Adaptive β-Cell Neogenesis in the Adult Mouse in Response to Glucocorticoid-Induced Insulin Resistance

Abstract

Both type 1 and type 2 diabetes are characterized by deficient insulin secretion and decreased b-cell mass. Thus, regenerative strategies to increase b-cell mass need to be developed. To characterize mechanisms of b-cell plasticity, we studied a model of severe insulin resistance in the adult mouse and defined how b-cells adapt. Chronic corticosterone (CORT) treatment was given to adult mice and led to rapid insulin resistance and adaptive increased insulin secretion. Adaptive and massive increase of b-cell mass was observed during treatment up to 8 weeks. b-Cell mass increase was partially reversible upon treatment cessation and reinduced upon subsequent treatment. b-Cell neogenesis was suggested by an increased number of islets, mainly close to ducts, and increased Sox9 and Ngn3 mRNA levels in islets, but lineagetracing experiments revealed that neoformed b-cells did not derive from Sox9-or Ngn3-expressing cells. CORT treatment after b-cell depletion partially restored b-cells. Finally, b-cell neogenesis was shown to be indirectly stimulated by CORT because serum from CORT-treated mice increased b-cell differentiation in in vitro cultures of pancreatic buds. Altogether, the results present a novel model of b-cell neogenesis in the adult mouse and identify the presence of neogenic factors in the serum of CORT-treated mice.

RETRACTED: Roles of Epigenetic Modifications in the Differentiation and Function of Pancreatic β-Cells

“…Any abnormality in the epigenetic regulatory mechanism will affect chromatin structure and gene expression, leading to the occurrence of a variety of diseases (Nilsson et al, 2018 ; Li S. et al, 2019 ; Perez and Lehner, 2019 ). Epigenetic changes are important regulatory mechanisms of islet β cell function and play irreplaceable roles in the normal physiological function of pancreatic β cells and insulin-secreting cells and apoptosis (Courty et al, 2019 ; Gong and Jiang, 2020 ; Makkar et al, 2020 ). There is no doubt that epigenetics research already becomes the focus of the study of pancreatic β cells in recent years.…”

Chronic hypercortisolism causes more persistent visceral adiposity than HFD-induced obesity

“…This insulin sensitivity impairment after recovery period was probably due, at least in part, to the persistently increased WAT and lipid content in skeletal muscle (Geer et al 2014, Hamrick et al 2016. Moreover, it is worth noting that recent data from studies using the same adult mice model of CS report a marked positive effect on β-cell mass until 4 weeks after remission of hypercortisolism (Courty et al 2019), despite the toxic effects due to GC previously observed in vitro (Lambillotte et al 1997, Rafacho et al 2014. Compared with CORT, HFD treatment induced glucose intolerance and insulin resistance, which fits with the increased adiposity and lipid content in liver and skeletal muscle (Winzell et al 2007, Montgomery et al 2017.…”

The difference between steroid diabetes mellitus and type 2 diabetes mellitus: a whole-body 18F-FDG PET/CT study

“…In clinical studies, Van et al [8] found that after prednisolone treatment, there was an impaired glucose tolerance, reduced C peptide secretion stimulated by arginine, and islet cell dysfunction in healthy volunteers. However, some studies reported that islet β cell function and mass increased following glucocorticoid treatment, due to the body's compensatory effect [9,10]. Skeletal muscle is the main organ involved in insulin-mediated glucose uptake (> 80%).…”