Trichostatin A affects the secretion pathways of beta and intestinal endocrine cells

Abstract

Histone deacetylase inhibitors (HDACi) were recently identified as having significant clinical potential in reversing β-cell functional inhibition caused by inflammation, a shared precursor of Type 1 and Type 2 diabetes. However, HDACi are highly complex and little is known of their direct effect on important cell secretion pathways for blood glucose regulation. The aims of the present study were to investigate the effect of HDACi on insulin secretion from β-cells, GLP-1 secretion from L-cells, and recombinant insulin secretion from engineered L-cells. The β-cell line βTC-tet, L-cell line GLUTag, or recombinant insulin-secreting L-cell lines were exposed to Trichostatin A for 24 hours. Effects on insulin or GLP-1 mRNA, intracellular protein content, processing efficiency, and secretion were measured by real-time PCR, ELISA, and radioimmunoassay. HDACi increased secretion per viable cell in a dose-dependent manner for all cell types. Effects on mRNA levels were variable, but enhanced intracellular polypeptide content and secretion were comparable among cell types. Enhanced recombinant insulin secretion was sustained for seven days in alginate microencapsulated L-cells. HDACi enhances β- and L-cell secretion fluxes in a way that could significantly improve blood glucose regulation in diabetes patients and holds potential as a novel method for enhancing insulin-secreting non-β or β-cell grafts.

HDAC7 is overexpressed in human diabetic islets and impairs insulin secretion in rat islets and clonal beta cells

“…Insulin secretion was also measured in transfected clonal beta cells at 2.8 and 16.7 mmol/l glucose levels in a secretion assay buffer (SAB) with normal (5.9 mmol/l) as well as elevated (35 mmol/l) K + concentrations, as previously described [ 15 ]. In addition, two HDAC inhibitors, MC1568 (1 μmol/l; Sigma-Aldrich) [ 16 ] and trichostatin A (TSA) (0.625 μmol/l; Sigma-Aldrich) [ 17 ] were added to the culture medium 24 h before secretion experiments, as indicated. Insulin was measured in the supernatant fraction using an insulin RIA (Siemens Diagnostics, Erlangen, Germany) or insulin ELISA and normalised to total protein, as determined by a bicinchoninic acid assay (Thermo Scientific).…”

A peripheral blood transcriptomic signature predicts autoantibody development in infants at risk of type 1 diabetes

“…Such agents could be repurposed or used to develop new therapeutic strategies for future prevention of diabetes in high-risk children. Twenty-three potentially novel drugs were identified, and the capacity of drugs such as trichostatin A and sodium phenylbutyrate to modulate autoimmunity, diabetes onset, or insulin metabolism has previously been suggested (22,42,43). The top hit was monorden (radicicol), which inhibits heat shock protein 90 (Hsp90), a molecular chaperone responsible for polypeptide maturation, rematuration, and folding of denatured proteins (44).…”

High dose of histone deacetylase inhibitors affects insulin secretory mechanism of pancreatic beta cell line

“…Recently, HDACis have been used clinically as anticancer drugs (Manal et al 2016;Newbold 2016). It has been reported that HDACis revert cytokine-induced beta cell toxicity (Larsen et al 2007;Susick et al 2008;Lundh et al 2012), improve insulin resistance (Christensen et al 2011;Lundh et al 2015), enhance insulin secretion (Tiernan et al 2015), and stimulate pancreatic beta cell proliferation (Khan and Jena 2014;Plaisance et al 2014). Th erefore, HDACis are considered to be possible anti-diabetic drugs (Christensen et al 2011; Khan and Jena 2015;Sharma and Taliyan 2016).…”