2013年10月27日訊 /生物谷BIOON/--據美國加州大學聖地牙哥分校醫學院研究人員證實，當前認為細胞葡萄糖水平升高，最終導致糖尿病腎病的理論可能是不正確的。
新的研究發現可能從根本上改變對糖尿病相關疾病如何發展的理解，可能幫助更好的治療疾病。研究論文發表在10月25日的Journal of Clinical Investigation雜誌上，加州大學聖地牙哥分校Kumar Sharma教授和他的同事有史以來第一次描述1型糖尿病活體小鼠腎臟中超氧化物的生成。
目前的理論認為人類以及小鼠糖尿病受損腎功能是長期高血糖（血糖）水平的結果，高血糖能迅速促進細胞線粒體產生過多的超氧陰離子自由基，一種高活性、毒性分子，最終導致下遊細胞損傷，器官功能障礙和疾病。
但新研究顛覆了這一理論。新研究沒有檢測糖尿病小鼠受損腎臟中高於正常水平的超氧化物，但研究人員卻發現超氧化物生成的減少和線粒體活動的抑制。
當他們通過激活一個關鍵的能量感應酶--AMPK來刺激線粒體，超氧化物產量增加，但糖尿病腎臟疾病的相關證據明顯消失。線粒體超氧化物似乎並不是糖尿病腎病的一個致病因素。
事實上，線粒體超氧化物的增加與AMPK激活增加相關，這表明改善線粒體功能和過氧化物的產生實際上是有利於糖尿病併發症發展的。研究人員Sharma說，AMPK活性降低可能是由於多餘的熱量導致的，多餘的熱量引發炎症相關的細胞失衡和纖維化。
Sharma指出，通過簡單生活方式的改變如減肥和鍛鍊，提高有益AMPK的活性是可實現的。研究將進一步開發新的激動劑藥物模擬或激活AMPK。（生物谷Bioon.com）
AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function
Laura L. Dugan, et al.
Diabetic microvascular complications have been considered to be mediated by a glucose-driven increase in mitochondrial superoxide anion production. Here, we report that superoxide production was reduced in the kidneys of a steptozotocin-induced mouse model of type 1 diabetes, as assessed by in vivo real-time transcutaneous fluorescence, confocal microscopy, and electron paramagnetic resonance analysis. Reduction of mitochondrial biogenesis and phosphorylation of pyruvate dehydrogenase (PDH) were observed in kidneys from diabetic mice. These observations were consistent with an overall reduction of mitochondrial glucose oxidation. Activity of AMPK, the major energy-sensing enzyme, was reduced in kidneys from both diabetic mice and humans. Mitochondrial biogenesis, PDH activity, and mitochondrial complex activity were rescued by treatment with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). AICAR treatment induced superoxide production and was linked with glomerular matrix and albuminuria reduction in the diabetic kidney. Furthermore, diabetic heterozygous superoxide dismutase 2 (Sod2+/–) mice had no evidence of increased renal disease, and Ampka2–/– mice had increased albuminuria that was not reduced with AICAR treatment. Reduction of mitochondrial superoxide production with rotenone was sufficient to reduce AMPK phosphorylation in mouse kidneys. Taken together, these results demonstrate that diabetic kidneys have reduced superoxide and mitochondrial biogenesis and activation of AMPK enhances superoxide production and mitochondrial function while reducing disease activity.