Both GLP-1 and GLP-2 are secreted from gut endocrine cells in the small and large intestine. Secretion of these peptides is predominantly regulated by nutrient intake, as shown in Brubaker PL, Crivici A, Izzo A, Ehrlich P, Tsai CH, Drucker DJ. Circulating and tissue forms of the intestinal growth factor, glucagon-like peptide-2. Endocrinology. 1997 Nov;138(11):4837-43.
Furthermore, GLP-2, like GLP-1 is subject to N-terminal degradation by the enzyme DPP-IV. Accordingly, GLP-2 analogues that are resistant to DPP-IV are more potent in vivo, as shown in Drucker D.J., Shi, Q., Crivici, A., Sumner-Smith, M., Tavares, W., Hill, M. DeForest, L., Cooper, S., and Brubaker, P.L. Regulation of the biological activity of glucagon-like peptide 2 in vivo by dipeptidyl peptidase IV Nature Biotechnology 1997 15:673-677
How is GLP-2 metabolized and cleared from the circulation? Wendy Tavares and colleagues present studies of GLP-2 clearance in +/+ and DP IV-/- rats in Am J Physiol Endocrinol Metab 2000 Jan;278(1):E134-E139 Enzymatic- and renal-dependent catabolism of the intestinotropic hormone glucagon-like peptide-2 in rats
Circulating GLP-2 in human subjects
Consistent with older data for glicentin, the intestinal PGDPs, and GLP-1, plasma levels of GLP-2 are regulated in a nutrient-dependent manner in normal subjects Radio-immunoassays for glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). Scand J Clin Lab Invest. 1987 Apr;47(2):165-74, and total GLP-2 immunoreactivity in human plasma reflects the presence of both GLP-2(1-33) and GLP-2(3-33), as outlined in Circulating and tissue forms of the intestinal growth factor, glucagon-like peptide-2. Endocrinology. 1997 Nov;138(11):4837-43
GLP-2 degradation and clearance was subsequently studied in human subjects by Hartmann, Holst and colleagues. These investigators administered GLP-2 by intravenous infusion or subcutaneous injection, and followed metabolism of the peptide by HPLC and N-terminal specific RIAs. About 69% of GLP-2(1-33) remained intact 1 hour after GLP-2 injection, with GLP-2 (3-33) the major degradation product detected. See J Clin Endocrinol Metab 2000 Aug;85(8):2884-8
Analysis of the levels and circulating forms of immunoreactive GLP-2 in human subjects with inflammatory bowel disease is described in Circulating levels of glucagon-like peptide-2 in human subjects with inflammatory bowel disease Am J Physiol Regul Integr Comp Physiol 2000 278(4):R1057-R1063. Intriguingly, acutely ill hospitalized patients with IBD appear to have a shift in the ratio of circulating bioactive GLP-2(1-33) vs bioinactive GLP-2 (3-33). In contrast, intestinal GLP-2 content and meal-stimulated levels of plasma GLP-2 were comparable in subjects (outpatients) with intestinal inflammation vs non-IBD controls, as described in Tissue levels and post-prandial secretion of the intestinal growth factor, glucagon-like peptide-2, in controls and inflammatory bowel disease: comparison with peptide YY. Eur J Gastroenterol Hepatol. 2005 Feb;17(2):207-12
Do patients with intestinal failure and short bowel syndrome exhibit relative GLP-2 deficiency? In a carefully designed study of 7 patients with short bowel syndrome, Jeppesen and colleagues from Denmark Impaired meal stimulated glucagon-like peptide 2 response in ileal resected short bowel patients with intestinal failure Gut 1999 Oct;45(4) :559-563 studied the meal-stimulated GLP-2 response in patients with short bowel syndrome (SBS). Patients with SBS exhibited an absent GLP-2 response to meal ingestion. These findings, taken together with the putative importance of GLP-2 for nutrient assimilation, gastric motility and maintenance of the mucosal epithelium, suggest that short bowel syndrome represents a relative form of GLP-2 hormone deficiency. The Copenhagen group suggests that GLP-2 therapy be evaluated in patients with short bowel syndrome and intestinal failure.
In contrast to the GLP-2 deficiency exhibited by short bowel patients without a colon, ileum-resected patients with a preserved colon often exhibit elevated levels of GLP-2, perhaps as part of an adaptive response to SB resection. See Gut 2000 Sep;47(3):370-376
Plasma levels of GLP-2 have been assessed in human infants with intestinal disorders. GLP-2 levels did not strictly correlate with nutrient absorption and plasma GLP-2 levels were correlated with residual small bowel length and may be predictive of outcome GLP-2 levels in infants with intestinal dysfunction. Pediatr Res. 2004 Sep;56(3):371-6. Limited information is available in regard to normal levels of GLP-2 in babies or infants. Analysis of plasma levels of circulating GLP-1 and GLP-2 in premature (29.6 weeks mean gestational age) infants demonstrated that plasma levels of both peptides are increased in the fasting state, and levels are proportionate to the amount of oral nutrient ingested Functional ontogeny of the proglucagon-derived peptide axis in the premature human neonate Pediatrics. 2008 Jan;121(1):e180-6
Plasma levels of GLP-2 have also been examined in children with cancer undergoing chemotherapy. No significant defects were observed in levels of plasma GLP-2 following nutrient ingestion as long as nutrient intake was adequate, as outlined in Glucagon-like peptide-2 (GLP-2) response to enteral intake in children during anti-cancer treatment. J Pediatr Gastroenterol Nutr. 2005 Jan;40(1):48-53
Circulating GLP-2 and intestinal injury/resection
The temporal changes in levels of circulating GLP-2 have also been studied in rats following 70% mid-jejunoileal resection or ileal transection. Following surgery, rats were maintained with total parenteral nutrition (TPN) or oral feeding. Small bowel mucosal hyperplasia was noted even in TPN fed rats, hence luminal nutrients are not essential for resection-induced adaptation as long as some residual ileum and colon are present. Intestinal resection was associated with transient increases in plasma bioactive GLP-2 in both TPN and enterally-fed animals, with increases in levels of proglucagon mRNA differentially observed in the colon of TPN-fed rats and ileum of orally fed rats. See Role of luminal nutrients and endogenous GLP-2 in intestinal adaptation to mid-small bowel resection Am J Physiol Gastrointest Liver Physiol 284: G670-G682, 2003
Increased plasma levels of GLP-2 after major small bowel resection was also reported in rodent studies using 2 assays, a GLP-2 RIA and a GLP-2 ELISA. Circulating levels of GLP-2 were significantly increased prior to and after feeding after 90% SBR in rats. The increase in plasma levels of GLP-2 after SBR was proportional to the amount of small bowel resected, as described in Nutrient-stimulated GLP-2 release and crypt cell proliferation in experimental short bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2005 Mar;288(3):G431-8.
As both GLP-1 and GLP-2 are co-secreted from the same gut L cells in the small and large bowel, factors identified as "GLP-1 secretagogues" are also likely to stimulate GLP-2. Hence, biguanides, known GLP-1 secretagogues, have also been shown to increase the plasma levels of GLP-2 in mice and rats, and the combination of metformin and the DPP-IV inhibitor Val-Pyr increased small bowel weight in mice treated with 5-FU, as shown in The combination of metformin and a dipeptidyl peptidase IV inhibitor prevents 5-fluorouracil-induced reduction of small intestine weight. Eur J Pharmacol. 2004 Mar 19;488(1-3):213-8