In utero growth restraint due to absent fetal insulin secretion did not persist postnatally. In individuals with loss-of-function INS mutations, after birth there was evidence of rapid, early catch-up growth of weight and length (Figure 1, C and D). Compared with birth size, there was a median gain of 2.97 SDS (IQR, 2.29 to 3.07 SDS) in weight and 2.11 SDS (IQR, –0.58 to 3.68 SDS) in length. Most recently available weight (n = 16) and height (n = 15) after the age of 2 years were within the normal ranges (Supplemental Table 4).

This study utilizing human monogenic disease as a model of absent fetal insulin has provided unique insights into the physiology of early growth.

Insulin-mediated fetal growth in humans contributes approximately 49% to birth weight at term, which is highest out of all species studied (2). Absent fetal insulin also reduced birth length, but its greater effect on weight confirms its main effects relate to fetal fat deposition. The high contribution of fetal insulin-mediated growth to birth weight could explain why, at birth, humans have a higher proportion of body fat compared with other species (3). This high proportion of fat at birth could confer a survival advantage, as lipids provide an efficient and vital fuel for the developing, large human brain (4). The relatively long length of gestation in humans could also result in a longer period of exposure to fetal insulin. We observed birth weight without fetal insulin to deviate further from the normal range as pregnancy progressed (Figure 1A), indicating that insulin-mediated growth becomes more important later in pregnancy.

A key regulator of fetal insulin-mediated growth is maternal glucose. Maternal glycemia has a substantial effect on birth weight (1 mmol/L higher maternal fasting glucose raises birth weight by 301 g; ref. 5). Similar to the situation in which insulin is replaced after birth following in utero deficiency, the effect of maternal glycemia is transient and rapidly lost in the first year of life, with catch-up and catch-down growth (6). In contrast, the lower birth weight in female individuals does not appear to have its origins in fetal insulin-mediated growth, and catch-up is not observed

Rapid catch-up growth once insulin is replaced in individuals with INS loss-of-function mutations is in marked contrast to the postnatal growth failure of those with severe insulin resistance secondary to biallelic mutations in the insulin receptor gene INSR (Donohue syndrome), despite similarly low birth weight (7). This is likely to reflect that, postnatally, it is not possible to correct the tissue insulin resistance in these individuals.

In conclusion, monogenic diseases resulting in absent fetal insulin have enabled us to answer fundamental questions about early growth in humans. We have used a monogenic human knockout of insulin to show that absence of fetal insulin reduces birth weight by approximately half and postnatally, there is rapid catch-up in weight and length. This establishes that insulin-mediated and noninsulin-mediated growth are equally important in humans. Whether other key modulators of fetal growth apart from maternal glucose act through fetal insulin is uncertain. In the future, all studies looking at fetal growth should determine whether insulin- or noninsulin-mediated growth are impacted, because the short- and long-term outcomes are likely to be different.