GLP-1; insulin secretion; mouse; neprilysin; type 2 diabetes; Endocrinology, Diabetes and Metabolism; Physiology; Physiology (medical)
Abstract :
[en] Type 2 diabetes is associated with the upregulation of neprilysin, a peptidase capable of cleaving glucoregulatory peptides such as glucagon-like peptide-1 (GLP-1). In humans, use of the neprilysin inhibitor sacubitril in combination with an angiotensin II receptor blocker was associated with increased plasma GLP-1 levels and improved glycemic control. Whether neprilysin inhibition per se is mediating these effects remains unknown. We sought to determine whether pharmacological neprilysin inhibition on its own confers beneficial effects on glycemic status and β-cell function in a mouse model of reduced insulin secretion, and whether any such effects are dependent on GLP-1 receptor (GLP-1R) signaling. High-fat-fed male wild-type (Glp1r+/+) and GLP-1R knockout (Glp1r-/-) mice were treated with low-dose streptozotocin (STZ) to recapitulate type 2 diabetes-associated β-cell dysfunction, or vehicle as control. Mice were continued on high-fat diet alone or supplemented with the neprilysin inhibitor sacubitril for 8 wk. At the end of the study period, β-cell function was assessed by oral or intravenous glucose-tolerance test. Fasting and fed glucose were significantly lower in wild-type mice treated with sacubitril, although active GLP-1 levels and insulin secretion during oral glucose challenge were unchanged. In contrast, insulin secretion in response to intravenous glucose was significantly enhanced in sacubitril-treated wild-type mice, and this effect was blunted in Glp1r-/- mice. Similarly, sacubitril enhanced insulin secretion in vitro in islets from STZ-treated Glp1r+/+ but not Glp1r-/- mice. Together, our data suggest the insulinotropic effects of pharmacological neprilysin inhibition in a mouse model of β-cell dysfunction are mediated via intra-islet GLP-1R signaling.NEW & NOTEWORTHY The neprilysin inhibitor, sacubitril, improves glycemic status in a mouse model of reduced insulin secretion. Sacubitril enhances intravenous but not oral glucose-mediated insulin secretion. The increased glucose-mediated insulin secretion is GLP-1 receptor-dependent. Neprilysin inhibition does not raise postprandial circulating active GLP-1 levels.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Esser, Nathalie ; Centre Hospitalier Universitaire de Liège - CHU > > Service de diabétologie, nutrition, maladies métaboliques ; Veterans Affairs Puget Sound Health Care System, Seattle, Washington ; Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, Washington ; ULiège - Université de Liège > GIGA-I3 > Laboratoire d'Immunométabolisme et Nutrition
Mongovin, Stephen M; Veterans Affairs Puget Sound Health Care System, Seattle, Washington
Parilla, Jacqueline; Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, Washington
Barrow, Breanne M; Veterans Affairs Puget Sound Health Care System, Seattle, Washington
Mundinger, Thomas O; Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, Washington
Fountaine, Brendy S; Veterans Affairs Puget Sound Health Care System, Seattle, Washington
Larmore, Megan J; Department of Comparative Medicine, University of Washington, Seattle, Washington
Castillo, Joseph J; Veterans Affairs Puget Sound Health Care System, Seattle, Washington ; Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, Washington
Akter, Rehana; Veterans Affairs Puget Sound Health Care System, Seattle, Washington ; Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, Washington
Hull, Rebecca L ; Veterans Affairs Puget Sound Health Care System, Seattle, Washington ; Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, Washington
Zraika, Sakeneh ; Veterans Affairs Puget Sound Health Care System, Seattle, Washington ; Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, Washington
Language :
English
Title :
Neprilysin inhibition improves intravenous but not oral glucose-mediated insulin secretion via GLP-1R signaling in mice with β-cell dysfunction.
Publication date :
01 March 2022
Journal title :
American Journal of Physiology - Endocrinology and Metabolism
BAEF - Belgian American Educational Foundation CFF - Cystic Fibrosis Foundation NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases UW - University of Washington
Funding text :
This work was supported by the research service of the Seattle VA Puget Sound Health Care System and Seattle Institute for Biomedical and Clinical Research, along with funding from the National Institutes of Health (NIH) Grants DK-098506 (to S.Z.) and P30 DK-017047 (University of Washington Diabetes Research Center, Cell Function Analysis Core and Cellular and Molecular Imaging Core). N.E. was supported by the Dick and Julia McAbee Endowed Fellowship from the University of Washington, the French Society of Diabetes, the Baillet-Latour Found and the Belgian American Educational Foundation, the Belgian Association of Diabetes, the Horlait-Dapsens Foundation, and the Leon Fredericq Foundation. J.J.C. was supported by NIH Grant T32 HL-007028 and a Cystic Fibrosis Foundation Fellowship (CASTIL20F0). R.A. was supported by NIH Grant T32 DK-007247.
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