A B ST R A C T The metabolic response to the first fast experienced by all mammals has been studied in the newborn rat. Levels of fuels and hormones have been compared in the fetal and maternal circulations at term. Then, after cesarean section just before the normal time of birth, sequential changes in the same parameters were quantified during the first 16 h of the neonatal period. No caloric intake was permitted, and the newborns were maintained at 370C. Activities of three key hepatic enzymes involved in glucose production were estimated.Marked differences in maternal and fetal hormones and fuels were observed. Lower levels of glucose, free fatty acids, and glycerol but higher levels of lactate, a-amino nitrogen, alanine, and glutamine were present in the fetus. Pyruvate, glutamate, and ketone bodies were not significantly different. The combination of a strikingly higher fetal immunoreactive insulin and a slightly lower immunoreactive glucagon (pancreatic) resulted in a profound elevation in the insulin-to-glucagon ratio, a finding consistent with an organism in an anabolic state.The rat at birth presents a body composition with respect to fuels available for mobilization and conversion which is dominated by carbohydrate and protein, since little fat is present. However, at birth a transient period of hypoglycemia occurred, associated with a rapid fall in insulin and rise in glucagon, causing reversal of the insulin-to-glucagon relationship toward ratios such as were observed in the mother. After a lag period, hepatic activities of phosphorylase, glucose-6-phosphatase, and phosphoenolpyruvate carboxykinase increased. Concurrent with these enzyme changes, the blood glucose returned to levels at or above those of the fetus. Interestingly, the fall observed in levels of the gluconeogenic precursors, lactate and amino acids, preceded the rise in enzyme activities and restoration of blood glucose. After 4 h, however, hypoglycemia recurred, during a period of decreasing hepatic glycogen content and blood lactate, pyruvate, and glycerol levels but of stable or increasing amino acid concentrations. Hepatic gluconeogenesis in this phase of depleted glycogen stores was insufficient to maintain euglycemia.Substrates derived from fat showed early changes of smaller magnitude. The rise in free fatty acids which occurred was less than twofold the value at birth, though this rise persisted up to 6 h. Whereas glycerol rose transiently, acetoacetate did not change and P-hydroxybutyrate concentration fell. Both ketone bodies showed a marked rise at 16 h, at a time of diminished free fatty acid levels. Plasma growth hormone, though higher in the fetal than the maternal circulation, showed no consistent change during the period of observation.The changes in levels of the endocrine pancreatic hormones at birth were appropriate in time, magnitude, and direction to be implicated as prime regulators of the metabolic response during the neonatal period in the rat.

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The hormone-substrate milieu has been investigated in male fasted lean (C57BL/6-+/+) mice and mutant obese mice of the same strain (C57BL/6-obob). The lean mouse, in winter, mobilized insufficient fat (due to inadequate stores) to permit survival beyong 3 days and was unable to achieve any degree of conservation of vital protein stores. By contrast, in summer, the same animals survived 7 days and showed evidence of greater and more sustained fat mobilization and ketosis and the ability to conserve protein. The insulin, glucagon, and insulin/glucagon molar ratios changed in both groups in a direction consistent with conversion to a catabolic state, and hence were probably largely responsible for the mobilization of substrates and stimulation of gluconeogenesis and ketogenesis. The seasonal difference in response is unexplained. The obob mice, generally employed as a model for obesity, hyperglycemia, and hyperinsulinemia showed these features but also adapted to fasting in a fashion permitting prolonged survival during this state. In a fashion analogous to that known to occur in man, these animals developed fall in glycemia, rise in circulating fat-derived substrates, and marked protein conservation. Profound fall in insulinemia was associated with a fall in glucagonemia, the latter from normal levels. Thus the initial markedly "anabolic" insulin/glucagon molar ratio diminished, but nevertheless remained higher than at any time in the lean mice. Pancreatic contents of insulin showed markedly different changes with fasting in obob compared with lean mice. The ability of the obese mouse to adapt to prolonged fasting in a fashion largely analogous to that of man renders it a useful model for the study of metabolism in this state, with the potential of applicability of findings to man.