# The Possible Role of Postnatal Biphasic Dysregulation of IGF-1 Tone in the Etiology of Idiopathic Autism Spectrum Disorder

## TL;DR

This paper explores how early life IGF-1 dysregulation may contribute to the development of idiopathic autism spectrum disorder.

## Contribution

It proposes a novel unifying hypothesis linking maternal insulin resistance and fetal growth insufficiency to postnatal IGF-1 dysregulation in autism etiology.

## Key findings

- Maternal insulin resistance and fetal growth insufficiency converge to dysregulate postnatal IGF-1 tone in offspring.
- Biphasic IGF-1 dysregulation may cause accelerated development followed by growth arrest in autism.
- The hypothesis explains various ASD risk factors like early growth abnormalities and male susceptibility.

## Abstract

Autism spectrum disorder (ASD) is a pervasive condition of neurodevelopmental origin with an increasing burden on society. Idiopathic ASD is notorious for its heterogeneous behavioral manifestations, and despite substantial efforts, its etiopathology is still unclear. An increasing amount of data points to the causative role of critical developmental alterations in the first year of life, although the contribution of fetal, environmental, and genetic factors cannot be clearly distinguished. This review attempts to propose a narrative starting from neuropathological findings in ASD, involving insulin-like growth factor 1 (IGF-1) as a key modulator and demonstrates how the most consistent gestational risk factors of ASD–maternal insulin resistance and fetal growth insufficiency–converge at the perinatal dysregulation of offspring anabolism in the critical period of early development. A unifying hypothesis is derived, stating that the co-occurrence of these gestational conditions leads to postnatal biphasic dysregulation of IGF-1 tone in the offspring, leading first to insulin-dependent accelerated development, then to subsequent arrest of growth and brain maturation in ASD as an etiologic process. This hypothesis is tested for its explanation of various widely reported risk factors and observations of idiopathic ASD, including early postnatal growth abnormalities, the pervasive spectrum of symptoms, familial predisposition, and male susceptibility. Finally, further directions of research are outlined.