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Front. Endocrinol. | doi: 10.3389/fendo.2018.00062

Clinical and Physiological Characterization of Elevated Plasma GLP-1 Levels (Hyperglipemia) in a DPP4 Mutation Carrier

 Dandan Zhao1, Shaoqian Zhao1, Xiao Wang1, Mingbo Su2, Wen Liu1, Jie Hong1, Weiqiong Gu1,  Qinyun Ma1,  Jingya Li2, Ruixin Liu1, Guang Ning1, 3,  Jiqiu Wang1* and Yifei Zhang1
  • 1China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China
  • 2National Center for Drug Screening, Shanghai Institute of Material Medical (SIMM), China Academy of Science (CAS), China
  • 3Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & Shanghai Jiao Tong University School of Medicine (SJTUSM), China

The clinical application of dipeptidyl peptidase IV inhibitors (DPP4i) increasing active glucagon-like peptide-1 (AGLP-1) levels has been linked to pancreatitis, pancreatic tumors and cardiovascular events. However, DPP4 mutations in humans or the long-term outcomes of high GLP-1 exposure have not been reported. A trio family with a proband showing an extremely high AGLP-1 level (defined here as hyperglipemia [hyper-Glucagon-Like Peptide-1-emia]) was conducted whole-exome sequencing for potential pathogenic genetic defects. One novel DPP4 mutation, p.V486M (c.1456 G>A), was identified in the proband and showed damaged enzymatic activity of DPP4. And ex vivo functional study further showed that the serum from the proband enhanced insulin production of primary rat islet cells. Furthermore, for the V486M variant and other eight DPP4 variants identified in our in-home database, seven of them showed decreased enzymatic activities than wild-type DPP4. Of note, the levels of glucose, lipids and tumor markers (especially for CA15-3 and CA125), increased gradually in the proband during a 4-year follow-up period, although no abnormal physical symptoms or imaging results were observed till now. The other two old carriers in the pedigree both had type 2 diabetes, and one of them had hyperlipidemia and myocarditis additionally. In summary, we firstly identified hyperglipemia in a female subject harboring a loss-of-function DPP4 mutation with decreased DPP4 activity. Other sporadic DPP4 mutations verified the low-frequency occurrence of genetic inhibition of DPP4 activity, at least in the Chinese population. These results may provide new evidence for evaluation of the potential long-term effects of DPP4i and GLP-1 analogues.

Keywords: Dipeptidyl peptidase IV, Glucagon-like peptide-1, β-cell function, type 2 diabetes, Incretin effect, hyperglipemia

Received: 28 Sep 2017; Accepted: 12 Feb 2018.

Edited by:

Robert K. Semple, University of Edinburgh, United Kingdom

Reviewed by:

Ben G. Challis, Wellcome Trust-MRC Institute of Metabolic Science, United Kingdom
Reshma Ramracheya, University of Oxford, United Kingdom  

Copyright: © 2018 Zhao, Zhao, Wang, Su, Liu, Hong, Gu, Ma, Li, Liu, Ning, Wang and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Jiqiu Wang, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China, wangjq@shsmu.edu.cn