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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.

frontiers in endocrinology

Clinical and Physiological Characterization of Elevated Plasma Glucagon-Like Peptide-1 Levels (Hyperglipemia) in a Dipeptidyl Peptidase IV Mutation Carrier