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Recently, more specific assays became available, therefore we systematically assessed glucagon and other proglucagon cleavage products and their relation to RESEARCH DESIGN AND METHODS: We used samples from 52 oral glucose tolerance tests (OGTT) that were randomly selected from persons with different categories of glucose tolerance in an extensively phenotyped study cohort.RESULTS: Glucagon concentrations quantified with RIA were non-suppressed at 2 hours of the OGTT in 36% of the samples. Non-suppressors showed lower fasting glucagon levels compared to suppressors (p=011). Similar to RIA measurements, ELISA-derived fasting glucagon was lower in non-suppressors (p<001). Glucagon 1-61 as well as glicentin and GLP-1 kinetics were significantly different between suppressors and non-suppressors (p=004, p=002, p=008 respectively) with higher concentrations of all three hormones in non-suppressors. Levels of insulin, C-peptide, and free fatty acids were comparable between groups. Non-suppressors were leaner and had lower plasma glucose concentrations (p=03 and p=047, respectively). Despite comparable liver fat content and insulin sensitivity (p≥0), they had lower 2-hour post-challenge glucose (p=01).CONCLUSIONS: Glucagon 1-61, glicentin and GLP-1 partially account for RIA-derived glucagon measurements due to cross-reactivity of the assay. However, this contribution is small, since the investigated proglucagon cleavage products contribute less than 10% to the variation in RIA measured glucagon. Altered glucagon levels and higher post-challenge incretins are associated with a Conflict of interest statement: Outside of the current work, RW does report lecture fees from Novo Nordisk, Sanofi-Aventis and travel grants from Eli Lilly. He served on the advisory board for Akcea Therapeutics, Daiichi Sankyo, Sanofi-Aventis and NovoNordisk. Outside of semaglutide injection , AF reports lecture fees and advisory board membership from Sanofi, Novo Nordisk, Eli Lilly, and AstraZeneca. In addition to his current work, AB reports lecture fees from AstraZeneca, Boehringer Ingelheim, and NovoNordisk. He served on advisory boards of AstraZeneca, Boehringer Ingelheim and NovoNordisk. Outside of the current work, MH, reports research grants from Boehringer Ingelheim and Sanofi (both to the University Hospital of Tübingen), advisory board for Boehringer Ingelheim, and lecture fees from Amryt, Novo Nordisk and Boehringer Ingelheim. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential PEGylated exendin-4, a modified GLP-1 analog exhibits more potent cardioprotection than its unmodified parent molecule on a dose to dose basis in a murine model of myocardial infarction.University, Xi'an, China 710032. ; 2. Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, MD Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, MD 20892-2281, USA. ; 3. Department of Cardiovascular Surgery, General Hospital of Guangzhou Military Command, Guangzhou 510010, Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, MD 20892-2281, USA.University, Xi'an, China 710032. ; 5. Department of Cardiology, Chinese PLA General Hospital, Beijing, 100853, China.A Site-specifically PEGylated exendin-4 (denoted as PEG-Ex4) is an exendin-4 (denoted as Ex4) analog we developed by site-specific PEGylation of exendin-4 with a high molecular weight trimeric poly(ethylene glycol) (tPEG). It has been shown to possess prolonged half-life in vivo with similar receptor binding affinity compared to unmodified exendin-4 by our previous work. This study is sought to test whether PEG-Ex4 is suitable for treating myocardial infarction (MI). In the MI model, PEG-Ex4 was administered every 3 days while equivalent amount of Ex4 was administered every 3 days or twice daily. Animal survival rate, heart function, remodeling and neoangiogenesis were evaluated and compared. Tube formation was examined in endothelial cells. In addition, Western blotting and histology were performed to determine the markers of cardiac hypertrophy and angiogenesis and to explore the possible molecular mechanism involved. PEG-Ex4 and Ex4 showed comparable binding affinity to GLP-1 receptor. In Pancreatic hormones and other blood sugar regulating drugs , PEG-Ex4 given at 3 days interval achieved similar extent of protection as Ex4 given twice daily, while Ex4 given at 3 days interval failed to produce protection. PEG-Ex4 elevated endothelial tube formation in vitro and capillary density in the border area of MI. PEG-Ex4 increased Akt activity and VEGF production in a GLP-1R dependent manner in endothelial cells and antagonism of GLP-1R, Akt or VEGF abolished the protection of PEG-Ex4 in the MI model. PEG-Ex4 is a potent long-acting GLP-1 receptor agonist for the treatment of chronic heart disease. Its protection might be attributed to enhanced angiogenesis mediated by the activation of Akt and VEGF.