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

Acta Histochem. 2022 Oct;124(7):151940. doi: 10.1016/j.acthis.2022.151940. Epub 2022 Aug 12.

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.

Keywords: Heterogeneity; Islet; TallyHo; Type 2 diabetes; β-cell identity.

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2* / genetics
  • Glucagon / metabolism
  • Glucose / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin-Secreting Cells* / metabolism
  • Male
  • Mice
  • Transcription Factors / metabolism
  • Vimentin / metabolism

Substances

  • Insulin
  • Transcription Factors
  • Vimentin
  • Glucagon
  • Glucose