ細胞量の減少やインスリン分泌低下へとつながる悪循環におちいっていることが示された。 　研究者らは「糖尿病の治療や予防では、膵β細胞の機能や量の低下を防ぐことも重要となる。PI3Kの活性を強める治療法を開発すれば、β細胞の機能改善や、骨格筋などでのブドウ糖の取り込みも改善できる可能性がある」と述べている。 Press release: Tokyo University Hospital

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