Oates Peter J
Pfizer Global Research and Development, Department of Cardiovascular Metabolic and Endocrine Diseases, MS8220-3064, Groton, CT 06340, USA.
Curr Drug Targets. 2008 Jan;9(1):14-36. doi: 10.2174/138945008783431781.
Aldose reductase (AR) enzymatically transforms cytosolic glucose into sorbitol, a molecule that poorly penetrates cell membranes and is sometimes slowly metabolized. Hyperglycemia can cause intracellular accumulation of sorbitol and its metabolite, fructose, which can create osmotic swelling and cell dysfunction. Driven by this simple paradigm, the "Osmotic Hypothesis," and armed with positive pre-clinical results on prototype AR inhibitors (ARIs), researchers worldwide have targeted diabetic neuropathy with ARIs for four decades. However, most double-blind placebo-controlled ARI diabetic neuropathy trial outcomes have been disappointing. Ironically, scientific evidence that AR plays a key pathogenic role in diabetic neuropathy has continued to mount. Diabetic mice lacking AR exhibit strong protection of nerve function. Diabetic mice overexpressing AR have accelerated nerve dysfunction and damage. Human diabetics with "high AR expression" alleles shows faster loss of maximum pupillary constriction velocity, an indicator of autonomic neuropathy, while those with "low AR expression" alleles have slower loss of foot hot thermal threshold, an indicator of sensory neuropathy. Evidence is now strong that the Osmotic Hypothesis and the nerve sorbitol endpoint were misleading. Reliance on nerve sorbitol to assess AR inhibition likely caused underestimation of doses needed for clinical efficacy and overestimation of drug safety margins. Current recognition of the pathogenic importance of oxidative stress and its strong link to metabolic flux through AR have led to a revitalized "Metabolic Flux Hypothesis" emphasizing cofactor turnover rather than polyol accumulation. Hopefully, these new insights will lead to novel ARIs that will effectively and safely slow the progression of diabetic neuropathy.
醛糖还原酶（AR）可将胞质中的葡萄糖酶促转化为山梨醇，山梨醇是一种难以穿透细胞膜且代谢有时较为缓慢的分子。高血糖会导致山梨醇及其代谢产物果糖在细胞内蓄积，进而引发渗透性肿胀和细胞功能障碍。在这种简单的“渗透假说”范式推动下，且基于原型醛糖还原酶抑制剂（ARIs）的阳性临床前结果，全球研究人员针对糖尿病神经病变使用ARIs进行了长达四十年的研究。然而，大多数双盲安慰剂对照的ARIs治疗糖尿病神经病变试验的结果都令人失望。具有讽刺意味的是，关于AR在糖尿病神经病变中起关键致病作用的科学证据却不断增加。缺乏AR的糖尿病小鼠表现出对神经功能的强大保护作用。过度表达AR的糖尿病小鼠神经功能障碍和损伤加速。携带“高AR表达”等位基因的人类糖尿病患者最大瞳孔收缩速度丧失更快，这是自主神经病变指标，而携带“低AR表达”等位基因的患者足部热阈值丧失较慢，这是感觉神经病变指标。现在有充分证据表明“渗透假说”和神经山梨醇终点具有误导性。依赖神经山梨醇来评估AR抑制作用可能导致对临床疗效所需剂量的低估以及对药物安全边际的高估。目前对氧化应激致病重要性及其与通过AR的代谢通量的紧密联系的认识，催生了一个重新焕发生机的“代谢通量假说”，该假说强调辅因子周转而非多元醇蓄积。希望这些新见解能带来新型ARIs，有效且安全地减缓糖尿病神经病变进展。
