Inhibition of human IAPP fibril formation does not prevent β-cell death:: evidence for distinct actions of oligomers and fibrils of human IAPP
Inhibition of human IAPP fibril formation does not prevent β-cell death:: evidence for distinct actions of oligomers and fibrils of human IAPP
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DOI：
10.1152/ajpendo.00082.2006
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发表时间：
2006-12-01
影响因子：
5.1
通讯作者：
Butler, Peter C.
中科院分区：
文献类型：
--
作者：
Meier, Juris J.;Kayed, Rakez;Butler, Peter C.
2型糖尿病（T2 DM）的特征是β细胞质量不足60%，β细胞凋亡增加，胰岛淀粉样蛋白多肽（IAPP）衍生的胰岛淀粉样蛋白。人IAPP（hIAPP）在体外水溶液中形成寡聚体，导致淀粉样蛋白原纤维或毒性寡聚体。hIAPP在细胞上的应用或hIAPP在细胞中的过表达诱导细胞凋亡。纤维或较小的毒性寡聚体是否诱导β细胞凋亡仍然存在争议。利福平可预防hIAPP淀粉样纤维形成，并已被提议作为预防T2 DM的潜在靶点。我们研究了利福平对hIAPP淀粉样纤维和毒性寡聚体形成的作用，以及其保护β细胞免受hIAPP应用或hIAPP内源性过表达（转基因大鼠和腺病毒转导的β细胞）的能力。本文报道利福平（Acocella G. Clin Pharmacokinet 3：108-127，1978）防止hIAPP原纤维形成，但不防止毒性hIAPP寡聚体的形成（Bates G. Lancet 361：1642 - 1644，2003），并且不能保护β-细胞免于由hIAPP的过表达或应用诱导的细胞凋亡。这些数据强调，有毒的hIAPP寡聚体，而不是hIAPP原纤维，启动β细胞凋亡和筛选工具，以确定抑制剂的淀粉样蛋白原纤维形成可能是不太有用的比那些确定抑制剂的有毒寡聚体形成。最后，利福平和相关分子似乎不是预防T2 DM的有效候选药物。
Type 2 diabetes mellitus (T2DM) is characterized by an similar to 60% deficit in beta-cell mass, increased beta-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide ( IAPP). Human IAPP (hIAPP) forms oligomers, leading to either amyloid fibrils or toxic oligomers in an aqueous solution in vitro. Either application of hIAPP on or overexpression of hIAPP in cells induces apoptosis. It remains controversial whether the fibrils or smaller toxic oligomers induce beta-cell apoptosis. Rifampicin prevents hIAPP amyloid fibril formation and has been proposed as a potential target for prevention of T2DM. We examined the actions of rifampicin on hIAPP amyloid fibril and toxic oligomer formation as well as its ability to protect beta-cells from either application of hIAPP or endogenous overexpression of hIAPP (transgenic rats and adenovirus-transduced beta-cells). We report that rifampicin (Acocella G. Clin Pharmacokinet 3: 108-127, 1978) prevents hIAPP fibril formation, but not formation of toxic hIAPP oligomers ( Bates G. Lancet 361: 1642 1644, 2003), and does not protect beta-cells from apoptosis induced by either overexpression or application of hIAPP. These data emphasize that toxic hIAPP oligomers, rather than hIAPP fibrils, initiate beta-cell apoptosis and that screening tools to identify inhibitors of amyloid fibril formation are likely to be less useful than those that identify inhibitors of toxic oligomer formation. Finally, rifampicin and related molecules do not appear to be useful as candidates for prevention of T2DM.