Clinical and Physiological Characterization of Elevated Plasma Glucagon-Like Peptide-1 Levels (Hyperglipemia) in a Dipeptidyl Peptidase IV Mutation Carrier
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 glucagon-like peptide-1...
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Frontiers Media S.A.
2018-03-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fendo.2018.00062/full |
| _version_ | 1818321553556766720 |
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| author | Dandan Zhao Shaoqian Zhao Xiao Wang Mingbo Su Wen Liu Qinyun Ma Jie Hong Weiqiong Gu Jingya Li Ruixin Liu Guang Ning Guang Ning Jiqiu Wang Yifei Zhang |
| author_facet | Dandan Zhao Shaoqian Zhao Xiao Wang Mingbo Su Wen Liu Qinyun Ma Jie Hong Weiqiong Gu Jingya Li Ruixin Liu Guang Ning Guang Ning Jiqiu Wang Yifei Zhang |
| author_sort | Dandan Zhao |
| collection | DOAJ |
| description | 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 glucagon-like peptide-1 (GLP-1) level 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)] were 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. Ex vivo functional study further showed that the serum from the proband markedly enhanced insulin production of primary rat islet cells. Furthermore, V486M variant and another eight DPP4 variants were identified in our in-home database and seven showed decreased enzymatic activities than wild-type DPP4, consistent with their alterations in their protein expression levels. 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 at present. The other two old carriers in the pedigree both had type 2 diabetes, and one of them also had hyperlipidemia and myocarditis. We first identified hyperglipemia in a female subject harboring a loss-of-function DPP4 mutation with decreased DPP4 activity. Other sporadic DPP4 mutations verified the low-frequent occurrence of genetic inhibition of DPP4 activity, at least in the Chinese population studied. These results may provide new evidence for evaluation of the potential long-term effects of DPP4i and GLP-1 analogs. |
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| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-12-13T10:42:44Z |
| publishDate | 2018-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-8779bb3f256146db80545ded24feb2952022-12-21T23:50:25ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922018-03-01910.3389/fendo.2018.00062302713Clinical and Physiological Characterization of Elevated Plasma Glucagon-Like Peptide-1 Levels (Hyperglipemia) in a Dipeptidyl Peptidase IV Mutation CarrierDandan Zhao0Shaoqian Zhao1Xiao Wang2Mingbo Su3Wen Liu4Qinyun Ma5Jie Hong6Weiqiong Gu7Jingya Li8Ruixin Liu9Guang Ning10Guang Ning11Jiqiu Wang12Yifei Zhang13Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, ChinaDepartment of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, ChinaDepartment of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, ChinaNational Center for Drug Screening, Shanghai Institute of Material Medical (SIMM), Chinese Academy of Science (CAS), Shanghai, ChinaDepartment of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, ChinaDepartment of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, ChinaDepartment of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, ChinaDepartment of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, ChinaNational Center for Drug Screening, Shanghai Institute of Material Medical (SIMM), Chinese Academy of Science (CAS), Shanghai, ChinaDepartment of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, ChinaDepartment of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, ChinaInstitute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, ChinaDepartment of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, ChinaDepartment of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, National Key Laboratory for Medical Genomes, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, ChinaThe 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 glucagon-like peptide-1 (GLP-1) level 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)] were 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. Ex vivo functional study further showed that the serum from the proband markedly enhanced insulin production of primary rat islet cells. Furthermore, V486M variant and another eight DPP4 variants were identified in our in-home database and seven showed decreased enzymatic activities than wild-type DPP4, consistent with their alterations in their protein expression levels. 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 at present. The other two old carriers in the pedigree both had type 2 diabetes, and one of them also had hyperlipidemia and myocarditis. We first identified hyperglipemia in a female subject harboring a loss-of-function DPP4 mutation with decreased DPP4 activity. Other sporadic DPP4 mutations verified the low-frequent occurrence of genetic inhibition of DPP4 activity, at least in the Chinese population studied. These results may provide new evidence for evaluation of the potential long-term effects of DPP4i and GLP-1 analogs.http://journal.frontiersin.org/article/10.3389/fendo.2018.00062/fulldipeptidyl peptidase IVglucagon-like peptide-1β-cell functiontype 2 diabetesincretin effect |
| spellingShingle | Dandan Zhao Shaoqian Zhao Xiao Wang Mingbo Su Wen Liu Qinyun Ma Jie Hong Weiqiong Gu Jingya Li Ruixin Liu Guang Ning Guang Ning Jiqiu Wang Yifei Zhang Clinical and Physiological Characterization of Elevated Plasma Glucagon-Like Peptide-1 Levels (Hyperglipemia) in a Dipeptidyl Peptidase IV Mutation Carrier Frontiers in Endocrinology dipeptidyl peptidase IV glucagon-like peptide-1 β-cell function type 2 diabetes incretin effect |
| title | Clinical and Physiological Characterization of Elevated Plasma Glucagon-Like Peptide-1 Levels (Hyperglipemia) in a Dipeptidyl Peptidase IV Mutation Carrier |
| title_full | Clinical and Physiological Characterization of Elevated Plasma Glucagon-Like Peptide-1 Levels (Hyperglipemia) in a Dipeptidyl Peptidase IV Mutation Carrier |
| title_fullStr | Clinical and Physiological Characterization of Elevated Plasma Glucagon-Like Peptide-1 Levels (Hyperglipemia) in a Dipeptidyl Peptidase IV Mutation Carrier |
| title_full_unstemmed | Clinical and Physiological Characterization of Elevated Plasma Glucagon-Like Peptide-1 Levels (Hyperglipemia) in a Dipeptidyl Peptidase IV Mutation Carrier |
| title_short | Clinical and Physiological Characterization of Elevated Plasma Glucagon-Like Peptide-1 Levels (Hyperglipemia) in a Dipeptidyl Peptidase IV Mutation Carrier |
| title_sort | clinical and physiological characterization of elevated plasma glucagon like peptide 1 levels hyperglipemia in a dipeptidyl peptidase iv mutation carrier |
| topic | dipeptidyl peptidase IV glucagon-like peptide-1 β-cell function type 2 diabetes incretin effect |
| url | http://journal.frontiersin.org/article/10.3389/fendo.2018.00062/full |
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