THE DISSOCIATION OF TUMOR-INDUCED WEIGHT-LOSS FROM HYPOGLYCEMIA IN A TRANSPLANTABLE PLURIPOTENT RAT ISLET TUMOR RESULTS IN THE SEGREGATION OF STABLE ALPHA-CELL AND BETA-CELL TUMOR PHENOTYPES
Od. Madsen et al., THE DISSOCIATION OF TUMOR-INDUCED WEIGHT-LOSS FROM HYPOGLYCEMIA IN A TRANSPLANTABLE PLURIPOTENT RAT ISLET TUMOR RESULTS IN THE SEGREGATION OF STABLE ALPHA-CELL AND BETA-CELL TUMOR PHENOTYPES, Endocrinology, 133(5), 1993, pp. 2022-2030
We previously established pluripotent transformed rat islet cell lines
, MSL-cells, of which certain clones have been used to study processes
of islet beta-cell maturation, including the transcriptional activati
on of the insulin gene induced by in vivo passage. Thus, successive sc
transplantation in NEDH rats resulted in stable hypoglycemic insulino
ma tumor lines, such as MSL-G2-IN. Occasionally, hypoglycemia as well
as severe weight loss were observed in the early tumor passages of MSL
-G and the subclone, NHI-5B, which carry the transfected neomycin and
human insulin genes as unique clonal markers. By selective transplanta
tion, it was possible to segregate stable anorectic normoglycemic tumo
r lines, MSL-G-AN and NHI-5B-AN, from both clones. These tumors cause
an abrupt onset of anorexia when they reach a size of 400-500 mg (<0.3
% of total body weight), and the observed weight loss parallels that o
f starved rats until death results from cachexia. After tumor resectio
n, animals immediately resume normal feeding behavior. Comparative stu
dies of hormone release and MRNA content in anorectic lines, MSL-G-AN
and NHI-5B-AN, vs. those in the insulinoma line, MSL-G2-IN, revealed s
elective glucagon gene expression in both of the anorectic tumors, whe
reas insulin and islet amyloid polypeptide gene expression were confin
ed to the insulinoma. Both tumor phenotypes produced cholecystokinin a
nd gastrin in variable small amounts, making it unlikely that these ho
rmones contribute to the anorectic phenotype. Tumor necrosis factor (c
achectin) was not produced by any of the tumors. Proglucagon was proce
ssed as in the fetal islet to products representative of both pancreat
ic alpha-cell and intestinal L-cell phenotypes, with glucagon and Glp-
1 (7-36)amide as the major extractable products. In contrast to the ad
ministration of cholecystokinin, neither glucagon, Glp-1 (7-36)amide,
nor their combination, affected feeding behavior in fasted mice, sugge
sting the presence of a hitherto unidentified anorectic substance rele
ased from the glucagonoma. We conclude 1) that glucagonomas and insuli
nomas can be derived from a common clonal origin of pluripotent MSL ce
lls, thus supporting the existence of a cell lineage relationship betw
een islet alpha- and beta-cells during ontogeny; and 2) that our gluca
gonomas release an anorexigenic substance(s) of unknown nature that ca
uses a severe weight loss comparable to that reported in animals carry
ing tumor necrosis factor-producing experimental tumors.