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Mechanisms underlying the rapid degradation and elimination of the incretin hormones GLP-1 and GIP

https://doi.org/10.1016/j.beem.2009.03.005Get rights and content

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP, gastric inhibitory peptide) are secreted from intestinal L and K cells and stimulate insulin secretion from pancreatic beta cells. However, they are immediately inactivated mainly via N-terminal degradation by dipeptidyl peptidase IV (DPP IV, CD26), a specialised enzyme located on the cell surface enzyme of endothelial, epithelial and some other cell types. Cleavage by neprilysin (neutral endopeptidase) is a minor degradation route, and renal clearance eliminates incretin/fragments, but appears of less importance for regulating incretin bioactivities. Based on these observations two novel types of drugs for the treatment of type 2 diabetes have been developed: DPP IV inhibitors and DPP IV-resistant incretin analogues. Both have distinct advantages and disadvantages. Potential side effects of DPP IV inhibitors may result from affecting the bioactivity of other hormones, neuropeptides or chemokines and also by their cross-reactivity with DPP IV-related enzymes.

Section snippets

Structural features of the incretin hormones GLP-1 and GIP

Incretin hormones are peptides that are released in response to nutrient ingestion from the gut and stimulate insulin secretion under physiological concentrations.1, 2, 3, 4 The main incretin hormones are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP; also known as gastric inhibitory peptide). The incretin effect may be further enhanced by other factors, for example, pituitary adenylate cyclase-activating polypeptide (PACAP) liberated from pancreatic

Inactivation of peptide hormones

Circulating small peptide hormones are inactivated either by renal filtration and/or by proteolytic degradation. Thus, constant stimuli resulting in unregulated information transfer are avoided. Proteolytic regulation of peptide hormone activity is accomplished by a small group of peptidases or oligopeptidases which act preferentially on 3–100 residue oligopeptides such as peptide hormones, neuropeptides and chemokines.19, 20 These (oligo)peptidases are mainly cell-surface peptidases (see Table

Inactivation of GLP-1 and GIP

After intravenous injection of radio-labelled GLP-1 (131I-GLP-1(7–36)amide) into rats, the peptide is rapidly cleared from the circulation.21 By renal filtration, it accumulates in the kidney (half-life 3.3 ± 0.6 min); however, GLP-1 undergoes simultaneous and even faster rapid proteolytic degradation. As main metabolite, the fragment GLP-1(9–36)amide has been identified in vitro and in vivo.*22, *23, *24, *25 In fact, as early as 2 min after its intravenous or subcutaneous injection into healthy

Dipeptidyl peptidase IV (DPP IV) and DPP IV-related enzymes

DPP IV had been initially discovered as a potential collagen-degrading protease based on its specificity for cleaving chromogenic substrates of the type Gly-Pro-4-nitranilide (or -2-naphthylamide).34, 35 Due to its ability to remove complete dipeptides (not subsequently two single residues) from the N-terminus of peptides, it was classified as a dipeptidyl (amino)peptidase (a specialised exopeptidase). However, later it turned out that DPP IV acts only on small peptides (up to about 70–100

Conclusions

The incretin hormones GLP-1 and GIP are rapidly degraded by the ubiquitous enzyme DPP IV yielding N-terminally truncated metabolites that are their major circulating forms and lack relevant physiological activity. Cleavage by DPP IV is the main, but not the only factor determining the survival of both peptides. Infused GLP-1 is partly also metabolised by neprilysin at the C-terminus. Truncated and the remaining intact peptides are eliminated finally by renal clearance, but this process appears

Acknowledgements

I thank Clemens Franke for carefully drawing the figure.

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