L-valine is a Powerful Stimulator of GLP-1 Secretion in Rodents and Stimulates Secretion Through ATP-sensitive Potassium Channels and Voltage-gated Calcium Channels

Overview

Journal Nutr Diabetes

Specialties Endocrinology
Nutritional Sciences

Date 2024 Jun 11

PMID 38862477

Authors

Ida Marie Modvig

Mark M Smits

Katrine Douglas Galsgaard

Anna Pii Hjorne

Anna Katarzyna Drzazga

Mette Marie Rosenkilde

Jens Juul Holst

Affiliations

Soon will be listed here.

Abstract

Background: We previously reported that, among all the naturally occurring amino acids, L-valine is the most powerful luminal stimulator of glucagon-like peptide 1 (GLP-1) release from the upper part of the rat small intestine. This makes L-valine an interesting target for nutritional-based modulation of GLP-1 secretion. However, the molecular mechanism of L-valine-induced secretion remains unknown.

Methods: We aimed to investigate the effect of orally given L-valine in mice and to identify the molecular details of L-valine stimulated GLP-1 release using the isolated perfused rat small intestine and GLUTag cells. In addition, the effect of L-valine on hormone secretion from the distal intestine was investigated using a perfused rat colon.

Results: Orally given L-valine (1 g/kg) increased plasma levels of active GLP-1 comparably to orally given glucose (2 g/kg) in male mice, supporting that L-valine is a powerful stimulator of GLP-1 release in vivo (P > 0.05). Luminal L-valine (50 mM) strongly stimulated GLP-1 release from the perfused rat small intestine (P < 0.0001), and inhibition of voltage-gated Ca-channels with nifedipine (10 μM) inhibited the GLP-1 response (P < 0.01). Depletion of luminal Na did not affect L-valine-induced GLP-1 secretion (P > 0.05), suggesting that co-transport of L-valine and Na is not important for the depolarization necessary to activate the voltage-gated Ca-channels. Administration of the K-channel opener diazoxide (250 μM) completely blocked the L-valine induced GLP-1 response (P < 0.05), suggesting that L-valine induced depolarization arises from metabolism and opening of K-channels. Similar to the perfused rat small intestine, L-valine tended to stimulate peptide tyrosine-tyrosine (PYY) and GLP-1 release from the perfused rat colon.

Conclusions: L-valine is a powerful stimulator of GLP-1 release in rodents. We propose that intracellular metabolism of L-valine leading to closure of K-channels and opening of voltage-gated Ca-channels are involved in L-valine induced GLP-1 secretion.

References

Nilsson M, Holst J, Bjorck I . Metabolic effects of amino acid mixtures and whey protein in healthy subjects: studies using glucose-equivalent drinks. Am J Clin Nutr. 2007; 85(4):996-1004. DOI: 10.1093/ajcn/85.4.996. View

Modvig I, Kuhre R, Jepsen S, Xu S, Engelstoft M, Egerod K . Amino acids differ in their capacity to stimulate GLP-1 release from the perfused rat small intestine and stimulate secretion by different sensing mechanisms. Am J Physiol Endocrinol Metab. 2021; 320(5):E874-E885. DOI: 10.1152/ajpendo.00026.2021. View

Engelstoft M, Egerod K, Holst B, Schwartz T . A gut feeling for obesity: 7TM sensors on enteroendocrine cells. Cell Metab. 2008; 8(6):447-9. DOI: 10.1016/j.cmet.2008.11.004. View

Kuhre R, Holst J . Mechanisms Underlying Gut Hormone Secretion Using the Isolated Perfused Rat Small Intestine. J Vis Exp. 2019; (144). DOI: 10.3791/58533. View

Greenfield J, Farooqi I, Keogh J, Henning E, Habib A, Blackwood A . Oral glutamine increases circulating glucagon-like peptide 1, glucagon, and insulin concentrations in lean, obese, and type 2 diabetic subjects. Am J Clin Nutr. 2008; 89(1):106-113. PMC: 4340573. DOI: 10.3945/ajcn.2008.26362. View

Masse K, Lu V . Short-chain fatty acids, secondary bile acids and indoles: gut microbial metabolites with effects on enteroendocrine cell function and their potential as therapies for metabolic disease. Front Endocrinol (Lausanne). 2023; 14:1169624. PMC: 10407565. DOI: 10.3389/fendo.2023.1169624. View

Adibi S, MERCER D . Protein digestion in human intestine as reflected in luminal, mucosal, and plasma amino acid concentrations after meals. J Clin Invest. 1973; 52(7):1586-94. PMC: 302429. DOI: 10.1172/JCI107335. View

Reimann F, Habib A, Tolhurst G, Parker H, Rogers G, Gribble F . Glucose sensing in L cells: a primary cell study. Cell Metab. 2008; 8(6):532-9. PMC: 2697331. DOI: 10.1016/j.cmet.2008.11.002. View

Trico D, Frascerra S, Baldi S, Mengozzi A, Nesti L, Mari A . The insulinotropic effect of a high-protein nutrient preload is mediated by the increase of plasma amino acids in type 2 diabetes. Eur J Nutr. 2018; 58(6):2253-2261. DOI: 10.1007/s00394-018-1778-y. View

10.

Svendsen B, Pedersen J, Albrechtsen N, Hartmann B, Torang S, Rehfeld J . An analysis of cosecretion and coexpression of gut hormones from male rat proximal and distal small intestine. Endocrinology. 2014; 156(3):847-57. DOI: 10.1210/en.2014-1710. View

11.

Cho H, Kosari S, Hunne B, Callaghan B, Rivera L, Bravo D . Differences in hormone localisation patterns of K and L type enteroendocrine cells in the mouse and pig small intestine and colon. Cell Tissue Res. 2014; 359(2):693-698. DOI: 10.1007/s00441-014-2033-3. View

12.

Rehfeld J . Gastrointestinal hormones and their targets. Adv Exp Med Biol. 2014; 817:157-75. DOI: 10.1007/978-1-4939-0897-4_7. View

13.

Thwaites D, Anderson C . H+-coupled nutrient, micronutrient and drug transporters in the mammalian small intestine. Exp Physiol. 2007; 92(4):603-19. PMC: 2803310. DOI: 10.1113/expphysiol.2005.029959. View

14.

Elovaris R, Fitzgerald P, Bitarafan V, Ullrich S, Horowitz M, Feinle-Bisset C . Intraduodenal Administration of L-Valine Has No Effect on Antropyloroduodenal Pressures, Plasma Cholecystokinin Concentrations or Energy Intake in Healthy, Lean Men. Nutrients. 2019; 11(1). PMC: 6356499. DOI: 10.3390/nu11010099. View

15.

Clemmensen C, Jorgensen C, Smajilovic S, Brauner-Osborne H . Robust GLP-1 secretion by basic L-amino acids does not require the GPRC6A receptor. Diabetes Obes Metab. 2016; 19(4):599-603. DOI: 10.1111/dom.12845. View

16.

Grunddal K, Ratner C, Svendsen B, Sommer F, Engelstoft M, Madsen A . Neurotensin Is Coexpressed, Coreleased, and Acts Together With GLP-1 and PYY in Enteroendocrine Control of Metabolism. Endocrinology. 2015; 157(1):176-94. DOI: 10.1210/en.2015-1600. View

17.

Chaudhri O, Small C, Bloom S . Gastrointestinal hormones regulating appetite. Philos Trans R Soc Lond B Biol Sci. 2006; 361(1471):1187-209. PMC: 1642697. DOI: 10.1098/rstb.2006.1856. View

18.

Modvig I, Kuhre R, Holst J . Peptone-mediated glucagon-like peptide-1 secretion depends on intestinal absorption and activation of basolaterally located Calcium-Sensing Receptors. Physiol Rep. 2019; 7(8):e14056. PMC: 6482282. DOI: 10.14814/phy2.14056. View

19.

Li Q, Wang H, Xu R, Su Y, Zhu W . Dynamic analysis of metabolomics reveals the potential associations between colonic peptides and serum appetite-related hormones. Food Res Int. 2023; 173(Pt 2):113376. DOI: 10.1016/j.foodres.2023.113376. View

20.

Bensaid A, Tome D, Gietzen D, Even P, Morens C, Gausseres N . Protein is more potent than carbohydrate for reducing appetite in rats. Physiol Behav. 2002; 75(4):577-82. DOI: 10.1016/s0031-9384(02)00646-7. View