Over-expression of AMP-activated protein kinase impairs pancreatic {beta}-cell function in vivo.
Over-expression of AMP-activated protein kinase impairs pancreatic {beta}-cell function in vivo.
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发表时间：
2005
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通讯作者：
S. Richards;L. Parton;I. Leclerc;G. A. Rutter;R. Smith
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作者：
S. Richards;L. Parton;I. Leclerc;G. A. Rutter;R. Smith
通过胰岛移植治疗1型糖尿病目前受到移植后功能性β细胞质量损失的限制。我们在此研究了腺病毒介导的AMP活化蛋白激酶（AMPK）活性的变化是否可能影响体内胰岛移植物的功能。在离体小鼠和大鼠胰岛中，17（vs 3）mmol/L葡萄糖刺激的胰岛素分泌被抑制36.5%（P<0.01）和43%（P<0.02），在过表达AMPK-（AMPK CA）后，（eGFP表达）病毒组和葡萄糖氧化组分别降低了38%（P<0.05）和26.6%（P<0.05）。凋亡指数增加（末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸生物素缺口末端标记）（TUNEL））也观察到AMPK CA-（22.8 +/- 3.6% TUNEL阳性细胞，P<0.001），但AMPK DN-（2.72 +/-3.9%，阳性细胞，P=0.05）感染的胰岛，相对于无效腺病毒处理的胰岛（0.68 +/- 0.36%阳性细胞）。相应地，将表达AMPK CA的胰岛移植到链脲佐菌素糖尿病C57 BL/6小鼠中改善血液病控制的效果低于移植无效（P<0.02）或AMPK-DN感染（P<0.01）的胰岛。我们的结论是AMPK的激活抑制了体内β细胞的功能，并可能成为胰岛移植治疗干预的靶点。
Treatment of type 1 diabetes by islet transplantation is currently limited by loss of functional beta-cell mass after transplantation. We investigated here whether adenovirus-mediated changes in AMP-activated protein kinase (AMPK) activity, previously shown to affect insulin secretion in vitro, might affect islet graft function in vivo. In isolated mouse and rat islets, insulin secretion stimulated by 17 (vs 3) mmol/l glucose was inhibited by 36.5% (P<0.01) and 43% (P<0.02) respectively after over-expression of constitutively-active AMPK- (AMPK CA) versus null (eGFP-expressing) viruses, and glucose oxidation was decreased by 38% (P<0.05) and 26.6% (P<0.05) respectively. Increases in apoptotic index (terminal deoxynucleotide transferase-mediated deoxyuridine trisphosphate biotin nick end-labelling) (TUNEL)) were also observed in AMPK CA- (22.8 +/- 3.6% TUNEL-positive cells, P<0.001), but not AMPK DN- (2.72 +/- 3.9%, positive cells, P=0.05) infected islets, versus null adenovirus-treated islets (0.68 +/- 0.36% positive cells). Correspondingly, transplantation of islets expressing AMPK CA into streptozotocin-diabetic C57 BL/6 mice improved glycaemic control less effectively than transplantation with either null (P<0.02) or AMPK-DN-infected (P<0.01) islets. We conclude that activation of AMPK inhibits beta-cell function in vivo and may represent a target for therapeutic intervention during islet transplantation.