Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Sec. 67, S.A.S. Nagar, Punjab 160 062, India.
Neuropharmacology. 2011 May;60(6):910-20. doi: 10.1016/j.neuropharm.2011.01.033. Epub 2011 Jan 26.
Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Pharmacological treatments presently available can slow down the progression of symptoms but can not cure the disease. Currently there is widening recognition that AD is closely associated with impaired insulin signaling and glucose metabolism in brain, suggesting it to be a brain-specific form of diabetes and so also termed as "type 3 diabetes". Hence investigating the role of pharmacological agents that could ameliorate neuronal insulin resistance merit attention in AD therapeutics, however the therapeutics for pathophysiological condition like neuronal insulin resistance itself is largely unknown. In the present study we have determined the effect of metformin on neuronal insulin resistance and AD-associated characteristics in an in vitro model of "type 3 diabetes" by differentiating neuronal cell line Neuro-2a under prolonged presence of insulin. We observed that prolonged hyperinsulinemic conditions in addition to generating insulin resistance also led to development of hallmark AD-associated neuropathological changes. Treatment with metformin sensitized the impaired insulin actions and also prevented appearance of molecular and pathological characteristics observed in AD. The results thus demonstrate possible therapeutic efficacy of peripheral insulin-sensitizer drug metformin in AD by its ability to sensitize neuronal insulin resistance. These findings also provide direct evidences linking hyperinsulinemia and AD and suggest a unique opportunity for prevention and treatment of "type 3 diabetes".
阿尔茨海默病（AD）是全球最常见的神经退行性疾病。目前可用的药物治疗可以减缓症状的进展，但不能治愈这种疾病。目前人们越来越认识到，AD 与大脑中胰岛素信号和葡萄糖代谢受损密切相关，这表明它是一种大脑特异性糖尿病，因此也被称为“3 型糖尿病”。因此，研究能够改善神经元胰岛素抵抗的药物在 AD 治疗中的作用值得关注，然而，对于神经元胰岛素抵抗等病理生理状况的治疗方法在很大程度上尚不清楚。在本研究中，我们通过在胰岛素长期存在的情况下分化神经元细胞系 Neuro-2a，确定了二甲双胍对“3 型糖尿病”体外模型中神经元胰岛素抵抗和 AD 相关特征的影响。我们观察到，除了产生胰岛素抵抗外，长期高胰岛素血症还导致了与 AD 相关的标志性神经病理学变化的发展。二甲双胍治疗可使受损的胰岛素作用敏感化，并可预防 AD 中观察到的分子和病理特征的出现。因此，这些结果表明，外周胰岛素增敏药物二甲双胍通过其使神经元胰岛素抵抗敏感化的能力，可能对 AD 具有治疗效果。这些发现还提供了直接证据，将高胰岛素血症与 AD 联系起来，并为预防和治疗“3 型糖尿病”提供了独特的机会。
