The gender insulin hypothesis: why girls are born lighter than boys, and the implications for insulin resistance

Abstract

Girls are born lighter than boys. The consistency of this observation across different populations is striking, suggesting that it may have fundamental significance for those conditions linked with lower birth weight, such as diabetes. Previous hypotheses relating low birth weight to subsequent diabetes have addressed differences in insulin resistance within the sexes, not between them. Here, we propose that gender-specific genes affecting insulin sensitivity are responsible for the gender difference in birth weight -the genetically more insulin resistant female fetus is less responsive to the trophic effects of insulin and is therefore smaller. These genes also render female subjects more susceptible to diabetes, explaining why reports of type 2 diabetes (T2D) in younger populations show a female preponderance. Consistent with our proposal, concentrations of insulin and/or its propeptides are higher at birth in female populations and they are intrinsically more insulin resistant throughout life, with attendant impact on their metabolism, and the regressions describing the relationship between insulin resistance and adiposity in female and male subjects have similar gradients, but different constants. These gender-specific genes have a demonstrable impact on fetal growth and insulin resistance. Diabetes and cardiovascular disease are thought to be driven by insulin resistance, and the observations reported here may help to focus the search for genes that control it.

Distribution of Adiponectin, Leptin, and Metabolic Correlates of Insulin Resistance: A Longitudinal Study in British Children; 1: Prepuberty (EarlyBird 15)

“…The sex difference in fasting insulin persists after correction for anthropometric variables, physical activity, resting energy expenditure, and gonadotropin status (25 ). We have speculated elsewhere on the wider significance of the sex differences we have observed (26 ). Insulin sensitivity increases progressively in both sexes between 5 and 8 years, although it tends level off between 7 and 8 years.…”

Established maternal obesity in the rat reprograms hypothalamic appetite regulators and leptin signaling at birth

“…31 In this study, insulin levels were higher in the female pups than male pups, as recorded earlier in the literature. 32 However, it was not significantly changed by maternal obesity. It has been suggested that leptin-signaling pathways in the neonatal hypothalamus do not develop until after the 6th postnatal day, 7,33 and the expression of Ob-Rb does not affect leptin penetrating the blood-brain barrier; 34 whereas a population of arcuate Ob-Rb expressing neurons can be directly accessed by circulating leptin.…”

Childhood poverty and abdominal obesity in adulthood: a systematic review

“…Females have more subcutaneous fat tissue since birth, which favors surviving early adverse conditions 49,50,51 . Periods of nutritional restriction in early childhood lead to permanent deficits in the amount of lean mass in adulthood 52 , but central adipose tissue appears to be selectively preserved 53 .…”

“…Even if nutrient supply improves over life, central fat distribution is maintained in adulthood, particularly in women, as demonstrated by Ravelli et al 54 in their study on hunger in the Netherlands during World War II. In adolescence, sex hormones lead to increased fat deposits in women, as an energy reserve to guarantee procreation and breastfeeding 49,50,51 , thereby increasing the differences between the sexes. The same hormonal action probably contributes to highlighting the effects of early poverty on central adiposity in women.…”