Early undernutrition induces glucagon resistance and insulin hypersensitivity in the liver of suckling rats

Lizarraga-Mollinedo E, Fernandez-Millan E, de Toro Martin J, Martinez-Honduvilla C, Escriva F, Alvarez C. Early undernutrition induces glucagon resistance and insulin hypersensitivity in the liver of suckling rats. Am J Physiol Endocrinol Metab 302: E1070-E1077, 2012. First published February 14, 2011; doi:10.1152/ajpendo.00495.2011.-Developing brains are vulnerable to nutritional insults. Early undernutrition alters their structure and neurochemistry, inducing long-term pathological effects whose causal pathways are not well defined. During suckling, the brain uses glucose and ketone bodies as substrates. Milk is a high-fat low-carbohydrate diet, and the liver must maintain high rates of gluconeogenesis and ketogenesis to address the needs of these substrates. Insulin and glucagon play major roles in this adaptation: throughout suckling, their blood concentrations are low and high, respectively, and the liver maintains low insulin sensitivity and increased glucagon responsiveness. We propose that disturbances in the endocrine profile and available plasma substrates along with undernutrition-related changes in brain cortex capacity for ketone utilization may cause further alterations in some brain functions. We explored this hypothesis in 10-day-old suckling rats whose mothers were severely food restricted from the 14th day of gestation. We measured the plasma/serum concentrations of glucose, ketone body, insulin and glucagon, and hepatic insulin and glucagon responses. Undernutrition led to hypoglycemia and hyperketonemia to 84% (P < 0.001) and 144% (P < 0.001) of control values, respectively. Liver responsiveness to insulin and glucagon became increased and reduced, respectively; intraperitoneal glucagon reduced liver glycogen by 90% (P < 0.01) in control and by 35% (P < 0.05) in restricted. Cortical enzymes of ketone utilization remained unchanged, but their carrier proteins were altered: monocarboxylate transporter (MCT) 1 increased: 73 +/- 14, controls; 169 +/- 20, undernourished (P < 0.01; densitometric units); MCT2 decreased: 103 +/- 3, controls; 37 +/- 4, undernourished (P < 0.001; densitometric units). All of these changes, coinciding with the brain growth spurt, may cause some harmful effects associated with early undernutrition.