Craft Suzanne, Asthana Sanjay, Cook David G, Baker Laura D, Cherrier Monique, Purganan Kristina, Wait Colby, Petrova Andreana, Latendresse Shawn, Watson G Stennis, Newcomer John W, Schellenberg Gerard D, Krohn Aaron J
Geriatric Research, Education, and Clinical Center, Veteran Affairs Puget Sound Health Care System, 1660 South Columbian Way, Seattle, WA 98108, USA.
Psychoneuroendocrinology. 2003 Aug;28(6):809-22. doi: 10.1016/s0306-4530(02)00087-2.
In previous studies, adults with Alzheimer's disease (AD) showed memory enhancement when plasma insulin levels were raised to 85 microU/ml, whereas normal adults' memory was unchanged. Degree of memory enhancement was also related to apolipoprotein E (apoE) genotype status for AD patients. Response differences between normal and AD groups could reflect dose-response differences for insulin. To examine this question, 22 adults with AD and 15 normal adults received five doses of insulin on separate days in counterbalanced order, resulting in five plasma insulin levels (10, 25, 35, 85 and 135 microU/ml), while plasma glucose levels of ~100 mg/dl were maintained. Cognitive performance and plasma APP levels were measured after 120 min of infusion. Relative to baseline, AD patients who were not apoE- epsilon 4 homozygotes had improved memory at higher insulin levels of 35 and 85 microuU/ml, whereas normal adults and AD patients who were epsilon 4 homozygotes showed improved memory at insulin levels of 25 microU/ml. Normal adults' memory was also improved at insulin levels of 85 microU/ml. Plasma APP was lowered for adults with AD without the epsilon 4 allele at higher levels (85 microU/ml) than for normal adults and epsilon 4 homozygotes, who showed decreased APP at the 35 microU/ml level. AD patients with a single epsilon 4 allele showed a different pattern of insulin effects on APP than did other subjects. In general, few effects of insulin were seen at the highest dose for any subject group. These results support a role for insulin in normal memory and APP modulation that follows a curvilinear response pattern, and suggest that AD patients who are not epsilon 4 homozygotes have reduced sensitivity to insulin that may interfere with such modulation.
在先前的研究中，患有阿尔茨海默病（AD）的成年人在血浆胰岛素水平升高至85微国际单位/毫升时，记忆力增强，而正常成年人的记忆力则无变化。记忆力增强的程度也与AD患者的载脂蛋白E（apoE）基因型状态有关。正常组和AD组之间的反应差异可能反映了胰岛素的剂量反应差异。为了研究这个问题，22名患有AD的成年人和15名正常成年人在不同的日子里以平衡的顺序接受了五剂胰岛素，从而产生了五个血浆胰岛素水平（10、25、35、85和135微国际单位/毫升），同时将血浆葡萄糖水平维持在约100毫克/分升。在输注120分钟后测量认知表现和血浆淀粉样前体蛋白（APP）水平。相对于基线，非apoE-ε4纯合子的AD患者在较高胰岛素水平35和85微国际单位/毫升时记忆力有所改善，而正常成年人和ε4纯合子的AD患者在胰岛素水平为25微国际单位/毫升时记忆力有所改善。正常成年人在胰岛素水平为85微国际单位/毫升时记忆力也有所改善。没有ε4等位基因的AD成年人在较高水平（85微国际单位/毫升）时血浆APP水平降低，而正常成年人和ε4纯合子在35微国际单位/毫升水平时APP水平降低。具有单个ε4等位基因的AD患者对APP的胰岛素作用模式与其他受试者不同。一般来说，任何受试者组在最高剂量时胰岛素的作用都很少见。这些结果支持胰岛素在正常记忆和APP调节中起作用，且遵循曲线反应模式，并表明非ε4纯合子的AD患者对胰岛素的敏感性降低，这可能会干扰这种调节。
