Diabetic drug effectiveness influenced by genetics

Tiny, naturally-occurring differences in DNA can alter the effectiveness of diabetes drugs, according to new research.
The study, conducted at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, indicates that disease treatments need to be more tailored to individual patients. It seems as though a blanket approach to treatment may be ineffective.
The researchers focused on the nuclear receptor PPAR-gamma, a fat cell which is targeted by thiazolidinediones (TZDs,) a class of type 2 diabetes drug. TZDs are unique among diabetes drugs in that they boost the patients response to insulin by affecting fat cells.
However, side effects such as bone loss, as well as reports that they could be linked to heart attack and bladder cancer, have led to TZDs falling out of favour. Moreover, 20 per cent of people taking TZDs do not improve their blood glucose control while taking the drugs.
TZDs affect fat cells by activating certain genes, which changes hormone levels. This is achieved by binding to DNA at the relevant switches.
The study found that naturally-occurring genetic differences in switch DNA can prevent PPAR-gamma and TZDs from properly activating the switches.
Multiple experiments were conducted before the findings were confirmed: the first ones on mice; and the second one in human fat tissue, which was taken from bariatric surgery patients.
The research raises the problem of ineffective drug prescription. According to the findings, many prescription drugs are ineffective because of genetic variations in patients. The problem is not limited to diabetes: according to senior author Mitchell Lazar, 20 per cent of all prescription drugs target PPAR-gamma protein, such as those for thyroid hormone and steroids.
Similar findings have led to the development of “personalised pharmacogenomics,” a field which aims to tailor treatments to individuals.
“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,” wrote Lazar.
“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.”
Research like this could lead to more precise diagnoses, which will be able to tell whether or not a particular medication will benefit a particular patient.
The research was published in Cell.