1784-P: Liraglutide Treatment Stimulates Alpha Cells to Produce Glucagon-Like Peptide-1 via Expression of Prohormone Convertase 1/3 in Mice and Human

Glucagon-like peptide (GLP)-1-(7--36) amide, a peptide product of the posttranslational processing of pancreatic and intestinal proglucagon, has been shown to regulate insulin secretion. Monoclonal antibodies to glucagon and GLP-1-(7--36) amide were generated to localize GLP-1-(7--36) amide in the pancreatic islets by immunocytochemistry and radioimmunoassay. GLP-1-(7--36) amide immunoreactivity was found in some, but not all, glucagon-containing alpha-cells. Displaceable receptor binding for GLP-1-(7--36) amide and nonamidated GLP-1-(7--37) on hormone secretion were investigated using isolated pancreatic islet preparations. GLP-1-(7--37) and -(7--36) amide significantly increased insulin and somatostatin release in the concentration range of 0.01-100 nM in 11.0 mM glucose. GLP-1-(7--37) and -(7--36) amide had no effect on glucagon secretion in the presence of 11.0 mM glucose. GLP-1-(7--36) amide was released from isolated islets in response to 2.25, 5.5, and 11.0 mM glucose. These results suggest that pancreatic GLP-1 may be important in the regulation of intra-islet hormone secretion.

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Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells

Nature Medicine ◽

10.1038/nm.2513 ◽

2011 ◽

Vol 17 (11) ◽

pp. 1481-1489 ◽

Cited By ~ 478

Author(s):

Helga Ellingsgaard ◽

Irina Hauselmann ◽

Beat Schuler ◽

Abdella M Habib ◽

Laurie L Baggio ◽

...

Keyword(s):

Insulin Secretion ◽

Interleukin 6 ◽

Alpha Cells ◽

L Cells ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Attenuated processing of proglucagon and glucagon-like peptide-1 in carboxypeptidase E-deficient mice

Journal of Endocrinology ◽

10.1677/joe.0.1690595 ◽

2001 ◽

Vol 169 (3) ◽

pp. 595-602 ◽

Cited By ~ 13

Author(s):

L Friis-Hansen ◽

KA Lacourse ◽

LC Samuelson ◽

JJ Holst

Keyword(s):

Great Reduction ◽

Prohormone Convertase ◽

Adult Onset ◽

Tissue Specific ◽

Carboxypeptidase E ◽

Mild Diabetes ◽

Obesity Phenotype ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Deficient Mice

The maturation of many peptide hormones is attenuated in carboxypeptidase E (CPE)-deficient fat/fat mice, leading to a slowly developing, adult-onset obesity with mild diabetes. To determine the contribution of the hormones generated from the proglucagon precursor to this phenotype, we studied the tissue-specific processing of glucagon and glucagon-like peptide-1 (GLP-1) in these mice. In all tissues examined there was a great reduction in mature amidated GLP-1. Furthermore, a lack of CPE attenuates prohormone convertase processing of proglucagon in both the pancreas and the intestine. These findings suggest that defects in proglucagon processing together with other endocrine malfunctions could contribute to the diabetic and obesity phenotype in fat/fat mice.

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Peptide production and secretion in GLUTag, NCI-H716, and STC-1 cells: a comparison to native L-cells

Journal of Molecular Endocrinology ◽

10.1530/jme-15-0293 ◽

2016 ◽

Vol 56 (3) ◽

pp. 201-211 ◽

Cited By ~ 42

Author(s):

Rune Ehrenreich Kuhre ◽

Nicolai Jacob Wewer Albrechtsen ◽

Carolyn Fiona Deacon ◽

Emilie Balk-Møller ◽

Jens Frederik Rehfeld ◽

...

Keyword(s):

Cell Lines ◽

Peptide Yy ◽

Prohormone Convertase ◽

Basal Secretion ◽

Human Gut ◽

Hormone Production ◽

L Cells ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Peptide Secretion

AbstractGLUTag, NCI-H716, and STC-1 are cell lines that are widely used to study mechanisms underlying secretion of glucagon-like peptide-1 (GLP-1), but the extent to which they resemble native L-cells is unknown. We used validated immunoassays for 14 different hormones to analyze peptide content (lysis samples;n= 9 from different passage numbers) or peptide secretion in response to buffer (baseline), and after stimulation with 50 mM KCl or 10 mM glucose + 10 µM forskolin/3-isobutyl-1-methylxanthine (n= 6 also different passage numbers). All cell lines produced and processed proglucagon into GLP-1, GLP-2, glicentin, and oxyntomodulin in a pattern (prohormone convertase (PC)1/3 dependent) similar to that described for human gut. All three cell lines showed basal secretion of GLP-1 and GLP-2, which increased after stimulation. In contrast to freshly isolated murine L-cells, all cell lines also expressed PC2 and secreted large amounts of pancreatic glucagon. Neurotensin and somatostatin storage was low and secretion was not consistently increased by stimulation. STC-1 cells released more glucose-dependent insulinotropic polypeptide than GLP-1 at baseline (P< 0.01) and KCl elevated its secretion (P< 0.05). Peptide YY, which normally co-localizes with GLP-1 in distal L-cells, was not detected in any of the cell lines. GLUTag and STC-1 cells also expressed vasoactive intestinal peptide, but none expressed pancreatic polypeptide or insulin. GLUTag contained and secreted large amounts of CCK, while NCI-H716 did not store this peptide and STC-1 contained low amounts. Our results show that hormone production in cell line models of the L-cell has limited similarity to the natural L-cells.

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A New Way for Beta Cell Neogenesis: Transdifferentiation from Alpha Cells Induced by Glucagon-Like Peptide 1

Journal of Diabetes Research ◽

10.1155/2019/2583047 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 7

Author(s):

Zhen Zhang ◽

Yinghui Hu ◽

Ningning Xu ◽

Wenjun Zhou ◽

Lei Yang ◽

...

Keyword(s):

Beta Cell ◽

Mrna Expression ◽

Beta Cells ◽

Cell Populations ◽

High Dose ◽

Alpha Cells ◽

Ductal Cells ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Beta Cell Neogenesis

Recent studies showed that alpha cells, especially immature cells and proalpha cells, might be the precursors of beta cells. Exposure to glucagon-like peptide 1 (GLP1) can ameliorate hyperglycemia in diabetic mice and restore the beta cell mass. In the present study, we adopted single high-dose (60 mg/kg, i.p.) streptozotocin (STZ) to model diabetes mellitus (DM) and randomly assigned short-tail (SD) rats to a normal group, a diabetic group, GLP1 groups (50 μg/kg, 100 μg/kg, and 200 μg/kg), a GLP1 (200 μg/kg) with exendin (9-39) group, and a GLP1 with LY294002 group. We found that the pancreatic insulin-glucagon-positive cell populations increased according to the increase in GLP1 exposure. By contrast, no insulin-amylase-positive cell populations or insulin/pan-cytokeratin cells were observed in the pancreatic sections. The GLP1 receptor antagonist exendin (9-39) and the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) family inhibitor LY294002 not only suppressed protein kinase B (Akt), pancreatic and duodenal homeobox 1 (Pdx1), forkhead box O 1 (FoxO1), and mast cell function-associated antigen A (MafA) mRNA expression but also increased MAFB expression. We concluded that treatment with GLP1 might result in beta cell neogenesis by promoting the transdifferentiation of alpha cells but not by pancreatic acinar cells, ductal cells, or the self-replication of beta cells. The regulation on the GLP1 receptor and its downstream transcription factor PI3K/AKT/FOXO1 pathway, which causes increased pancreatic and duodenal homeobox 1 (Pdx1) and MafA mRNA expression but causes decreased MAFB expression, may be the mechanism involved in this process.

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Intestinal Bile Acid Composition Modulates Prohormone Convertase 1/3 (PC1/3) Expression and Consequent GLP-1 Production in Male Mice

Endocrinology ◽

10.1210/en.2015-1551 ◽

2016 ◽

Vol 157 (3) ◽

pp. 1071-1081 ◽

Cited By ~ 10

Author(s):

Kohkichi Morimoto ◽

Mitsuhiro Watanabe ◽

Taichi Sugizaki ◽

Jun-ichiro Irie ◽

Hiroshi Itoh

Keyword(s):

Gene Expression ◽

Bile Acid ◽

Acid Composition ◽

Prohormone Convertase ◽

Activated T Cells ◽

Antidiabetic Therapy ◽

Dipeptidyl Peptidase 4 ◽

Prohormone Convertase 1 ◽

Glucagon Like Peptide 1 ◽

Essential Enzyme

Abstract Besides an established medication for hypercholesterolemia, bile acid binding resins (BABRs) present antidiabetic effects. Although the mechanisms underlying these effects are still enigmatic, glucagon-like peptide-1 (GLP-1) appears to be involved. In addition to a few reported mechanisms, we propose prohormone convertase 1/3 (PC1/3), an essential enzyme of GLP-1 production, as a potent molecule in the GLP-1 release induced by BABRs. In our study, the BABR colestimide leads to a bile acid-specific G protein-coupled receptor TGR5-dependent induction of PC1/3 gene expression. Here, we focused on the alteration of intestinal bile acid composition and consequent increase of total TGR5 agonistic activity to explain the TGR5 activation. Furthermore, we demonstrate that nuclear factor of activated T cells mediates the TGR5-triggered PC1/3 gene expression. Altogether, our data indicate that the TGR5-dependent intestinal PC1/3 gene expression supports the BABR-stimulated GLP-1 release. We also propose a combination of BABR and dipeptidyl peptidase-4 inhibitor in the context of GLP-1-based antidiabetic therapy.

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