Metabolism of glucagon by dipeptidyl peptidase IV (CD26)

Pospisilik, J. Andrew; Hinke, Simon A.; Pederson, Raymond A.; Hoffmann, Torsten; Rosche, Fred; Schlenzig, Dagmar; Glund, Konrad; Heiser, Ulrich; McIntosh, Christopher H.S.; Demuth, Hans‐Ulrich

doi:10.1016/s0167-0115(00)00170-1

Cited by 71 publications

(61 citation statements)

References 35 publications

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“…The mass spectrum from peak 1 contained ions corresponding to the parent glucagon molecule, whilst peak 6 contained ions corresponding to the 3+ and 4+ Figure 2) [10] .Such cyclisation may be performed by a transglutaminase serum enzyme such as glutaminyl cyclase. [28] It is possible that such enzymes are less active in plasma than in buffered serum, thereby allowing significant levels of glucagon to remain.…”

Section: Figurementioning

confidence: 99%

“…Top (injection of the "diluted extract"); Middle+ Bottom (injection of the "concentrated extract"). [10] .…”

Section: Figurementioning

confidence: 99%

“…For example, glucagon , glucagon , and glucagon [1][2][3][4][5][6][7][8][9][10][11][12][13] are formed by hepatocytes in the liver [4] [5] . Glucagon [1][2][3][4][5][6][7][8][9][10][11][12][13] and glucagon [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] , and the minor metabolites glucagon [1][2][3][4][5][6][7][8]…”

Section: Introductionmentioning

confidence: 99%

“…Glucagon [1][2][3][4][5][6][7][8][9][10][11][12][13] and glucagon [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] , and the minor metabolites glucagon [1][2][3][4][5][6][7][8][9][10] , glucagon [14][15][16][17][18][19][20][21][22][23][24][25] and glucagon [23][24]…”

Section: Introductionunclassified

“…However in serum diluted to 20% with Tris buffer (0.1 mM, pH 7.6) , it has been reported that DPP IV hydrolyses glucagon to glucagon , which then undergoes immediate conversion to exclusively form pyroglutamyl glucagon ([pGlu] 3 glucagon ) [10] . This may partially account for the instability glucagon shows in human plasma.…”

Section: Introductionmentioning

confidence: 99%

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Identification of plasma protease derived metabolites of glucagon and their formation under typical laboratory sample handling conditions

Howard

Kay²,

Tan

et al. 2014

Rapid Comm Mass Spectrometry

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RATIONALE Glucagon modulates glucose production, and it is also a biomarker for several pathologies. It is known to be unstable in human plasma, and consequently stabilisers are often added to samples, although these are not particularly effective. Despite this, there have not been any studies to identify in vitro plasma protease derived metabolites; such a study is described here. Knowledge of metabolism should allow the development of more effective sample stabilisation strategies. METHODS Several novel metabolites resulting from the incubation of glucagon in human plasma were identified using high‐resolution mass spectrometry with positive electrospray ionisation. Tandem mass spectrometric (MS/MS) scans were acquired for additional confirmation using a QTRAP. Separation was performed using reversed‐phase ultra‐high‐performance liquid chromatography. The formation of these metabolites was investigated during a time‐course experiment and under specific stress conditions representative of typical laboratory handling conditions. Clinical samples were also screened for metabolites. RESULTS Glucagon3‐29 and [pGlu]3glucagon3‐29 were the major metabolites detected, both of which were also present in clinical samples. We also identified two oxidised forms of [pGlu]3glucagon3‐29 as well as glucagon19‐29, or 'miniglucagon', along with the novel metabolites glucagon20‐29 and glucagon21‐29. The relative levels of these metabolites varied throughout the time‐course experiment, and under the application of the different sample handling conditions. Aprotinin stabilisation of samples had negligible effect on metabolite formation. CONCLUSIONS Novel plasma protease metabolites of glucagon have been confirmed, and their formation characterised over a time‐course experiment and under typical laboratory handling conditions. These metabolites could be monitored to assess the effectiveness of new sample stabilisation strategies, and further investigations into their formation could suggest specific enzyme inhibitors to use to increase sample stability. In addition the potential of the metabolites to affect immunochemistry‐based assays as a result of cross‐reactivity could be investigated. Copyright © 2014 John Wiley & Sons, Ltd.

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Section: Figurementioning

confidence: 99%

“…Top (injection of the "diluted extract"); Middle+ Bottom (injection of the "concentrated extract"). [10] .…”

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionunclassified

Section: Introductionmentioning

confidence: 99%

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Identification of plasma protease derived metabolites of glucagon and their formation under typical laboratory sample handling conditions

Howard

Kay²,

Tan

et al. 2014

Rapid Comm Mass Spectrometry

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Molecular Machines for Protein Degradation

Bochtler¹,

Groll

Brandstetter

et al. 2008

Protein Science Encyclopedia

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Within cells or subcellular compartments misfolded and/or short-lived regulatory proteins are degraded by protease machines, cage-forming multi-subunit assemblages. Their proteolytic active sites are sequestered within the particles and located on the inner walls. Access of protein substrates is regulated by protein subcomplexes or protein domains which may assist in substrate unfolding dependent of ATP. Five protease machines will be described displaying different subunit structures, oligomeric states, enzymatic mechanisms, and regulatory properties.

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