Rakatzi I, Mueller H, Ritzeler O, Tennagels N, Eckel J
Department of Clinical Biochemistry and Pathobiochemistry, German Diabetes Research Institute, Düsseldorf, Germany.
Diabetologia. 2004 Feb;47(2):249-58. doi: 10.1007/s00125-003-1293-3. Epub 2004 Jan 13.
AIMS/HYPOTHESIS: Pancreatic beta-cell apoptosis is a common feature of Type 1 and Type 2 diabetes and leptin exerts an anti-apoptotic function in these cells. The beta-cell line INS-1 was used to test the hypothesis that the adipocyte hormone adiponectin might mediate an anti-apoptotic effect comparable to leptin.
Apoptosis was induced by culturing cells with a cytokine combination (interleukin-1beta/interferon-gamma) or palmitic acid in absence or presence of leptin or the globular domain of adiponectin (gAcrp30), respectively.
INS-1 cells had a prominent sensitivity towards cytokine- and fatty acid-induced apoptosis, resulting in about three- and six-fold increases in caspase 3 activation and DNA fragmentation, respectively. gAcrp30 strongly (50-60%) inhibited palmitic acid-induced apoptosis, with a weaker effect against cytokine-induced apoptosis (35%). The same result was observed for leptin with both adipokines being non-additive. Reduction of apoptosis by an inhibitor of IkappaB-kinase (IKK) indicated the involvement of the nuclear factor (NF)-kappaB pathway in both cytokine- and fatty acid-induced apoptosis, however, leptin and gAcrp30 were unable to block NF-kappaB activation. Cytokine- and fatty-acid-induced suppression of glucose/forskolin-stimulated insulin secretion was completely prevented through the action of gAcrp30, whereas leptin was only effective against lipotoxicity-mediated beta-cell dysfunction.
CONCLUSION/INTERPRETATION: Our data show that gAcrp30 partially rescues beta cells from cytokine- and fatty-acid-induced apoptosis and completely restores autoimmune- and lipotoxicity-induced dysfunction of insulin-producing cells. We suggest that gAcrp30 exerts its anti-apoptotic function without modulating NF-kappaB activation. This novel beta cell protective function of gAcrp30 might serve to counteract autoimmune- and lipotoxicity-induced beta-cell destruction.
目的/假设：胰岛β细胞凋亡是1型和2型糖尿病的共同特征，而瘦素在这些细胞中发挥抗凋亡作用。使用β细胞系INS-1来验证以下假设：脂肪细胞激素脂联素可能介导与瘦素相当的抗凋亡作用。
分别在不存在或存在瘦素或脂联素球状结构域（gAcrp30）的情况下，用细胞因子组合（白细胞介素-1β/干扰素-γ）或棕榈酸培养细胞来诱导凋亡。
INS-1细胞对细胞因子和脂肪酸诱导的凋亡具有显著敏感性，分别导致半胱天冬酶3激活和DNA片段化增加约3倍和6倍。gAcrp30强烈（50%-60%）抑制棕榈酸诱导的凋亡，对细胞因子诱导的凋亡作用较弱（35%）。瘦素也得到相同结果，两种脂肪因子无相加作用。IκB激酶（IKK）抑制剂减少凋亡表明核因子（NF）-κB途径参与细胞因子和脂肪酸诱导的凋亡，然而，瘦素和gAcrp30无法阻断NF-κB激活。gAcrp30的作用完全阻止了细胞因子和脂肪酸诱导的对葡萄糖/福斯高林刺激的胰岛素分泌的抑制，而瘦素仅对脂毒性介导的β细胞功能障碍有效。
结论/解读：我们的数据表明，gAcrp30可部分挽救β细胞免受细胞因子和脂肪酸诱导的凋亡，并完全恢复自身免疫和脂毒性诱导的胰岛素生成细胞功能障碍。我们认为，gAcrp30发挥其抗凋亡功能而不调节NF-κB激活。gAcrp30这种新的β细胞保护功能可能有助于对抗自身免疫和脂毒性诱导的β细胞破坏。
