Skeletal muscle-induced hypoglycemia risk, not life history energy trade-off, links high child brain glucose use to slow body growth

Kuzawa et al. (1) find an “inverse relationship between the brain’s demand for glucose and body-weight growth rate” that supports “the hypothesis that human brain development is sufficiently costly to require a compensatory reduction in expenditure on body growth”.

However, energy expenditure on body growth is low. One gram of body growth in mammals requires 53 kJ (2), the energy equivalent of 3.3 g of glucose. A child in its 5th y gains 1,600 g, equivalent to 5,280 g of glucose; 1.02% of the 517,205 g glucose used by the brain in its 5th y [data in the paper by Kuzawa et al. (1), table S2].

Kuzawa et al. (1) overlook the threat of exercise-induced hypoglycemia to the child’s brain and the adaptive advantage to minimize it by limiting skeletal muscle mass through growth retardation. Skeletal muscle, after initial utilization of glycogen stores, uses plasma glucose that is largely matched in adults by increased hepatic glucose production. However, even in adults a shortfall can occur when exertion is prolonged and intense (3). The hepatic production of glucose in children has less reserve capacity as liver glycogenolysis and gluconeogenesis is already high compared with the adult due to the pediatric brain’s greater glucose needs. The immature brain would be particularly vulnerable to hepatic failure to match skeletal muscle glucose plasma depletion as it undergoes neuroglycopenia at a lesser lowering in plasma glucose than the adult brain (4).

Child exercise is regulated to limit the need for increased hepatic glucose production. Although children engage in more low and moderate exercise than at older ages, they avoid intense prolonged (i.e., glucose-using) exertion. For example, 95% of intense exercise in children in one study was less than 15 s in duration (5). Other factors exist that reduce the need for increased glucose production: When exerted child skeletal muscle compared with that in adults is (i) less anaerobic (and so more energy efficient in using glucose), (ii) biased to the metabolism of free fatty acids rather than the uptake of glucose, and (iii) contains less type II fiber (fast-twitch oxidative–glycolytic pathways biased to use glucose) than type I (slow-twitch biased to utilize fatty acids). Citations to these and following issues can be found in supporting literature reviews.*^,†.

Growth retardation limits the skeletal muscle mass of a child’s body (5 y of age: 5.6 kg; adult male: 29 kg; adult female: 17.5 kg). This would adaptively minimize the potential diversion of hepatic glucose production away from the high glucose-using child brain. Additional benefits include reducing the risk of exercise hyperthermia, dehydration, hypoxia, and hyperammonemia–homeostatic disruptions to which the immature brain has greater liability than the adult one.

Alongside Kuzawa et al.’s (1) life history account, consideration is needed of the adaptive advantage of growth retardation (via reduced skeletal muscle mass) upon the hepatic capability to supply the immature brain’s high glucose needs.