Giacomini to lead largest study of genetic, ethnic differences in effectiveness of leading diabetes drug

Giacomini to lead largest study of genetic, ethnic differences in effectiveness of leading diabetes drug

In people with type 2 diabetes, the body is less able to use the hormone insulin to regulate blood sugar. The disease affects 350 million patients globally—including 29 million in the United States, where it is the leading cause of blindness, kidney failure, and non-accident-related amputations.

Metformin is the most widely used initial medication for controlling blood sugar (glucose) in type 2 diabetes and is one of the most prescribed drugs worldwide. But more than a third of patients do not achieve acceptable blood glucose control from the drug. Studies to date have found major differences among ethnic groups in terms of how the body processes the drug and in its effectiveness. These studies also show that genetic factors affect metformin response.

Now UCSF School of Pharmacy faculty member Kathy Giacomini, PhD, will lead a four-year, $3 million study funded by National Institutes of Health (NIH) to systematically identify the genetic variations underlying differences in metformin response among patients and ethnic groups. The study will also determine how those variations cause the altered drug response.

The new study—the largest to examine the genetics of metformin response—seeks to discover predictive biomarkers to determine in advance how effective this first-line drug would be for a particular patient. This will allow for more rational prescribing and more precise, effective diabetes treatment.

Project co-investigators are Jose Florez, MD, PhD, a faculty member of Harvard Medical School, and Monique Hedderson, PhD, a research scientist at the Kaiser Permanente Northern California Division of Research.

Research to include diverse patient populations

To date, there has been only a single published study in which the complete genetic blueprints (genomes) of large groups of patients with varying responses to metformin were analyzed and compared (i.e., a genome-wide association study), and that research involved only patients of European descent.

The Giacomini-led study will analyze the genomes of two large multi-ethnic groups of patients who have been prescribed metformin and have corresponding medical records showing individuals’ blood glucose response:

  • 15,000 Northern California Kaiser Permanente patients, who have agreed to participate in the health plan’s Research Program on Genes, Environment, and Health and have contributed their genetic data as well as information about health conditions, lifestyle factors, and environmental exposures
  • About 10,000 patients in the Metformin Genetics Consortium, an international consortium that includes multiple groups of patients from Europe and the United States who are taking metformin

Zeroing in on genetic variants and mechanisms altering drug response

Researchers in the Giacomini Lab will take a multi-tier approach—first using their genome-wide studies to identify the variations underlying differences in metformin response, then carrying out more detailed analyses (resequencing) to determine specific differences that alter relevant gene function (rare causal variants).

Scientists here will then engineer those variants into cells—mostly from the liver, where metformin acts to reduce glucose production, as well as from the kidneys, where the drug is removed from the blood and excreted in urine. They will then perform experiments to determine which of those specific variants significantly alter the engineered cells’ response to metformin (functional variants)—and how they do so.

Finally, study collaborators at Massachusetts General Hospital will conduct clinical studies to further confirm the effects of the discovered gene variants in patients taking metformin and to understand the mechanisms by which those genetic differences translate into differences in drug response.

Previous findings: transporters and proteins that regulate genes

The Giacomini Lab regularly focuses on the role of transporters—proteins in cell membranes that regulate the passage of molecules, including drugs, into and out of cells—and how genetic variations may alter their activity and thus patients’ responses to drugs.

In previously published research, Giacomini and collaborators found variations in transporters in liver and kidney cells that were associated with differences in metformin’s therapeutic effects and its uptake by the kidneys and subsequent excretion from the body (clearance) in urine.

diagram of transporters

Illustration of liver (top left) and kidney nephron (which filters blood, excretes urine; bottom left) with transporter proteins (shown as blue tubes) in membranes of the organs’ cells. These transporters have been identified as affecting the body’s response to metformin and the drug’s clearance.

In addition, the scientists found “upstream” genetic differences. For example, transcription factors are protein molecules that help to turn genes on and off. The research discovered variations in genes that generate (express) transcription factors that modulate genes that, in turn, express metformin-relevant transporters, and those variations correlated with differences in drug response and clearance rates.

The Giacomini Lab is based in the Department of Bioengineering and Therapeutic Sciences, a joint department of the UCSF Schools of Pharmacy and Medicine.
 


About the School: The UCSF School of Pharmacy is a premier graduate-level academic organization dedicated to improving health through precise therapeutics. It succeeds through innovative research, by educating PharmD health professional and PhD science students, and by caring for the therapeutics needs of patients while exploring innovative new models of patient care. The School was founded in 1872 as the first pharmacy school in the American west. It is an integral part of UC San Francisco, a leading university dedicated to promoting health worldwide.