葡萄糖、胰岛素指标与AD病理无关

《美国医学会杂志-神经病学》(JAMA Neurology)7月29日发表的一项大型前瞻性队列研究表明，葡萄糖不耐受和胰岛素抵抗可能不参与阿尔茨海默病(AD)的发病机制(JAMA Neurol. 2013 July 29 [doi:10.1001/jamaneurol.2013.284])。


Madhav Thambisetty博士

在这项研究中，美国国立衰老研究所的Madhav Thambisetty博士及其同事采用巴尔的摩老化纵向研究(BLSA)的数据，对糖尿病和葡萄糖不耐受可能是AD危险因素的观点进行了探讨。在BLSA研究中，研究者对老年男性和女性受试者定期进行口服葡萄糖耐量试验(OGTT)，并定期进行神经系统检查和神经心理试验。BLSA包含一项针对同意死后行脑检查的受试者的尸检分支研究和一项采用碳11标记匹兹堡化合物B(C-PiB)定期评估体内纤维状β淀粉样蛋白水平的神经成像分支研究。

Thambisetty博士等人的分析对象为研究入组时认知和神经功能正常且死亡时年龄≥69岁(平均死亡年龄88岁)的197例受试者。在平均随访22年间，受试者接受了至少2次OGTT，53例受试者还接受了C-PiB脑成像检查。所有受试者均接受脑尸检，包括β-淀粉样蛋白斑块定量。该研究中有95%的受试者为白人。

在第一项数据分析中，研究者根据平均一生空腹或120分钟葡萄糖、胰岛素或胰岛素抵抗值将197例受试者分成三分位数。研究者发现，这些组在任何AD病理指标方面均无显著差异。

对个体而非分组的葡萄糖和胰岛素指标进行的第2项分析也显示，在校正死亡年龄和性别的效应后，任何AD病理指标与任何葡萄糖或胰岛素稳态指标之间均无显著关联。

第3项分析探讨了每名受试者一生的葡萄糖和胰岛素值变化率，结果也显示AD病理评分低、中或高的受试者之间无显著差异。

根据有(101例)无(96例)痴呆对受试者进行分类，空腹葡萄糖(100/98 mg/dl)、空腹胰岛素(9.6/9.0 mIU/ml)、空腹稳态模型评估(HOMA, 2.4/2.2)、120分钟葡萄糖(156/149 mg/dl)、120分钟胰岛素(63/57 mIU/ml)和120分钟HOMA (25/22)在平均非痴呆/痴呆值方面无显著差异。

在进行定期C-PiB脑扫描的亚组患者中，未发现平均一生空腹或120分钟葡萄糖、胰岛素或胰岛素抵抗值最高的受试者与最低的受试者之间的β-淀粉样蛋白沉积存在显著差异。

此外，β-淀粉样蛋白沉积水平最高的受试者和最低的受试者在葡萄糖代谢或胰岛素抵抗方面也无显著差异。当分析仅限于后扣带回/楔前叶和内侧颞叶(这两个部位是AD早期β-淀粉样蛋白沉积的部位)的β-淀粉样蛋白沉积时，发现代谢指标也无差异。

对于相对年轻时(平均年龄53岁)的代谢指标进行分析，发现AD病理与葡萄糖、胰岛素和胰岛素抵抗之间无显著关联。

最后，研究者重点分析了30例死亡之前一直服用糖尿病药物且接受尸检的受试者，结果在任何AD病理指标方面均未观察到显著差异，不论受试者死亡时是否正在服用药物。

研究者表示，脑胰岛素抵抗可能与外周胰岛素抵抗指标无关联，未来有必要进一步探讨该问题。此外，AD是一种复杂的疾病，涉及的因素不止β-淀粉样蛋白沉积，因此开展长期治疗试验对阐明该问题也具有重要意义。

该研究获美国国立衰老研究所和Burroughs Wellcome基金会转化研究奖支持。研究者声明无经济利益冲突。

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By: MARY ANN MOON, Internal Medicine News Digital Network

Serial measures of glucose and insulin homeostasis taken over 20 years’ time show no association with the development of Alzheimer’s disease symptoms or pathology, according to a report published July 29 in JAMA Neurology.

These findings, from a large, prospective, cohort study that included multiple physical and cognitive assessments during middle and old age as well as autopsy results, indicate that glucose intolerance and insulin resistance likely do not play a role in Alzheimer’s disease (AD) pathogenesis, said Dr. Madhav Thambisetty of the National Institute on Aging, Baltimore, and his associates.

"Our results concur with other studies that found no association between diabetes mellitus and AD pathology, and we extend these observations more broadly to include hyperglycemia and insulin resistance," they noted.

Dr. Thambisetty and his colleagues used data from the Baltimore Longitudinal Study of Aging (BLSA) to examine the assertion that diabetes and glucose intolerance may be risk factors for AD. Some studies have reported excess cognitive impairment and lower cognitive performance in patients with metabolic derangements, as well as a doubling of the risk for AD in those with full-blown diabetes. Other studies have not confirmed any such links.

The BLSA is a longitudinal study involving older men and women who undergo periodic oral glucose tolerance testing (OGTT) as part of serial comprehensive physical examinations, as well as periodic neurologic examination and neuropsychological testing. The BLSA includes an autopsy substudy of subjects who agreed to postmortem brain examinations and a neuroimaging substudy of subjects who had periodic in-vivo assessment of fibrillar amyloid-beta levels using carbon-11-labeled Pittsburgh Compound B (C-PiB).

For their analysis, Dr. Thambisetty and his associates focused on 197 subjects who were cognitively and neurologically normal at study entry and were aged at least 69 years at the time of death (mean age at death was 88 years). During a mean follow-up period of 22 years, the participants underwent at least two OGTTs during follow-up, and 53 also underwent C-PiB brain imaging. All participants underwent brain autopsy that included quantification of beta-amyloid plaques. Overall, 95% of subjects in the study were white.

The study design, with its serial assessments over a long period of time, allowed the investigators "to determine the effect of prolonged burdens of hyperglycemia and insulin resistance on pathological findings in the brain." The study results indicate that these metabolic measures show no association with AD pathology even at its earliest stages, they said.

In the first analysis of the data, the 197 study subjects were divided into tertiles according to mean lifetime fasting or 120-minute glucose, insulin, or insulin resistance values. The investigators found no significant difference among these groups in any measure of AD pathology.

A further analysis of individual, rather than grouped glucose and insulin measures also found no significant association between any measure of AD pathology and any measure of glucose or insulin homeostasis after controlling for the effects of age and sex at death.

A third analysis that examined the rates of change in glucose and insulin values over the lifetime of each participant also showed no significant differences among subjects with low, medium, or high AD pathology scores, the investigators said (JAMA Neurol. 2013 July 29 [doi:10.1001/jamaneurol.2013.284]).

When the participants were categorized by the absence (96 subjects) or presence (101 subjects) of dementia, there were no significant differences in mean nondementia/dementia values for fasting glucose (100/98 mg per dL), fasting insulin (9.6/9.0 micro IU/mL), fasting homeostasis modeling assessment (HOMA, 2.4/2.2), 120-minute glucose (156/149 mg per dL), 120-minute insulin (63/57 micro IU/mL), and 120-minute HOMA (25/22).

In the subgroup of subjects who underwent periodic C-PiB brain scanning, no significant differences were found in beta-amyloid deposition between those with the highest and those with the lowest mean lifetime fasting or 120-minute glucose, insulin, or insulin resistance values.

In addition, there was no significant difference between subjects with the highest and those with the lowest levels of beta-amyloid deposition in glucose metabolism or insulin resistance. And there were no differences in metabolic measures when the analysis was restricted to beta-amyloid deposition in the posterior cingulate/precuneus and the medial temporal lobe, "two areas where fibrillar beta-amyloid is deposited early in the course of AD," Dr. Thambisetty and his colleagues wrote.

When the investigators limited their analyses to metabolic measures obtained at relatively younger ages (mean age of 53 years), they found no significant relationship between AD pathology and glucose, insulin, and insulin resistance.

In a final analysis, the researchers focused on the 30 subjects who had been taking diabetes medications at the time of death and who had undergone autopsy. "We found no significant difference in any measure of AD pathology, whether or not the participant was taking the medication," they wrote.

It is possible that insulin resistance within the brain doesn’t correlate with peripheral measures of insulin resistance, so further study of this question is warranted. Moreover, AD is a complex process that involves more than just beta-amyloid accumulation, so "long-term therapeutic trials [also] are important to elucidate this issue," the investigators added.

This study was supported by the National Institute on Aging and the Burroughs Wellcome Fund for Translational Research. No financial conflicts of interest were reported.