Intestinal Proliferation and Delayed Intestinal Transit in a Patient with a GLP-1-, GLP-2- and PYY-Producing Neuroendocrine Carcinoma

Abstract

Glucagon-like peptides (GLP) 1 and 2 are hormones derived from the post-translational processing of proglucagon in the intestinal L cells that influence intestinal motility and small bowel growth, respectively. We describe a patient with a neuroendocrine tumor of unknown primary origin with peritoneal carcinomatosis and diffuse liver metastases, who presented with constipation and nocturnal itching for over 3 years. Small bowel follow-through showed decreased small intestinal motility and marked intestinal hypertrophy. Biopsies from mesenterial lymph nodes showed, histologically, a well-differentiated neuroendocrine tumor (G1), with positive immunostaining for chromogranin A, GLP-1, GLP-2 and polypeptide YY (PYY). Jejunal biopsy demonstrated marked intestinal mucosal hypertrophy. HPLC analysis combined with RIA of tumor and serum extracts revealed that the tumor was producing and releasing fasting levels of GLP-1 of 738±20.7 pg/ml (normal levels (nl) <100 pg/ml), GLP-2 of 3,150±9 pg/ml (nl <100 pg/ml) as well as PYY 550 pg/ml (nl <100 pg/ml). Octreotide administration decreased levels of GLP-1 and GLP-2 and reduced small intestinal transit time from 150 to 50 min. However, tumor growth was not inhibited by octreotide, interferon or dacarbazine therapy and the patient died 8 months later. This is the first case report demonstrating the overproduction of GLP-1, GLP-2 and PYY from an neuroendocrine tumor, in a patient with intestinal hypertrophy and delayed intestinal transit time.

Exogenous glucagon-like peptide 1 reduces contractions in human colon circular muscle

“…This mechanism is consonant with the GLP1 capacity of delaying gastrointestinal transit not only in humans but also in rodents (Tolessa et al 1998a,b, Näslund et al 2001, Miki et al 2005, Schirra et al 2009, Hellström 2011. Moreover, our results could provide a mechanistic explanation for the observations that GLP1-secreting tumors are associated with severe constipation and delayed colonic transit (Byrne et al 2001, Brubaker et al 2002), and for the constipation observed in prolonged treatment with liraglutide (Jeong & Yoo 2011). Our finding seem in contrast with previous findings that showed weak contractions in response to GLP1 in isolated circular smooth muscle cells from the human colon, which are likely due to an increase in the availability of glucose energy (Ayachi et al 2005).…”

“…Few studies have analyzed the role of GLP1 in the regulation of colonic contractility, and the results remain controversial because both GLP1 stimulatory (Gülpinar et al 2000, Ayachi et al 2005 and inhibitory (Byrne et al 2001, Amato et al 2010 effects have been described. Interestingly, constipation has been reported among the side effects in treatment with liraglutide, a human GLP1R agonist, successfully used for the treatment of type 2 diabetes mellitus (Seino et al 2010, Jeong & Yoo 2011.…”

MANAGEMENT OF ENDOCRINE DISEASE: A clinical update on tumor-induced hypoglycemia

“…However, severe hypoglycemia is not always associated with GLP1 tumor secretion. In fact, two other patients with GLP1-and GLP2-producing NETs and with the absence of symptomatic hypoglycemia have been previously reported (86,87). …”

A Thirty-Seven-Year Follow-Up of Peutz–Jeghers Syndrome across Three Generations / Tridesetsedmogodišnje praćenje Pojc-Jegersovog sindroma kroz tri generacije

“…This finding corresponds to the fact that, although these hamartomatous polyps themselves do not have malignant potential, patients with the syndrome must have an increased risk of developing adenocarcinoma (7)(8)(9)(10). When gastrointestinal adenocarcinoma occurs, it probably arises from coincidental adenomatous lesions that we have observed inside the polypous bulk surrounding the largest ileal polyp.…”