Dipeptidyl peptidase-4 inhibitors: Novel mechanism of actions
The pharmacological actions of the glucagon-like peptide-1 receptor agonists (GLP-1RA) are largely predictable as they interact directly with GLP-1 receptors on beta cells to mediate their glucose lowering effects by increasing GLP-1 in pharmacological range and not at all dependent upon endogenous...
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| Format: | Article |
| Language: | English |
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Wolters Kluwer Medknow Publications
2014-01-01
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| Series: | Indian Journal of Endocrinology and Metabolism |
| Subjects: | |
| Online Access: | http://www.ijem.in/article.asp?issn=2230-8210;year=2014;volume=18;issue=6;spage=753;epage=759;aulast=Singh |
| _version_ | 1818333249493008384 |
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| author | Awadhesh Kumar Singh |
| author_facet | Awadhesh Kumar Singh |
| author_sort | Awadhesh Kumar Singh |
| collection | DOAJ |
| description | The pharmacological actions of the glucagon-like peptide-1 receptor agonists (GLP-1RA) are largely predictable as they interact directly with GLP-1 receptors on beta cells to mediate their glucose lowering effects by increasing GLP-1 in pharmacological range and not at all dependent upon endogenous GLP-1 secretion. The mechanism of action of dipeptidyl peptidase-4 inhibitors (DPP-4I) are relatively less clear although classical mechanism is to inhibit the endogenous GLP-1 metabolism and thereby increasing GLP-1 level in the physiological range. DPP-4I also increase the half-life of GLP-1 to some extent by inhibiting their quick degradation by DPP enzyme ubiquitously present in the body. Interestingly, even with the effective blockade with currently existing DPP-4I, the half-life of GLP-1 only increases from 1 min to 5 min and therefore its residual time in plasma still remains pretty short. Intriguingly, this GLP-1 rise is so modest and so short-lived that it may be difficult to believe that this would sufficiently engage and activate the GLP-1 receptor in beta cell to produce significant insulinotropic effect. However, in clinical trials as well as in real life scenario, the anti-glycemic efficacies seen with DPP-4I are quite satisfactory and sometime very much competitive to GLP-1RA as evident from their head-to-head trials including meta-analysis. This efficacy outcome challenges the "only" GLP-1 dependent mechanism of glucose lowering and provokes an insight that other neuro-endocrine pathway may be playing a second fiddle. This review will collate those emerging concept and put a perspective as to how DPP-4I might be working though other pathway besides direct GLP-1 mediated receptor activation. |
| first_indexed | 2024-12-13T13:48:38Z |
| format | Article |
| id | doaj.art-d402007753b04261a3e2e2e160e7a14d |
| institution | Directory Open Access Journal |
| issn | 2230-8210 2230-9500 |
| language | English |
| last_indexed | 2024-12-13T13:48:38Z |
| publishDate | 2014-01-01 |
| publisher | Wolters Kluwer Medknow Publications |
| record_format | Article |
| series | Indian Journal of Endocrinology and Metabolism |
| spelling | doaj.art-d402007753b04261a3e2e2e160e7a14d2022-12-21T23:43:17ZengWolters Kluwer Medknow PublicationsIndian Journal of Endocrinology and Metabolism2230-82102230-95002014-01-0118675375910.4103/2230-8210.141319Dipeptidyl peptidase-4 inhibitors: Novel mechanism of actionsAwadhesh Kumar SinghThe pharmacological actions of the glucagon-like peptide-1 receptor agonists (GLP-1RA) are largely predictable as they interact directly with GLP-1 receptors on beta cells to mediate their glucose lowering effects by increasing GLP-1 in pharmacological range and not at all dependent upon endogenous GLP-1 secretion. The mechanism of action of dipeptidyl peptidase-4 inhibitors (DPP-4I) are relatively less clear although classical mechanism is to inhibit the endogenous GLP-1 metabolism and thereby increasing GLP-1 level in the physiological range. DPP-4I also increase the half-life of GLP-1 to some extent by inhibiting their quick degradation by DPP enzyme ubiquitously present in the body. Interestingly, even with the effective blockade with currently existing DPP-4I, the half-life of GLP-1 only increases from 1 min to 5 min and therefore its residual time in plasma still remains pretty short. Intriguingly, this GLP-1 rise is so modest and so short-lived that it may be difficult to believe that this would sufficiently engage and activate the GLP-1 receptor in beta cell to produce significant insulinotropic effect. However, in clinical trials as well as in real life scenario, the anti-glycemic efficacies seen with DPP-4I are quite satisfactory and sometime very much competitive to GLP-1RA as evident from their head-to-head trials including meta-analysis. This efficacy outcome challenges the "only" GLP-1 dependent mechanism of glucose lowering and provokes an insight that other neuro-endocrine pathway may be playing a second fiddle. This review will collate those emerging concept and put a perspective as to how DPP-4I might be working though other pathway besides direct GLP-1 mediated receptor activation.http://www.ijem.in/article.asp?issn=2230-8210;year=2014;volume=18;issue=6;spage=753;epage=759;aulast=SinghDipeptidyl peptidase-4 inhibitorsglucose-dependent intestinal polypeptideglucagon-like peptide-1glucagon-like peptide-1 agonistincretintype 2 diabetes |
| spellingShingle | Awadhesh Kumar Singh Dipeptidyl peptidase-4 inhibitors: Novel mechanism of actions Indian Journal of Endocrinology and Metabolism Dipeptidyl peptidase-4 inhibitors glucose-dependent intestinal polypeptide glucagon-like peptide-1 glucagon-like peptide-1 agonist incretin type 2 diabetes |
| title | Dipeptidyl peptidase-4 inhibitors: Novel mechanism of actions |
| title_full | Dipeptidyl peptidase-4 inhibitors: Novel mechanism of actions |
| title_fullStr | Dipeptidyl peptidase-4 inhibitors: Novel mechanism of actions |
| title_full_unstemmed | Dipeptidyl peptidase-4 inhibitors: Novel mechanism of actions |
| title_short | Dipeptidyl peptidase-4 inhibitors: Novel mechanism of actions |
| title_sort | dipeptidyl peptidase 4 inhibitors novel mechanism of actions |
| topic | Dipeptidyl peptidase-4 inhibitors glucose-dependent intestinal polypeptide glucagon-like peptide-1 glucagon-like peptide-1 agonist incretin type 2 diabetes |
| url | http://www.ijem.in/article.asp?issn=2230-8210;year=2014;volume=18;issue=6;spage=753;epage=759;aulast=Singh |
| work_keys_str_mv | AT awadheshkumarsingh dipeptidylpeptidase4inhibitorsnovelmechanismofactions |