Tolbutamide inhibits gluconeogenesis in the tumor-influenced hepatocyte.
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.
Blumberg
D
D
Surgical Metabolism Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York 10021.
Burt
M E
ME
Kher
U
U
Brennan
M F
MF
D000409:Alanine / Q000378:metabolism; D000818:Animals; D005943:Gluconeogenesis / Q000187:drug effects*; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008748:Methylcholanthrene; D009368:Neoplasm Transplantation; D051381:Rats; D011916:Rats, Inbred F344; D012513:Sarcoma, Experimental / Q000139:chemically induced / Q000378:metabolism*; D014044:Tolbutamide / Q000494:pharmacology*
D007773:Lactates; D019344:Lactic Acid; D008748:Methylcholanthrene; D014044:Tolbutamide; D000409:Alanine