The deleterious effect of chronic activation of the IL-1β system on type 2 diabetes and other metabolic diseases is well documented. However, a possible physiological role for IL-1β in glucose metabolism has remained unexplored. Here we found that feeding induced a physiological increase in the number of peritoneal macrophages that secreted IL-1β, in a glucose-dependent manner. Subsequently, IL-1β contributed to the postprandial stimulation of insulin secretion. Accordingly, lack of endogenous IL-1β signaling in mice during refeeding and obesity diminished the concentration of insulin in plasma. IL-1β and insulin increased the uptake of glucose into macrophages, and insulin reinforced a pro-inflammatory pattern via the insulin receptor, glucose metabolism, production of reactive oxygen species, and secretion of IL-1β mediated by the NLRP3 inflammasome. Postprandial inflammation might be limited by normalization of glycemia, since it was prevented by inhibition of the sodium–glucose cotransporter SGLT2. Our findings identify a physiological role for IL-1β and insulin in the regulation of both metabolism and immunity.
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We thank R. Sharfmann (Université Paris-Descartes, Institut Cochin, Paris, France) for the human β-cell line ENDOC; technicians M. Borsigova, K. Dembinski and S. Haeuselmann for technical assistance; S. Dimeloe, E. Traunecker and D. Labes for technical advice; G. Bantug for technical and editorial advice; and the Center for Transgenic Models of the University of Basel and D. Klewe-Nebenius for supporting production of the Il1bfl/fl mouse. Supported by the Swiss National Research Foundation (166519 to M.Y.D.) and the European Genomic Institute for Diabetes (ANR-10-LABX-46 to F.P.).
M.Y.D. is listed as the inventor on a patent filed in 2003 for the use of an IL-1 receptor antagonist for the treatment of or prophylaxis for type 2 diabetes.
Integrated supplementary information
Supplementary Figure 1 Feeding stimulates intraperitoneal macrophages, which are primed by the gut microbiota to produce IL-1β in a glucose-dependent manner.
(a) Representative standard curve (blue) from IL-1β MSD assay including data points of samples (red dots) from refeeding experiments (sera) or from supernatants of cultivated macrophages. (b) Gating strategy and staining: live, single peritoneal cells were stained for CD11b and F4/80 (macrophages) or CD3e (T cells), CD19 (B cells), Siglec-F (eosinophils) and GR-1 (granulocytes). (c) Design of transgenic allele of the EUCOMM ES cell and the generation of Il1bfl/flLyz2-Cre+/- and littermate control mice. (d) Glycosuria (dark blue) in mice injected with the SGLT2 inhibitor canagliflozin (asterisks) compared to placebo treated mice (glucose negative; yellow). (e) Blood glucose levels and (f) circulating insulin levels before (fasted) or after refeeding (refed) in mice treated with or without the SGLT2 inhibitor canagliflozin (n=13 per group). (g) Il1b and (h) Cxcl1 gene expression in omental fat isolated from refed mice pretreated with or without ABX (n=11 per group). (i) Circulating IL-1β levels before (fasted) or after refeeding (refed) in mice treated with or without antibiotics (control; n=11, ABX; n=13). Food intake of mice treated with or without ABX during (j) a 2-hour refeeding experiment and (k) during ABX treatment (one week, n=2 experiments). (l) Number of peritoneal cells isolated from control or 1 week ABX treated mice (n=11 and 10, respectively). *P < 0.0001. Statistical significance (P) was determined by ANOVA. All error bars denote s.e.m.
(a) Blood glucose levels before (fasted) or after refeeding (refed) in WT and Il1b–/– littermate mice (n=12 and 6, respectively). (b) Representative FACS plot of peritoneal macrophage (CD11b+, F4/80+) depletion in WT mice 3 days after injection of 10 ml/kg clodronate or PBS liposomes, gated on live single cells. (c) Blood glucose levels following acute injections of saline or 10 mg/kg IL-1Ra in refed WT mice (n=26 and 23, respectively). *P<0.05, **P < 0.01. Statistical significance (P) was determined by Student's t test and in (a) by ANOVA. All error bars denote s.e.m.
Supplementary Figure 3 Acute exposure to IL-1β induces insulin secretion without changing insulin sensitivity.
(a) Circulating active GLP-1 protein levels in WT mice injected with saline or 1 μg/kg IL-1β. (b) Glucose and (c) insulin levels during i.p. GTT with Gipr-/-/Glp1r-/- double knockout (KO; n=7) or WT (n=8) mice. (d) Insulin tolerance test 18 minutes after an injection of saline (n=5) or 1 μg/kg IL-1β (n=6) in WT mice. (e) Circulating glucose and (f) insulin levels during an i.p. GTT with IRAK4 knockout mice, pretreated with saline or 1 μg/kg IL-1β (n=6). (g-i) Insulin concentrations in culture media of islets isolated from mice (g; left to right: n=9, 13, 9, 12; 3 experiments) and humans (h; left to right: n=44, 9, 34, 15; 8 experiments) and of human ENDOC cells (i; n=9; 3 experiments) pre-incubated with the indicated doses of IL-1β (priming) during glucose stimulated insulin secretion assays. *P < 0.05, **P < 0.001, ***P < 0.0001. Statistical significance (P) was determined by Student's t test and in (g-i) by ANOVA. All error bars denote s.e.m.
Supplementary Figure 4 Insulin stimulates the secretion of IL-1β by macrophages via metabolism and the NLRP3 inflammasome.
(a) InsR protein levels in naive (M0), pro-inflammatory M1 and alternative M2 polarized macrophages (n=3 experiments). (b) Insulin-induced (s473) phospho-AKT in M0, M1 and M2 polarized macrophages, data presented as ratio of insulin to non-insulin treated cells after normalization to total AKT (n=3 experiments). (c) Extracellular acidification rate (ECAR; mpH/min) from M0 or M2 polarized macrophages incubated for 2 hours in the presence or absence of 1 μg/ml insulin (n=12 and 15, respecively; 3 experiments). (d) Two-hour TNFα, IL-6, and CXCL1 secretion from 2 hour M1 polarized WT or Nlrp3-/- macrophages treated with or without 1 μg/ml insulin (n=5 mice each). (e) Gene expression profiles in M1 polarized macrophages with or without 2-hour treatment with 1 μg/ml insulin; data are expressed as fold change from untreated M0 controls (n=9, 3 experiments). (f) Cell survival as detected by annexin V and dapi staining of 2-hour M1 polarized macrophages treated for 2 hours with or without 1 μg/ml insulin. (g) Circulating CXCL1 protein concentration in mice treated with or without 1 unit/kg insulin (60 minutes post injection; n=10). *P < 0.05, **P<0.01. Statistical significance (P) was determined by ANOVA and in (g) by student’s t test. All error bars denote s.e.m.
(a) Blood glucose levels during an oral glucose tolerance (oGTT) 18 minutes after a single injection of 1 μg/kg IL-1β in Rag2-/- and littermate heterozygous mice (n=6-7). (b) Representative flow cytometry plot of peritoneal macrophage (CD11b+, F4/80+) depletion in Rag2-/- deficient mice 3 days after injection of liposomes containing clodronate or PBS.
Supplementary Figure 6 Proposed model for the physiological role of IL-1β and insulin in the regulation of glucose metabolism in response to food intake.
Food ingestion during feeding increases the number of peritoneal macrophages. These macrophages are stimulated by bacterial products and glucose to increase the production and release of IL-1β. Increased IL-1β concentrations will then enhance the continuous postprandial insulin secretion from pancreatic β cells via the highly expressed IL-1 receptor 1 (IL-1R1) and the IL-1 receptor-associated kinase-4 (IRAK4). The secreted insulin binds to its receptor (InsR) on macrophages, leading to enhanced glucose uptake through the glucose transporter GLUT1, AKT phosphorylation (pAKT) as well as hexokinase 2 (HK2) and glycolytic activity leading to ROS production. This further stimulates macrophage- derived pro-IL-1β-maturation by the NLRP3 inflammasome. Finally, increased levels of IL-1β and insulin stimulate glucose uptake into muscle, adipose tissue and immune cells that consequently decrease glycemia, thereby limiting the postprandial inflammatory response.
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Dror, E., Dalmas, E., Meier, D. et al. Postprandial macrophage-derived IL-1β stimulates insulin, and both synergistically promote glucose disposal and inflammation. Nat Immunol 18, 283–292 (2017). https://doi.org/10.1038/ni.3659
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