Durability of Linear Small‐Intestinal Growth Following Treatment Discontinuation of Long‐Acting Glucagon‐Like Peptide 2 (GLP‐2) Analogues

2020 ◽  
Author(s):  
Tierah Hinchliffe ◽  
Mirielle L. Pauline ◽  
Pamela R. Wizzard ◽  
Patrick N. Nation ◽  
Patricia Brubaker ◽  
...  
Keyword(s):  
Treatment Discontinuation ◽  
Intestinal Growth ◽  
Glucagon Like Peptide ◽  
Small Intestinal ◽  
Long Acting

Role of phosphatidylinositol-3 kinase-γ in the actions of glucagon-like peptide-2 on the murine small intestine

2007 ◽  
Vol 292 (6) ◽  
pp. E1599-E1606 ◽  
Author(s):  
Younes Anini ◽  
Angelo Izzo ◽  
Gavin Y. Oudit ◽  
Peter H. Backx ◽  
Patricia L. Brubaker
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Mucous Cell ◽  
Cell Number ◽  
Phosphatidylinositol 3 Kinase ◽  
Intestinal Growth ◽  
Glucagon Like Peptide ◽  
Small Intestinal ◽  
Long Acting ◽  
Phosphatidylinositol 3

Glucagon-like peptide-2 (GLP-2) enhances intestinal growth and function through a cAMP-linked G protein-coupled receptor (GPCR) expressed in the mucosal layer and enteric nervous system. Because the type 1B γ-isoform of phosphatidylinositol 3-kinase (PI3-K) is activated by GPCRs, we determined whether this enzyme plays a role in the intestinal actions of GLP-2 by using PI3-Kγ knockout (KO) mice. Wild-type (WT), heterozygous, and KO mice were treated with vehicle or 1 μg Gly2-GLP-2 (a long-acting analog) twice daily for 10 days and analyzed for changes in intestinal growth, motility, and cAMP production. Basal small intestinal wet weight was increased in KO mice in association with enhanced crypt-villus height and crypt cell proliferation ( P < 0.05–0.01). However, the GLP-2-induced changes in these parameters were not different between KO and WT animals. GLP-2 treatment also enhanced the number of mucous cells in the intestinal epithelium, but this effect was lost in the PI3-Kγ KO mice. Both basal and GLP-2-induced suppression of intestinal transit were normal in KO mice. In contrast, the ability of GLP-2 to stimulate cAMP levels in isolated muscle strips was abrogated by loss of PI3-Kγ, despite the expression of GLP-2 receptor mRNA transcripts in this tissue. Together, the results of this study demonstrate a role for PI3-Kγ in basal but not GLP-2-induced small intestinal mucosal growth. However, PI3-Kγ is important for the enhancement of mucous cell number by GLP-2 and in the ability of the GLP-2 receptor to couple to cAMP in the enteric nervous system.

Intestinal growth is associated with elevated levels of glucagon-like peptide 2 in diabetic rats

1997 ◽  
Vol 273 (4) ◽  
pp. E815-E820 ◽  
Author(s):  
Kirk D. Fischer ◽  
Savita Dhanvantari ◽  
Daniel J. Drucker ◽  
Patricia L. Brubaker
Keyword(s):  
Experimental Diabetes ◽  
Plasma Concentrations ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Villus Height ◽  
Intestinal Growth ◽  
Glucagon Like Peptide ◽  
Small Intestinal ◽  
The Relationship ◽  
Intestinal Weight

Glucagon-like peptide 2 (GLP-2) has recently been identified as a novel intestinal growth factor. Because experimental diabetes is associated with bowel growth, we examined the relationship between GLP-2 and intestinal growth in rats made diabetic by streptozotocin (STZ) injection and treated with or without insulin for 3 wk. Ileal concentrations of the intestinal proglucagon-derived peptides, i.e., glicentin + oxyntomodulin, and GLPs 1 and 2, were increased by 57 ± 20% above those of controls in untreated STZ diabetes ( P < 0.05–0.001). Similar increases in plasma concentrations of glicentin + oxyntomodulin (77 ± 15% above controls, P < 0.01) and GLP-2 (91 ± 32% above controls, P < 0.05) were seen in untreated STZ diabetes. Both wet and dry small intestinal weight increased by 74 ± 20% above controls ( P < 0.01) in STZ diabetes, and macromolecular analysis indicated parallel increases in both protein ( P < 0.001) and lipid ( P < 0.05) content. Villus height ( P < 0.001) and crypt depth ( P < 0.01) were also increased in untreated diabetic rat intestine. Insulin therapy prevented the changes in plasma GLP-2 and intestinal mass seen in untreated STZ diabetes. Thus STZ diabetes is associated with both increased production of GLP-2 and enhanced bowel weight, thereby suggesting a role for GLP-2 in diabetes-associated bowel growth.

scholarly journals Carcinogenic Effects of Exogenous and Endogenous Glucagon-Like Peptide-2 in Azoxymethane-Treated Mice

Endocrinology ◽  
2009 ◽  
Vol 150 (9) ◽  
pp. 4033-4043 ◽  
Author(s):  
Roman Iakoubov ◽  
Lina M. Lauffer ◽  
Shivangi Trivedi ◽  
Young-In J. Kim ◽  
Patricia L. Brubaker
Keyword(s):  
Body Weight ◽  
Colon Carcinogenesis ◽  
Aberrant Crypt Foci ◽  
Carcinogenic Effects ◽  
Human Therapy ◽  
Intestinal Proliferation ◽  
Glucagon Like Peptide ◽  
Small Intestinal ◽  
Long Acting ◽  
Intestinal Weight

Abstract Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent intestinotropic hormone that promotes intestinal growth, via increased intestinal proliferation and decreased apoptosis, as well as increases in nutrient absorption and barrier function. The long-acting analog h(Gly2)GLP-2[1-33] is currently being tested for treatment of short bowel syndrome and Crohn’s disease. However, the role of GLP-2 in colon carcinogenesis is controversial. To assess the intestinotropic effects of exogenous and endogenous GLP-2, C57BL6/J mice were injected with 1μg h(Gly2)GLP-2[1-33]; 30 or 60 ng hGLP-2[3-33], a GLP-2 receptor antagonist; or PBS (4 wk, twice a day, sc). Chronic h(Gly2)GLP-2[1-33] increased small intestinal weight/body weight (P &lt; 0.001), villus height (P &lt; 0.001), crypt depth (P &lt; 0.001), and crypt cell proliferation, as measured by expression of the proliferative marker Ki67 (P &lt; 0.05–0.01). In contrast, chronic hGLP-2[3-33] decreased small intestinal weight/body weight (P &lt; 0.05) and colon weight/body weight (P &lt; 0.05). To assess the carcinogenic effects of endogenous and exogenous GLP-2, separate mice were injected with azoxymethane (10 mg/kg, 4 wk, every 7 d, ip), followed by 1.5 μg h(Gly2)GLP-2[1-33], 30 ng hGLP-2[3-33], or PBS (4 wk, twice a day, sc) 2 or 12 wk thereafter. At 10 or 46 wk after azoxymethane treatment, the numbers of aberrant crypt foci increased with h(Gly2)GLP-2[1-33] (P &lt; 0.001) and decreased with hGLP-2[3-33] (P &lt; 0.01–0.05) treatment. Furthermore, mucin-depleted aberrant foci, consistent with progressive dysplasia, were almost exclusively present in h(Gly2)GLP-2[1-33]-treated mice (P &lt; 0.01–0.001). Additionally, adenocarcinomas developed in h(Gly2)GLP-2[1-33]-treated mice but not in those receiving hGLP-2[3-33] or PBS. Taken together, these studies indicate that chronic treatment with GLP-2 enhances colon carcinogenesis, whereas antagonism of the GLP-2 receptor decreases dysplasia, with possible implications for human therapy.

Intestinal function in mice with small bowel growth induced by glucagon-like peptide-2

1997 ◽  
Vol 272 (6) ◽  
pp. E1050-E1058 ◽  
Author(s):  
P. L. Brubaker ◽  
A. Izzo ◽  
M. Hill ◽  
D. J. Drucker
Keyword(s):  
Glucose Transporter ◽  
Intestinal Epithelial ◽  
Multidrug Resistance Gene ◽  
Intestinal Growth ◽  
Glucose Transporter 1 ◽  
Sodium Dependent ◽  
Glucagon Like Peptide ◽  
Small Intestinal ◽  
Glutamyl Transpeptidase

Glucagon-like peptide-2 (GLP-2) stimulates small intestinal growth through induction of intestinal epithelial proliferation. To examine the physiology of GLP-2-induced bowel, mice were treated with GLP-2 (2.5 micrograms) or vehicle for 10 days. Small intestinal weight increased to 136 +/- 2% of controls in GLP-2-treated mice, in parallel with 1.4 +/- 0.1- and 1.9 +/- 0.5-fold increments in duodenal RNA and protein content, respectively (P < 0.05-0.001). Similarly, the activities of duodenal maltase, sucrase, lactase, glutamyl transpeptidase, and dipeptidyl-peptidase IV (215 +/- 28% of controls; P < 0.001) were increased by GLP-2. Oral or duodenal administration of glucose or maltose did not reveal any differences in the ability of GLP-2-treated mice to absorb these nutrients, possibly because of decreases in expression of the glucose transporters sodium-dependent glucose transporter-1 (SGLT-1) and GLUT-2. In contrast, absorption of leucine plus triolein was increased after duodenal administration in GLP-2-treated mice (P < 0.01-0.001). Finally, GLP-2 did not alter other markers of intestinal or pancreatic gene expression, including levels of mRNA transcripts for ornithine decarboxylase, multidrug resistance gene, amylase, proglucagon, proinsulin, and prosomatostatin. Thus induction of intestinal growth by GLP-2 in wild-type mice results in a normal-to-increased capacity for nutrient digestion and absorption in vivo.

scholarly journals IGF Binding Protein-4 is Required for the Growth Effects of Glucagon-Like Peptide-2 in Murine Intestine

Endocrinology ◽  
2014 ◽  
Vol 156 (2) ◽  
pp. 429-436 ◽  
Author(s):  
Kaori Austin ◽  
Nuvair A. Imam ◽  
John E. Pintar ◽  
Patricia L. Brubaker
Keyword(s):  
Protein A ◽  
Jejunal Mucosa ◽  
Igf Binding Proteins ◽  
Intestinal Growth ◽  
Fetal Rat ◽  
Negative Effect ◽  
Igf Binding ◽  
Glucagon Like Peptide ◽  
Small Intestinal ◽  
Intestinal Weight

Glucagon-like peptide-2 (GLP-2) is an enteroendocrine hormone that stimulates the growth of the intestinal epithelium. We have previously demonstrated that GLP-2 exerts its intestinotropic effect through an indirect mechanism that requires both IGF-1 and the intestinal epithelial IGF-1 receptor. However, the biological activity of IGF-1 is modulated by IGF binding proteins (IGFBPs), including IGFBP-4, which is highly expressed in the intestine. To determine the role of IGFBP-4 in the tropic effects of GLP-2, IGFBP-4 knockout (KO) and control mice were treated with degradation-resistant GLP-2 or vehicle for 10 days. Comparable levels of IGFBP-1–3/5–7 mRNAs were observed in the intestinal mucosa of all animals. IGFBP-4 KO mice had greater small intestinal weight and length, and deeper crypts (P &lt; .05) as compared with controls, suggesting that IGFBP-4 has an inhibitory role in basal intestinal growth. However, small intestinal weight, crypt-villus height and crypt cell proliferation increased in response to GLP-2 in control mice (P &lt; .05), and these changes were abrogated with IGFBP-4 KO. In contrast, pregnancy-associated plasma protein-A KO mice, which have increased levels of circulating IGFBP-4, demonstrated a normal intestinotropic response to GLP-2. Finally, GLP-2 treatment of control mice significantly increased IGFBP-4 mRNA expression in the jejunal mucosa (P &lt; .05), a finding that was recapitulated by GLP-2 treatment of fetal rat intestinal cells in culture (10−8M for 2 h; P &lt; .05). Collectively, these results indicate that the IGF-I-modulating protein, IGFBP-4, exerts a negative effect on basal intestinal growth but plays a positive regulatory role in the intestinotropic actions of GLP-2.

scholarly journals α-Lactalbumin Hydrolysate Stimulates Glucagon-Like Peptide-2 Secretion and Small Intestinal Growth in Suckling Rats

2009 ◽  
Vol 139 (7) ◽  
pp. 1322-1327 ◽  
Author(s):  
Hirohisa Izumi ◽  
Satoshi Ishizuka ◽  
Ayako Inafune ◽  
Tohru Hira ◽  
Kazuhiro Ozawa ◽  
...  
Keyword(s):  
Intestinal Growth ◽  
Suckling Rats ◽  
Glucagon Like Peptide ◽  
Small Intestinal ◽  
Lactalbumin Hydrolysate

scholarly journals Oleoylethanolamide modulates glucagon-like peptide-1 receptor agonist signaling and enhances exendin-4-mediated weight loss in obese mice

2018 ◽  
Vol 315 (4) ◽  
pp. R595-R608 ◽  
Author(s):  
Jacob D. Brown ◽  
Danielle McAnally ◽  
Jennifer E. Ayala ◽  
Melissa A. Burmeister ◽  
Camilo Morfa ◽  
...  
Keyword(s):  
Weight Loss ◽  
Energy Expenditure ◽  
Receptor Agonist ◽  
Day Treatment ◽  
Mtor Pathway ◽  
Obese Mice ◽  
Promote Weight Loss ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Long Acting

Long-acting glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists (GLP-1RA), such as exendin-4 (Ex4), promote weight loss. On the basis of a newly discovered interaction between GLP-1 and oleoylethanolamide (OEA), we tested whether OEA enhances GLP-1RA-mediated anorectic signaling and weight loss. We analyzed the effect of GLP-1+OEA and Ex4+OEA on canonical GLP-1R signaling and other proteins/pathways that contribute to the hypophagic action of GLP-1RA (AMPK, Akt, mTOR, and glycolysis). We demonstrate that OEA enhances canonical GLP-1R signaling when combined with GLP-1 but not with Ex4. GLP-1 and Ex4 promote phosphorylation of mTOR pathway components, but OEA does not enhance this effect. OEA synergistically enhanced GLP-1- and Ex4-stimulated glycolysis but did not augment the hypophagic action of GLP-1 or Ex4 in lean or diet-induced obese (DIO) mice. However, the combination of Ex4+OEA promoted greater weight loss in DIO mice than Ex4 or OEA alone during a 7-day treatment. This was due in part to transient hypophagia and increased energy expenditure, phenotypes also observed in Ex4-treated DIO mice. Thus, OEA augments specific GLP-1RA-stimulated signaling but appears to work in parallel with Ex4 to promote weight loss in DIO mice. Elucidating cooperative mechanisms underlying Ex4+OEA-mediated weight loss could, therefore, be leveraged toward more effective obesity therapies.

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