Inhibition of dipeptidyl peptidase IV activity by oral metformin in Type 2 diabetes

Lindsay, John R.; Duffy, Nicola; McKillop, Aine; Ardill, Joy; O’Harte, Finbarr; Flatt, Peter R.; Bell, P. M.

doi:10.1111/j.1464-5491.2005.01461.x

Cited by 145 publications

(106 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Alternatively, DPP-4 activity might be inhibited by metformin, resulting in an increase in GLP-1 levels in the plasma. Indeed, DPP-4 activity in the circulation has been reported to be reduced in rodents or humans treated with metformin [14,15]. Yet, contrary to these findings, metformin does not directly inhibit DPP-4 activity in vitro [9,14,16].…”

Section: Ampk Amp-activated Protein Kinase Dpp-4contrasting

confidence: 48%

New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser

Cho

Kieffer

2010

Diabetologia

View full text Add to dashboard Cite

The two major deficits in type 2 diabetes, insulin resistance and impaired beta cell function, are often treated with metformin and incretin-based drugs, respectively. However, there may be unappreciated benefits of this combination of therapies. In this issue of Diabetologia, Maida et al. (doi:10.1007Maida et al. (doi:10. /s00125-010-1937 report that metformin acutely increases plasma levels of glucagon-like peptide 1 (GLP-1) in mice. Moreover, they show that metformin enhances the expression of the genes encoding the receptors for both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in mouse islets and also increases the effects of GIP and GLP-1 on insulin secretion from beta cells. Interestingly, these incretin-sensitising effects of metformin appear to be mediated by a peroxisome proliferator-activated receptor α-dependent pathway, as opposed to the more commonly ascribed pathway of metformin action involving AMP-activated protein kinase. These provocative findings by Maida et al. extend our understanding of the mechanism of action of metformin and provide further insights into the benefits of combining metformin with incretin-based drugs to combat diabetes.

show abstract

Section: Ampk Amp-activated Protein Kinase Dpp-4contrasting

confidence: 48%

New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser

Cho

Kieffer

2010

Diabetologia

View full text Add to dashboard Cite

show abstract

“…In addition, acute ingestion of drug inhibitors (metformin) in T2DM subjects reduced plasma DPP-IV activity for up to 6 h (83) . Food protein-derived peptide inhibitors of DPP-IV are yet to be fully evaluated in vivo.…”

Section: Management Of Type 2 Diabetesmentioning

confidence: 99%

Food protein hydrolysates as a source of dipeptidyl peptidase IV inhibitory peptides for the management of type 2 diabetes

2013

View full text Add to dashboard Cite

The prevalence of type 2 diabetes mellitus (T2DM) is increasing and it is estimated that by 2030 approximately 366 million people will be diagnosed with this condition. The use of dipeptidyl peptidase IV (DPP-IV) inhibitors is an emerging strategy for the treatment of T2DM. DPP-IV is a ubiquitous aminodipeptidase that cleaves incretins such as glucagon like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), resulting in a loss in their insulinotropic activity. Synthetic DPP-IV drug inhibitors are being used to increase the half-life of the active GLP-1 and GIP. Dietary intervention is accepted as a key component in the prevention and management of T2DM. Therefore, identification of natural food protein-derived DPP-IV inhibitors is desirable. Peptides with DPP-IV inhibitory activity have been identified in a variety of food proteins. This review aims to provide an overview of food protein hydrolysates as a source of the DPP-IV inhibitory peptides with particular focus on milk proteins. In addition, the proposed modes of inhibition and structure–activity relationship of peptide inhibitors are discussed. Milk proteins and associated peptides also display insulinotropic activity and help regulate blood glucose in healthy and diabetic subjects. Therefore, milk protein derived peptide inhibitors may be a unique multifunctional peptide approach for the management of T2DM.

show abstract

“…Alternatively, SG may affect the tumour stroma by modulating production of cytokines and extracellular matrix remodelling enzymes (Ta et al, 2010). Our findings are likely to be relevant to human tumours because of recent reports that patients being treated for type 2 diabetes with Metformin, another CD26 inhibitor, show a reduced incidence of certain cancers (Lindsay et al, 2005;Landman et al, 2010).…”

Section: Discussionmentioning

confidence: 68%

Upregulation of CD26 expression in epithelial cells and stromal cells during wound-induced skin tumour formation

et al. 2011

View full text Add to dashboard Cite

We have previously described InvEE transgenic mice in which non-dividing, differentiating epidermal cells express oncogenically activated MAPK kinase 1 (MEK1). Skin wounding triggers tumour formation in InvEE mice via a mechanism that involves epidermal release of IL-1a and attraction of a pro-tumorigenic inflammatory infiltrate. To look for potential effects on the underlying connective tissue, we screened InvEE and wild-type epidermis for differential expression of cytokines and immune modulators. We identified a single protein, CD26 (dipeptidyl peptidase-4). CD26 serum levels were not increased in InvEE mice. In contrast, CD26 was upregulated in keratinocytes expressing mutant MEK1 and in the epithelial compartment of InvEE tumours, where it accumulated at cell-cell borders. CD26 expression was increased in dermal fibroblasts following skin wounding but was downregulated in tumour stroma. CD26 activity was stimulated by calcium-induced intercellular adhesion in keratinocytes, suggesting that the upregulation of CD26 in InvEE epidermis is due to expansion of the differentiated cell layers. IL-1a treatment of dermal fibroblasts stimulated CD26 activity, and therefore epidermal IL-1a release may contribute to the upregulation of CD26 expression in wounded dermis. Pharmacological blockade of CD26, via Sitagliptin, reduced growth of InvEE tumours, while combined inhibition of IL-1a and CD26 delayed tumour onset and reduced tumour incidence. Our results demonstrate that inappropriate activation of MEK1 in the epidermis leads to changes in dermal fibroblasts that, like the skin inflammatory infiltrate, contribute to tumour formation.

show abstract

Inhibition of dipeptidyl peptidase IV activity by oral metformin in Type 2 diabetes

Abstract: Oral metformin effectively inhibits DPP IV activity in Type 2 diabetic patients, suggesting that the drug may have potential for future combination therapy with incretin hormones.

Cited by 145 publications

References 13 publications

New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser

New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser

Food protein hydrolysates as a source of dipeptidyl peptidase IV inhibitory peptides for the management of type 2 diabetes

Upregulation of CD26 expression in epithelial cells and stromal cells during wound-induced skin tumour formation

Contact Info

Product

Resources

About