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

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.