In an attempt to define the relationship between
tumor burden (
cachexia) and host hepatocyte gluconeogenesis, the following experiments were performed with the use of an F344 male rat bearing a transplantable
sarcoma. Food intake of
tumor-bearing (TB) rats was constant until day 24 following implant and a
tumor burden of 18 +/- 5.2% (mean +/- SD), at which time food intake progressively declined daily.
Tumor burden was arbitrarily divided at 12.8% to determine if any measured changes occurred prior to or following the approximate time when a significant decline in food intake occurred. Plasma
glucose levels decreased with
tumor burden. Whole-blood
lactate levels increased with
tumor burden. Fasting plasma
alanine levels decreased with
tumor burden. Plasma
3-methylhistidine levels increased with
tumor burden. Plasma
glucagon levels increased with
tumor burden, whereas plasma
insulin levels decreased.
Hormone changes were noted at small
tumor burdens prior to a decline in food intake. Viable hepatocytes were isolated from 4 groups: non-
tumor-bearing (NTB), small
tumor burden [(STB) 3.5% total
body weight (TBW)], moderate
tumor burden [(MTB) 14% TBW], and large
tumor burden [(LTB) 23% TBW]. As expected in NTB rats, hepatocytes produced significantly more
glucose with 20 mM
lactate than 20 mM
alanine or than
Hanks' balanced salt solution (HBSS) alone. Hepatocytes from STB rats demonstrated the same basic relationship for
lactate,
alanine, and HBSS, but they produced significantly more
glucose from
lactate and HBSS alone than NTB hepatocytes. With
alanine as substrate, the rates of
glucose production by hepatocytes were not affected by the presence or size of
tumor. However, with
lactate as substrate, hepatocytes from MTB and LTB rats produced progressively less
glucose as
tumor burden increased (r = -0.85, p less than .001), which may partly explain the reduction in
blood glucose and elevation in blood
lactate levels observed. Elevated gluconeogenesis in TB rats occurred early prior to a decline in food intake. The key precursor appeared to be
lactate. The balance between
glucagon and
insulin appeared to promote the abnormal host carbohydrate metabolism observed.