[en] The peptidase neprilysin modulates glucose homeostasis by cleaving and inactivating insulinotropic peptides, including some produced in the intestine such as glucagon-like peptide-1 (GLP-1). Under diabetic conditions, systemic or islet-selective inhibition of neprilysin enhances beta-cell function through GLP-1 receptor (GLP-1R) signaling. While neprilysin is expressed in intestine, its local contribution to modulation of beta-cell function remains unknown. We sought to determine whether acute selective pharmacological inhibition of intestinal neprilysin enhanced glucose-stimulated insulin secretion under physiological conditions, and whether this effect was mediated through GLP-1R. Lean chow-fed Glp1r+/+ and Glp1r-/- mice received a single oral low dose of the neprilysin inhibitor thiorphan or vehicle. To confirm selective intestinal neprilysin inhibition, neprilysin activity in plasma and intestine (ileum and colon) was assessed 40 minutes after thiorphan or vehicle administration. In a separate cohort of mice, an oral glucose tolerance test was performed 30 minutes after thiorphan or vehicle administration to assess glucose-stimulated insulin secretion. Systemic active GLP-1 levels were measured in plasma collected 10 minutes after glucose administration. In both Glp1r+/+ and Glp1r-/- mice, thiorphan inhibited neprilysin activity in ileum and colon without altering plasma neprilysin activity or active GLP-1 levels. Further, thiorphan significantly increased insulin secretion in Glp1r+/+ mice, whereas it did not change insulin secretion in Glp1r-/- mice. In conclusion, under physiological conditions, acute pharmacological inhibition of intestinal neprilysin increases glucose-stimulated insulin secretion in a GLP-1R-dependent manner. Since intestinal neprilysin modulates beta-cell function, strategies to inhibit its activity specifically in the intestine may improve beta-cell dysfunction in type 2 diabetes.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Esser, Nathalie ; Centre Hospitalier Universitaire de Liège - CHU > > Service de diabétologie, nutrition, maladies métaboliques ; Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA ; Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA 98195, USA
Mundinger, Thomas O; Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA 98195, USA
Barrow, Breanne M ; Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
Zraika, Sakeneh ; Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA ; Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA 98195, USA
Language :
English
Title :
Acute Inhibition of Intestinal Neprilysin Enhances Insulin Secretion via GLP-1 Receptor Signaling in Male Mice.
NIH - National Institutes of Health [US-MD] [US-MD] SFD - French Society of Diabetes [FR] BAEF - Belgian American Educational Foundation [BE] Fonds Baillet Latour [BE] ABD - Belgian Diabetes Association [BE] Horlait-Dapsens Foundations [BE] Leon Fredericq Foundation [BE]
Funding text :
Dick and Julia McAbee Endowed Postdoctoral Fellowship
Standeven KF, Hess K, Carter AM, et al. Neprilysin, obesity and the metabolic syndrome. Int J Obes (Lond). 2011;35(8):1031-1040.
Willard JR, Barrow BM, Zraika S. Improved glycaemia in high-fat-fed neprilysin-deficient mice is associated with reduced DPP-4 activity and increased active GLP-1 levels. Diabetologia. 2017;60(4):701-708.
Jordan J, Stinkens R, Jax T, et al. Improved insulin sensitivity with angiotensin receptor neprilysin inhibition in individuals with obesity and hypertension. Clin Pharmacol Ther. 2017;101(2):254-263.
Seferovic JP, Claggett B, Seidelmann SB, et al. Effect of sacubitril/ valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: A post-hoc analysis from the PARADIGM-HF trial. Lancet Diabetes Endocrinol. 2017;5(5):333-340.
Wijkman MO, Claggett B, Vaduganathan M, et al. Effects of sacubitril/valsartan on glycemia in patients with diabetes and heart failure: The PARAGON-HF and PARADIGM-HF trials. Cardiovasc Diabetol. 2022;21(1):110.
Esser N, Barrow BM, Choung E, Shen NJ, Zraika S. Neprilysin inhibition in mouse islets enhances insulin secretion in a GLP-1 receptor dependent manner. Islets. 2018;10(5):175-180.
Esser N, Schmidt C, Barrow BM, et al. Insulinotropic effects of neprilysin and/or angiotensin receptor inhibition in mice. Front Endocrinol (Lausanne). 2022;13:888867. https://doi. org/ 10. 3389/fendo. 2022. 888867
Hupe-Sodmann K, McGregor GP, Bridenbaugh R, et al. Characterisation of the processing by human neutral endopeptidase 24. 11 of GLP-1(7-36) amide and comparison of the substrate specificity of the enzyme for other glucagon-like peptides. Regul Pept. 1995;58(3):149-156.
Windelov JA, Wewer Albrechtsen NJ, Kuhre RE, et al. Why is it so difficult to measure glucagon-like peptide-1 in a mouse? Diabetologia. 2017;60(10):2066-2075.
Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87(4):1409-1439.
Grasset E, Puel A, Charpentier J, et al. A specific gut microbiota dysbiosis of type 2 diabetic mice induces GLP-1 resistance through an enteric NO-dependent and gut-brain axis mechanism. Cell Metab. 2017;25(5):1075-1090. e1075.
Marchetti P, Lupi R, Bugliani M, et al. A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets. Diabetologia. 2012;55(12):3262-3272.
Song Y, Koehler JA, Baggio LL, Powers AC, Sandoval DA, Drucker DJ. Gut-proglucagon-derived peptides are essential for regulating glucose homeostasis in mice. Cell Metab. 2019;30(5):976-986. e3.
Wideman RD, Covey SD, Webb GC, Drucker DJ, Kieffer TJ. A switch from prohormone convertase (PC)-2 to PC1/3 expression in transplanted alpha-cells is accompanied by differential processing of proglucagon and improved glucose homeostasis in mice. Diabetes. 2007;56(11):2744-2752.
Chambers AP, Sorrell JE, Haller A, et al. The role of pancreatic preproglucagon in glucose homeostasis in mice. Cell Metab. 2017;25(4):927-934. e923.
Traub S, Meier DT, Schulze F, et al. Pancreatic alpha cell-derived glucagon-related peptides are required for beta cell adaptation and glucose homeostasis. Cell Rep. 2017;18(13):3192-3203.
Esser N, Mongovin SM, Parilla J, et al. Neprilysin inhibition improves intravenous but not oral glucose-mediated insulin secretion via GLP-1R signaling in mice with ?-cell dysfunction. Am J Physiol Endocrinol Metab. 2022;322(3):E307-E318.
Bunnett NW, Wu V, Sternini C, et al. Distribution and abundance of neutral endopeptidase (EC 3. 4. 24. 11) in the alimentary tract of the rat. Am J Physiol. 1993;264(3 Pt 1):G497-G508.
Waget A, Cabou C, Masseboeuf M, et al. Physiological and pharmacological mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice. Endocrinology. 2011;152(8):3018-3029.
Mulvihill EE, Varin EM, Gladanac B, et al. Cellular sites and mechanisms linking reduction of dipeptidyl peptidase-4 activity to control of incretin hormone action and glucose homeostasis. Cell Metab. 2017;25(1):152-165.
Burcelin R, Serino M, Cabou C. A role for the gut-To-brain GLP-1-dependent axis in the control of metabolism. Curr Opin Pharmacol. 2009;9(6):744-752.
Donath MY, Burcelin R. GLP-1 effects on islets: hormonal, neuronal, or paracrine? Diabetes Care. 2013;36(Suppl 2):S145-S148.
Varin EM, Mulvihill EE, Baggio LL, et al. Distinct neural sites of GLP-1R expression mediate physiological versus pharmacological control of incretin action. Cell Rep. 2019;27(11):3371-3384. e3373.
Nie Y, Nakashima M, Brubaker PL, et al. Regulation of pancreatic PC1 and PC2 associated with increased glucagon-like peptide 1 in diabetic rats. J Clin Invest. 2000;105(7):955-965.
Pacini G, Thomaseth K, Ahrén B. Contribution to glucose tolerance of insulin-independent vs. Insulin-dependent mechanisms in mice. Am J Physiol Endocrinol Metab. 2001;281(4):E693-E703.
Trebbien R, Klarskov L, Olesen M, Holst JJ, Carr RD, Deacon CF. Neutral endopeptidase 24. 11 is important for the degradation of both endogenous and exogenous glucagon in anesthetized pigs. Am J Physiol Endocrinol Metab. 2004;287(3):E431-E438.
Kjeldsen SAS, Hansen LH, Esser N, et al. Neprilysin inhibition increases glucagon levels in humans and mice with potential effects on amino acid metabolism. J Endocr Soc. 2021;5(9):bvab084.
Wewer Albrechtsen NJ, Møller A, Martinussen C, et al. Acute effects on glucose tolerance by neprilysin inhibition in patients with type 2 diabetes. Diabetes Obes Metab. 2022;24(10):2017-2026.
Raasch W, Dominiak P, Dendorfer A. Angiotensin I-converting enzyme-dependent and neutral endopeptidase-dependent generation and degradation of angiotensin II contrarily modulate noradrenaline release: implications for vasopeptidase-inhibitor therapy? J Hypertens. 2005;23(8):1597-1604.
Deschodt-Lanckman M, Strosberg AD. In vitro degradation of the C-Terminal octapeptide of cholecystokinin by enkephalinase A . FEBS Lett. 1983;152(1):109-113.
Andersen U, Terzic D, Wewer Albrechtsen NJ, et al. Sacubitril/valsartan increases postprandial gastrin and cholecystokinin in plasma. Endocr Connect. 2020;9(5):438-444.
Medeiros MD, Turner AJ. Processing and metabolism of peptide-YY: pivotal roles of dipeptidylpeptidase-IV, aminopeptidase-P, and endopeptidase-24. 11. Endocrinology. 1994;134(5):2088-2094.
Deschodt-Lanckman M, Pauwels S, Najdovski T, Dimaline R, Dockray GJ. In vitro and in vivo degradation of human gastrin by endopeptidase 24. 11. Gastroenterology. 1988;94(3):712-721.
