The Effect of Euglycemic Hyperinsulinemia on Cerebral Cortical Glucose Metabolism in Newborn Beagles

Abstract

ABSTRACT. There is a paucity of information on the significance of insulin on neonatal cerebral glucose metabolism. The effect of insulin on neonatal cerebral glucose uptake and cerebral cortical metabolic intermediates was investigated with the euglycemic hyperinsulinemic clamp in unanesthetized beagles during the first day of life. Insulin was infused at various rates to sustain an elevated steady state plasma insulin concentration in individual pups. Furthermore, blood glucose and 2-deoxyglucose levels were also maintained ("clamped") in a steady state by infusion of glucose and 2-deo~y-['~C]-glucose. Mean ( f SD) plasma insulin levels were 20 f 12 and 2971 f 3386 (33-14330) pU/ml in control and hyperinsulinemic pups. Blood glucose concentration was 4.43 f 2.64 mM during basal periods and 4.54 f 2.87 mM during the clamp period in study pups. Basal fasting glucose utilization in study pups was 43.9 f 24 pmol/kg/min and increased to 60.9 f 35.2 pmol/ kg/min (p < 0.001) during hyperinsulinemia. Immediately after the euglycemic hyperinsulinemic clamp or fasting in control pups, the cerebral cortex was frozen to the temperature of liquid nitrogen. No differences were noted for any cerebral cortical intermediate between the two pup groups. In addition, there was no relationship between the cerebral intermediates concentration when analyzed as a function of plasma insulin levels. The uptake of cerebral Z-deoxyglucose was analyzed as a function of plasma insulin concentration (120-6900 pU/ml). Brain tissue demonstrated a positive linear relationship for 2-deoxyglucose uptake as a function of plasma insulin concentration. Although static determination of brain metabolites were not influenced by hyperinsulinemia, there was a positive effect of insulin on cerebral glucose uptake. Either directly or indirectly, insulin may increase brain glucose utilization in the newborn dog. (Pediatr Res 23: 474-479, 1988) Glucose is considered the major substrate for brain energy metabolism. While it is know that insulin affects glucose uptake and metabolism in peripheral tissues, it is a matter of speculation whether insulin affects the uptake and utilization of glucose by the brain. Presently the results of studies that have investigated the effects of insulin on brain glucose uptake are inconclusive (1-8). Although the central nervous system is not considered an insulin sensitive tissue, recent studies have demonstrated high concentrations of insulin in the brain (9), and the presence of insulin receptors in microvessels (10, 11) as well as within the brain substance (12-15). Difficulties of interpretation of the present data may be related to the use of in vitro techniques and in vivo investigations that do not have a steady state of blood glucose or insulin levels.Investigations on the effects of insulin on the developing nervous system suggest that insulin may have an action on cerebral macromolecule synthesis (16,17). In the developing brain, insulin stimulates protein, and RNA and DNA synthesis in vitro (1 6, 17).Although i...

Effects of Euglycemic Hyperinsulinemia on Neonatal Canine Hepatic and Muscle Metabolism

“…Immediately at the end of the clamp studies, which was after 105 min of sustained hyperinsulinemia, the pups were killed. Samples of liver and muscle from the hindquarter were collected and immediately freeze-clamped, placed in liquid N2, and later stored at -80°C until further analyses of tissue glycolytic intermediates and 2-DG radioactivity (7,21). In addition, some pups also received an additional primed constant infusion of [l-14C]palmitate during the entire 195 min of the clamp.…”

“…The homogenization and extraction of liver and muscle were performed as reported previously (7,21). Glucose, glycogen, UDP-Glc, glucose 6-P, fructose 6-P, F 1,6P, phosphoenolpyruvate, pyruvate, lactate, citrate, a-KG, ATP, alanine, glutamine, glutamate, pyruvate kinase, glycogen synthase, and glycogen phosphorylase were assayed as reported previously (7, 2 1).…”

“…After delivery, newborn pups were dried and maintained in incubators at 37°C and 70% humidity. After stabilization, umbilical arterial and venous catheters were placed without trauma or stress and the pups rested in incubators during the remainder of the study (7,(19)(20)(21).…”