Glucose-mediated insulin secretion is improved in FHL2-deficient mice and elevated FHL2 expression in humans is associated with type 2 diabetes

J.J. Habibe, M.P. Clemente-Olivo, T.P.M. Scheithauer, E. Rampanelli, H. Herrema, M. Vos, A. Mieremet, M. Nieuwdorp, D.H. van Raalte, E.C. Eringa, C.J.M. de Vries*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Aims/hypothesis The general population is ageing, involving an enhanced incidence of chronic diseases such as type 2 diabetes. With ageing, DNA methylation of FHL2 increases, as well as expression of the four and a half LIM domains 2 (FHL2) protein in human pancreatic islets. We hypothesised that FHL2 is actively involved in glucose metabolism.Methods Publicly available microarray datasets from human pancreatic islets were analysed for FHL2 expression. In FHL2-deficient mice, we studied glucose clearance and insulin secretion. Gene expression analysis and glucose-stimulated insulin secretion (GSIS) were determined in isolated murine FHL2-deficient islets to evaluate insulin-secretory capacity. Moreover, knockdown and overexpression of FHL2 were accomplished in MIN6 cells to delineate the underlying mechanism of FHL2 function.Results Transcriptomics of human pancreatic islets revealed that individuals with elevated levels of HbA(1c) displayed increased FHL2 expression, which correlated negatively with insulin secretion pathways. In line with this observation, FHL2-deficient mice cleared glucose more efficiently than wild-type littermates through increased plasma insulin levels. Insulin sensitivity was comparable between these genotypes. Interestingly, pancreatic islets isolated from FHL2-deficient mice secreted more insulin in GSIS assays than wild-type mouse islets even though insulin content and islet size was similar. To support this observation, we demonstrated increased expression of the transcription factor crucial in insulin secretion, MAF BZIP transcription factor A (MafA), higher expression of GLUT2 and reduced expression of the adverse factor c-Jun in FHL2-deficient islets. The underlying mechanism of FHL2 was further delineated in MIN6 cells. FHL2-knockdown led to enhanced activation of forkhead box protein O1 (FOXO1) and its downstream genes such as Mafa and Pdx1 (encoding pancreatic and duodenal homeobox 1), as well as increased glucose uptake. On the other hand, FHL2 overexpression in MIN6 cells blocked GSIS, increased the formation of reactive oxygen species and increased c-Jun activity.Conclusions/interpretation Our data demonstrate that FHL2 deficiency improves insulin secretion from beta cells and improves glucose tolerance in mice. Given that FHL2 expression in humans increases with age and that high expression levels of FHL2 are associated with beta cell dysfunction, we propose that enhanced FHL2 expression in elderly individuals contributes to glucose intolerance and the development of type 2 diabetes.Data availability The human islet microarray datasets used are publicly available and can be found on https://www.ncbi.nlm.nih.gov/geo/.
Original languageEnglish
Article numbers00125-022-05750-1
Pages (from-to)1721-1733
Number of pages13
JournalDiabetologia
Volume65
Issue number10
Early online date8 Jul 2022
DOIs
Publication statusPublished - Oct 2022

Keywords

  • FHL2
  • Four and a half LIM domains protein 2
  • Gene expression
  • Glucose tolerance test
  • Glucose-stimulated insulin secretion
  • GSIS
  • GTT
  • MIN6
  • Pancreatic islets
  • ONLY PROTEIN FHL2
  • TRANSCRIPTION FACTORS
  • GENES
  • MAFA
  • COACTIVATOR
  • REGULATOR
  • ISLETS

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