Episodic β-cell death and dedifferentiation during diet-induced obesity and dysglycemia in male mice

Sarah A. Tersey, Esther M. Levasseur, Farooq Syed, Thomas B. Farb, Kara S. Orr, Jennifer B. Nelson, Janice L. Shaw, Krister Bokvist, Kieren J. Mather, Raghavendra G. Mirmira

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Loss of functional islet β-cell mass through cellular death or dedifferentiation is thought to lead to dysglycemia during the progression fromobesity to type 2 diabetes. To assess these processes in amousemodel of obesity, we performed measures of circulating cell-free differentially methylated insulin II (Ins2) DNA as a biomarker of β-cell death and aldehyde dehydrogenase 1 familymemberA3 (ALDH1A3) and forkhead box 01 (Foxo1) immunostaining asmarkers ofβ-cell dedifferentiation. Eight-week-old, C57BL/6J micewere fed a low-fatdiet (LFD; 10% kcal from fat) or a high-fat diet (HFD; 60% kcal from fat) and were followed longitudinally for up to 13 wk to measure glycemic control and β-cellmass, death, and dedifferentiation. Compared with LFD controls, β-cell mass increased during the feeding period in HFD animals, and statistically greater β-cell death (unmethylated Ins2) was detectable at 2 and 6 wk after diet initiation. Those times correspond to periods when significant step increases in fasting glucose and glucose intolerance, respectively, were detected. ALDH1A3 and Foxo1 immunostaining of the pancreas revealed evidence of β-cell dedifferentiation by 13 wk when fed an HFD, but not in LFD controls. In conclusion, early episodic β-cell death may be a feature of cellular turnover correlated with changes in glycemia during β-cell mass accrual in obesity, whereas β-cell dedifferentiation may be a feature seen later in established disease.

Original languageEnglish (US)
Pages (from-to)6150-6158
Number of pages9
JournalFASEB Journal
Volume32
Issue number11
DOIs
StatePublished - Nov 2018

Keywords

  • Cell dedifferentiation
  • Glucose intolerance
  • Islet

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Tersey, S. A., Levasseur, E. M., Syed, F., Farb, T. B., Orr, K. S., Nelson, J. B., Shaw, J. L., Bokvist, K., Mather, K. J., & Mirmira, R. G. (2018). Episodic β-cell death and dedifferentiation during diet-induced obesity and dysglycemia in male mice. FASEB Journal, 32(11), 6150-6158. https://doi.org/10.1096/fj.201800150RR