Obese mice (C57BL/6J ob/ob) and their lean littermates were studied at various ages from immediately post weaning until 62 weeks of age, at which mortality increased markedly. Several age-related changes were noted. 1) Plasma glucose levels were elevated in obese mice 5-20 weeks and 62 weeks of age, but were similar to those in the lean mice at 20-60 weeks of age. Plasma insulin levels were elevated in obese mice, and there were no age-related differences. 2) Brain serotonin was elevated in obese mice at all ages and increased with age in both obese and lean animals. 3) Pituitary contents of ACTH and beta-endorphin were elevated in young obese mice and increased further as these mice approached their life expectancy. 4) The ratios of ACTH to beta-endorphin immunoreactivities were similar in obese and lean mice, except in obese mice over 50 weeks of age where this ratio was increased. We conclude that: 1) the obese mouse is characterized by hyperinsulinemia and hyperadrenocorticism throughout its life; 2) the insulin resistance of the obese mouse improves at 20 weeks of age, yet deteriorates as its life expectancy is approached; 3) the obese mouse has an elevated brain serotonin content similar to previously described elevations of the putative neurotransmitters dopamine and norepinephrine in these mice; and 4) as the obese mouse approaches its life expectancy, abnormalities may occur in the synthesis, processing, or secretion of ACTH and/or beta-endorphine.

1. The oral antidiabetic glycodiazine (2-benzene sulfonamido-5-~-methoxyethoxy pyrimidine), an inhibitor of hepatic lipolysis, was used to investigate the metabolic role of liver lipid in glucogenesis in the perfused livers of fasted (24-30 h) rats. I n a concentration of 10 mM, glycodiazine inhibited almost completely endogenous ketone body formation.2 . Perfusion with pyruvate as substrate, in the presence of glycodiazine, resulted in a higher rate of pyruvate oxidation and suppressed the rate of glucose synthesis in comparison to livers perfused with pyruvate alone. Thus, maximal rates of gluconeogenesis from pyruvate would seem to require an adequate supply and oxidation of fatty acids.3. Oleate, even in the presence of glycodiazine, stimulates glucose synthesis from pyruvate. Uptake of and ketone body formation from oleate were also not affected by glycodiazine. These results allow the conclusion that glycodiazine specifically inhibits liver lipolysis.4. Glucagon (57 nM), although having no significant effect on gluconeogenesis from pyruvate a t this concentration, overcame the inhibitory effects of glycodiazine on glucose formation and suppressed the elevated pyruvate oxidation which results from the inhibition of endogenous lipid mobilization.5. Glucagon, in the absence of added substrates, stimulated gluconeogenesis, urea production and ketogenesis. The increase in gluconeogenesis due to glucagon was not impaired by glycodiazine. This indicates that intermediates arising from fatty acid oxidation do not limit the rate of gluconeogenesis under these conditions.

After intravenous injections, we have found the immunological half-life of purified porcine proinsulin to be more prolonged than purified porcine single-component insulin in both swine (22 and 9 min, respectively) and in baboons (18 and 8 min, respectively). Studies in humans have also indicated a longer half-life of proinsulin than insulin (1). These findings have prompted the present investigation of the in vitro degradation of insulin, proinsulin, and the connecting peptide that links the A and B chains of insulin in the proinsulin molecule, using an isolated liver perfusion system.Methods. Intact livers, weighing 4.5-6.8 g, from male Wistar rats, fasted for 48 hr, were cyclically perfused by the method of Hems et al. ( 2 ) . The perfusion fluid consisted of washed human erythrocytes, 2 g/lOO ml bovine serum albumin (Cohn, Fraction V ) , and Krebs-Henseleit buffer, pH 7.4, with a hemoglobin concentration of approximately 3 g/lOO ml. After complete isolation from the circulation, the livers were perfused in situ by adjusting the hydrostatic pressure of the perfusate to give maximal perfusion rates without liver swelling. This was approximately 2-3 ml/g wet weight of liver. The total perfusion volume was 150 ml at the beginning of the experiment. After a 40-min equilibration period, purified porcine single-component insulin (Lilly ), proinsulin (Lilly ), or con-

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