Inhibiting class IIa histone deacetylases may represent a new therapeutic approach to treating type 2 diabetes, according to researchers at the Salk Institute for Biological Sciences in La Jolla, CA. Building on the results of previous boinformatics screens, a series of in vitro and in vivo studies by Reuben J. Shaw, Ph.D., and colleagues, led to the finding that blocking three HDACs in mouse models of diabetes allows restoration of blood glucose levels.
The Salk Institute research is described in Nature in a paper titled “Class IIa Histone Deacetylases Are Hormone-Activated Regulators of FOXO.”
Insulin produced in response to a meal triggers decreased glucose production by the liver and storage of glucose by muscle and fat cells, explain Dr. Shaw and colleagues. Conversely, during fasting, increased levels of glucagon trigger the liver to increase glucose production so that blood sugar levels can be maintained. Gluconeogenesis is largely regulated at the transcriptional level of rate-limiting enzymes including glucose-6-phophatase (G6Pase) via the hormonal modulation of transcription factors including the FOXO family in the liver.
The researchers had previously identified HDACs as direct targets for AMPK, the target of the type 2 diabetes drug metformin. Building on these findings, they carried out a series of in vitro studies demonstrating that in response to glucagon, class IIa HDACs in the cytoplasm are rapidly dephosphorylated and translocated to the nucleus, where they where they associate with G6Pase, leading to activation of FOXO, a key metabolic regulator that triggers glucose production and which prior research has shown is normally shut down by insulin production. Blocking the class IIa HDACs in mouse liver cells resulted in inhibition of FOXO target genes, lowering blood glucose and resulting in increased glycogen storage.
When they then simultaneously blocked the production of HDAC4, HDAC5, and HDAC7 using shRNAs in mice, the animals increased production of glucagon and decreased glucose production. The team then looked to see whether inhibiting HDAC4/5/7 function would be enough to restore glucose homeostasis in different mouse models of type 2 diabetes. As expected, they found that HDAC expression in these diabetic mouse models led to FOXO hyperacetylation, decreased expression of FOXO target genes, and reduction of hyperglycemia.
“Perhaps most unexpectedly, the results here suggest that class I and class IIa HDACs in the liver of type 2 diabetic rodent models actively contribute to the hyperglycemic phenotype of these animals,” the authors note. They suggest that given the dramatic effect of knocking out specific HDACs in reducing glucose levels in diabetic mice, “these results suggest that small molecules that inhibit class I/IIa HDACs may be useful as diabetes therapeutics. Given the intense ongoing effort in the pharmaceutical industry to develop HDAC inhibitors as anticancer agents, their potential utility for the treatment of metabolic disease warrants investigation.”
Dr. Shaw adds, “The key will be to specifically block HDACs involved in glucose control. But the fact that gluconeogenesis takes place in the liver makes this task easier as most drugs sooner or later travel to the liver once they hit the bloodstream.”