I dati attuali degli studi sia clinici che pre-clinici sull'uomo suggeriscono che l'attivazione dell'inflammasoma NLRP3 promuove le risposte infiammatorie associate ai disordini metabolici quali obesità, DMT2 e diabate gestazionale. Tuttavia, gli studi clinici non forniscono una chiara relazione tra l'attivazione dell’inflammosoma NLRP3 e disordini metabolici.
Lo sviluppo di modelli sperimentali ha permesso di comprendere meglio il ruolo fisiopatologico dell’inflammosoma NLRP3 in queste condizioni patologiche. Infatti, è stato dimostrato che l'attivazione di NLRP3 contribuisce alle disfunzioni metaboliche. Infatti, la delezione genica dei componenti dell'inflammasoma o la modulazione farmacologica di NLRP3 in vivo con farmaci che agiscono a livelli diversi della cascata dell'inflammasoma in modelli
animali, sono in grado di contrastare la progressione delle alterazioni metaboliche.
Sulla base di queste considerazioni, è concepibile che il complesso dell'inflammosoma NLRP3 rappresenta un sensore immunitario-infiammatorio che contribuisce a modulare le risposte immunitarie / infiammatorie ed a sostenere gli eventi fisiopatologici alla base di queste malattie metaboliche. Tuttavia, la maggior parte degli attuali studi umani e pre-clinici hanno focalizzato la loro attenzione sul ruolo dell'attivazione canonica dell'inflammasoma NLRP3, trascurando così la valutazione dei possibili contributi delle vie di attivazione NLRP3 non canoniche dipendenti da caspasi-8 e caspasi-11. Inoltre, il ruolo di altri inflammasomi, inclusi NLRP6, NLRP1, AIM2 e NLRC4, nella fisiopatologia dei disturbi metabolici rimane poco chiaro e scarsamente studiato [126–128]. Di conseguenza, vi è una forte necessità di ulteriori studi volti a caratterizzare il ruolo dei percorsi dell’inflammasoma NLRP3 non canonici e di altri inflammasomi nella fisiopatologia delle malattie metaboliche.
Sebbene nonostante diversi aspetti sul ruolo di NLRP3 nella fisiopatologia delle malattie metaboliche devono ancora essere determinati, gli effetti benefici derivanti dalla modulazione NLRP3 da parte di composti naturali in vari modelli sperimentali suggesriscono che l'inibizione di NLRP3 con fitocomposti potrebbe rappresentare un utile approccio terapeutico per il trattmento dei disordini
metabolici e comorbidità correlate. A questo proposito, le prove attuali mostrano che polifenoli, quali flavonoidi, stilbenoidi e fenoli, triterpenoidi, isotiocianati e carotenoidi, agendo su diversi steps della cascata di attivazione dell'inflammasoma NLRP3, contrastano l’infiammazione, le alterazioni metaboliche e relative comorbidità in modelli animali di malattie metaboliche. In particolare, gli attuali studi preclinici mostrano che diversi composti fitochimici possono esercitare effetti benefici nei disturbi metabolici attraverso diverse modalità di inibizione dell'attivazione dell'inflammasoma NLRP3. I principali meccanismi molecolari alla base del blocco di NLRP3 da parte di sostanze naturali sono stati attribuiti alla loro capacità di:
1. inibire l'attivazione di NLRP3 a monte mediante la soppressione della generazione di ROS;
2. bloccare direttamente i passaggi di trascrizione mediati da NF-kB e / o l'oligomerizzazione NLRP3;
3. attivare le vie antinfiammatorie, tra cui AMPK / SIRT1 / PGC-1α, che, a loro volta, potrebbero aumentare l'espressione di diversi enzimi disintossicanti ROS e inibire direttamente l'assemblaggio di NLRP3.
Tuttavia, in quest'area, restano da chiarire una serie di questioni:
1. Qual è il meccanismo attraverso cui i polifenoli bloccano l'assemblaggio NLRP3?
2. I fitocomposti in grado di bloccare l'attivazione dell'inflammasoma sia canonica che non canonica potrebbero essere considerati come approcci più affidabili per la gestione delle malattie metaboliche?
3. Una dieta contenente fitochimici può prevenire o contrastare l’insorgenza di disordini metabolici?
4. I fitochimici possono esercitare effetti benefici nelle malattie metaboliche attraverso l'inibizione di altri inflammasomi, inclusi NRLP1, NLRP6, AIM2 e NLRC4?
Per chiarire questi punti, si dovrebbero indirizzare intensi sforzi di ricerca per indagare, mediante approcci molecolari, biochimici e farmacologici, gli effetti di composti naturali che inibiscono l'inflammasoma NLRP3 e altri inflammasomi in esperimenti in vitro su cellule in coltura e in differenti modelli sperimentali. Un importante aspetto che necessita di essere considerato riguarda la mancanza di prove traslazionali sugli effetti dei fitocomposti in pazienti con malattie metaboliche. Infatti, nonostante alcuni studi clinici che hanno dimostrato gli effetti benefici dei fitochimici in pazienti con disturbi metabolici, non sono
attualmente disponibili prove sugli effetti dei composti naturali che prendono di mira la NLRP3 negli esseri umani.
Pertanto, una traslazione delle evidenze precliniche nella pratica clinica potrebbe consentire una migliore comprensione degli effetti protettivi dei composti naturali che agiscono su NLRP3 in pazienti con disturbi metabolici. Svelare questi aspetti potrebbe aprire la strada a nuove opzioni terapeutiche sia per la prevenzione che per la gestione clinica delle malattie metaboliche.
Bibliografia
[1] https://www.news-medical.net/life-sciences/What-is-the-Inflammasome-.aspx [2] M.F.L.A.C.B.V.C. e. Pellegrini C, Phytochemicals as Novel Therapeutic Strategies for NLRP3 Inflammasome-Related Neurological, Metabolic, and Inflammatory Diseases 20:2876. https://doi.org/10.3390/ijms20122876, 2019
[3] Sharma, D .; Kanneganti, TD La biologia cellulare degli inflammasomi: meccanismi di attivazione e regolazione degli inflammasomi. J. Cell Biol. 2016 , 213 , 617–629.
[4] https://legatumoriprato.it/wp-content/uploads/2019/07/INFLAMMASOMI- OPUSCOLO-17X24-8-LUGLIO.pdf “Gli inflammosomi” Roberto Benelli. Estratto da: Stili di vita, infiammazione cronica e patologie correlate, Ed 2019
[5] Alcocer-Gomez et al. Inflammasomes in clinical practice . Ed. Springer, 2018 [6] Tschopp J. Mitochondria: Sovereign of inflammation Eur J Immunol, 2011
[7] Liu et al. NF-kB signaling in inflammation. Signal Transduction and Targeted Therapy, 2017
[8] Lee et al. Physical activity protects NLRPe inflammasome-associated coronary vascular dysfunction in obese mice. Physiol Reports, 2018)
[9] D.J.A.B, D.T.W.Y.W. S.B.Y, Z.A.G.T, J.P. Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling. Proc. Natl.
Acad. Sci. USA 2007, 104, 8041–8046.
[10] N.K.D.J.Y.D.Y He, The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation 20:3328. https://doi.org/10.3390/ijms20133328, 2019
[11] Duncan, J.A.; Bergstralh, D.T.; Wang, Y.; Willingham, S.B.; Ye, Z.; Zimmermann, A.G.; Ting, J.P.-Y. Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling. Proc. Natl. Acad. Sci. USA 2007, 104, 8041–8046.
[12] Coll, R.C.; Hill, J.R.; Day, C.J.; Zamoshnikova, A.; Boucher, D.; Massey, N.L.; Chitty, J.L.; Fraser, J.A.; Jennings, M.P.; Robertson, A.A.B.; et al. MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition. Nat. Chem. Biol. 2019, 15, 556.
[13] Hafner-Bratkovič, I.; Sušjan, P.; Lainšček, D.; Tapia-Abellán, A.; Cerović, K.; Kadunc, L.; Angosto-Bazarra, D.; Pelegrίn, P.; Jerala, R. NLRP3 lacking the leucine- rich repeat domain can be fully activated via the canonical inflammasome pathway. Nat. Commun. 2018, 9, 5182.
[14] Latz, E.; Xiao, T.S.; Stutz, A. Activation and regulation of the inflammasomes.
Nat. Rev. Immunol. 2013, 13, 397–411.
[15] Gurung, P.; Anand, P.K.; Malireddi, R.K.S.; Walle, L.V.; Opdenbosch, N.V.; Dillon, C.P.; Weinlich, R.; Green, D.R.; Lamkanfi, M.; Kanneganti, T.-D. FADD and Caspase-8 Mediate Priming and Activation of the Canonical and Noncanonical Nlrp3 Inflammasomes. J. Immunol. 2014, 192, 1835–1846.
[16] Bauernfeind, F.G.; Horvath, G.; Stutz, A.; Alnemri, E.S.; MacDonald, K.; Speert, D.; Fernandes-Alnemri, T.; Wu, J.; Monks, B.G.; Fitzgerald, K.A.; et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol. 2009, 183, 787–791.
[17] Pellegrini. C; A.L; LC.G; B.C; F.M. Canonical and Non-Canonica Activation of NLRP3 Inflammasome at the Crossroad between Immune Tolerance and Intestinal
Inflammation. Front. Immunol. 2017, 8, 36.
[18] Latz, E.; Xiao, T.S.; Stutz, A. Activation and regulation of the inflammasomes.
Nat. Rev. Immunol. 2013, 13, 397–411.
[19] Lu, B.; Wang, H.; Andersson, U.; Tracey, K.J. Regulation of HMGB1 release by inflammasomes. Protein Cell 2013, 4, 163–167.
[20] Antonopoulos, C.; Russo, H.M.; El Sanadi, C.; Martin, B.N.; Li, X.; Kaiser, W.J.; Mocarski, E.S.; Dubyak, G.R. Caspase-8 as an E↵ector and Regulator of NLRP3 Inflammasome Signaling. J. Biol. Chem. 2015, 290, 20167–20184.
[21] Clapham, D.E. Calcium signaling. Cell 2007, 131, 1047–1058.
[22] Hagar, J.A.; Powell, D.A.; Aachoui, Y.; Ernst, R.K.; Miao, E.A. Cytoplasmic LPS Activates Caspase-11: Implications in TLR4-Independent Endotoxic Shock. Science 2013, 341, 1250–1253.
[23] Shi, J.; Zhao, Y.; Wang, Y.; Gao, W.; Ding, J.; Li, P.; Hu, L.; Shao, F. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 2014, 514, 187–192.
[24] Broz, P.; Ruby, T.; Belhocine, K.; Bouley, D.M.; Kayagaki, N.; Dixit, V.M.; Monack, D.M. Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1. Nature 2012, 490, 288–291.
[25] Yang, D.; He, Y.; Muñoz-Planillo, R.; Liu, Q.; Núñez, G. Caspase-11 Requires the Pannexin-1 Channel and the Purinergic P2X7 Pore to Mediate Pyroptosis and Endotoxic Shock. Immunity 2015, 43, 923–932.
[26] Pelegrin, P.; Surprenant, A. Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. EMBO J. 2006, 25, 5071– 5082.
[27] Piccini, A.; Carta, S.; Tassi, S.; Lasiglié, D.; Fossati, G.; Rubartelli, A. ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1β and IL-18 secretion in an autocrine way. Proc. Natl. Acad. Sci. USA 2008, 105, 8067–8072.
[28] Alves, L.A.; de Melo Reis, R.A.; de Souza, C.A.M.; de Freitas, M.S.; Teixeira, P.C.N.; Neto Moreira Ferreira, D.; Xavier, R.F. The P2X7 receptor: Shifting from a low- to a high-conductance channel—An enigmatic phenomenon? Biochim. Biophys. Acta BBA-Biomembr. 2014, 1838, 2578–2587.
[29] Chu, L.H.; Indramohan, M.; Ratsimandresy, R.A.; Gangopadhyay, A.; Morris, E.P.; Monack, D.M.; Dorfleutner, A.; Stehlik, C. The oxidized phospholipid oxPAPC protects from septic shock by targeting the non-canonical inflammasome in macrophages. Nat. Commun. 2018, 9, 996.
[30] Gaidt, M.M.; Ebert, T.S.; Chauhan, D.; Schmidt, T.; Schmid-Burgk, J.L.; Rapino, F.; Robertson, A.A.B.; Cooper, M.A.; Graf, T.; Hornung, V. Human Monocytes Engage an Alternative Inflammasome Pathway. Immunity 2016, 44, 833–846.
[31] He, Y.; Franchi, L.; Núñez, G. TLR Agonists Stimulate Nlrp3-Dependent IL-1β Production Independently of the Purinergic P2X7 Receptor in Dendritic Cells and In Vivo. J. Immunol. 2013, 190, 334–339.
[32] https://www.ansa.it/canale_saluteebenessere/notizie/diabete/2019/03/26/obesita- nel-mondo-coinvolge-14-mld-di-adulti dati OMS_92dcc32e-222c-4009- bbfd-137b43d9907a.html DATI OMS
[33] 64. Gregor MF, Hotamisligil GS. 2011. Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 29:415–45
[34] Samuel VT, Shulman GI. 2012. Mechanisms for insulin resistance: common threads and missing links. Cell 148:852–71
[35] Ota, T., Obesity-induced inflammation and insulin resistance. Frontiers in
endocrinology 2014, 5, 204.
[36] Esser, N.; Legrand-Poels, S.; Piette, J.; Scheen, A. J.; Paquot, N., Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes research
and clinical practice 2014, 105, (2), 141-50.
[37] Vandanmagsar, B.; Youm, Y. H.; Ravussin, A.; Galgani, J. E.; Stadler, K.; Mynatt, R. L.; Ravussin, E.; Stephens, J. M.; Dixit, V. D., The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nature medicine 2011, 17, (2), 179-88.
[38] Rheinheimer, J.; de Souza, B. M.; Cardoso, N. S.; Bauer, A. C.; Crispim, D., Current role of the NLRP3 inflammasome on obesity and insulin resistance: A systematic review. Metabolism: clinical and experimental 2017, 74, 1-9.
[39] Stienstra, R.; van Diepen, J. A.; Tack, C. J.; Zaki, M. H.; van de Veerdonk, F. L.; Perera, D.; Neale, G. A.; Hooiveld, G. J.; Hijmans, A.; Vroegrijk, I.; van den Berg, S.; Romijn, J.; Rensen, P. C.; Joosten, L. A.; Netea, M. G.; Kanneganti, T. D., Inflammasome is a central player in the induction of obesity and insulin resistance.
Proceedings of the National Academy of Sciences of the United States of America
2011, 108, (37), 15324-9.
[40] Goossens, G. H.; Blaak, E. E.; Theunissen, R.; Duijvestijn, A. M.; Clement, K.; Tervaert, J. W.; Thewissen, M. M., Expression of NLRP3 inflammasome and T cell population markers in adipose tissue are associated with insulin resistance and impaired glucose metabolism in humans. Molecular immunology 2012, 50, (3), 142-9. [41] Lee, H. M.; Kim, J. J.; Kim, H. J.; Shong, M.; Ku, B. J.; Jo, E. K., Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes 2013, 62, (1), 194-204.
[42] Donath, M. Y.; Boni-Schnetzler, M.; Ellingsgaard, H.; Halban, P. A.; Ehses, J. A., Cytokine production by islets in health and diabetes: cellular origin, regulation and function. Trends in endocrinology and metabolism: TEM 2010, 21, (5), 261-7.
[43] Wen, H.; Gris, D.; Lei, Y.; Jha, S.; Zhang, L.; Huang, M. T.; Brickey, W. J.; Ting, J. P., Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nature immunology 2011, 12, (5), 408-15.
[44] McGillicuddy, F. C.; Harford, K. A.; Reynolds, C. M.; Oliver, E.; Claessens, M.; Mills, K. H.; Roche, H. M., Lack of interleukin-1 receptor I (IL-1RI) protects mice from high-fat diet-induced adipose tissue inflammation coincident with improved glucose homeostasis. Diabetes 2011, 60, (6), 1688-98.
[45] Zhou, R.; Tardivel, A.; Thorens, B.; Choi, I.; Tschopp, J., Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nature immunology 2010, 11, (2), 136-40.
[46] Stienstra, R.; Joosten, L. A.; Koenen, T.; van Tits, B.; van Diepen, J. A.; van den Berg, S. A.; Rensen, P. C.; Voshol, P. J.; Fantuzzi, G.; Hijmans, A.; Kersten, S.; Muller, M.; van den Berg, W. B.; van Rooijen, N.; Wabitsch, M.; Kullberg, B. J.; van der Meer, J. W.; Kanneganti, T.; Tack, C. J.; Netea, M. G., The inflammasome- mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell metabolism 2010, 12, (6), 593-605.
[47] http://www.siditalia.it/divulgazione/conoscere-il-diabete. Società italiana di diabetologia.
[48] Am. Diet. Assoc. 2013. Economic costs of diabetes in the US in 2012. Diabetes Care 36:103346
[49] Bunout D, Munoz C, Lopez M, de la Maza MP, Schlesinger L, et al. 1996. Interleukin 1 and tumor necrosis factor in obese alcoholics compared with normal- weight patients. Am. J. Clin. Nutr. 63:373–76
[50] Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB. 1995. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J. Clin. Investig. 95:2111–19 [51] Aguirre V, Uchida T, Yenush L, Davis R, White MF. 2000. The c-Jun NH2- terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser307. J. Biol. Chem. 275:9047–54
[52] Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. 1996. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α- and obesity-induced insulin resistance. Science 271:665–68
[53] Samuel VT, Shulman GI. 2012. Mechanisms for insulin resistance: common threads and missing links. Cell 148:852–71
[54] Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, et al. 2006. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J. Clin. Investig. 116:115–24
[ 5 5 ] K a n d a H , T a t e y a S , T a m o r i Y , K o t a n i K , H i a s a K , e t a l . 2006.MCP-1contributestomacrophageinfiltra- tion into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Investig. 116:1494–505
[56] Konner AC, Bruning JC. 2011. Toll-like receptors: linking inflammation to metabolism. Trends En-docrinol. Metab. 22:16–23
[57] Donath MY, Shoelson SE. 2011. Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11:98–107
[58] Tanti JF,Ceppo F,Jager J,Berthou F.2012. Implication of inflammatory signaling pathways in obesity-induced insulin resistance. Front. Endocrinol. 3:181
[59] Saberi M, Woods NB, de Luca C, Schenk S, Lu JC, et al. 2009. Hematopoietic cell–specific deletionof Toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell Metab. 10:419–29
[60] Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. 2006. TLR4 l inks innate immunity and fatty acid–induced insulin resistance. J. Clin. Investig. 116:3015– 25
[ 6 1 ] Va n d a n m a g s a r B , Yo u m Y H , R a v u s s i n A , G a l g a n i J E , S t a d l e r K , e t a l . 2011.TheNLRP3inflammasome
instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17:179–88 [ 6 2 ] S t i e n s t r a R , J o o s t e n L A , K o e n e n T, v a n Ti t s B , v a n D i e p e n J A , e t a l . 2010.Theinflammasome-mediated
caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab. 12:593–605
[63] Wen H, Gris D, Lei Y, Jha S, Zhang L, et al. 2011. Fatty acid–induced NLRP3- ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12:408–15
[64] Jager J, Gremeaux T, Cormont M, Le Marchand-Brustel Y, Tanti JF. 2007. Interleukin-1β-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. Endocrinology 148:241–51
[65] Ehses JA, Lacraz G, Giroix MH, Schmidlin F, Coulaud J, et al. 2009. IL-1 antagonism reduces hyper- glycemia and tissue inflammation in the type 2 diabetic GK rat. Proc. Natl. Acad. Sci. USA 106:13998–4003
[66] Osborn O, Gram H, Zorrilla EP, Conti B, Bartfai T. 2008. Insights into the roles of the inflammatory mediators IL-1, IL-18 and PGE2 in obesity and insulin resistance. Swiss Med. Wkly. 138:665–73
[67] De Nardo D, Latz E. 2011. NLRP3 inflammasomes link inflammation and metabolic disease. Trends Immunol. 32:373–79
[68] Stienstra R, Joosten LA, Koenen T, van Tits B,van Diepen JA, etal. 2010. The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab. 12:593–605
[69] Dinarello CA, Donath MY, Mandrup-Poulsen T. 2010. Role of IL-1β in type 2 diabetes. Curr. Opin. Endocrinol. Diabetes Obes. 17:314–21
[70] Larsen CM, Faulenbach M, Vaag A, Volund A, Ehses JA, et al. 2007. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356:1517–26
[71] Eguchi K, Manabe I, Oishi-Tanaka Y, Ohsugi M, Kono N, et al. 2012. Saturated fatty acid and TLR signaling link β cell dysfunction and islet inflammation. Cell Metab. 15:518–33
[72] Seino S. 2001. S20G mutation of the amylin gene is associated with type II diabetes in Japanese. Study Group of Comprehensive Analysis of Genetic Factors in Diabetes Mellitus. Diabetologia 44:906–9
[73] Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, et al. 2010. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat. Immunol. 11:897–904
[74] Zhou R, Tardivel A, Thorens B, ChoiI, Tschopp J.2010.Thioredoxin interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11:136–40
[75] Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. National Diabetes Data Group. Diabetes. 1979;28:1039–1057. [PubMed] [Google Scholar]
[76] Blumer I, Hadar E, Hadden DR, Jovanovič L, Mestman JH, Murad MH, et al. Diabetes and pregnancy: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2013;98:4227–4249. [PubMed] [Google Scholar]
[77] Bevier WC, Jovanovic-Peterson L, Peterson CM. Pancreatic disorders of pregnancy. Diagnosis, management, and outcome of gestational diabetes. Endocrinol Metab Clin North Am. 1995;24:103–138. [PubMed] [Google Scholar]
[78] American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2011;34(Suppl 1):S62–S69. [PMC free article] [PubMed] [Google Scholar]
[79] International Association of Diabetes and Pregnancy Study Groups Consensus Panel. Metzger BE, Gabbe SG, Persson B, Buchanan TA, Catalano PA, et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33:676–682. [PMC free article] [PubMed] [Google Scholar]
[80] HAPO Study Cooperative Research Group. Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358:1991–2002. [PubMed] [Google Scholar]
[81] Kjos SL, Buchanan TA. Gestational diabetes mellitus. N Engl J Med. 1999;341:1749–1756. [PubMed] [Google Scholar]
[82] Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS, et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352:2477–2486. [PubMed] [Google Scholar]
[83] Landon MB, Spong CY, Thom E, Carpenter MW, Ramin SM, Casey B, et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med. 2009;361:1339–1348. [PMC free article] [PubMed] [Google Scholar]
[84] Catalano PM, Tyzbir ED, Roman NM, Amini SB, Sims EA. Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women. Am J Obstet Gynecol. 1991;165:1667–1672. [PubMed] [Google Scholar]
[85] Barbour LA, McCurdy CE, Hernandez TL, Kirwan JP, Catalano PM, Friedman JE. Cellular mechanisms for insulin resistance in normal pregnancy and gestational diabetes. Diabetes Care. 2007;30(Suppl 2):S112–S119. [PubMed] [Google Scholar] [86] Solomon CG, Willett WC, Carey VJ, Rich-Edwards J, Hunter DJ, Colditz GA, et al. A prospective study of pregravid determinants of gestational diabetes mellitus. JAMA. 1997;278:1078–1083. [PubMed] [Google Scholar]
[87] Kim C, Newton KM, Knopp RH. Gestational Diabetes and the Incidence of Type 2 Diabetes A systematic review. Diabetes Care. 2002;25:1862–1868. [PubMed] [Google Scholar]
[88] Dabelea D, Pettitt D. Intrauterine diabetic environment confers risks for type 2 diabetes mellitus and obesity in the offspring, in addition to genetic susceptibility. J Pediatr Endocrinol Metab. 2001;14:1085–1091. [PubMed] [Google Scholar]
[89] Alfadhli EM. Gestational diabetes mellitus. Saudi Med J. 2015;36:399–406. doi: 10.15537/smj.2015.4.10307. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
[90] Cypryk K, Szymczak W, Czupryniak L, Sobczak M, Lewinski A. Gestational diabetes mellitus - an analysis of risk factors. Endokrynol Pol. 2008;59:393–397. [PubMed] [Google Scholar]
[91] Homko C, Sivan E, Chen X, Reece EA, Boden G. Insulin secretion during and after pregnancy in patients with gestational diabetes mellitus. J Clin Endocrinol Metab. 2001;86:568–573. [PubMed] [Google Scholar]
[92] Stienstra R, van Diepen JA, Tack CJ, Zaki MH, van de Veerdonk FL, Perera D, Neale GA, Hooiveld GJ, Hijmans A, Vroegrijk I, et al. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc Natl Acad Sci U S A. 2011;108:15324–15329. doi: 10.1073/pnas.1100255108. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
[93] Kaufmann RC, Amankwah KS, Dunaway G, Maroun L, Arbuthnot J, Roddick JW., Jr An animal model of gestational diabetes. Am J Obstet Gynecol. 1981;141:479– 482. doi: 10.1016/S0002-9378(15)33263-4. [PubMed] [CrossRef] [Google Scholar] [94] AIDAP associazione italiana dell’alimentazione e del peso.
[95] ISTAT 2015, Associazione Ricerca & Diabete SID, Italian Diabetes & Obesity Barometer Report 2017, Ministero della Salute
[96] European Association for the Study of Diabetes (EASD) Barcellona, 2019
[97] Feinkohl I, Keller M, Robertson CM, et al. Clinical and subclinical macrovascular disease as predictors of cognitive decline in older patients with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes Care 2013;36:2779-86. [98] Lunetta M, Damanti AR, Fabbri G, et al. Evidence by magnetic resonance imaging of cerebral alterations of atrophy type in young insulin-dependent diabetic patients. J Endocrinol Invest 1994;17:241-5
[99] Saedi E, Gheini MR, Faiz F, et al. Diabetes mellitus and cognitive impairments. World J Diabetes 2016;7:412-22.
[100] Sheen YJ, Sheu WH. Association between hypoglycemia and dementia in patients with type 2 diabetes. Diabetes Res Clin Pract 2016;116:279-87.
[101] Wessels AM, Lane KA, Gao S, et al. Diabetes and cognitive decline in elderly African Americans: a 15 year followup study. Alzheimers Dement 2011;7:418-24. [102] O’Sullivan J, Mahan C. Criteria for the oral glucose tolerance test in pregnancy. Diabetes. 1964;13:278–285. [PubMed] [Google Scholar]
[103] Carpenter M, Coustan DRW. Criteria for screening tests for gestational diabetes. Am J Obstet Gynecol. 1982;144:768–773. [PubMed] [Google Scholar]
[104] https://www.nice.org.uk/guidance/ng3/chapter/1-Recommendations#gestational- diabetes-2
[ 1 0 5 ] h t t p : / / w w w. s t a n d a r d i t a l i a n i . i t / s k i n / w w w. s t a n d a r d i t a l i a n i . i t / pdfSTANDARD_2016_June20.pdf
[106] http://care.diabetesjournals.org/content/40/Supplement_1/S114
[107] Honda, H.; Nagai, Y.; Matsunaga, T.; Okamoto, N.; Watanabe, Y.; Tsuneyama, K.; Hayashi, H.; Fujii, I.; Ikutani, M.; Hirai, Y.; et al. Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet-induced adipose tissue inflammation. J. Leukoc. Biol. 2014, 96, 1087–1100.
[108] Shim, D.W.; Han, J.W.; Ji, Y.E.; Shin, W.Y.; Koppula, S.; Kim, M.K.; Kim, T.K.; Park, P.J.; Kang, T.B.; Lee, K.H. Cichorium intybus Linn. Extract Prevents Type 2 Diabetes Through Inhibition of NLRP3 Inflammasome Activation. J. Med. Food 2016,
19, 310–317.
[109] Zhou, R.; Yazdi, A.S.; Menu, P.; Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 2011, 469, 221–225.
[110] Hara, H.; Tsuchiya, K.; Kawamura, I.; Fang, R.; Hernandez-Cuellar, E.; Shen, Y.; Mizuguchi, J.; Schweigho↵er, E.; Tybulewicz, V.; Mitsuyama, M. Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity. Nat. Immunol. 2013, 14, 1247–1255.
[111] Li, A.; Zhang, S.; Li, J.; Liu, K.; Huang, F.; Liu, B. Metformin and resveratrol inhibit Drp1-mediated mitochondrial fission and prevent ER stress-associated NLRP3 inflammasome activation in the adipose tissue of diabetic mice. Mol. Cell. Endocrinol. 2016, 434, 36–47.
[112] Ding, T.; Wang, S.; Zhang, X.; Zai, W.; Fan, J.; Chen, W.; Bian, Q.; Luan, J.; Shen, Y.; Zhang, Y.; et al. Kidney protection e↵ects of dihydroquercetin on diabetic nephropathy through suppressing ROS and NLRP3 inflammasome. PhytoMed. Int. J.
Phytother. Phytopharm. 2018, 41, 45–53.
[113] Wang, W.; Wang, C.; Ding, X.Q.; Pan, Y.; Gu, T.T.; Wang, M.X.; Liu, Y.L.; Wang, F.M.; Wang, S.J.; Kong, L.D. Quercetin and allopurinol reduce liver thioredoxin-interacting protein to alleviate inflammation and lipid accumulation in diabetic rats. Br. J. Pharmacol. 2013, 169,1352–1371.
[114] Wang, J.; Wang, L.; Zhou, J.; Qin, A.; Chen, Z. The protective e↵ect of formononetin on cognitive impairment in streptozotocin (STZ)-induced diabetic mice.
Biomed. Pharmacother. Biomed. Pharmacother. 2018, 106, 1250–1257.
[115] Wang, X.; Zhang, Z.F.; Zheng, G.H.; Wang, A.M.; Sun, C.H.; Qin, S.P.; Zhuang, J.; Lu, J.; Ma, D.F.; Zheng, Y.L. The Inhibitory E↵ects of Purple Sweet Potato Color on Hepatic Inflammation Is Associated with Restoration of NAD