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Diabetologia

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01-09-2014 | Article

Dipeptidyl peptidase 4 (DPP-4) is expressed in mouse and human islets and its activity is decreased in human islets from individuals with type 2 diabetes

Authors: Bilal A. Omar, Liu Liehua, Yuchiro Yamada, Yutaka Seino, Piero Marchetti, B. Ahrén

Published in: Diabetologia | Issue 9/2014

Abstract

Aims/hypothesis

Inhibition of the enzyme dipeptidyl peptidase 4 (DPP-4), which cleaves and inactivates glucagon-like peptide 1 (GLP-1), is a glucose-lowering strategy in type 2 diabetes. Since DPP-4 is a ubiquitously distributed enzyme, we examined whether it is expressed in islets and whether an islet effect to inhibit DPP-4 may result in stimulated insulin secretion.

Methods

We investigated DPP-4 expression and activity in the islets of mouse models of obesity as well as human islets from non-diabetic and type 2 diabetic donors. We further investigated whether inhibition with DPP-4 inhibitors could promote insulin secretion via islet GLP-1 in isolated islets.

Results

DPP-4 was readily detected in mouse and human islets with species-specific cellular localisation. In mice, DPP-4 was expressed predominantly in beta cells, whereas in humans it was expressed nearly exclusively in alpha cells. DPP-4 activity was significantly increased in islets from diet-induced obese mice compared with mice fed a control diet. In humans, DPP-4 activity was significantly lower in islets from type 2 diabetic donors than in non-diabetic donors. In human islets, there was a significant positive correlation between DPP-4 activity and insulin secretory response to 16.7 mmol/l glucose. Treatment of mouse islets with the DPP-4 inhibitors, NVPDPP728 and vildagliptin, resulted in a significant potentiation of insulin secretion in a GLP-1-dependent manner, as this was inhibited by the GLP-1 receptor antagonist, Exendin (9-39), and was retained in glucose-dependent insulinotropic polypeptide (GIP) receptor-deficient mice but lost in mice lacking GLP-1 receptors or both incretin receptors. Human islets treated with the DPP-4 inhibitor, vildagliptin, showed increased secretion of insulin and intact GLP-1.

Conclusions/interpretation

We conclude that DPP-4 is present and active in mouse and human islets, is regulated by the disease state, and that inhibition of islet DPP-4 activity can have direct effects on islet function. Inhibiting islet DPP-4 activity may therefore contribute to the insulin-secretory and glucose-lowering action of DPP-4 inhibition.

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Title: Dipeptidyl peptidase 4 (DPP-4) is expressed in mouse and human islets and its activity is decreased in human islets from individuals with type 2 diabetes
Authors: Bilal A. Omar
Liu Liehua
Yuchiro Yamada
Yutaka Seino
Piero Marchetti
B. Ahrén
Publication date: 01-09-2014
Publisher: Springer Berlin Heidelberg
Published in: Diabetologia / Issue 9/2014
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-014-3299-4

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Conclusions/interpretation

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