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Journal Club

Journal Club. Sloan-Lancaster J, Abu- Raddad E, Polzer J, Miller JW, Scherer JC, De Gaetano A, Berg JK, Landschulz WH.

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Journal Club

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  1. Journal Club Sloan-Lancaster J, Abu-Raddad E, Polzer J, Miller JW, Scherer JC, De Gaetano A, Berg JK, Landschulz WH. Double-Blind, Randomized Study Evaluating the Glycemic and Anti-inflammatory Effects of Subcutaneous LY2189102, a Neutralizing IL-1β Antibody, in Patients With Type 2 Diabetes. Diabetes Care. 2013 Aug;36(8):2239-46. doi: 10.2337/dc12-1835. EllenbroekJH, Töns HA, Westerouen van Meeteren MJ, de Graaf N, Hanegraaf MA, Rabelink TJ, Carlotti F, de Koning EJ. Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice. Diabetologia. 2013 Sep;56(9):1980-6. doi: 10.1007/s00125-013-2957-2. 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 2013年9月5日8:30-8:55 ８階　医局

  2. SfikakisPP, Markomichelakis N, Theodossiadis GP, Grigoropoulos V, Katsilambros N, Theodossiadis PG. Regression of sight-threatening macular edema in type 2 diabetes following treatment with the anti-tumor necrosis factor monoclonal antibody infliximab. Diabetes Care. 2005 Feb;28(2):445-7.

  3. Volunteers received three infusions (wks 0, 2 and 6) of infliximab or placebo. Insulin resistance was measured at baseline and after 70 d by homeostatic model assessment (HOMA) index. WascherTC, Lindeman JH, Sourij H, Kooistra T, Pacini G, Roden M. Chronic TNF-α neutralization does not improve insulin resistance or endothelial function in "healthy" men with metabolic syndrome. Mol Med. 2011 Mar-Apr;17(3-4):189-93. doi: 10.2119/molmed.2010.00221.

  4. IL-1a Anakinra IL-1b IL-1は主に単球やマクロファージから産生される分子量約 17000の糖蛋白質であり,等電点の違いからα型,β型に分類されている.α型とβ型はそれぞれをコードする遺伝子は異なっているもののレセプターは同 一であり,生物活性も同一である事が明らかにされている. IL-1の作用は非常に多彩であり,特に現在,免疫,炎症を制御する重要な因子として認識されている.IL-1の生物活性として,T細胞,B細胞,NK細胞,内皮細胞などの活性化,好中球増加,接着分子の発現促進,IL-1～IL-8の誘導,TNF,IFN,CSF等の誘導などが知られている. Anakinra（商品名Kineret　キネレット？カイネレット？と呼ぶのかな)はアメリカのAmgen（アムジェン）という会社で開発された薬。2001年11月にFDAの許可がおり、中等度以上で18歳以上のリウマチ患者さんに使用できる。

  5. 1Chorus, Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana; the 2Institute for Systems Analysis and Informatics A. Ruberti, National Research Council of Italy, Rome, Italy; and 3Cetero Research, San Antonio, Texas. Diabetes Care 36:2239–2246, 2013

  6. OBJECTIVE Inflammation is associated with pancreatic b-cell apoptosis and reduced insulin sensitivity. Literature suggests that interleukin (IL)-1bmay contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). This study aimed to determine the efficacy, safety, and tolerability of LY2189102, a neutralizing IL-1bantibody, in T2DM patients.

  7. RESEARCH DESIGN AND METHODS Phase II, randomized, double-blind, parallel, placebo-controlled study of subcutaneous LY2189102 (0.6, 18, and 180 mg) administered weekly for 12 weeks in T2DM patients on diet and exercise, with or without approved antidiabetic medications.

  8. RESULTS LY2189102 reduced HbA1c at 12 weeks (adjusted mean differences versus placebo: 20.27, 20.38 and 20.25% for 0.6, 18 and 180 mg doses, respectively), and fasting glucose at multiple time points compared with placebo. LY2189102 also reduced postprandial glycemia, and inflammatory biomarkers, including hs-CRP and IL-6. LY2189102 was generally well tolerated.

  9. CONCLUSIONS Weekly subcutaneous LY2189102 for 12 weeks was well tolerated, modestly reduced HbA1c and fasting glucose, and demonstrated significant anti-inflammatory effects in T2DM patients. Neutralizing IL-1b holds promise as a convenient adjuvant treatment for T2DM.

  10. Message 　膵臓のβ細胞は炎症で減少し、ひいてはインスリン感受性を下げると見られている。従来、炎症に関わるIL-1βは2型糖尿病につながると見られてきた。研究グループはIL-1βの中和抗体であるLY2189102を作製し、血糖抑制効果を検証した。 　研究は第2相試験として実施したもので、患者を抗体群と非抗体群に分けて、抗体群には通常の治療に加えて、12週間にわたって、LY2189102の1週間1回の皮下投与を実施した。投与量は0.6mg、18mg、180mgで、投与の結果、それぞれHbA1cは-0.27、-0.38、－0.25％の低下が確認された。空腹時血糖、食後血糖の低下も認められたほか、炎症指標となるhs-CRP、IL-6も低下していた。抗体療法の認容性も問題なかった。 　研究グループは2型糖尿病の補助療法として抗体療法は有望と指摘している。

  11. Diabetes 62:2595–2604, 2013

  12. Figure 5. Pancreatic glucagon expressing neuroendocrine tumor and microadenoma. (A) Grossly visible lesion and (B) corresponding H&E-stained section of the clinically undetected glucagon expressing neuroendocrine tumor in the pancreas of nPOD case 6185, type 2 diabetes after prior Sitagliptin therapy. (C) Gross specimen and (D) corresponding H&E-stained section of a glucagon expressing microadenoma in case nPOD case 6206, type 2 diabetes after Sitagliptin therapy. Inset shows high power view of representative cells stained for glucagon by immunohistochemistry. Diabetes 62:2595–2604, 2013

  13. Department of Nephrology, Leiden University Medical Center, Postal Zone C7-P, PO Box 9600, 2300 RC Leiden, the Netherlands

  14. Aims/hypothesis Incretin-based therapies improve glycaemic control in patients with type 2 diabetes. In animal models of diabetes, glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase beta cell mass. GLP-1RAs are also evaluated in nondiabetic individuals with obesity and cardiovascular disease. However, their effect on beta cell mass in normoglycaemic conditions is not clear. Here, we investigate the effects of the GLP-1RA liraglutide on beta cell mass and function in normoglycaemic mice.

  15. Methods C57BL/6J mice were treated with the GLP-1RA liraglutide or PBS and fed a control or high-fat diet (HFD) for 1 or 6 weeks. Glucose and insulin tolerance tests were performed after 6 weeks. BrdU was given to label proliferating cells 1 week before the animals were killed. The pancreas was taken for either histology or islet isolation followed by a glucose-induced insulin-secretion test.

  16. Fig. 3 Beta cell and alpha cell mass in control and HFD-fed mice after liraglutide (black bars) or PBS (white bars) treatment. (a) Beta cell mass after 6 weeks of treatment (n=6 mice). (b) Beta cell cluster area after 6 weeks of treatment (n=6 mice). (c) Insulin content from isolated islets corrected for DNA content (n=24). (d) Beta cell apoptosis, identified by TUNEL+/insulin+ staining, after 6 weeks of treatment (n=6). (e) Beta cell proliferation in control mice after 1 and 6 weeks of treatment, BrdUlabelling during the final 7 days (n=6 mice). (f) Beta cell proliferation in HFD-fed mice after 1 and 6 weeks of treatment, BrdUlabelling during the final 7 days (n=6 mice). (g) Representative picture of proliferating beta cells (arrows), BrdU (brown) and insulin (red). Scale bar=50 μm. (h) Alpha cell mass after 6 weeks of treatment (n=6 mice). (i) Ratio of alpha cell area to beta cell area after 6 weeks of treatment (n=6 mice). *p<0.05, **p<0.01 and ***p<0.001

  17. Results Treatment with liraglutide for 6 weeks led to increased insulin sensitivity and attenuation of HFD-induced insulin resistance. A reduction in beta cell mass was observed in liraglutide-treated control and HFD-fed mice at 6 weeks, and was associated with a lower beta cell proliferation rate after 1 week of treatment. A similar reduction in alpha cell mass occurred, resulting in an unchanged alpha to beta cell ratio. In contrast, acinar cell proliferation was increased. Finally, islets isolated from liraglutide-treated control mice had enhanced glucose-induced insulin secretion.

  18. Conclusions/interpretation Our data show that GLP-1RA treatment in normoglycaemic mice leads to increases in insulin sensitivity and beta cell function that are associated with reduced beta cell mass to maintain normoglycaemia. Ductal proliferation is also associated with the development of pancreatic adenocarcinoma but the relationship between GLP-1-based treatment and the development of new pancreatic malignant lesions is not clear.

  19. Message 糖尿病治療に広がるインクレチン関連薬剤は、正常血糖でも肥満や心血管疾患のある患者に効果があるとの考え方もある。一方で、インスリン感受性やβ細胞への影響はよく分かっていない。 　オランダの研究グループは、正常血糖のマウスを用いてインクレチン関連薬剤のGLP-1受容体刺激薬リラグルチドを投与し、インスリン抵抗性への影響を調べた。1週間あるいは6週間にわたって、リラグルチドまたはリン酸緩衝生理食塩水を投与し、通常食あるいは高脂肪食を与えたときの影響を調べた。細胞増殖の状況や取り出した膵島を使ったグルコース負荷によるインスリン分泌試験も実施した。 　この結果、リラグルチドの投与によりインスリン感受性が高まることを確認。高脂肪食によるインスリン抵抗性の進行が緩和されることも見いだした。さらに、リラグルチド投与によって、β細胞の減少が起こることも確認。β細胞の増殖抑制も確認した。同時にα細胞の増殖抑制も確認し、β細胞とα細胞の比率に変化がないという結果を得た。取り出した膵島にグルコース負荷をかけると、リラグルチド投与でインスリン分泌の亢進が起こると示した。 　研究グループは、正常血糖の状態ではGLP-1受容体刺激薬はインスリン感受性を高め、β細胞の機能を高めると指摘。正常血糖の維持のためにβ細胞の減少が起こると報告した。結果をどう解釈するか、今後議論になりそうだ。

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