Data from: GLP-1 receptor blockade reduces stimulated insulin secretion in fasted subjects with low circulating GLP-1

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  • Context: Glucagon-like peptide 1 (GLP-1), an insulinotropic peptide released into the circulation from intestinal enteroendocrine cells, is considered a hormonal mediator of insulin secretion. However, the physiological actions of circulating GLP-1 have long been questioned because of the short half-life of the active peptide. Moreover, there is mounting evidence for localized, intra-islet mediation of GLP-1 receptor (GLP-1r) signaling including a role for islet dipeptidyl-peptidase 4 (DPP4).

    Objective: To determine whether GLP-1r signaling contributes to insulin secretion in the absence of enteral stimulation and increased plasma levels, and whether this is affected by DPP4.
    Setting: Single-site study conducted at an academic medical center.
    Participants: 20 nondiabetic subjects and 13 subjects with type 2 diabetes.
    Design & Interventions: Cross-over study in which subjects received either a DPP4 inhibitor (DPP4i; sitagliptin) or placebo on two separate days. On each day they received a bolus of intravenous (IV) arginine during sequential 60 minute infusions of the GLP-1r blocker exendin[9-39] (Ex-9) and saline.

    Main Outcome Measures: Arginine-stimulated secretion of C-Peptide (C-PArg) and insulin (InsArg).

    Results: Plasma GLP-1 remained at fasting levels throughout the experiments and IV arginine stimulated both - and β-cell secretion in all subjects. Ex-9 infusion reduced C-PArg in both the diabetic and nondiabetic groups by ~14% (p < 0.03 for both groups). Sitagliptin lowered baseline glycemia but did not affect the primary measures of insulin secretion. However, a significant interaction between sitagliptin and Ex-9 suggested a greater effect of GLP-1r activation with DPP4i treatment in diabetic subjects.
    Conclusions: GLP-1r activation contributes to β-cell secretion in diabetic and nondiabetic humans during -cell activation, but in the absence of increased circulating GLP-1. These results are compatible with regulation of β-cells by paracrine signals from -cells. This process may be affected by DPP4 inhibition.     ... [Read More]

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  • D'Alessio, D., Gray, S., Hoselton, A., Krishna, R., Slentz, C. (2022). Data from: GLP-1 receptor blockade reduces stimulated insulin secretion in fasted subjects with low circulating GLP-1. Duke Research Data Repository. V2 https://doi.org/10.7924/r41n87v9d
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  • 10.7924/r41n87v9d
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  • ark:/87924/r41n87v9d
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  • 10.7924/r4ks6tf5q
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  • Gray SM, Hoselton AL, Krishna R, Slentz CA, D'Alessio DA. GLP-1 Receptor Blockade Reduces Stimulated Insulin Secretion in Fasted Subjects With Low Circulating GLP-1. J Clin Endocrinol Metab. 2022 Aug 18;107(9):2500-2510. doi: 10.1210/clinem/dgac396. PMID: 35775723; PMCID: PMC9387711.  https://doi.org/10.1210/clinem/dgac396
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  • The supplemental PDF file has been updated with a new table (Table 8) after peer-review.
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  • Data from: GLP-1 receptor blockade reduces stimulated insulin secretion in fasted subjects with low circulating GLP-1
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Thumbnail Title Date Uploaded Actions
file details DAlessio_GLP-1Insulin_ReadMe.txt 2022-06-16 Public Download
file details GlucoseHormoneValues.csv 2022-06-16 Public Download
file details jc2021-02246_Supplement_rev.pdf 2022-06-16 Public Download
file details ValidationGLP-1assay.xlsx 2022-06-16 Public Download
file details ValidationGlucagonAssay.xlsx 2022-06-16 Public Download

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Version DOI Comment Publication Date
2 10.7924/r41n87v9d The supplemental PDF file has been updated with a new table (Table 8) after peer-review. 2022-06-16
1 10.7924/r4ks6tf5q 2022-01-26

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