Genetic variation influences effectiveness of anti-diabetic drug

A study shows that small person-to-person variations in DNA can have a big effect on genes that control how we respond to certain drugs.

By showing for the first time that the effectiveness of an anti-diabetic drug depends on small, natural differences in DNA among individuals, researchers highlight the need to tailor some disease treatments to individual patients.

Their study shows that small variations in DNA sequences - something as small as a single-letter change - can have a big effect on switches that control genes that determine how cells and proteins respond to drugs.
The DNA sequences where the variations occur do not have to be in the same place as the coding genes they affect - they can even be found in the so-called "dark matter" or non-coding part of the genome.

The team - including senior author Mitchell Lazar, professor of medicine and genetics at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia - describes the work that led to these findings in the journal Cell.

The researchers aim to use the discovery to develop personalized approaches to treat diabetes and other metabolic disorders.

For their study, Prof. Lazar and colleagues focused on the nuclear receptor PPAR-gamma. This fat cell molecule is the target of a class of type 2 diabetes drugs called thiazolidinediones (TZDs).

DNA differences influence switch-activating ability of PPAR-gamma, TZDs

TZDs are the only diabetes drugs that target fat cells and boost the patient's own response to insulin. But they have recently fallen into disuse because they can give rise to side effects like bone loss and edema, and there have also been reports of raised risk of bladder cancer and heart attack.

Also - and this point is particularly relevant to the findings - around 20% of patients with type 2 diabetes fail to improve their control of the disease on TZDs.

PPAR-gamma activates certain genes in a fat cell, resulting in the storage of fat and changes in hormone levels. It does this by binding to DNA at the switches that affect these genes.

In their study, the researchers show that natural genetic differences in the DNA of the switches - which often reside in the "dark matter" of the genome that does not contain the code for making proteins - can influence the effectiveness of PPAR-gamma and TZDs as switch activators.
The team used several experiments to establish these findings - at first in mice and then in human fat tissue from obese bariatric surgery patients. They also referred to genome-wide association studies (GWAS) to supplement and confirm some of the findings.

Study increases understanding in 'personalized pharmacogenomics'

The team also found different variations in DNA sequences in the PPAR-gamma switches are linked to different areas of disease risk. For example, one variation is linked to blood fats - including HDL ("good" cholesterol) and triglycerides. Another is linked to type 2 diabetes, while others are linked to high blood pressure and waist-hip ratio (a measure of body shape in obesity).

All these risk areas form a cluster known as the "metabolic syndrome."

The researchers say the study has implications beyond PPAR-gamma and TZDs. Prof. Lazar notes that 20% of all prescriptions are for drugs that target nuclear receptor proteins related to PPAR-gamma, such as thyroid hormone and steroids.

The fact that a person's genetic makeup can determine how they respond to different drugs has spurred a new field called "personalized pharmacogenomics." Prof. Lazar explains how their findings increases understanding in this field:

"Our study provides proof-of-concept that naturally occurring regulatory genetic variation can affect nuclear receptor-mediated gene activation and, more generally, drug response in living animals.
This has special significance for TZDs, which have powerful anti-diabetic effects but limited clinical utility due to non-response, side effects, and adverse events."

The researchers suggest approaches like the ones they used in their study will one day be used as part of precision medicine to predict which patients are most likely to benefit from drugs like TZDs.

Funding for the study came from the National Institute of Diabetes and Digestive and Kidney Diseases and the JPB Foundation.

Medical News Today recently learned of a new screening tool that has discovered a potential new type 2 diabetes drug. The scientists that developed the screening tool say the drug acts on a key pathway in the "endoplasmic reticulum" of cells which, when stressed, leads to insulin resistance.

Written by Catharine Paddock PhD
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