To explore mechanisms whereby unabsorbed nutrients in the ileum inhibit the upper gut ("ileal brake"), we perfused the canine ileum or colon and monitored phase 3 in the duodenum. Fasting motility was recorded when the ileum or colon was perfused with 154 mM NaCl, a mixed isotonic nutrient solution (Ensure), or individual nutrients (maltose, casein hydrolysates, or sodium oleate). Blood samples were collected before and during the perfusions. The ileum was also perfused with 154 mM NaCl while peptide YY (PYY) was infused by vein. In both sets of experiments, plasma levels of PYY, neurotensin, and glucagon-like peptide-1 (GLP-1) were measured. Ileal or colonic perfusion of Ensure delayed phase 3 [migrating motor complexes (MMC)] in the duodenum, inhibited ileal motility, and increased plasma levels of PYY and GLP-1. Ileal casein and oleate and colonic casein also delayed the duodenal MMC. The MMC cycle length and plasma levels of PYY were closely correlated. Intravenous PYY prolonged the MMC cycle; an intravenous dose of 100 pmol.kg-1.h-1 of PYY mimicked the effects of ileal Ensure. These results support the hypothesis that PYY, and possibly GLP-1, participate in the ileal brake. This negative feedback loop also affects the distal small bowel. The proximal colon also triggers the feedback inhibition of gut motility (colonic brake).

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Unfortunately the dose of the GLP-1 bolus during the hyperglycaemic clamp was incorrectly given as 0.6 pmol/kg body weight, instead of 4.5 pmol/kg body weight.The authors apologise for this mistake.

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 activation of the insulin gene induced by in vivo passage. Thus, successive sc transplantation in NEDH rats resulted in stable hypoglycemic insulinoma 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 transplantation, it was possible to segregate stable anorectic normoglycemic tumor 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 of starved rats until death results from cachexia. After tumor resection, animals immediately resume normal feeding behavior. Comparative studies 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 selective glucagon gene expression in both of the anorectic tumors, whereas insulin and islet amyloid polypeptide gene expression were confined to the insulinoma. Both tumor phenotypes produced cholecystokinin and gastrin in variable small amounts, making it unlikely that these hormones contribute to the anorectic phenotype. Tumor necrosis factor (cachectin) was not produced by any of the tumors. Proglucagon was processed as in the fetal islet to products representative of both pancreatic alpha-cell and intestinal L-cell phenotypes, with glucagon and Glp-1 (7-36)amide as the major extractable products. In contrast to the administration of cholecystokinin, neither glucagon, Glp-1 (7-36)amide, nor their combination, affected feeding behavior in fasted mice, suggesting the presence of a hitherto unidentified anorectic substance released from the glucagonoma. We conclude 1) that glucagonomas and insulinomas can be derived from a common clonal origin of pluripotent MSL cells, thus supporting the existence of a cell lineage relationship between islet alpha- and beta-cell during ontogeny; and 2) that our glucagonomas release an anorexigenic substance(s) of unknown nature that causes a severe weight loss comparable to that reported in animals carrying tumor necrosis factor-producing experimental tumors.

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