The
tumor-bearing state is associated with an increase in gluconeogenesis which may contribute to the development of
cancer cachexia. The purpose of this study was to determine if
tolbutamide, a
drug known to decrease gluconeogenesis in diabetes, could decrease gluconeogenesis in hepatocytes isolated from
tumor-bearing rats. Hepatocytes from 24-hr fasted normal and
methylcholanthrene-induced
sarcoma-bearing rats (5-10%
tumor burden) were isolated by in situ
collagenase liver perfusion. Hepatocytes (n = 12 samples) from non-
tumor-bearing (NTB) controls and
tumor-bearing (TB) rats were incubated with
lactate (10 mM) and
alanine (10 mM) with and without 1 mM
tolbutamide. Supernatant
glucose concentration was measured at 30-min intervals for 2 hr. Rates of gluconeogenesis (+/- standard error) were calculated by linear regression and are expressed as nmole
glucose/10(6) cells/min. Comparisons were made by two-way analysis of variance and significance defined as P < 0.05. TB hepatocytes had an increased rate of gluconeogenesis (P < 0.0001) from
alanine and
lactate (3.8 +/- 0.30 and 2.2 +/- 0.10, respectively) compared with NTB hepatocytes (0.66 +/- 0.10 and 1.2 +/- 0.04, respectively). TB hepatocytes treated with
tolbutamide had a decreased (P < 0.0001) rate of gluconeogenesis from
alanine and
lactate (3.1 +/- 0.10 and 1.1 +/- 0.10, respectively) compared with untreated TB hepatocytes (5.3 +/- 0.10 and 2.1 +/- 0.10, respectively).
Tolbutamide inhibits gluconeogenesis from
lactate and
alanine in
tumor-influenced hepatocytes.