Can Epigenetics Help Cure Diabetes and Obesity?
Sunitha Meruvu1, John Bowman2, Mahua Choudhury1
1Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Kingsville, TX, USA
2 Department of Pharmacy Practice, Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Kingsville, TX, USA
Obesity poses a serious burden on society, affecting more than one-third of the US population. Genetic research has failed to identify genes that predict obesity, but genome-wide association studies (GWAS) have identified regions in the genome that predispose an individual to unhealthy body fat distribution and body mass index, which are risk factors for type 2 diabetes. These regions can be modified by epigenetic changes, and the altered epigenome is passed down to subsequent generations. Epigenetics refers to heritable changes in gene activity and expression with no change to the DNA sequence. For example, gene expression can be modified through DNA methylation and changes to histones, like methylation and acetylation. Although the changes can be passed from parent to child, epigenetic changes may also be reversible; thus, they are potential targets for therapeutic intervention as well as diagnostic or prognostic biomarkers.
A new concept in today’s medicine is the development of epidrugs or drugs that target epigenetic modifications in the treatment of diseases such as obesity and diabetes. Some of the drugs targeting epigenetic modifications are DNA methyltransferase inhibitors (DNMTis), histone deacetylase inhibitors (HDACis), histone acetyltransferase inhibitors (HATis), protein arginine methyltransferase inhibitors (PRMTis), histone demethylating inhibitors (HDMis), and sirtuin-activating compounds (STACs). A significant increase in recent publications on epigenetics mirrors the increased interest in epigenetic drugs. Our recent review1 gives an update on the drugs with epigenetic properties which are already in the marketplace for other diseases and which are repurposed as epidrugs for the potential treatment of diabetes and obesity.
HDACis have emerged as new drugs in the treatment of diabetes and obesity because of the role they play in β-cell functions, insulin resistance, and adipogenesis. Among HDACis, valproic acid (an antiepileptic drug) and sodium phenylbutyrate (used in urea cycle disorders) are already in clinical trials for diabetes and obesity. A natural polyphenol, curcumin is an HATi and has been widely used as a spice in Asia for thousands of years (turmeric). A Phase IV clinical study on curcumin in a prediabetic population significantly lowered the number of individuals who would have otherwise developed type II diabetes making it a highly promising interventional drug. Tranylcypromine is an FDA-approved drug which is used to treat major depressive disorder. It is now known to be a histone demethylase inhibitor targeting lysine-specific demethylase (LSD1 and LSD2). LSD1 inhibition has been shown to enhance energy metabolism in high-fat diet conditions. Therefore, there is a potential to repurpose this antidepressant drug for the treatment of diabetes and obesity. Another natural polyphenol, resveratrol is found in red wine, grapes, and chocolate. It activates Sirtuin 1 which is an NAD-dependent HDAC. Sirtuins have been implicated in aging, inflammation, and stress resistance, as well as energy metabolism. Resveratrol has been extensively tested in humans for diabetes and obesity. A recent meta-analysis of 11 clinical trials concluded that resveratrol consumption significantly improved glucose control and insulin sensitivity in patients with type 2 diabetes without any side-effects in nondiabetic participants. DNA methyltransferase regulation has also been shown to have a role in the development of diabetes. Hydralazine and procainamide (hypertensive and antiarrhythmic drugs respectively) are DNMTis, which are currently in clinical trials for diabetes treatment.
In conclusion, epigenetic drugs are new to the treatment of various diseases, especially obesity, and its complications. Several epigenetic drugs are now being tested in clinical trials for the treatment of diabetes and obesity. The Choudhury lab at Texas A&M Health Science Center is currently working on detection of early epigenetic biomarkers in children having a familial history of diabetes and obesity. Our main goal is to identify the early onset of obesity and diabetes and control this metabolic disease through epigenetics. Our knowledge of epigenetic modifications in diabetes and obesity is still incomplete. However, epigenetic drugs and epigenetic biomarkers represent a novel approach to prevention and treatment.
Arguelles AO, Meruvu S, Bowman JD, & Choudhury M (2015). Are epigenetic drugs for diabetes and obesity at our door step? Drug discovery today PMID: 26697737