title: Inhibition of the Inflammasome NLRP3 by Arglabin Attenuates Inflammation, Protects Pancreatic β-Cells from Apoptosis, and Prevents Type 2 Diabetes Mellitus Development in ApoE2Ki Mice on a Chronic High-Fat Diet.
abstract: Intraperitoneal injection of arglabin (2.5 ng/g of body weight, twice daily, 13 weeks) into female human apolipoprotein E2 gene knock-in (ApoE2Ki) mice fed a high-fat Western-type diet (HFD) reduced plasma levels of glucose and insulin by ∼20.0% ± 3.5% and by 50.0% ± 2.0%, respectively, in comparison with vehicle-treated mice. Immunohistochemical analysis revealed the absence of active caspase-3 in islet sections from ApoE2Ki mice fed a HFD and treated with arglabin. In addition, arglabin reduced interleukin-1β (IL-1β) production in a concentration-dependent manner in Langerhans islets isolated from ApoE2Ki mice treated with lipopolysaccharide (LPS) and with cholesterol crystals. This inhibitory effect is specific for the inflammasome NOD-like receptor family, pyrin domain-containing 3 (NLRP3) because IL-1β production was abolished in Langerhans islets isolated from Nlrp3(-/-) mice. In the insulin-secreting INS-1 cells, arglabin inhibited, in a concentration-dependent manner, the maturation of pro-IL-1β into biologically active IL-1β probably through the inhibition of the maturation of procaspase-1 into active capsase-1. Moreover, arglabin reduced the susceptibility of INS-1 cells to apoptosis by increasing Bcl-2 levels. Similarly, autophagy activation by rapamycin decreased apoptosis susceptibility while autophagy inhibition by 3-methyladenin treatment promoted apoptosis. Arglabin further increased the expression of the autophagic markers Bcl2-interacting protein (Beclin-1) and microtubule-associated protein 1 light chain 3 II (LC3-II) in a concentration-dependent manner. Thus, arglabin reduces NLRP3-dependent inflammation as well as apoptosis in pancreatic β-cells in vivo and in the INS-1 cell line in vitro, whereas it increases autophagy in cultured INS-1 cells, indicating survival-promoting properties of the compound in these cells. Hence, arglabin may represent a new promising compound to treat inflammation and type 2 diabetes mellitus development.
authors.affiliation: Biological Adaptation and Ageing, Institute of Biology Paris-Seine, UMR-8256/INSERM ERL-U1164 (A.A., K.E.H., E.B., D.C., M.R.), and Cordeliers Research Center, INSERM, UMR 872 (N.B.), University Pierre & Marie Curie, Paris, France; Biochemistry Laboratory, Faculty of Medicine, Monastir, Tunisia (M.-N.S.); Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany (B.B., T.S.).
authors.forename: Amna
authors.initials: A
authors.lastname: Abderrazak
authors.affiliation: Biological Adaptation and Ageing, Institute of Biology Paris-Seine, UMR-8256/INSERM ERL-U1164 (A.A., K.E.H., E.B., D.C., M.R.), and Cordeliers Research Center, INSERM, UMR 872 (N.B.), University Pierre & Marie Curie, Paris, France; Biochemistry Laboratory, Faculty of Medicine, Monastir, Tunisia (M.-N.S.); Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany (B.B., T.S.).
authors.forename: Khadija
authors.initials: K
authors.lastname: El Hadri
authors.affiliation: Biological Adaptation and Ageing, Institute of Biology Paris-Seine, UMR-8256/INSERM ERL-U1164 (A.A., K.E.H., E.B., D.C., M.R.), and Cordeliers Research Center, INSERM, UMR 872 (N.B.), University Pierre & Marie Curie, Paris, France; Biochemistry Laboratory, Faculty of Medicine, Monastir, Tunisia (M.-N.S.); Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany (B.B., T.S.).
authors.forename: Elodie
authors.initials: E
authors.lastname: Bosc
authors.affiliation: Biological Adaptation and Ageing, Institute of Biology Paris-Seine, UMR-8256/INSERM ERL-U1164 (A.A., K.E.H., E.B., D.C., M.R.), and Cordeliers Research Center, INSERM, UMR 872 (N.B.), University Pierre & Marie Curie, Paris, France; Biochemistry Laboratory, Faculty of Medicine, Monastir, Tunisia (M.-N.S.); Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany (B.B., T.S.).
authors.forename: Bertrand
authors.initials: B
authors.lastname: Blondeau
authors.affiliation: Biological Adaptation and Ageing, Institute of Biology Paris-Seine, UMR-8256/INSERM ERL-U1164 (A.A., K.E.H., E.B., D.C., M.R.), and Cordeliers Research Center, INSERM, UMR 872 (N.B.), University Pierre & Marie Curie, Paris, France; Biochemistry Laboratory, Faculty of Medicine, Monastir, Tunisia (M.-N.S.); Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany (B.B., T.S.).
authors.forename: Mohamed-Naceur
authors.initials: MN
authors.lastname: Slimane
authors.affiliation: Biological Adaptation and Ageing, Institute of Biology Paris-Seine, UMR-8256/INSERM ERL-U1164 (A.A., K.E.H., E.B., D.C., M.R.), and Cordeliers Research Center, INSERM, UMR 872 (N.B.), University Pierre & Marie Curie, Paris, France; Biochemistry Laboratory, Faculty of Medicine, Monastir, Tunisia (M.-N.S.); Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany (B.B., T.S.).
authors.forename: Berthold
authors.initials: B
authors.lastname: Büchele
authors.affiliation: Biological Adaptation and Ageing, Institute of Biology Paris-Seine, UMR-8256/INSERM ERL-U1164 (A.A., K.E.H., E.B., D.C., M.R.), and Cordeliers Research Center, INSERM, UMR 872 (N.B.), University Pierre & Marie Curie, Paris, France; Biochemistry Laboratory, Faculty of Medicine, Monastir, Tunisia (M.-N.S.); Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany (B.B., T.S.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Simmet
authors.affiliation: Biological Adaptation and Ageing, Institute of Biology Paris-Seine, UMR-8256/INSERM ERL-U1164 (A.A., K.E.H., E.B., D.C., M.R.), and Cordeliers Research Center, INSERM, UMR 872 (N.B.), University Pierre & Marie Curie, Paris, France; Biochemistry Laboratory, Faculty of Medicine, Monastir, Tunisia (M.-N.S.); Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany (B.B., T.S.).
authors.forename: Dominique
authors.initials: D
authors.lastname: Couchie
authors.affiliation: Biological Adaptation and Ageing, Institute of Biology Paris-Seine, UMR-8256/INSERM ERL-U1164 (A.A., K.E.H., E.B., D.C., M.R.), and Cordeliers Research Center, INSERM, UMR 872 (N.B.), University Pierre & Marie Curie, Paris, France; Biochemistry Laboratory, Faculty of Medicine, Monastir, Tunisia (M.-N.S.); Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany (B.B., T.S.) mustapha.rouis@upmc.fr.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Rouis
mesh_terms: D000818:Animals; D053329:Apolipoprotein E2 / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D020170:Caspase 1 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D059305:Diet, High-Fat / Q000009:adverse effects*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D055879:Gene Knock-In Techniques; D006801:Humans; D058847:Inflammasomes / Q000037:antagonists & inhibitors*; D007249:Inflammation / Q000188:drug therapy; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000096:biosynthesis; D051379:Mice; D051381:Rats; D012717:Sesquiterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D045789:Sesquiterpenes, Guaiane; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D053329:Apolipoprotein E2; D001786:Blood Glucose; D058847:Inflammasomes; D007328:Insulin; D053583:Interleukin-1beta; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; D051028:bcl-2-Associated X Protein; C083346:arglabin; D053148:Caspase 3; D020170:Caspase 1