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GLP-1 Receptor Blockade Reduces Stimulated Insulin Secretion in Fasted Subjects With Low Circulating GLP-1.

Publication ,  Journal Article
Gray, SM; Hoselton, AL; Krishna, R; Slentz, CA; D'Alessio, DA
Published in: J Clin Endocrinol Metab
August 18, 2022

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 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. METHODS: Single-site study conducted at an academic medical center of 20 nondiabetic subjects and 13 subjects with type 2 diabetes. This was a crossover study in which subjects received either a DPP4 inhibitor (DPP4i; sitagliptin) or placebo on 2 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. The main outcome measures were 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 α- and β-cell secretion in all subjects. Ex-9 infusion reduced C-PArg in both the diabetic and nondiabetic groups by ~14% (P < .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 more GLP-1r activation with DPP4i treatment in subjects with diabetes. CONCLUSION: GLP-1r activation contributes to β-cell secretion in diabetic and nondiabetic people during α-cell activation, but in the absence of increased circulating GLP-1. These results are compatible with regulation of β-cells by paracrine signals from α-cells. This process may be affected by DPP4 inhibition.

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Published In

J Clin Endocrinol Metab

DOI

EISSN

1945-7197

Publication Date

August 18, 2022

Volume

107

Issue

9

Start / End Page

2500 / 2510

Location

United States

Related Subject Headings

  • Sitagliptin Phosphate
  • Insulin Secretion
  • Insulin
  • Humans
  • Glucagon-Like Peptide-1 Receptor
  • Glucagon-Like Peptide 1
  • Fasting
  • Endocrinology & Metabolism
  • Dipeptidyl Peptidase 4
  • Diabetes Mellitus, Type 2
 

Citation

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Chicago
ICMJE
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Gray, S. M., Hoselton, A. L., Krishna, R., Slentz, C. A., & D’Alessio, D. A. (2022). GLP-1 Receptor Blockade Reduces Stimulated Insulin Secretion in Fasted Subjects With Low Circulating GLP-1. J Clin Endocrinol Metab, 107(9), 2500–2510. https://doi.org/10.1210/clinem/dgac396
Gray, Sarah M., Andrew L. Hoselton, Radha Krishna, Cris A. Slentz, and David A. D’Alessio. “GLP-1 Receptor Blockade Reduces Stimulated Insulin Secretion in Fasted Subjects With Low Circulating GLP-1.J Clin Endocrinol Metab 107, no. 9 (August 18, 2022): 2500–2510. https://doi.org/10.1210/clinem/dgac396.
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):2500–10.
Gray, Sarah M., et al. “GLP-1 Receptor Blockade Reduces Stimulated Insulin Secretion in Fasted Subjects With Low Circulating GLP-1.J Clin Endocrinol Metab, vol. 107, no. 9, Aug. 2022, pp. 2500–10. Pubmed, doi:10.1210/clinem/dgac396.
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.
Journal cover image

Published In

J Clin Endocrinol Metab

DOI

EISSN

1945-7197

Publication Date

August 18, 2022

Volume

107

Issue

9

Start / End Page

2500 / 2510

Location

United States

Related Subject Headings

  • Sitagliptin Phosphate
  • Insulin Secretion
  • Insulin
  • Humans
  • Glucagon-Like Peptide-1 Receptor
  • Glucagon-Like Peptide 1
  • Fasting
  • Endocrinology & Metabolism
  • Dipeptidyl Peptidase 4
  • Diabetes Mellitus, Type 2