The insulin hypersecretion hypothesis: cause or effect? Reply to Polychronakos C [letter].
The insulin hypersecretion hypothesis: cause or effect? Reply to Polychronakos C [letter].
复制标题
胰岛素分泌过多假说：原因还是结果？
DOI：
10.1007/s00125-021-05632-y
复制
发表时间：
2022
期刊：
影响因子：
8.2
通讯作者：
Dabelea,Dana
中科院分区：
文献类型：
--
作者：
Perng,Wei;Dabelea,Dana
To the Editor: We appreciate the thoughtful comments by Polychronakos regarding our paper [1] and are delighted at the interest with which they read this work. In the letter, the author put forth the possibility that genetic inheritance may explain the observed association between in utero overnutrition and insulin resistance (HOMA-IR) across adolescence and pointed out the chicken/egg issue regarding the direction of associations between insulin hypersecretion and insulin resistance. We discuss these points below. First, we agree that any association between maternal diabetes during pregnancy and offspring diabetes and related metabolic traits is partially due to shared genes between the mother and child. The issue of confounding by genetics has been previously addressed, among others, by discordant sibship studies in which one sibling was born before and another was born after the mother was diagnosed with type 2 diabetes. Such studies have shown that risk of type 2 diabetes in offspring is significantly higher (eg OR 3.6, p= 0.02 [2]) in siblings born after (vs before) the mother had developed diabetes, thereby demonstrating an unambiguous effect of overnutrition in utero on offspring metabolic health in addition to genetic susceptibility. Additionally, we recently showed in the Exploring Perinatal Outcomes among Children (EPOCH) cohort that a type 2 diabetes genetic risk score (GRS) derived in adults was not associated with markers of insulin resistance (HOMA-IR) but was associated with markers of beta cell dysfunction (insulinogenic index, disposition index) in youth [3]. This is not surprising since most type 2 diabetes GRSs comprise genes associated with beta cell dysfunction as opposed to insulin resistance [3]. However, we also found a positive association of the GRS with fasting and 2 h OGTT glucose levels, but only among youth who were exposed to maternal gestational diabetes mellitus [GDM])[4]. This suggests that genetics alone may not cause hyperglycaemia in youth without an environmental component. Second, the main question explored in our paper was whether overnutrition in utero (maternal obesity and/or GDM) results in direct beta cell overstimulation and increased insulin output as a first step or whether compensatory insulin secretion in response to reduced insulin sensitivity is the primary metabolic abnormality. We acknowledge here and in the published paper that our data cannot determine with certainty that direct beta cell overstimulation is the primary metabolic abnormality leading to insulin resistance, development of adiposity and dysglycaemia later in life. However, we designed this analysis to get as close as possible, within the confines of an observational study, to addressing this question. Specifically, we restricted the analysis to youth who were normal weight at the baseline examination and adjusted for differences in markers of visceral adiposity (eg waist/height ratio, visceral adipose tissue [VAT]/subcutaneous adipose tissue [SAT] depot ratio) to minimise the possibility that baseline insulin levels reflected adiposity and, thus, adiposity-related insulin resistance. As Polychronakos noted, however, HOMA-IR was slightly higher at baseline among exposed youth (difference of 0.2 units, p= 0.10). This, again, leaves room for
