glucagon-like-peptide-2 and Diabetes-Mellitus

The glucagon-like peptides GLP-1 and GLP-2 are produced in enteroendocrine L cells of the small and large intestine and secreted in a nutrient-dependent manner. GLP-1 regulates nutrient assimilation via inhibition of gastric emptying and food intake. GLP-1 controls blood glucose following nutrient absorption via stimulation of glucose-dependent insulin secretion, insulin biosynthesis, islet proliferation, and neogenesis and inhibition of glucagon secretion. Experiments using GLP-1 antagonists and GLP-1 receptor-/- mice indicate that the glucoregulatory actions of GLP-1 are essential for glucose homeostasis. In the central nervous system, GLP-1 regulates hypothalamic-pituitary function and GLP-1-activated circuits mediate the CNS response to aversive stimulation. GLP-2 maintains the integrity of the intestinal mucosal epithelium via effects on gastric motility and nutrient absorption, crypt cell proliferation and apoptosis, and intestinal permeability. Both GLP-1 and GLP-2 are rapidly inactivated in the circulation as a consequence of amino-terminal cleavage by the enzyme dipeptidyl peptidase IV (DP IV). The actions of these peptides on nutrient absorption and energy homeostasis and the efficacy of GLP-1 and GLP-2 in animal models of diabetes and intestinal diseases, respectively, suggest that analogs of these peptides may be clinically useful for the treatment of human disease.

Topics: Animals; Central Nervous System; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Intestinal Diseases; Intestines; Pancreas; Peptide Fragments; Peptides; Protein Precursors

Glucagon-like peptides 1 and 2 (GLP-1 and GLP-2) are coencoded within a single mammalian proglucagon precursor, and are liberated in the intestine and brain. GLP-1 exerts well known actions on islet hormone secretion, gastric emptying, and food intake. Recent studies suggest GLP-1 plays a central role in the development and organization of islet cells. GLP-1 receptor signaling appears essential for beta cell signal transduction as exemplified by studies of GLP-1R-/- mice. GLP-2 promotes energy assimilation via trophic effects on the intestinal mucosa of the small and large bowel epithelium via a recently cloned GLP-2 receptor. The actions of GLP-2 are preserved in the setting of small and large bowel injury and inflammation. The biological actions of the glucagon-like peptides suggest they may have therapeutic efficacy in diabetes (GLP-1) or intestinal disorders (GLP-2).

Topics: Animals; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucagon-Like Peptide-1 Receptor; In Vitro Techniques; Intestinal Diseases; Intestinal Mucosa; Islets of Langerhans; Mice; Mice, Knockout; Peptide Fragments; Peptides; Protein Precursors; Receptors, Glucagon; Signal Transduction

Biliopancreatic diversion (BPD) is a predominantly malabsorptive procedure. Glucagon-like peptide 2 (GLP-2) plays predominantly trophic effects on the gut. A significant increase in GLP-2 after BPD in rats was previously observed, but there are no studies investigating the effect of BPD in GLP-2 levels in humans.. The aim of this study is to evaluate the influence of BPD on the release of GLP-2.. This is a prospective cohort study that evaluated diabetic individuals with class I obesity which underwent BPD (Scopinaro operation) and were followed up for 12 months. Of 12 individuals, four did not comply with the proposed follow-up and were excluded from the analysis. GLP-2 levels were determined by means of an enzyme-linked immunosorbent assay (ELISA), and we collected serial lab samples through a standard meal tolerance test (MTT) in the immediate preoperative period and 12 months after surgery.. During standard MTT, we observed significant increases of GLP-2 levels from 15 to 60 min (respectively, at 15 min, 5.7 ± 3.4 versus 12.4 ± 4.3, p = 0.029; 30 min, 6 ± 3.5 versus 14.6 ± 3.9; p = 0.004; 45 min, 5.6 ± 4.1 versus 12.6 ± 5.2, p = 0.013; 60 min, 5.8 ± 2.9 versus 10.6 ± 5.6, p = 0.022); then it began to gradually decrease to levels close to the basal.. Our findings have confirmed that there is a significant increase in GLP-2 levels after BPD in humans. GLP-2 plays a number of roles which may be adaptive, compensatory, and beneficial in the context of BPD. The clinical implications of this finding remain to be completely understood.

Topics: Adult; Animals; Biliopancreatic Diversion; Diabetes Complications; Diabetes Mellitus; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Male; Middle Aged; Obesity; Postprandial Period; Prospective Studies; Rats

Supraphysiological doses of glucagon-like peptide-2 (GLP-2) have been shown to induce intestinal growth by increasing villus height and crypt depth and by decreasing apoptosis, but a physiological effect of GLP-2 has not yet been demonstrated. Earlier, we found elevated levels of endogenous GLP-2 in untreated streptozotocin diabetic rats associated with marked intestinal growth. In the present study, we investigated the role of endogenous GLP-2 for this adaptive response. We included four groups of six rats: (1) diabetic rats treated with saline, (2) diabetic rats treated with non-specific antibodies, (3) diabetic rats treated with polyclonal GLP-2 antibodies and (4) non-diabetic control rats treated with saline. All animals were treated with once daily intraperitoneal injections for 13 days and killed on day 14. Diabetic rats treated with saline or non-specific antibodies had a significantly (P<0.01) increased area of mucosa (13.00+/-0.64 and 13.37+/-0.60 mm(2), respectively) in the proximal part of the small intestine compared with non-diabetic controls (7.97+/-0.70 mm(2)). In contrast, diabetic rats treated with GLP-2 antibodies had a significantly (P<0.01) smaller increase in area of mucosa in the proximal part of the small intestine (10.84+/-0.44 mm(2)). Antibody treatment had no effect on body weight, blood glucose concentrations and food intake. Thus, blocking of endogenous GLP-2 in a model of adaptive intestinal growth reduces the growth response, providing strong evidence for a physiological growth factor function of GLP-2.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Eating; Female; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Intestinal Mucosa; Intestines; Neutralization Tests; Organ Size; Peptides; Rats; Rats, Wistar