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. Graphical abstract

Understanding the Long-Lasting Effects of Fetal Nutrient Restriction versus Exposure to an Obesogenic Diet on Islet-Cell Mass and Function

“…In 1998, Hattersley and Tooke put forth the ‘fetal insulin’ hypothesis as an alternative explanation for the association between low birth weight and risk of T2D. This hypothesis proposes that both phenotypes are the result of a genetic predisposition for reduced insulin secretion and action leading to decreased growth in fetal life and a decreased capacity to secrete and respond to insulin and, therefore, higher T2D risk [ 7 , 8 ]. Support for the ‘fetal insulin’ hypothesis emerged from genome-wide association studies showing that a number of T2D risk loci are associated with lower birthweight.…”

“…Support for the ‘fetal insulin’ hypothesis emerged from genome-wide association studies showing that a number of T2D risk loci are associated with lower birthweight. Furthermore, the strongest associations are at loci that primarily affect beta-cell function (reviewed in [ 8 ]). However, it has since been argued that genetic susceptibility does not solely account for the relationship between low birth weight and T2D; in a study of monozygotic twins discordant for T2D, the diabetic twin had a lower birth weight compared to their genetically identical non-diabetic co-twin [ 9 ].…”

Association of birthweight and penetrance of diabetes in individuals with HNF4A-MODY: a cohort study

“…Fetal insulin secretion is known to be a major determinant of birthweight, particularly in humans [ 4 , 5 ]. Our analysis of individuals with complete absence of fetal insulin secretion, due to mutations in the insulin gene or pancreatic agenesis, have shown they are half the normal birthweight [ 5 ].…”

“…Fetal insulin secretion is known to be a major determinant of birthweight, particularly in humans [ 4 , 5 ]. Our analysis of individuals with complete absence of fetal insulin secretion, due to mutations in the insulin gene or pancreatic agenesis, have shown they are half the normal birthweight [ 5 ]. Additionally, in individuals with HNF4A mutations, macrosomia has been reported as always occurring in those with neonatal hyperinsulinaemic hypoglycaemia [ 2 ].…”

“…Data from genetic testing referral forms was extracted for all individuals with birthweight data and a rare (absent from gnomAD v2.1.1 [ 5 ]) pathogenic HNF4A mutation (Molecular Genetics laboratory, Exeter, UK [ n = 204], and Motol University Hospital, Prague, Czech Republic [ n = 59]). Due to a lack of population-level sequencing data, which is needed to confidently define variant penetrance and pathogenicity, we then excluded a small number of individuals self-reported as non-White ( n = 7).…”