The Prohormone Convertase Enzyme 2 (PC2) Is Essential for Processing Pro-Islet Amyloid Polypeptide at the NH2-Terminal Cleavage Site

Wang, Jing; Xu, Jun; Finnerty, Jennifer; Furuta, Machi; Steiner, Donald F.; Verchere, C. Bruce

doi:10.2337/diabetes.50.3.534

Cited by 104 publications

(91 citation statements)

References 29 publications

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“…The almost identical hyperplasia of the pancreas and ␣ cell mass of this individual to the Gcgr Ϫ/Ϫ mouse indicates glucagon signaling via its receptor is important for normal pancreatic endocrine and possibly exocrine cell proliferation in humans as well as mice. In addition, mice deficient in prohormone convertase 2 (PC2), which lack mature glucagon due to defective proglucagon processing, display a similar reduction in BG, islet ␣ and ␦ cell hyperplasia (24), and similar shallow glucose tolerance curves (25). However, these mice also have defects in processing many islet hormones (24,26) and neuropeptides (27).…”

Section: Discussionmentioning

confidence: 99%

Lower blood glucose, hyperglucagonemia, and pancreatic α cell hyperplasia in glucagon receptor knockout mice

Gelling

Dichmann

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

511

613

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Glucagon, the counter-regulatory hormone to insulin, is secreted from pancreatic ␣ cells in response to low blood glucose. To examine the role of glucagon in glucose homeostasis, mice were generated with a null mutation of the glucagon receptor (Gcgr ؊/؊ ). These mice display lower blood glucose levels throughout the day and improved glucose tolerance but similar insulin levels compared with control animals. Gcgr ؊/؊ mice displayed supraphysiological glucagon levels associated with postnatal enlargement of the pancreas and hyperplasia of islets due predominantly to ␣ cell, and to a lesser extent, ␦ cell proliferation. In addition, increased proglucagon expression and processing resulted in increased pancreatic glucogen-like peptide 1 (GLP-1) (1-37) and GLP-1 amide (1-36 amide) content and a 3-to 10-fold increase in circulating GLP-1 amide. Gcgr ؊/؊ mice also displayed reduced adiposity and leptin levels but normal body weight, food intake, and energy expenditure. These data indicate that glucagon is essential for maintenance of normal glycemia and postnatal regulation of islet and ␣ and ␦ cell numbers. Furthermore, the lean phenotype of Gcgr ؊/؊ mice suggests glucagon action may be involved in the regulation of whole body composition.

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Section: Discussionmentioning

confidence: 99%

Lower blood glucose, hyperglucagonemia, and pancreatic α cell hyperplasia in glucagon receptor knockout mice

Gelling

Dichmann

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

511

613

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“…Islet studies in vitro indicate increased production of N-terminal intact proIAPP under stimulated secretory conditions [74] and immunoreactivity for the N-terminal peptide of proIAPP has been identified in islet amyloid deposits in insulinomas and T2DM [75]. N-terminal intact proIAPP has been identified in a PC2 knockout, hIAPP transgenic mouse model [76]. This suggests that, not only is inappropriately processed proinsulin secreted under these conditions, but also that proIAPP secreted in T2DM is incorporated into deposits.…”

Section: Aberrant Prohormone Processingmentioning

confidence: 99%

Islet amyloid: a complication of islet dysfunction or an aetiological factor in Type 2 diabetes?

2004

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The role of islet amyloidosis in the onset and progression of Type 2 diabetes remains obscure. Islet amyloid polypeptide is a 37 amino-acid, beta-cell peptide which is co-stored and co-released with insulin. Human islet amyloid polypeptide refolds to a β-conformation and oligomerises to form insoluble fibrils; proline substitutions in rodent islet amyloid polypeptide prevent this molecular transition. Pro-islet amyloid polypeptide (67 amino acids in man) is processed in secretory granules. Refolding of islet amyloid polypeptide may be prevented by intragranular heterodimer formation with insulin (but not proinsulin). Diabetes-associated abnormal proinsulin processing could contribute to de-stabilisation of granular islet amyloid polypeptide. Increased pro-islet amyloid polypeptide secretion as a consequence of islet dysfunction could promote fibrillogenesis; the propeptide forms fibrils and binds to basement membrane glycosamino-glycans. Islet amyloid polypeptide gene polymorphisms are not universally associated with Type 2 diabetes. Transgenic mice expressing human islet amyloid polypeptide gene have increased islet amyloid polypeptide concentrations but develop islet amyloid only against a background of obesity and/or high fat diet. In transgenic mice, obese monkeys and cats, initially small perivascular deposits progressively increase to occupy 80% islet mass; the severity of amyloidosis in animal models is related to the onset of hyperglycaemia, suggesting that islet amyloid and the associated destruction of islet cells cause diabetes. In human diabetes, islet amyloid can affect less than 1% or up to 80% of islets indicating that islet amyloidosis largely results from diabetes-related pathologies and is not an aetiological factor for hyperglycaemia. However, the associated progressive betacell destruction leads to severe islet dysfunction and insulin requirement. [Diabetologia (2004) 47:157-169]

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“…Mature IAPP is produced by cleavage of proIAPP at its COOH-and NH 2 -termini by the prohormone convertase 1/3 (PC1/3) and PC2, respectively, the two key enzymes also responsible for processing of proinsulin [32,33]. Cleavage by PC1/3 occurs early in the beta cell secretory pathway whereas cleavage by PC2 occurs mainly in the beta cell granules [28].…”

Section: Introductionmentioning

confidence: 99%

The glucagon-like peptide-1 receptor agonist exenatide restores impaired pro-islet amyloid polypeptide processing in cultured human islets: implications in type 2 diabetes and islet transplantation

Park

Kieffer

et al. 2012

Diabetologia

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Aims/hypothesis Islet amyloid, formed by aggregation of human islet amyloid polypeptide (hIAPP), is associated with beta cell death in type 2 diabetes as well as in cultured and transplanted human islets. Impaired prohIAPP processing due to beta cell dysfunction is implicated in hIAPP aggregation. We examined whether the glucagon-like peptide-1 receptor (GLP-1R) agonist exenatide can restore impaired prohIAPP processing and reduce hIAPP aggregation in cultured human islets and preserve beta cell function/mass during culture conditions used in clinical islet transplantation. Methods Isolated human islets (n010 donors) were cultured with or without exenatide in normal or elevated glucose for 2 or 7 days. Beta cell apoptosis, proliferation, mass, function, cJUN N-terminal kinase (JNK) and protein kinase B (PKB) activation and amyloid formation were assessed. ProhIAPP, its intermediates and mature hIAPP were detected. Results Exenatide-treated islets had markedly lower JNK and caspase-3 activation and beta cell apoptosis, resulting in higher beta/alpha cell ratio and beta cell area than nontreated cultured islets. Exenatide improved beta cell function, manifested as higher insulin response to glucose and insulin content, compared with non-treated cultured islets. Phospho-PKB immunoreactivity was detectable in exenatide-treated but not untreated cultured islets. Islet culture caused impaired prohIAPP processing with decreased mature hIAPP and increased NH 2 -terminally unprocessed prohIAPP levels resulting in higher release of immature hIAPP. Exenatide restored prohIAPP processing and reduced hIAPP aggregation in cultured islets. Conclusions/interpretation Exenatide treatment enhances survival and function of cultured human islets and restores impaired prohIAPP processing in normal and elevated glucose conditions thereby reducing hIAPP aggregation. GLP-1R agonists may preserve beta cells in conditions associated with islet amyloid formation.

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The Prohormone Convertase Enzyme 2 (PC2) Is Essential for Processing Pro-Islet Amyloid Polypeptide at the NH2-Terminal Cleavage Site

Cited by 104 publications

References 29 publications

Lower blood glucose, hyperglucagonemia, and pancreatic α cell hyperplasia in glucagon receptor knockout mice

Lower blood glucose, hyperglucagonemia, and pancreatic α cell hyperplasia in glucagon receptor knockout mice

Islet amyloid: a complication of islet dysfunction or an aetiological factor in Type 2 diabetes?

The glucagon-like peptide-1 receptor agonist exenatide restores impaired pro-islet amyloid polypeptide processing in cultured human islets: implications in type 2 diabetes and islet transplantation

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