(−)-Epicatechin Reverses Glucose Intolerance in Rats Housed at Thermoneutrality^{[ # ]}

Abstract

Diabetes is a life-threatening and debilitating disease with pathological hallmarks, including glucose intolerance and insulin resistance. Plant compounds are a source of novel and effective therapeutics, and the flavonoid (−)-epicatechin, common to popular foods worldwide, has been shown to improve carbohydrate metabolism in both clinical studies and preclinical models. We hypothesized that (−)-epicatechin would alleviate thermoneutral housing-induced glucose intolerance. Male rats were housed at either thermoneutral (30 °C) or room temperature (24 °C) for 16 weeks and gavaged with either 1 mg/kg body weight or vehicle for the last 15 days before sacrifice. Rats housed at thermoneutrality had a significantly elevated serum glucose area under the curve (p < 0.05) and reduced glucose-mediated insulin secretion. In contrast, rats at thermoneutrality treated with (−)-epicatechin had improved glucose tolerance and increased insulin secretion (p < 0.05). Insulin tolerance tests revealed no differences in insulin sensitivity in any of the four groups. Pancreatic immunohistochemistry staining showed significantly greater islet insulin positive cells in animals housed at thermoneutrality. In conclusion, (−)-epicatechin improved carbohydrate tolerance via increased insulin secretion in response to glucose challenge without a change in insulin sensitivity.

Key words

(−)-epicatechin - Theobroma cacao - Sterculiaceae - insulin secretion - glucose tolerance

^# Dedicated to Professor Dr. A. Douglas Kinghorn on the occasion of his 75th birthday.

Publikationsverlauf

Eingereicht: 15. November 2021

Angenommen nach Revision: 04. April 2022

Artikel online veröffentlicht:
01. Juli 2022

• References

• 1 WHO. Diabetes fact sheet. News Room 2021. Accessed November 5, 2021 at: https://www.who.int/news-room/fact-sheets/detail/diabetes
• 2 Santangelo C, Zicari A, Mandosi E, Scazzocchio B, Mari E, Morano S, Masella R. Could gestational diabetes mellitus be managed through dietary bioactive compounds? Current knowledge and future perspectives. Br J Nutr 2016; 115: 1129-1144
• 3 Oh YS, Jun HS. Role of bioactive food components in diabetes prevention: Effects on Beta-cell function and preservation. Nutr Metab Insights 2014; 7: 51-59
• 4 Hanhineva K, Torronen R, Bondia-Pons I, Pekkinen J, Kolehmainen M, Mykkanen H, Poutanen K. Impact of dietary polyphenols on carbohydrate metabolism. Int J Mol Sci 2010; 11: 1365-1402
• 5 Martin MA, Ramos S. Dietary flavonoids and insulin signaling in diabetes and obesity. Cells 2021; 10: 1474
• 6 Keller A, Hull SE, Elajaili H, Johnston A, Knaub LA, Chun JH, Walker L, Nozik-Grayck E, Reusch JEB. (−)-Epicatechin modulates mitochondrial redox in vascular cell models of oxidative stress. Oxid Med Cell Longev 2020; 2020: 6392629
• 7 Galleano M, Bernatova I, Puzserova A, Balis P, Sestakova N, Pechanova O, Fraga CG. (−)-Epicatechin reduces blood pressure and improves vasorelaxation in spontaneously hypertensive rats by NO-mediated mechanism. IUBMB Life 2013; 65: 710-715
• 8 Tanabe K, Tamura Y, Lanaspa MA, Miyazaki M, Suzuki N, Sato W, Maeshima Y, Schreiner GF, Villarreal FJ, Johnson RJ, Nakagawa T. Epicatechin limits renal injury by mitochondrial protection in cisplatin nephropathy. Am J Physiol Renal Physiol 2012; 303: F1264-F1274
• 9 Litterio MC, Vazquez Prieto MA, Adamo AM, Elesgaray R, Oteiza PI, Galleano M, Fraga CG. (−)-Epicatechin reduces blood pressure increase in high-fructose-fed rats: Effects on the determinants of nitric oxide bioavailability. J Nutr Biochem 2015; 26: 745-751
• 10 Dower JI, Geleijnse JM, Gijsbers L, Zock PL, Kromhout D, Hollman PC. Effects of the pure flavonoids epicatechin and quercetin on vascular function and cardiometabolic health: A randomized, double-blind, placebo-controlled, crossover trial. Am J Clin Nutr 2015; 101: 914-921
• 11 Grassi D, Lippi C, Necozione S, Desideri G, Ferri C. Short-term administration of dark chocolate is followed by a significant increase in insulin sensitivity and a decrease in blood pressure in healthy persons. Am J Clin Nutr 2005; 81: 611-614
• 12 Gutierrez-Salmean G, Ortiz-Vilchis P, Vacaseydel CM, Garduno-Siciliano L, Chamorro-Cevallos G, Meaney E, Villafana S, Villarreal F, Ceballos G, Ramirez-Sanchez I. Effects of (−)-epicatechin on a diet-induced rat model of cardiometabolic risk factors. Eur J Pharmacol 2014; 728: 24-30
• 13 Ruzaidi A, Amin I, Nawalyah AG, Hamid M, Faizul HA. The effect of Malaysian cocoa extract on glucose levels and lipid profiles in diabetic rats. J Ethnopharmacol 2005; 98: 55-60
• 14 Tomaru M, Takano H, Osakabe N, Yasuda A, Inoue K, Yanagisawa R, Ohwatari T, Uematsu H. Dietary supplementation with cacao liquor proanthocyanidins prevents elevation of blood glucose levels in diabetic obese mice. Nutrition 2007; 23: 351-355
• 15 Radosinska J, Horvathova M, Frimmel K, Muchova J, Vidosovicova M, Vazan R, Bernatova I. Acute dark chocolate ingestion is beneficial for hemodynamics via enhancement of erythrocyte deformability in healthy humans. Nutr Res 2017; 39: 69-75
• 16 Regecova V, Jurkovicova J, Babjakova J, Bernatova I. The effect of a single dose of dark chocolate on cardiovascular parameters and their reactivity to mental stress. J Am Coll Nutr 2020; 39: 414-421
• 17 Prince PS. A biochemical, electrocardiographic, electrophoretic, histopathological and in vitro study on the protective effects of (−)epicatechin in isoproterenol-induced myocardial infarcted rats. Eur J Pharmacol 2011; 671: 95-101
• 18 Prince PS. (−) Epicatechin prevents alterations in lysosomal glycohydrolases, cathepsins and reduces myocardial infarct size in isoproterenol-induced myocardial infarcted rats. Eur J Pharmacol 2013; 706: 63-69
• 19 Stanely Mainzen Prince P. (−) Epicatechin attenuates mitochondrial damage by enhancing mitochondrial multi-marker enzymes, adenosine triphosphate and lowering calcium in isoproterenol induced myocardial infarcted rats. Food Chem Toxicol 2013; 53: 409-416
• 20 Kingma BR, Frijns AJ, Schellen L, van Marken Lichtenbelt WD. Beyond the classic thermoneutral zone: Including thermal comfort. Temperature (Austin) 2014; 1: 142-149
• 21 Romanovsky AA, Ivanov AI, Shimansky YP. Selected contribution: Ambient temperature for experiments in rats: a new method for determining the zone of thermal neutrality. J Appl Physiol (1985) 2002; 92: 2667-2679
• 22 Poole S, Stephenson JD. Body temperature regulation and thermoneutrality in rats. Q J Exp Physiol Cogn Med Sci 1977; 62: 143-149
• 23 Fischer AW, Cannon B, Nedergaard J. Optimal housing temperatures for mice to mimic the thermal environment of humans: An experimental study. Mol Metab 2018; 7: 161-170
• 24 Keijer J, Li M, Speakman JR. What is the best housing temperature to translate mouse experiments to humans?. Mol Metab 2019; 25: 168-176
• 25 Overton JM. Phenotyping small animals as models for the human metabolic syndrome: thermoneutrality matters. Int J Obes (Lond) 2010; 34: S53-S58
• 26 Stemmer K, Kotzbeck P, Zani F, Bauer M, Neff C, Muller TD, Pfluger PT, Seeley RJ, Divanovic S. Thermoneutral housing is a critical factor for immune function and diet-induced obesity in C57BL/6 nude mice. Int J Obes (Lond) 2015; 39: 791-797
• 27 Ganeshan K, Chawla A. Warming the use to model human diseases. Nat Rev Endocrinol 2017; 13: 458-465
• 28 Swoap SJ, Overton JM, Garber G. Effect of ambient temperature on cardiovascular parameters in rats and mice: a comparative approach. Am J Physiol Regul Integr Comp Physiol 2004; 287: R391-R396
• 29 Maloney SK, Fuller A, Mitchell D, Gordon C, Overton JM. Translating animal model research: does it matter that our rodents are cold?. Physiology (Bethesda) 2014; 29: 413-420
• 30 Gutierrez-Salmean G, Meaney E, Lanaspa MA, Cicerchi C, Johnson RJ, Dugar S, Taub P, Ramirez-Sanchez I, Villarreal F, Schreiner G, Ceballos G. A randomized, placebo-controlled, double-blind study on the effects of (−)-epicatechin on the triglyceride/HDLc ratio and cardiometabolic profile of subjects with hypertriglyceridemia: Unique in vitro effects. Int J Cardiol 2016; 223: 500-506
• 31 Gutierrez-Salmean G, Ortiz-Vilchis P, Vacaseydel CM, Rubio-Gayosso I, Meaney E, Villarreal F, Ramirez-Sanchez I, Ceballos G. Acute effects of an oral supplement of (−)-epicatechin on postprandial fat and carbohydrate metabolism in normal and overweight subjects. Food Funct 2014; 5: 521-527
• 32 Mahler RJ. The relationship between the hyperplastic pancreatic islet and insulin insensitivity in obesity. Acta Diabetol Lat 1981; 18: 1-17
• 33 Huang HH, Novikova L, Williams SJ, Smirnova IV, Stehno-Bittel L. Low insulin content of large islet population is present in situ and in isolated islets. Islets 2011; 3: 6-13
• 34 Bitner BF, Ray JD, Kener KB, Herring JA, Tueller JA, Johnson DK, Tellez Freitas CM, Fausnacht DW, Allen ME, Thomson AH, Weber KS, McMillan RP, Hulver MW, Brown DA, Tessem JS, Neilson AP. Common gut microbial metabolites of dietary flavonoids exert potent protective activities in beta-cells and skeletal muscle cells. J Nutr Biochem 2018; 62: 95-107
• 35 Yang K, Chan CB. Epicatechin potentiation of glucose-stimulated insulin secretion in INS-1 cells is not dependent on its antioxidant activity. Acta Pharmacol Sin 2018; 39: 893-902
• 36 Hii CS, Howell SL. Effects of epicatechin on rat islets of Langerhans. Diabetes 1984; 33: 291-296
• 37 Cremonini E, Daveri E, Mastaloudis A, Oteiza PI. (−)-Epicatechin and anthocyanins modulate GLP-1 metabolism: Evidence from C57BL/6J mice and GLUTag cells. J Nutr 2021; 151: 1497-1506
• 38 Rowley 4th TJ, Bitner BF, Ray JD, Lathen DR, Smithson AT, Dallon BW, Plowman CJ, Bikman BT, Hansen JM, Dorenkott MR, Goodrich KM, Ye L, OʼKeefe SF, Neilson AP, Tessem JS. Monomeric cocoa catechins enhance beta-cell function by increasing mitochondrial respiration. J Nutr Biochem 2017; 49: 30-41
• 39 Mussa BM, Srivastava A, Mohammed AK, Verberne AJM. Nitric oxide interacts with cholinoceptors to modulate insulin secretion by pancreatic beta cells. Pflugers Arch 2020; 472: 1469-1480
• 40 Shahraki ZS, Karbalaei N, Nemati M. Improving effect of combined inorganic nitrate and nitric oxide synthase inhibitor on pancreatic oxidative stress and impaired insulin secretion in streptozotocin induced-diabetic rats. J Diabetes Metab Disord 2020; 19: 353-362
• 41 Bahadoran Z, Mirmiran P, Ghasemi A. Role of nitric oxide in insulin secretion and glucose metabolism. Trends Endocrinol Metab 2020; 31: 118-130
• 42 Mohamed RH, Karam RA, Amer MG. Epicatechin attenuates doxorubicin-induced brain toxicity: Critical role of TNF-alpha, iNOS and NF-kappaB. Brain Res Bull 2011; 86: 22-28
• 43 Kim MJ, Ryu GR, Kang JH, Sim SS, Min DS, Rhie DJ, Yoon SH, Hahn SJ, Jeong IK, Hong KJ, Kim MS, Jo YH. Inhibitory effects of epicatechin on interleukin-1beta-induced inducible nitric oxide synthase expression in RINm5F cells and rat pancreatic islets by down-regulation of NF-kappaB activation. Biochem Pharmacol 2004; 68: 1775-1785
• 44 Gheibi S, Samsonov AP, Gheibi S, Vazquez AB, Kashfi K. Regulation of carbohydrate metabolism by nitric oxide and hydrogen sulfide: Implications in diabetes. Biochem Pharmacol 2020; 176: 113819
• 45 Ramirez-Sanchez I, Maya L, Ceballos G, Villarreal F. (−)-Epicatechin activation of endothelial cell endothelial nitric oxide synthase, nitric oxide, and related signaling pathways. Hypertension 2010; 55: 1398-1405
• 46 Taub PR, Ramirez-Sanchez I, Ciaraldi TP, Perkins G, Murphy AN, Naviaux R, Hogan M, Maisel AS, Henry RR, Ceballos G, Villarreal F. Alterations in skeletal muscle indicators of mitochondrial structure and biogenesis in patients with type 2 diabetes and heart failure: Effects of epicatechin rich cocoa. Clin Transl Sci 2012; 5: 43-47
• 47 Stote KS, Clevidence BA, Novotny JA, Henderson T, Radecki SV, Baer DJ. Effect of cocoa and green tea on biomarkers of glucose regulation, oxidative stress, inflammation and hemostasis in obese adults at risk for insulin resistance. Eur J Clin Nutr 2012; 66: 1153-1159
• 48 Davison K, Coates AM, Buckley JD, Howe PR. Effect of cocoa flavanols and exercise on cardiometabolic risk factors in overweight and obese subjects. Int J Obes (Lond) 2008; 32: 1289-1296
• 49 Desideri G, Kwik-Uribe C, Grassi D, Necozione S, Ghiadoni L, Mastroiacovo D, Raffaele A, Ferri L, Bocale R, Lechiara MC, Marini C, Ferri C. Benefits in cognitive function, blood pressure, and insulin resistance through cocoa flavanol consumption in elderly subjects with mild cognitive impairment: The Cocoa, Cognition, and Aging (CoCoA) study. Hypertension 2012; 60: 794-801
• 50 Ramirez-Sanchez I, Taub PR, Ciaraldi TP, Nogueira L, Coe T, Perkins G, Hogan M, Maisel AS, Henry RR, Ceballos G, Villarreal F. (−)-Epicatechin rich cocoa mediated modulation of oxidative stress regulators in skeletal muscle of heart failure and type 2 diabetes patients. Int J Cardiol 2013; 168: 3982-3990
• 51 Ramirez-Sanchez I, De los Santos S, Gonzalez-Basurto S, Canto P, Mendoza-Lorenzo P, Palma-Flores C, Ceballos-Reyes G, Villarreal F, Zentella-Dehesa A, Coral-Vazquez R. (−)-Epicatechin improves mitochondrial-related protein levels and ameliorates oxidative stress in dystrophic delta-sarcoglycan null mouse striated muscle. FEBS J 2014; 281: 5567-5580
• 52 Kaiyala KJ, Morton GJ, Thaler JP, Meek TH, Tylee T, Ogimoto K, Wisse BE. Acutely decreased thermoregulatory energy expenditure or decreased activity energy expenditure both acutely reduce food intake in mice. PLoS One 2012; 7: e41473
• 53 Keller AC, He K, Briallantes AM, Kennelly EJ. A characterized saponin-rich fraction of Momordica charantia shows antidiabetic activity in C57BLK/6 mice fed a high fat diet. Phytomedicine Plus 2021; 1: 100134
• 54 Ramirez DG, Abenojar E, Hernandez C, Lorberbaum DS, Papazian LA, Passman S, Pham V, Exner AA, Benninger RKP. Contrast-enhanced ultrasound with sub-micron sized contrast agents detects insulitis in mouse models of type1 diabetes. Nat Commun 2020; 11: 2238