Potential impact of sitagliptin on collagen-derived dipeptides in diabetic osteoporosis.
It is known that diabetes coincides with an increased risk of osteoporosis. While a disturbed collagen metabolism is proposed as a possible cause, much remains unknown about the enzymes involved and changes in the collagen-derived dipeptides and amino acids. Therefore, we sought to study this intricate pathway and the effect of dipeptidyl peptidase 4 (DPP4) inhibitors. Control and streptozotocin-nicotinamide-induced diabetic rats were treated for 12 weeks with vehicle or sitagliptin, a DPP4 inhibitor (Con/VH, Con/SG, DM/VH and DM/SG). The activities of four key enzymes involved in collagen breakdown were determined in serum (DPP4, matrix metalloproteinase 2 and 9 and prolidase). Dipeptide (Ala-Pro, Gly-Pro, Pro-Pro and Pro-Hyp) and amino acid (Pro and Hyp) concentrations were measured by liquid chromatography coupled to mass spectrometry. We found three-fold higher MMP9 activities in DM/VH than in controls, while in DM/SG this rise was attenuated. MMP2 and prolidase did not differ in the investigated groups. Furthermore, we are the first to report on two-fold higher Ala-Pro and Pro-Pro levels in diabetes compared to controls. In contrast, Pro-Hyp concentrations were lower in diabetes (DM/VH and DM/SG). DPP4 inhibition does not seem to have a direct influence on the collagen metabolism in streptozotocin-nicotinamide-induced diabetic rats. Instead, it probably acts through its effect on osteoprotective substrates. In diabetes, increased MMP9 activities seem to favour the production of Ala-Pro and Pro-Pro containing collagen fragments. The high Pro-Hyp levels in untreated controls might have a bone-stimulating effect. Nevertheless, the biological significance of these dipeptides is not yet clear and should be further investigated.
Laboratory of Medical Biochemistry, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Electronic address: lesley.baerts@uantwerpen.be.
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Baerts
Laboratory of Pathophysiology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Electronic address: lorenzo.glorie@uantwerpen.be.
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Glorie
Toxicological Center, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Electronic address: walid.maho@uantwerpen.be.
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Maho
Laboratory of Medical Biochemistry, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Electronic address: anke_eelen@hotmail.com.
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Eelen
Laboratory of Pathophysiology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Electronic address: anja.verhulst@uantwerpen.be.
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Verhulst
Laboratory of Pathophysiology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Electronic address: patrick.dhaese@uantwerpen.be.
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D'Haese
Toxicological Center, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Electronic address: adrian.covaci@uantwerpen.be.
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Covaci
Laboratory of Medical Biochemistry, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Electronic address: ingrid.demeester@uantwerpen.be.
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De Meester
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D003094:Collagen / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004151:Dipeptides / Q000378:metabolism*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009536:Niacinamide / Q000494:pharmacology; D010024:Osteoporosis / Q000188:drug therapy* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D000068900:Sitagliptin Phosphate / Q000494:pharmacology*; D013311:Streptozocin / Q000494:pharmacology
D000596:Amino Acids; D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D009536:Niacinamide; D013311:Streptozocin; D003094:Collagen; D018819:Dipeptidyl Peptidase 4; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000068900:Sitagliptin Phosphate
Collagen; Diabetes; Dipeptides; Dipeptidyl peptidase 4 (DPP4); Matrix metalloproteinases (MMP); Sitagliptin (PubChem CID: 4369359)