Two decades since the fetal insulin hypothesis: what have we learned from genetics?

Abstract

In 1998 the fetal insulin hypothesis proposed that lower birthweight and adult-onset type 2 diabetes are two phenotypes of the same genotype. Since then, advances in research investigating the role of genetics affecting insulin secretion and action have furthered knowledge of fetal insulin-mediated growth and the biology of type 2 diabetes. In this review, we discuss the historical research context from which the fetal insulin hypothesis originated and consider the position of the hypothesis in light of recent evidence. In summary, there is now ample evidence to support the idea that variants of certain genes which result in impaired pancreatic beta cell function and reduced insulin secretion contribute to both lower birthweight and higher type 2 diabetes risk in later life when inherited by the fetus. There is also evidence to support genetic links between type 2 diabetes secondary to reduced insulin action and lower birthweight but this applies only to loci implicated in body fat distribution and not those influencing insulin resistance via obesity or lipid metabolism by the liver. Finally, we also consider how advances in genetics are being used to explore alternative hypotheses, namely the role of the maternal intrauterine environment, in the relationship between lower birthweight and adult cardiometabolic disease.

Keywords: Birthweight; Fetal growth restriction; Fetal insulin; Genome-wide association studies; Mendelian randomisation; Neonatal diabetes; Pregnancy; Review; Type 2 diabetes.

Fig. 1

Principles of the fetal insulin hypothesis compared with the thrifty phenotype hypothesis. This figure is available as part of a downloadable slideset

Fig. 2

Birthweight according to parental diabetes status in the UK Biobank study [43]. **p<0.001 vs birthweight where neither parent was reported to have diabetes. Figure adapted from Tyrell et al [43] under the terms of the Creative Commons Attribution 3.0 Unported License. This figure is available as part of a downloadable slideset

Fig. 3

The effect of fetal type 2 diabetes (T2D) risk alleles on birthweight (BW) clustered by their likely underlying biology (beta cell function, proinsulin secretion and insulin resistance secondary to obesity, lipodystrophy-like fat distribution or disrupted liver lipid metabolism) [81]. SNPs within each cluster are ordered from top to bottom by highest to lowest T2D risk (established from a genome-wide association study of participants of European ancestry [61]). SNPs that appear in more than one cluster (ADCY5, CCND2, CDC123/CAMK1D, HSD17B12, HNF4A) are shown by an accompanying number in parentheses. There are two distinct signals at ANKRD55 (shown as ANKRD55_1 and ANKRD55_2). The error bars show the 95% CIs for the estimated fetal effect on birthweight in Europeans (independent of any maternal effect [59]), with 1 SD change in birthweight being equivalent to ~450 g. This figure is available as part of a downloadable slideset

Fig. 4

Principles of using Mendelian randomisation to explore the roles of pregnancy exposures and fetal genetics in the relationship between birthweight and risk of adult cardiometabolic disease. The example in this figure shows that the relationship between lower birthweight and higher offspring SBP is mediated by a combination of intrauterine effects on birthweight and fetal genetic susceptibility to higher adult SBP. Figure adapted from Lawlor et al [75] under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium. This figure is available as part of a downloadable slideset