Advertisement

Diabetologia

, Volume 62, Issue 6, pp 993–999 | Cite as

Macrophage alterations in islets of obese mice linked to beta cell disruption in diabetes

  • Jeng Yie Chan
  • Kailun Lee
  • Emma L. Maxwell
  • Cassandra Liang
  • D. Ross LaybuttEmail author
Short Communication

Abstract

Aims/hypothesis

Mild islet inflammation has been suggested as a contributing factor to beta cell failure in type 2 diabetes. Macrophage levels are elevated in the islets of humans and mice with type 2 diabetes, but their effects on beta cells are not understood. Our goal was to examine the gene expression changes in islet-associated macrophages in obesity models with opposing disposition to diabetes development and to assess their potential contribution to beta cell (mal)adaptation.

Methods

Islets were isolated from lean control mice, obese diabetes-prone db/db mice and obese diabetes-resistant ob/ob mice. Macrophages were sorted using flow cytometry. Islets were treated ex vivo with clodronate-containing liposomes to deplete macrophages. Gene expression was assessed by real-time RT-PCR.

Results

Macrophage levels were increased in islets from db/db mice but not in islets from ob/ob mice compared with lean control mice. Macrophages from db/db and ob/ob islets displayed distinct changes in gene expression compared with control islet macrophages, suggesting differential shifts in functional state. Macrophages from db/db islets displayed increased expression of interferon regulatory factor 5 (Irf5), IL-1 receptor antagonist (Il1rn) and mannose receptor C-type 1 (Mrc1), whereas macrophages from ob/ob islets showed elevated levels of transforming growth factor beta 1 (Tgfb1) and reduced IL-1β (Il1b). Clodronate-liposome treatment of islets depleted macrophages, as evidenced by reduced mRNA expression of Cd11b (also known as Itgam) and F4/80 (also known as Adgre1) compared with PBS-liposome-treated islets. The depletion of macrophages in db/db islets increased the expression of genes related to beta cell identity. The mRNA levels of islet-associated transcription factors (Mafa and Pdx1), glucose transporter (Glut2 [also known as Slc2a2]), ATP-sensitive K+ channel (Kcnj11), incretin receptor (Gipr) and adaptive unfolded protein response (UPR) genes (Xbp1, Hspa5, Pdia4 and Fkbp11) were increased in db/db islets after macrophage depletion, whereas the mRNA levels of the deleterious UPR effector, Ddit3, were reduced. In contrast, depletion of macrophages in islets of ob/ob mice did not affect beta cell identity gene expression.

Conclusions/interpretation

The findings of this study suggest that distinct alterations in islet macrophages of obese mice are critically important for the disruption of beta cell gene expression in diabetes.

Keywords

Beta cell Gene expression Inflammation Islets Macrophage Type 2 diabetes Unfolded protein response 

Abbreviation

UPR

Unfolded protein response

Notes

Acknowledgements

We thank L. M. Thai and E. Lam (Garvan Flow Facility) for technical assistance.

Contribution statement

JYC and DRL conceived and designed experiments, acquired and analysed data and wrote the manuscript. KL, ELM and CL acquired and analysed data and critically reviewed the manuscript. All authors approved the final version of the manuscript. DRL is the guarantor of this work.

Funding

This work was supported by a grant from the National Health and Medical Research Council (NHMRC) of Australia and the Diabetes Australia Research Program. JYC is supported by an NHMRC Early Career Fellowship.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2019_4844_MOESM1_ESM.pdf (277 kb)
ESM (PDF 277 kb)

References

  1. 1.
    Bensellam M, Jonas JC, Laybutt DR (2018) Mechanisms of beta-cell dedifferentiation in diabetes: recent findings and future research directions. J Endocrinol 236:R109–R143CrossRefPubMedGoogle Scholar
  2. 2.
    Talchai C, Xuan S, Lin HV, Sussel L, Accili D (2012) Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell 150:1223–1234CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Engin F, Nguyen T, Yermalovich A, Hotamisligil GS (2014) Aberrant islet unfolded protein response in type 2 diabetes. Sci Rep 4:4054CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Chan JY, Luzuriaga J, Bensellam M, Biden TJ, Laybutt DR (2013) Failure of the adaptive unfolded protein response in islets of obese mice is linked with abnormalities in beta-cell gene expression and progression to diabetes. Diabetes 62:1557–1568CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Donath MY, Dalmas E, Sauter NS, Boni-Schnetzler M (2013) Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity. Cell Metab 17(6):860–872.  https://doi.org/10.1016/j.cmet.2013.05.001 CrossRefPubMedGoogle Scholar
  6. 6.
    Ehses JA, Perren A, Eppler E et al (2007) Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56:2356–2370CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Eguchi K, Nagai R (2017) Islet inflammation in type 2 diabetes and physiology. J Clin Invest 127:14–23CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Everett BM, Donath MY, Pradhan AD et al (2018) Anti-inflammatory therapy with canakinumab for the prevention and management of diabetes. J Am Coll Cardiol 71:2392–2401CrossRefPubMedGoogle Scholar
  9. 9.
    Lee AH, Heidtman K, Hotamisligil GS, Glimcher LH (2011) Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion. Proc Natl Acad Sci U S A 108:8885–8890CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ferris ST, Zakharov PN, Wan X et al (2017) The islet-resident macrophage is in an inflammatory state and senses microbial products in blood. J Exp Med 214:2369–2385CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Jeng Yie Chan
    • 1
  • Kailun Lee
    • 1
  • Emma L. Maxwell
    • 1
  • Cassandra Liang
    • 1
  • D. Ross Laybutt
    • 1
    Email author
  1. 1.Garvan Institute of Medical Research, St Vincent’s Clinical SchoolUNSW SydneySydneyAustralia

Personalised recommendations