Processing of Mouse Proglucagon by Recombinant Prohormone Convertase 1 and Immunopurified Prohormone Convertase 2 in Vitro

Rothenberg, M.E.; Eilertson, Carmen D.; Klein, Kathy; Yi, Zili; Lindberg, Iris; McDonald, John K.; Mackin, Robert B.; Noe, Bryan D.

doi:10.1074/jbc.270.17.10136

Cited by 70 publications

(47 citation statements)

References 55 publications

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“…Studies on the localization of primarily PC1/3 within intestinal cells in conjunction with previous reports regarding the L-cells as the primary site of GLP-1 production strongly pointed to PC1/3 as the prohormone convertase responsible for the processing of proglucagon to GLP-1, supported by studies utilizing cell lines expressing either PC1/3 or PC2 [26,27,[56][57][58][59]. Building on these findings in conjunction with the detection of small quantities of GLP-1 in αTC1.6 cells, studies were performed to determine if this α-cell line also expressed PC1/3.…”

Section: The Role Of Pc1/3 In Glp-1 Production In α-Cellssupporting

confidence: 48%

“…Unlike the easily detectable PC2 that is responsible for the processing of glucagon, no PC1/3 could be detected using Northern blotting analysis. However, in another study, using immunohistochemical analyses with antibodies against PC1/3 and PC2, the presence of small quantities of PC1/3 was detected within these αTC1.6 cells [26]. Using prolonged exposure time in the Northern blotting assays, PC1/3 mRNA was successfully detected, although its level was considerably lower than PC2 mRNA [26].…”

Section: The Role Of Pc1/3 In Glp-1 Production In α-Cellsmentioning

confidence: 99%

“…However, in another study, using immunohistochemical analyses with antibodies against PC1/3 and PC2, the presence of small quantities of PC1/3 was detected within these αTC1.6 cells [26]. Using prolonged exposure time in the Northern blotting assays, PC1/3 mRNA was successfully detected, although its level was considerably lower than PC2 mRNA [26]. These data suggest that PC1/3 is expressed in αTC1.6 cells at very low level, and thus may be responsible for the low level of GLP-1 production in these α-cells.…”

Section: The Role Of Pc1/3 In Glp-1 Production In α-Cellsmentioning

confidence: 99%

“…Furthermore, GLP-1 exists in three different forms: the full length GLP-1 (1-37), the N-terminally truncated GLP-1 (7-37), and an amidated version of the truncated form-GLP-1 (7-36) amide. Among them, GLP-1 (7-36) amide has the highest biological activity, although some other studies have shown the non-amidated and amidated forms of the truncated GLP-1 peptide are equally effective in stimulating insulin release from perfused rat pancreas [2,[26][27][28][29][30]. Journal of Diabetes and Metabolism The debate regarding tissue-specific GLP-1 expression arose as researchers attempted to specify the tissues and cell types responsible for the expression of this incretin hormone.…”

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confidence: 99%

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Pancreatic Glucagon-Like Peptide 1: What is known?

Fava¹,

2014

J Diabetes Metab 2013

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Glucagon-like peptide-1 (GLP-1) is an incretin hormone encoded together with glucagon by the proglucagon gene. It has been widely accepted that GLP-1 and glucagon are derived from distinct post-translational processing of proglucagon in a tissue specific manner. GLP-1 is produced in intestinal L-cells where proglucagon is processed by prohormone convertase 1/3 (PC1/3), while glucagon is produced in pancreatic α-cells via PC2-mediated cleavage. Nonetheless, emerging evidence has now demonstrated GLP-1 is also produced in pancreatic islets, although its concentration is much lower than glucagon. Further studies have shown GLP-1 production and secretion can be up-regulated by various factors, in particular, hyperglycemia and β-cell damage. The importance of locally produced GLP-1 in pancreas for β-cell function has started to be recognized. Similar to circulating GLP-1, α-cell produced GLP-1 can promote insulin secretion, protect β-cells and enhance β-cell proliferation, thus is vital for β-cell function. This review focuses on these recent discoveries regarding GLP-1 production in pancreatic islets and its action within pancreatic tissue.Keywords: GLP-1; Alpha cells; Islets; Diabetes; PC1/3 GLP-1: An OverviewGlucagon-like peptide-1 (GLP-1) is one of the peptide hormones encoded by the proglucagon gene, which gives rise to a number of individual peptides through posttranslational processing [1][2][3][4][5]. Based on its origin within the intestine and its vital role in stimulating insulin secretion, GLP-1 is considered a member of the incretin family. GLP-1 is intimately involved in the regulation of circulating blood glucose, acting to increase insulin secretion and sensitivity in a glucosedependent manner. It is well established that GLP-1 has many effects on multiple organ systems related to nutrient ingestion and blood glucose homeostasis [6,7]. In the gastrointestinal system, GLP-1 inhibits gastrointestinal motility, reduces gastric acid secretion, and slows gastric emptying [8][9][10][11]. GLP-1 has been shown to suppress appetite in both normal and obese individuals, thereby reducing food intake [12][13][14][15]. In the pancreas, GLP-1 stimulates insulin secretion from β-cells in a blood-glucose dependent manner, while also inhibiting glucagon secretion in α-cells, thus playing an essential role in blood glucose regulation [6,7].GLP-1 and glucagon share ~50% homology, deriving from the same precursor-proglucagon. The diversification takes place at the posttranslational stage in a tissue-specific manner (Figure 1). In pancreatic α-cells, proglucagon is mainly cleaved by prohormone Convertase 2 (PC2), giving rise to glucagon, Intervening Peptide-1 (IP-1), GlicentinRelated Polypeptide (GRPP), and the Major Proglucagon Fragment (MPGF) [16][17][18]. In contrast, in enteroendocrine L-cells, proglucagon is processed by prohormone convertase 1/3 (PC1/3), resulting in the production of GLP-1, GLP-2, glicentin, and several other small peptides [19,20].Nonetheless, emerging evidence has now demonstrated that GL...

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Section: The Role Of Pc1/3 In Glp-1 Production In α-Cellssupporting

confidence: 48%

Section: The Role Of Pc1/3 In Glp-1 Production In α-Cellsmentioning

confidence: 99%

Section: The Role Of Pc1/3 In Glp-1 Production In α-Cellsmentioning

confidence: 99%

mentioning

confidence: 99%

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Pancreatic Glucagon-Like Peptide 1: What is known?

Fava¹,

2014

J Diabetes Metab 2013

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“…Oligonucleotide primers used for the amplification of p-actin, insulin, glucokinase, and GLUT2 mRNAs were described previously (18). Oligonucleotides used for glucagon and IAPP mRNAs were all synthesized as 20mers and the nucleotide numbers of the 5' end of primers used for the reverse transcription were 332 (19) and 543 (20), respectively. Those for the PCR primers for glucagon cDNA were -4 and 245 (19), and those for IAPP were 252 and 488 (20).…”

Section: Methodsmentioning

confidence: 99%

PDX-1 Induces Insulin and Glucokinase Gene Expressions in αTC1 Clone 6 Cells in the Presence of Betacellulin

Watada¹,

Kajimoto²,

Miyagawa

et al. 1996

Diabetes

167

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The pancreatic P-and a-cells are developmentally related to each other but reveal diverse gene expression patterns. Among the two important transcription factors for insulin gene expression, IEF1 is present both in a-and p-cells, but PDX-1/IPF1/STF-1/IDX-1, a homeodomain-containing transcription factor, is present in P-cells but not in a-cells. To elucidate the function of PDX-1 in the expression of P-cell-specific genes, we established stable aTCl clone 6 (aTC1.6)-derived transfectants expressing PDX-1 and examined the changes in the gene expression patterns in them. The exogenous expression of PDX-1 in aTCl.6 cells alone could induce islet amyloid polypeptide (IAPP) mRNA expression in the cells but not the expression of insulin, glucokinase, or GLUT2 gene. However, when betacellulin was added to the medium, the PDX-1-expressing aTCl.6 cells, but not the control aTCl.6 cells, came to express insulin and glucokinase mRNAs. This did not occur with other growth factors such as epidermal growth factor, transforming growth factor a, and insulin-like growth factor I. GLUT2 mRNA remained undetectable in the PDX-1-expressing aTCl.6 cells. These observations demonstrate the potency of PDX-1 for the expression of the insulin, glucokinase, and IAPP genes and suggest that certain regulatory factors, which can partially be modified by betacellulin, also contribute to the p-cell specificity of gene expression.

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Islet Amyloid Polypeptide/GLP‐1/Exendin

Baggio

Drucker

2003

International Textbook of Diabetes Mellitus

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Gastrointestinal peptides exert important physiological roles in the control of feeding behavior, gut motility, nutrient absorption, and energy assimilation. Islet amyloid polypeptide is secreted from islet β‐cells, and exerts inhibitory actions on appetite, gastric motility, and glucagon secretion. Glucagon‐like peptide 1 (GLP‐1) is released from enteroendocrine cells and regulates food intake, gastric emptying, insulin and glucagon secretion, and β‐cell proliferation and apoptosis. Exendin‐4, a lizard‐derived peptide, is a potent and stable GLP‐1R agonist that exerts GLP‐1‐like actions in vivo . The overlapping glucose‐lowering properties of these peptides have fostered considerable interest in their development as new therapeutic agents for the treatment of diabetes mellitus.

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Processing of Mouse Proglucagon by Recombinant Prohormone Convertase 1 and Immunopurified Prohormone Convertase 2 in Vitro

Cited by 70 publications

References 55 publications

Pancreatic Glucagon-Like Peptide 1: What is known?

Pancreatic Glucagon-Like Peptide 1: What is known?

PDX-1 Induces Insulin and Glucokinase Gene Expressions in αTC1 Clone 6 Cells in the Presence of Betacellulin

Islet Amyloid Polypeptide/GLP‐1/Exendin

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