Heterogeneity and altered β-cell identity in the TallyHo model of early-onset type 2 diabetes

Sarah McDonald, Phil Ray, Robert C. Bunn, John L. Fowlkes, Kathryn M. Thrailkill, Iuliana Popescu

Research output: Contribution to journalArticlepeer-review

Abstract

A primary underlying defect makes β-cells “susceptible” to no longer compensate for the peripheral insulin resistance and to trigger the onset of type 2 diabetes (T2D). New evidence suggests that in T2D, β-cells are not destroyed but experience a loss of identity, reverting to a progenitor-like state and largely losing the ability to sense glucose and produce insulin. We assessed (using fluorescence microscopy and histomorphometry correlated with the glycaemic status) the main β-cell identity modifications as diabetes progresses in the TallyHo/JngJ (TH) male mice, a polygenic model of spontaneous T2D, akin to the human phenotype. We found that: 1) conversion to overt diabetes is paralleled by a progressive reduction of insulin-expressing cells and expansion of a glucagon-positive population, together with alteration of islet size and shape; 2) the β-cell population is highly heterogeneous in terms of insulin content and specific transcription factors like PDX1 and NKX6.1, that are gradually lost during diabetes progression; 3) GLUT2 expression is altered early and strongly reduced at late stages of diabetes; 4) an endocrine developmental program dependent on NGN3-expressing progenitors is revived when hyperglycaemia becomes severe; and 5) the re-expression of the EMT-associated factor vimentin occurs as diabetes worsens, representing a possible regenerative response to β-cell loss. Based on these results, we formulated additional hypotheses for the β-cell identity alteration in the TH model, together with several limitations of the study, that constitute future research directions.

Original languageEnglish
Article number151940
JournalActa Histochemica
Volume124
Issue number7
DOIs
StatePublished - Oct 2022

Bibliographical note

Funding Information:
This work was supported by the US National Institutes of Health grants [ 1R21AR070620-01 ] to K.M.T. and [ 7R01DK084045-04 ] to J.L.F. Additional funding was provided by the University of Kentucky, Barnstable Brown Diabetes Center Pediatric Laboratory Endowment (USA). No specific funding was allocated to this project. S.M. was enrolled in the BIO395 Mentored Research Program at the University of Kentucky, under the mentorship of I.P.; she received a Summer Undergraduate Research Fellowship via the NIEHS grant [ R25ES027684 ] from the American Society of Pharmacology and Experimental Therapeutics (ASPET) and the Department of Pharmacology and Nutritional Sciences of the University of Kentucky (USA).

Funding Information:
We thank George M. Mussman for technical support, Rene Donahue for providing the db/db mice, Catherine Hagan for valuable veterinarian advice, and Ed Leiter and Juergen Naggert for enriching scientific discussions. We also thank Dr. Thomas Wilkop, from the Light Microscopy Core at the University of Kentucky, Lexington KY for imaging services and valuable advice regarding the SIM experiment. This research was supported by the Biospecimen Procurement & Translational Pathology Shared Resource Facility of the University of Kentucky Markey Cancer Center [P30CA177558].

Publisher Copyright:
© 2022 Elsevier GmbH

Keywords

  • Heterogeneity
  • Islet
  • TallyHo
  • Type 2 diabetes
  • β-cell identity

ASJC Scopus subject areas

  • Histology
  • Cell Biology

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