Reciprocal modulation of adult beta cell maturity by activin A and follistatin

• Published in: Diabetologia 2010-08, Vol.53 (8), p.1680-1689
• Main Authors: Szabat, M, Johnson, J. D, Piret, J. M
• Format: Article
• Language: English
• Subjects: Activins - metabolism; Activins - pharmacology; Animals; Beta cells; Biological and medical sciences; Cell Count; Cell Proliferation - drug effects; Cells; Cells, Cultured; Design of experiments; Diabetes; Diabetes. Impaired glucose tolerance; Differentiation; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Flow Cytometry; Follistatin - metabolism; Follistatin - pharmacology; Gene expression; Growth factors; Human and mouse islets; Human Physiology; Humans; Infections; Insulin; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Internal Medicine; Laboratories; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; MIN6; PDX1; Physiology; Proteins; Reporter lentivirus; Reverse Transcriptase Polymerase Chain Reaction
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-010-1758-0

Aims/hypothesis The functional maturity of pancreatic beta cells is impaired in diabetes mellitus. We sought to define factors that can influence adult beta cell maturation status and function. Methods MIN6 cells labelled with a Pdx1 monomeric red fluorescent protein-Ins1 enhanced green fluorescent protein dual reporter lentivirus were used to screen candidate growth and/or differentiation factors using image-based approaches with confirmation by real-time RT-PCR and assays of beta cell function using primary mouse islets. Results Activin A strikingly decreased the number of mature beta cells and increased the number of immature beta cells. While activins are critical for pancreatic morphogenesis, their role in adult beta cells remains controversial. In primary islets and MIN6 cells, activin A significantly decreased the expression of insulin and several genes associated with beta cell maturity (e.g. Pdx1, Mafa, Glut2 [also known as Slc2a2]). Genes found in immature beta cells (e.g. Mafb) tended to be upregulated by activin A. Insulin secretion was also reduced by activin A. In addition, activin A-treated MIN6 cells proliferated faster than non-treated cells. The effects of endogenous activin A on beta cells were completely reversed by exogenous follistatin. Conclusions/interpretation These results suggest that autocrine and/or paracrine activin A signalling exerts a suppressive effect on adult beta cell maturation and function. Thus, the maturation state of adult beta cells can be modulated by external factors in culture. Interventions inhibiting activin or its signalling pathways may improve beta cell function. Understanding of maturation and plasticity of adult pancreatic tissue has significant implications for islet regeneration and for in vitro generation of functional beta cells.