The HDAC Inhibitor Butyrate Impairs ß Cell Function and Activates the Disallowed Gene Hexokinase I.

Histone deacetylase (HDAC) inhibitors such as butyrate have been reported to reduce diabetes risk and protect insulin-secreting pancreatic ß cells in animal models. However, studies on insulin-secreting cells in vitro have found that butyrate treatment resulted in impaired or inappropriate insulin secretion. Our study explores the effects of butyrate on insulin secretion by BRIN BD-11 rat pancreatic ß cells and examined effects on the expression of genes implicated in ß cell function. Robust HDAC inhibition with 5 mM butyrate or trichostatin A for 24 h in ß cells decreased basal insulin secretion and content, as well as insulin secretion in response to acute stimulation. Treatment with butyrate also increased expression of the disallowed gene hexokinase I, possibly explaining the impairment to insulin secretion, and of TXNIP, which may increase oxidative stress and ß cell apoptosis. In contrast to robust HDAC inhibition (>70% after 24 h), low-dose and acute high-dose treatment with butyrate enhanced nutrient-stimulated insulin secretion. In conclusion, although protective effects of HDAC inhibition have been observed in vivo, potent HDAC inhibition impairs ß cell function in vitro. The chronic low dose and acute high dose butyrate treatments may be more reflective of in vivo effects.

Butyrate generated by gut microbiota and its therapeutic role in metabolic syndrome.

Metabolic syndrome (MetS) and the associated incidence of cardiovascular disease and type 2 diabetes represents a significant contributor to morbidity and mortality worldwide. Butyrate, a short-chain fatty acid produced by the gut microbiome, has long been known to promote growth in farmed animals and more recently has been reported to improve body weight and composition, lipid profile, insulin sensitivity and glycaemia in animal models of MetS. In vitro studies have examined the influence of butyrate on intestinal cells, adipose tissue, skeletal muscle, hepatocytes, pancreatic islets and blood vessels, highlighting genes and pathways that may contribute to its beneficial effects. Butyrate's influences in these cells have been attributed primarily to its epigenetic effects as a histone deacetylase inhibitor, as well as its role as an agonist of free fatty acid receptors, but clear mechanistic evidence is lacking. There is also uncertainty whether results from animal studies can translate to human trials due to butyrate's poor systemic availability and rapid clearance. Hitherto, several small-scale human clinical trials have failed to show significant benefits in MetS patients. Further trials are clearly needed, including with formulations designed to improve butyrate's availability. Regardless, dietary intervention to increase the rate of butyrate production may be a beneficial addition to current treatment. This review outlines the current body of evidence on the suitability of butyrate supplementation for MetS, looking at mechanistic effects on the various components of MetS and highlighting gaps in the knowledge and roadblocks to its use in humans.

Glutamine deprivation induces metabolic adaptations associated with beta cell dysfunction and exacerbate lipotoxicity.

Studies have reported that plasma glutamine is reduced in type 2 diabetes (T2D) patients. Glutamine supplementation improves glycaemic control, however the mechanisms are unclear. Here, we evaluated in vitro the pancreatic beta cell bioenergetic and insulin secretory responses to various levels of glutamine availability, or treatment in the presence of an inhibitor of intracellular glutamine metabolism. The impact of glutamine deprivation to the pathological events induced by the saturated fatty acid palmitate was also investigated. Glutamine deprivation induced a reduction in mitochondrial respiration and increase in glucose uptake and utilization. This phenotype was accompanied by impairment in beta cell function, as demonstrated by diminished insulin production and secretion, and activation of the unfolded protein response pathway. Palmitate led to insulin secretory dysfunction, loss of viability and apoptosis. Importantly, glutamine deprivation significantly exacerbated these phenotypes, suggesting that low glutamine levels could participate in the process of beta cell dysfunction in T2D.