Inflammation; Macrophages; Microbiota; NLRP3; Obesity; Type 2 diabetes; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Humans; Inflammasomes/metabolism; Inflammation/metabolism; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism; Obesity/complications; Diabetes Mellitus, Type 2/etiology; Gastrointestinal Microbiome; Diabetes Mellitus, Type 2; Medicine (all)
Abstract :
[en] Type 2 diabetes is characterized by chronic hyperglycaemia in a context of insulin resistance and ?-cell dysfunction. A chronic low-grade inflammation is observed in obesity and has been associated with the development of metabolic disorders. The molecular mechanisms underlying this inflammation are not fully understood. Production of interleukin-1 beta by macrophages infiltrating insulin-sensitive tissues and pancreatic islets plays a major role in the pathogenesis of type 2 diabetes. This pro-inflammatory cytokine is produced through the activation of the NLRP3 inflammasome in response to danger signals that accumulate during obesity, including saturated fatty acids. The composition of the intestinal microbiota differs in obese subjects compared with lean individuals, particularly in response to high saturated fat diet. These modifications could trigger a chronic low-grade inflammation and promote the emergence of type 2 diabetes. The microbiota could therefore constitutes a therapeutic target in the prevention and management of metabolic abnormalities associated with obesity. [fr] Le diabète de type 2 est caractérisé par une hyperglycémie chronique survenant dans un contexte de résistance à l’insuline et de déficit de sécrétion d’insuline par les cellules ? du pancréas. Un état inflammatoire chronique à bas bruit est observé dans l’obésité et est associé au développement d’anomalies métaboliques. Les mécanismes moléculaires à l’origine de cette inflammation ne sont pas encore bien compris. La production d’interleukine-1 bêta par les macrophages infiltrant les tissus cibles de l’insuline et les îlots pancréatiques joue un rôle important dans la pathogénie du diabète de type 2. Cette cytokine pro-inflammatoire est produite via l’activation de l’inflammasome NLRP3 en réponse à divers signaux de danger s’accumulant avec l’obésité, dont les acides gras saturés. La composition du microbiote intestinal diffère chez les sujets obèses par rapport aux individus minces, notamment en réponse à une alimentation riche en graisses saturées. Ces modifications pourraient entraîner le déclenchement d’un état inflammatoire chronique et favoriser l’émergence d’un diabète de type 2. Le microbiote pourrait, dès lors, constituer une cible thérapeutique dans la prévention et la prise en charge des anomalies métaboliques associées à l’obésité.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Esser, Nathalie ; Centre Hospitalier Universitaire de Liège - CHU > > Service de diabétologie, nutrition, maladies métaboliques
PAQUOT, Nicolas ; Centre Hospitalier Universitaire de Liège - CHU > > Service de diabétologie, nutrition, maladies métaboliques
Language :
French
Title :
Inflammation, obésité et diabète de type 2. Rôle de l’inflammasome NLRP3 et du microbiote intestinal.
Alternative titles :
[en] Inflammation, obesity and type 2 diabetes. Role of the NLRP3 inflammasome and gut microbiota.
World Health Organization. Global Report on Diabetes (WHO, 2016). https://www.who.int/publications/i/ item/9789241565257. Accessed 01 March 2021.
Féry F, Paquot N. Etiopathogénie et physiopathologie du diabète de type 2. Rev Med Liege 2005;60:361-8.
Esser N, Legrand-Poels S, Piette J, et al. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract 2014;105:141-50.
Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 2015;21:677-87.
Vandanmagsar B, Youm YH, Ravussin A, et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 2011;17:179-88.
Esser N, L'Homme L, De Roover A, et al. Obesity phenotype is related to NLRP3 inflammasome activity and immunological profile of visceral adipose tissue. Diabetologia 2013;56:2487-97.
Masters SL, Dunne A, Subramanian SL, et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat Immunol 2010;11:897-904.
Lee HM, Kim JJ, Kim HJ, et al. Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes 2013;62:194-204.
Westwell-Roper C, Nackiewicz D, Dan M, Ehses JA. Tolllike receptors and NLRP3 as central regulators of pancreatic islet inflammation in type 2 diabetes. Immunol Cell Biol 2014;92:314-23.
Clemente JC, Ursell LK, Parfrey LW, Knight R. The impact of the gut microbiota on human health: an integrative view. Cell 2012;148:1258-70.
Kau AL, Ahern PP, Griffin NW, et al. Human nutrition, the gut microbiome and the immune system. Nature 2011;474:327-36.
Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. N Engl J Med 2016;375:2369-79.
Wong JM, de Souza R, Kendall CW, et al. Colonic health: fermentation and short chain fatty acids. J Clin Gastroenterol 2006;40:235-43.
Bäckhed F, Ley RE, Sonnenburg JL, et al. Host-bacterial mutualism in the human intestine. Science 2005;307:1915-20.
Meijnikman AS, Gerdes VE, Nieuwdorp M, Herrema H. Evaluating causality of gut microbiota in obesity and diabetes in humans. Endocr Rev 2018;39:133-53.
Falony G, Joossens M, Vieira-Silva S, et al. Population-level analysis of gut microbiome variation. Science 2016;352:560-4.
Brown K, DeCoffe D, Molcan E, Gibson DL. Diet-induced dysbiosis of the intestinal microbiota and the effects on immunity and disease. Nutrients 2012;4:1095-119.
Esser N, Paquot N, Scheen AJ. Inflammatory markers and cardiometabolic diseases. Acta Clin Belg 2015;70:193-9.
Ying W, Fu W, Lee YS, Olefsky JM. The role of macrophages in obesity-associated islet inflammation and β-cell abnormalities. Nat Rev Endocrinol 2020;16:81-90.
Tanti JF, Jager J. Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation. Curr Opin Pharmacol 2009;9:753-62.
Esser N, Paquot N, Scheen AJ. Anti-inflammatory agents to treat or prevent type 2 diabetes, metabolic syndrome and cardiovascular disease. Expert Opin Investig Drugs 2015;24:283-307.
Esser N, Paquot N, Scheen AJ. Diabète de type 2 et médicaments anti-inflammatoires: nouvelles perspectives thérapeutiques ? Rev Med Suisse 2011;7:1614-8, 20.
Jager J, Grémeaux T, Cormont M, et al. Interleukin-1betainduced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. Endocrinology 2007;148:241-51.
Duewell P, Kono H, Rayner KJ, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010;464:1357-61.
Wen H, Ting JP, O'Neill LA. A role for the NLRP3 inflammasome in metabolic diseases - did Warburg miss inflammation? Nat Immunol 2012;13:352-7.
Kim SR, Lee SG, Kim SH, et al. SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease. Nat Commun 2020;11:2127.
L'Homme L, Esser N, Riva L, et al. Unsaturated fatty acids prevent activation of NLRP3 inflammasome in human monocytes/ macrophages. J Lipid Res 2013;54:2998-3008.
Gianfrancesco MA, Dehairs J, L'Homme L, et al. Saturated fatty acids induce NLRP3 activation in human macrophages through K(+) efflux resulting from phospholipid saturation and Na, K-ATPase disruption. Biochim Biophys Acta Mol Cell Biol Lipids 2019;1864:1017-30.
Legrand-Poels S, Esser N, L'Homme L, et al. Free fatty acids as modulators of the NLRP3 inflammasome in obesity/type 2 diabetes. Biochem Pharmacol 2014;92:131-41.
Zhou R, Tardivel A, Thorens B, et al. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol 2010;11:136-40.
Templin AT, Mellati M, Meier DT, et al. Low concentration IL-1β promotes islet amyloid formation by increasing hIAPP release from humanised mouse islets in vitro. Diabetologia 2020;63:2385-95.
Wilkin C, Colonval M, Dehairs J, et al. New insights on the PBMCs phospholipidome in obesity demonstrate modulations associated with insulin resistance and glycemic status. Nutrients 2021;13:3461.
Sohail MU, Althani A, Anwar H, et al. Role of the gastrointestinal tract microbiome in the pathophysiology of diabetes Mellitus. J Diabetes Res 2017;2017:9631435.
Cunningham AL, Stephens JW, Harris DA. Intestinal microbiota and their metabolic contribution to type 2 diabetes and obesity. J Diabetes Metab Disord 2021;20:1855-70.
Canfora EE, Jocken JW, Blaak EE. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol 2015;11:577-91.
Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006;444:1027-31.
Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007;56:1761-72.
Paquot N, De Flines J, Rorive M. L'obésité: un modèle d'interactions complexes entre génétique et environnement. Rev Med Liege 2012;67:332-6.
Scheen AJ, Paquot N. Le diabète de type 2: voyage au coeur d'une maladie complexe. Rev Med Liege 2012; 67:326-31.
Cani PD, Bibiloni R, Knauf C, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008;57:1470-81.
Wu H, Esteve E, Tremaroli V, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med 2017;23:850-8.
Wu H, Tremaroli V, Schmidt C, et al. The gut microbiota in prediabetes and diabetes: a population-based cross-sectional study. Cell Metab 2020;32:379-90.e3.
