过早或过晚添加辅食均增加糖尿病风险

《JAMA儿科学》7月8日在线发表的一项纵向观察性研究表明，与在4~5个月时添加辅食的婴儿相比，在4个月前或6个月后添加辅食的婴儿罹患1型糖尿病(T1DM)的风险显著增加(JAMA Pediatr. July [doi:10.1001/jamapediatrics.2013.317])。

美国科罗拉多大学的Brittni Frederiksen及其同事报告称，年轻人糖尿病自身免疫研究(DAISY)所纳入的1,835例存在T1DM高遗传风险的儿童可分为两组，一组是脐带血筛查发现HLA区域存在糖尿病易感等位基因，另一组是有一级亲属患T1DM但尚未累及本人。本次分析所纳入的儿童都是从出生即开始接受随访，并且在第9、15和24月龄时完成了诊室访视，之后每年随访1次。

结果显示，53例儿童在随访期内患上了T1DM。在校正人白细胞抗原(HLA)-DR基因型、一级亲属患T1DM、母亲教育、分娩类型等因素之后，研究者发现，过早或过晚添加辅食都是罹患T1DM的显著预测因子[校正危险比(HR)分别为1.91和3.02]。

具体而言，过早添加水果以及过晚添加大米/燕麦(不含麸质的食物)均与T1DM发病风险增加相关(HR分别为2.23和2.88)。

研究者指出，值得注意的是，在添加小麦/大麦(含麸质的食物)时仍在接受母乳喂养的婴儿发生T1DM的风险显著下降(HR，0.47)，这表明母乳喂养对T1DM具有一定的保护作用。

在这一DAISY队列中，添加蔬菜和肉类的时间与T1DM发病风险无关。

上述研究结果与之前的DAISY报告相吻合，表明“添加谷物的最佳时间窗是4~6月龄，提前或推迟均会增加儿童出现胰岛自身免疫(临床前T1DM)的风险。”鉴于目前全球的T1DM发病率呈上升趋势，这一研究结果具有十分重要的意义。研究者指出，在年龄小于5岁的儿童中，T1DM发病率上升得最快。

至于过早或过晚添加辅食与T1DM发病之间的相关性机制，研究者说，过早添加所预测的风险“可能与易感个体尚未发育成熟的肠道免疫系统对辅食抗原的异常免疫应答有关”，而过晚添加所预测的风险“可能与较大年龄的儿童初次添加辅食的量更大有关”。此外，如果在母乳已经不能满足婴儿的能量和营养需求时才添加辅食，可能导致婴儿营养缺乏从而增加T1DM的发病风险。同样，过晚添加辅食可能与添加辅食前断奶有关，这会导致母乳的保护效应缺失。

研究者总结道，虽然上述研究结果尚需在更大规模的队列中接受验证，但的确为辅食的添加带来了一些启示。“关于婴儿饮食和T1DM的研究大多关注单种抗原(即牛奶或麸质)的添加时间，而我们的研究数据表明多种食物/抗原都会起到一定的作用，婴儿辅食添加的时间和类型与T1DM风险之间存在复杂的关系。总之，添加辅食的安全时间窗是4~5月龄时；并且添加辅食时应继续坚持母乳喂养以尽可能地降低遗传易感儿童的T1DM风险。”

这项研究由美国国立卫生研究院以及糖尿病内分泌研究中心临床研究与生物信息学核心提供的研究经费资助。作者声明无相关经济利益冲突。

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By: SHARON WORCESTER, Clinical Endocrinology News Digital Network

Babies who are first exposed to solid food before the age of 4 months or at age 6 months or older are significantly more likely to develop type 1 diabetes mellitus than those with a first exposure at 4-5 months of age, findings from a longitudinal observational study have shown.

Of 1,835 children at increased genetic risk for type 1 diabetes mellitus (T1DM) who were included in the Diabetes Autoimmunity Study in the Young (DAISY), 53 developed the disease during follow-up. After adjustment for the human leukocyte antigen (HLA)-DR genotype, a first-degree relative with T1DM, maternal education, and delivery type, both the early and late first solid food exposures significantly predicted T1DM development (adjusted hazard ratios, 1.91 and 3.02, respectively), Brittni Frederiksen of the University of Colorado, Aurora, and her colleagues reported online on July 8 in JAMA Pediatrics.

Specifically, babies with early exposure to fruit and those with late exposure to rice/oat (non–gluten-containing foods) were at increased risk of T1DM development (HR, 2.23 and 2.88, respectively), the investigators found (JAMA Pediatr. July [doi:10.1001/jamapediatrics.2013.317]).
 
Of note, babies who were still breastfeeding at the time of introduction to wheat/barley (gluten-containing food) had a significantly reduced risk of T1DM development (HR, 0.47), suggesting that breastfeeding confers some protection against the disease, they said.

The timing of the introduction of vegetables and meat did not predict T1DM in the DAISY cohort.

DAISY participants included two groups of children at increased genetic risk for developing T1DM – a group found to have diabetes-susceptibility alleles in the HLA region on cord blood screening, and a group of unaffected children with a first-degree relative with T1DM. Children included in the current analysis were those followed from birth, who completed clinic visits at 9, 15, and 24 months, and annually thereafter.

The findings, which support those from an earlier DAISY report demonstrating "a window of time for introduction of cereals, 4-6 months, outside of which the risk for development of islet autoimmunity (preclinical T1DM) increased." are important given the increasing worldwide incidence of T1DM. That increase is most rapid among children younger than age 5 years, the investigators noted.

As for the mechanisms of associations between early and late food exposures and T1DM development, the risk predicted by early exposure "might suggest a mechanism involving an abnormal immune response to solid food antigens in an immature gut immune system in susceptible individuals," and the increased risk predicted by late exposures "may be related to the larger amounts given at initial exposure to older children," the investigators said.

Also, the late introduction of solid foods, when breast milk no longer meets energy and nutrient needs, could lead to nutrient deficiencies that could increase T1DM risk. Similarly, late solid food exposures may be related to the cessation of breastfeeding before solid food introduction, resulting in the loss of the protective effects of breast milk in that setting, they suggested.

Although the findings require confirmation in a larger cohort, they provide some guidance for the introduction of solid foods.

"While much of the focus of infant diet and T1DM research has been on the timing of the introduction of a single antigen (i.e., milk or gluten), our data suggest multiple foods/antigens play a role and that there is a complex relationship between the timing and type of infant food exposures and T1DM risk. In summary, there appears to be a safe window in which to introduce solid foods between 4 and 5 months of age; solid foods should be introduced while continuing to breastfeed to minimize T1DM risk in genetically susceptible children," the investigators concluded.

This study was supported by a National Institutes of Health grant and a Diabetes Endocrine Research Center Clinical Investigation and Bioinformatics Core grant. The authors reported having no relevant financial disclosures.