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Adipsin preserves beta cells in diabetic mice and associates with protection from type 2 diabetes in humans

Nature Medicine volume 25, pages 1739–1747 (2019)Cite this article

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Abstract

Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function1,2. Currently, there are no therapies proven to prevent beta cell loss and some, namely insulin secretagogues, have been linked to accelerated beta cell failure, thereby limiting their use in type 2 diabetes3,4. The adipokine adipsin/complement factor D controls the alternative complement pathway and generation of complement component C3a, which acts to augment beta cell insulin secretion5. In contrast to other insulin secretagogues, we show that chronic replenishment of adipsin in diabetic db/db mice ameliorates hyperglycemia and increases insulin levels while preserving beta cells by blocking dedifferentiation and death. Mechanistically, we find that adipsin/C3a decreases the phosphatase Dusp26; forced expression of Dusp26 in beta cells decreases expression of core beta cell identity genes and sensitizes to cell death. In contrast, pharmacological inhibition of DUSP26 improves hyperglycemia in diabetic mice and protects human islet cells from cell death. Pertaining to human health, we show that higher concentrations of circulating adipsin are associated with a significantly lower risk of developing future diabetes among middle-aged adults after adjusting for body mass index (BMI). Collectively, these data suggest that adipsin/C3a and DUSP26-directed therapies may represent a novel approach to achieve beta cell health to treat and prevent type 2 diabetes.

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Fig. 1: Adipsin prevents islet atrophy and ameliorates hyperglycemia in diabetic mice.
Fig. 2: Adipsin prevents beta cell failure in db/db mice by blocking beta cell death and dedifferentiation.
Fig. 3: Adipsin/C3a regulates Dusp26, a phosphatase that regulates beta cell identity and survival.
Fig. 4: DUSP26 inhibition protects human beta cells and circulating adipsin is associated with protection from future diabetes in humans.

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Data availability

All requests for raw and analyzed data will be reviewed to verify if the request is subject to any intellectual property or confidentiality obligations. Any data and materials that can be shared will be released via a Material Transfer Agreement. Data from Framingham Heart Study participants are publicly available at dbGap according to NIH data sharing policies (study accession no. phs000007.v29.p10).

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Acknowledgements

N.G.-B. is supported by an American Diabetes Association postdoctoral fellowship (1-18-PMF-032). J.S.G. was supported by an MGH NIH T32 Training Grant (HL007208), the John S. LaDue Memorial Fellowship and the MGH Physician Scientist Development Program. This work was supported by a Weill Cornell Department of Medicine Seed Grant for Innovative Research to J.C.L., the JPB Foundation (to B.M.S.), Jill Roberts IBD Institute (to G.P.) and NIH grants DK097303 (to J.C.L.), R03 DK111762 (to J.C.L.), R01 DK121844 (to J.C.L.), R01 HL140224 (to J.E.H.) and R01 HL134893 (to J.E.H.). This work was partially supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (contracts N01-HC-25195 and HHSN268201500001I) and by the Division of Intramural Research (to P.C., G.S., C.L., S.-J.H. and D.L.) of the National Heart, Lung and Blood Institute. We acknowledge support from the Yale Mouse Metabolic Phenotyping Center via NIH grants nos. U24 DK-059635, R01 DK116774, R01 DK114793 and P30 DK045735 (all to G.I.S.). We acknowledge the Microscopy and Image Analysis Core Facility at Weill Cornell Medicine for analysis of the images presented in this study, J. Cao for his help with confocal microscopy and the Human Islet and Adenovirus Core of the Einstein–Sinai Diabetes Research Center (NIH grant no. P30 DK020541-38) for the human islet studies. The views expressed in this Letter are those of the authors and do not necessarily represent the views of the National Institute of Diabetes and Digestive and Kidney Diseases, National Heart, Lung and Blood Institute, the National Institutes of Health or the US Department of Health and Human Services.

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Authors and Affiliations

  1. Weill Center for Metabolic Health and Division of Cardiology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA

    Nicolás Gómez-Banoy, Alfonso Rubio-Navarro, Tong Chen, BreAnne Poirier, Maria A. Pabón & James C. Lo

  2. Corrigan Minehan Heart Center, Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    J. Sawalla Guseh, Vijeta Bhambhani & Jennifer E. Ho

  3. Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA

    Ge Li, Sushmita Mukherjee & Mingming Hao

  4. Jill Roberts Institute for Research in Inflammatory Bowel Disease, Department of Medicine, Weill Cornell Medicine, New York, NY, USA

    Gregory Putzel

  5. Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Carolina Rosselot & Adolfo Garcia-Ocana

  6. Departments of Internal Medicine and Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT, USA

    João Paulo Camporez, Rachel J. Perry & Gerald I. Shulman

  7. Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Shih-Jen Hwang, Chen Yao & Daniel Levy

  8. Framingham Heart Study, Framingham, MA, USA

    Shih-Jen Hwang, Chen Yao, Martin G. Larson & Daniel Levy

  9. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

    Martin G. Larson

  10. Sandra and Edward Meyer Cancer Center, Department of Medicine, Weill Cornell Medicine, New York, NY, USA

    Lukas E. Dow & Noah Dephoure

  11. Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    Bruce M. Spiegelman

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  1. Nicolás Gómez-Banoy
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Contributions

J.C.L. and N.G.-B. designed the animal, cellular and molecular studies. J.E.H. and J.S.G. designed the human study. N.G.-B., G.L., A.R.-N., T.C., B.P., M.A.P., J.P.C. and R.J.P. performed and analyzed the animal experiments. N.G.-B, A.R.-N., T.C., B.P. and C.R. developed the in vitro experiments. J.E.H., J.S.G., V.B., S.-J.H., C.Y., D.L. and M.G.L. analyzed the human study data. S.M. analyzed microscope images. N.D. developed and analyzed proteomics experiments. G.P. analyzed RNA sequencing experiments. L.E.D., G.I.S., A.G.-O., M.H. and B.M.S. provided scientific input and analyzed the data. J.C.L., J.E.H., N.G.-B. and J.S.G. wrote the manuscript, and all authors contributed to writing and provided feedback. J.C.H. (jho1@mgh.harvard.edu) is the contact for the Framingham studies.

Corresponding authors

Correspondence to Jennifer E. Ho or James C. Lo.

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Competing interests

Cornell University has filed a provisional patent application that covers the use of DUSP26 inhibitors for the treatment of type 2 diabetes. (US patent application no. 62/740744; N.G.-B. and J.C.L.). V.B. is currently an employee of Fractyl Laboratories Inc. and all analyses were conducted during employment at Massachusetts General Hospital.

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Peer review information Joao Monteiro was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Islet area in the eye is correlated with beta cell area in the pancreas and lower fasting glucose.

(a) Scatterplot of fasting glucose levels and eye islet area in db/db mice transplanted with islets in the anterior chamber of the eye and treated with AAV-Adipsin or AAV GFP (n = 5 per group). (b) Scatterplot of beta cell area and eye islet area in db/db mice transplanted with islets in the anterior chamber of the eye and treated with AAV-Adipsin or AAV-GFP (n = 5 per group). (c) Representative immunohistochemistry images of insulin (brown) performed in pancreatic sections from db/db-GFP and db/db-Adipsin mice. IHC was performed at least twice independently with similar results. Scale bars, 100 µm. (d) Quantification of beta cell area in db/db mice transplanted with islets in the anterior chamber of the eye and treated with AAV-Adipsin or AAV-GFP (n = 5 per group). Data were analyzed by two-tailed unpaired t-test. (p = 0.027). (e) Western blot for adipsin from sera of B6 WT mice injected with GFP-AAV or adipsin-AAV after 5 months (n = 4 per group) along with quantification. (f) Quantification of islet area in the eye over time in WT-GFP and WT-Adipsin mice (n = 5 WT-Adipsin, n = 6 WT-GFP). Eye imaging was repeated at least 3 times independently with similar results. (g) Reporter islets transplanted into the anterior chamber of the eyes of WT-GFP and WT-Adipsin mice were serially imaged by light microscopy. Representative images are from a single mouse in each treatment group at the indicated time points. Islets are outlined within dashed white circles. Islets are amplified inside the white box. Eye imaging was repeated at least 3 times independently with similar results. Scale bars, 1 mm. Data are expressed as mean ± s.e.m. *P < 0.05, ** P < 0.01, *** P < 0.001.

Source data

Extended Data Fig. 2 Treatment with AAV-Adipsin prevents beta cell failure without affecting body weight or insulin sensitivity.

(a) Cfd mRNA levels were quantified by qPCR in the indicated tissues from db/db mice transduced with AAV-Adipsin or AAV-GFP at 1 month post-transduction (iWAT: n = 3 db/db-Adipsin, n = 4 db/db-GFP. vWAT: n = 3 for both groups. Liver: n = 4 for both groups. Kidney: n = 6 db/db-Adipsin, n = 5 db/db GFP. Islets: n = 2 for both groups). (b) Mouse serum adipsin levels were measured by ELISA (n = 5 db/db-GFP, n = 5 db/db-Adipsin, n = 2 B6 WT, n = 3 Adipsin KO). (c) Body weights of db/db mice transduced with AAV-Adipsin versus AAV-GFP at the indicated time points (n = 8 mice per group at 1 month post transduction and n = 15-16 mice per group at 1.5-months post transduction). (d) Glucose infusion rate during hyperinsulinemic euglycemic clamp in db/db mice treated with adipsin versus controls (n = 5 db/db-Adipsin, n = 6 db/db-GFP). (e) Scatterplot of fasting glucose and beta cell mass in db/db mice transduced with AAV-Adipsin versus controls (n = 18-21 per group). (f) Scatterplot of fasting insulin and beta cell mass in db/db mice injected with AAV-Adipsin versus controls (n = 18-21 per group). (g) Representative IHC staining for insulin (brown) in pancreases of two control and two adipsin transduced db/db mice. Areas in the dashed boxes are amplified in the panels at the right of each image. IHC was repeated at least twice independently with similar results. Scale bars, 1 mm left panels, 100 µm amplified regions. Data are expressed as mean ± s.e.m.

Extended Data Fig. 3 Adipsin prevents beta cell death and prevents loss of beta cell transcriptional identity.

(a) Representative images of immunofluorescence (IF) staining for insulin and TUNEL assay in pancreases of db/db mice injected with AAV-Adipsin versus controls. White dashed box indicates region magnified in white panel. IF was repeated at least twice independently with similar results. (b) Quantification of TUNEL + beta cells as determined by IF. (n = 4 mice per group at 1.5 months, n = 5 mice per group at 6 months). Data were analyzed by two-tailed unpaired t-test. (p = 0.03). (c) Representative images of immunofluorescence (IF) staining for insulin and Ki67 in pancreases of the indicated groups of mice. White dashed box indicates region magnified in white panel. IF was repeated at least twice independently with similar results. (d) Quantification of Ki67 + beta cells as determined by IF (At 1.5 months; n = 6 mice per group. At 6 months n = 3 db/db-Adipsin, n = 4 db/db-GFP). (e) Glucagon positive cells were quantitated by IHC in the pancreases of db/db mice transduced with AAV-Adipsin versus controls. Representative images are shown. IHC was repeated at least three times independently with similar results. (f) Quantification of alpha cell mass in B6 WT mice, db/db mice treated with AAV-GFP and db/db mice treated with adipsin AAV at the indicated time points (Pre AAV; n = 4 db/db, n = 4 B6 WT. At 1.5 months post-AAV; n = 6 db/db-Adipsin, n = 5 db/db-GFP, n = 2 B6 WT. At 6 months post-AAV; n = 13 db/db-Adipsin, n = 16 db/db-GFP, n = 4 B6 WT). Data were analyzed by two-tailed unpaired t-test. (At 1.5 months post-AAV db/db-GFP vs db/db-Adipsin p = 0.03). (g) Quantification of the ratio between alpha cell mass and beta cell mass in pancreases from the specified groups at the indicated time points (Pre AAV; n = 4 db/db, n = 4 B6 WT. At 1.5 months post-AAV; n = 6 db/db-Adipsin, n = 5 db/db-GFP, n = 2 B6 WT. At 6 months post-AAV; n = 13 db/db-Adipsin, n = 16 db/db-GFP, n = 4 B6 WT). Data were analyzed by two-tailed unpaired t-test. (At 6 months post-AAV db/db-GFP vs db/db-Adipsin p = 0.029). (h) Fasting serum glucagon levels in db/db mice transduced with AAV-GFP or AAV-Adipsin (n = 8 per group). Scale bars, 100 µm (a, c and e). Data are expressed as mean ± s.e.m. *P < 0.05, ** P < 0.01, *** P < 0.001.

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Extended Data Fig. 4 Adipsin increases the expression of beta cell transcription factors and decreases gastrin expression.

(a,b) Representative images (a) of MAFA and insulin IF in B6 WT mice, db/db mice injected with AAV-Adipsin or AAV-GFP along with quantification (b) of MAFA + beta cells (n = 4 mice for B6 WT, n = 6 mice per db/db treatment group). Data were analyzed by two-tailed unpaired t-test. (p = 0.029). (c,d) Representative images (c) of NKX2-2 and insulin IF in the indicated groups along with quantification (d) of NKX2-2 + beta cells (n = 5 mice per group). Data were analyzed by two-tailed unpaired t-test. (p = 0.027). (e,f) Representative images (e) of gastrin and insulin IF in the indicated groups along with quantification (f) of gastrin + beta cells (n = 5 mice per group). White dashed box indicates region magnified in white panel. Data were analyzed by two-tailed unpaired t-test. (p = 0.038). Scale bars, 100 µm (a, b and c). Data are expressed as mean ± s.e.m. *P < 0.05, ** P < 0.01, *** P < 0.001.

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Extended Data Fig. 5 Adipsin/C3a increases insulin secretion and protects from beta cell death by inhibiting DUSP26.

(a) Ins1 beta cells were subjected to a glucose-stimulated insulin secretion assay at 0 or 17 mM glucose with or without C3a (n = 8 per group). Results are representative of three independent experiments. Data were analyzed by two-tailed unpaired t-test. (Glc 0 mM vs glc 17 mM p = 0.0019, glc 17 mM vs glc 17 mM + C3a p = 0.009). (b) Representative gating strategy for islet cells. (c) Heatmap of genes significantly changed by palmitate treatment and counter-regulated by C3a in WT islets (n = 3 per group) Colors show raw z-scores of mean normalized counts. (d) GO biological process analysis of genes whose expression were downregulated by palmitate and counter-regulated (increased) by C3a. Data were analyzed by Fisher/binominal test with Bonferroni-adjusted P value (n = 33 genes) (e) GO biological process analysis of genes whose expression were upregulated by palmitate and counter-regulated (decreased) by C3a. Data were analyzed by Fisher/binominal test with Bonferroni-adjusted P value (n = 43 genes) (f) Pathway analysis from the DEPOD database depicting significant phosphatase substrates in islets that are regulated at the gene expression level by C3a from Fig. 3d. (n = 76 genes) Data were analyzed by Fisher/binominal test with Bonferroni-adjusted P value (g) Ins2 and Gcg were determined by qPCR in isolated pancreatic islets from WT mice transduced with Dusp26 or control lentivirus (n = 4 GFP, n = 3 Dusp26). Data are representative of 3 independent experiments. Data were analyzed by two-tailed unpaired t-test. (Ins2 p = 0.0284, Gcg p = 0.033). (h) Cell viability was determined in INS-1 cells transduced with Dusp26 and controls (n = 6 per group). Data are representative of 3 independent experiments. Data were analyzed by two-tailed unpaired t-test. (GFP in veh vs GFP in Pa p = 0.022, Dusp26 in veh vs Dusp26 in Pa p = 0.0000047, GFP in Pa vs Dusp26 in Pa p = 0.0004). (i) Representative western blot analysis of DUSP26 in INS-1 cells treated with shRNA against Dusp26 versus control shRNA. Data are representative of 3 independent experiments. (j) Quantification of DUSP26 expression for Supplementary Figure 8d from 3 independent experiments. Data were analyzed by two-tailed unpaired t-test. (p = 0.028). (k) Body weight in db/db mice treated for 2 weeks with NSC-87877 and controls at the indicated time points (n = 15 NSC-87877 group, n = 16 saline group). (l) Representative western blot analysis for FLAG after immunoprecipitation of the DUSP26 protein complex using FLAG-M2 antibodies in lysates of INS-1 cells overexpressing control GFP, intact DUSP26 (D26) and catalytically inactive DUSP26 mutant (C152S). Data are representative of at least 3 independent experiments. (m) KEGG pathway analysis of proteins enriched in DUSP26 immunoprecipitation experiment. Proteins with log2 ≥ 1.5 between control GFP and DUSP26 mutant (C152S) were included in the analysis. Top and selected pathways are shown. Data were analyzed by Fisher/binominal test with Bonferroni-adjusted P value (n = 253 genes) (n) Heatmap of selected proteins belonging to relevant pathways and significantly enriched in the DUSP26 mutant (C152S) pulldown. (n = 2 per group). Colors show log2 fractional intensity. Data are expressed as mean ± s.e.m. *P < 0.05, ** P < 0.01, *** P < 0.001.

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Extended Data Fig. 6 Baseline participant characteristics.

The average adipsin concentration was 900 ± 273 ng/mL (mean ± s.d.) Values depict mean ± standard deviation where appropriate.

Extended Data Fig. 7 Clinical correlates of adipsin.

(a) In cross-section multivariable analyses, higher adipsin levels associate with lower odds of diabetes (OR 0.69) and with higher odds of obesity (OR 1.68). Adipsin is associated with a number of clinical traits including BMI, waist circumference, diastolic blood pressure reduction and reduced HDL cholesterol. Additionally, higher levels associate with significantly lower fasting glucose, with a trend toward improved insulin resistance as measured by HOMA-IR that did not meet the Bonferroni-corrected p-value threshold for significance. Analyses were multivariable linear (t statistic) or logistic regression models (Wald Chi-square test) with two-sided p-values deemed significant at a Bonferroni-corrected p-value threshold of p = 0.05/10 primary traits = 0.005. Similar results were obtained in secondary analyses stratified by Framingham cohort (Offspring vs. Third Generation). (b) Cross-sectional radiographic anatomically specific adiposity volumes were obtained from participants of the Third-Generation Framingham cohort (n = 3068, 2002 to 2005). In secondary analyses, volumetric measures of adiposity reveal that adipsin is strongly associated with subcutaneous (SAT) and intrathoracic adipose volumes and not visceral adipose volumes. With regard to subcutaneous adipose, a one standard deviation rise in adipsin was associated with a 0.4 standard deviation increase in subcutaneous adipose volume. Analyses were multivariable linear regression models (t statistic) with two-sided p-values deemed significant at a p-value threshold of p = 0.05.

Extended Data Fig. 8 GWAS of adipsin levels in the Framingham Cohort.

A genome-wide association study of adipsin levels was conducted among n = 6791 individuals with available genetic data using an additive genetic model (t statistic). (a) A quintile-quintile plot of the observed and expected P-values. Each dot represents observed data while the solid line represents the null hypothesis of no association. (b) A regional plot of the sentinel SNP (rs2930902) associated with elevated plasma adipsin level is housed intronically within the MED16. Other significant cis-SNPs are also shown.

Extended Data Fig. 9 Significant cis variant SNPs with phenotypic association, eQTL analysis, and associated metabolites from published databases.

The lead SNP on chromosome 19 rs2930902 is an intron variant in the MED16 locus and is associated with type 2 diabetes. Tissue specific cis-eQTL’s reveal that this SNP is significantly associated with adipsin expression in a number of tissues but notably in subcutaneous (but not visceral) adipose tissue. Moreover, the same SNP is associated with known branch chain amino acid metabolites (glycine and valine) known to predict incident type 2 diabetes mellitus. Three additional SNPs associated with adipisin expression are shown.

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Gómez-Banoy, N., Guseh, J.S., Li, G. et al. Adipsin preserves beta cells in diabetic mice and associates with protection from type 2 diabetes in humans. Nat Med 25, 1739–1747 (2019). https://doi.org/10.1038/s41591-019-0610-4

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