News & analysis at the convergence of health, science, technology and innovation
The Research Engine

Unlocking the genetic links for Type 2 diabetes and heart disease

Brown University epidemiologist Simin Liu and his team of researchers identify similar pathways, specific driver genes that may connect the diseases

Photo by Richard Asinof

Simin Liu, a professor of Epidemiology and Medicine at Brown University, has conducted breakthrough research that identifies the similar genetic pathways and key driver genes that are shared by Type 2 diabetes and cardiovascular disease.

Courtesy of Simin Liu

The genetic networks identified by researcher Simin Liu and his team in a new study.

By Richard Asinof
Posted 1/19/15
The groundbreaking research by Simin Liu and his team have identified genetic drivers and similar pathways connecting Type 2 diabetes and cardiovascular disease, opening up new doors to explore the reasons behind the worldwide epidemic in obesity and diabetes in the last three decades. The next research challenge, Liu believes, is to identify potential causes disrupting the biological processes.
Can researchers identify the way that persistent endocrine disruptors in our environment and our food from pesticides interact with the genomic similarities and key driver genes identified by Liu and his team? Can Rhode Island’s Congressional delegation make securing research for this work a priority? Will glyphosate, the key herbicide used in GMO foods and seeds produced by Monsanto, ever be studied in the kind of comprehensive research being undertaken by Liu and his colleagues?
On the economic development front in Rhode Island, tremendous energy has been invested in developing the potential of the state’s food sector, focused on locally grown produce and new restaurants. The push has been on the development of new incubators for emerging food companies and products, the distribution of fresh, healthier foods to underserved populations. There have been new startups launched to look at the potential of food as medicine.
More than calamari being designated as the state’s appetizer, however, there needs to be a better understanding of the connections between poor diet, lack of exercise, too much sugar [call it white death] and high fructose corn syrup. More than developing new interventions, what’s needed is outcome-based research that quantifies the metrics for what works – and why.

PROVIDENCE – If tuberculosis was the disease of the Industrial Age, and cancer the disease of the Post-Industrial Age, then obesity and Type 2 diabetes have emerged as the epidemic of our 21st century world.

In the United States, in 2012, there were estimated to be about 29 million people with diabetes. In adults 20 and older, more than one in every 10 people had diabetes; in seniors 65 and older, the number rose to one in four.

In China, there are now estimates that some 100 million people have Type 2 diabetes, according to Simin Liu, a professor of epidemiology and medicine at Brown University.

“I would argue that diabetes is the key epidemic of our time, especially if you look at it from a global perspective,” Liu said in a recent interview with ConvergenceRI. “About 70 to 80 percent of the people who have diabetes ultimately die from heart disease, and they have a greater [likelihood to develop] a number of cancers.”

The dramatic rise in Type 2 diabetes, particularly in countries such as India and China, is related to the tremendous economic and epidemiological transitions in a short time span – only three decades, according to Liu. By contrast, in the past five or six decades, at the population level, Liu continued, “Our human genome has changed very little.”

Liu is the co-senior author of a ground-breaking new study published in the American Heart Association journal, Circulation: Cardiovascular Genetics, that identified eight molecular pathways common to both Type 2 diabetes and cardiovascular disease, as well as 10 “key driver” genes that may specifically influence both diseases.

In identifying the key driver genes, the study team also discussed how such pathways could potentially connect to the two diseases.

Axon guidance, for instance, considered important in how growing fetuses construct their nervous systems, involves processes that support beta cells in the pancreas, which is central to diabetes, according to review of the study written by Brett Smith.

“A malfunction in this pathway could make the cells far more vulnerable, having an effect on the processing of blood sugar,” Smith wrote.

The size and diversity of the cohort in the study reinforced the findings. It drew upon genetic samples and health records from some 15,000 women who were part of the Women’s Health Initiative – 8,155 black women, 3,494 Hispanic women, and 3,697 white women.

The study also pointed the way toward new follow-up research and investigations, targeting interventions to develop and test potential treatments to fix problems in the biologic mechanisms. The research also opens the door to examine the way that environmental factors – such as chemical endocrine disruptors and high-sugar diets – are changing the biology.

ConvergenceRI sat down to talk with Liu in his office to discuss the ground-breaking research and the ways that it may shape future research opportunities and new drug development strategies.

ConvergenceRI: What sets your study linking genetic pathways between diabetes and cardiovascular disease apart from previous studies?
For the first time, we tried a new approach to look at the genetic variants and their potential interactions in affecting disease development prospectively. We identified some similar genetic networks and potential key drivers for both Type 2 diabetes and cardiovascular disease.

We had several studies converge, a combination of research conducted over the past five or six years. 

We had another research paper that just came out, investigating the effect of early gene/nutrition interaction, as indicated by low-birth weight on the risk of developing diabetes later in life, due to several critical biological [interactions] in these women. 

ConvergenceRI: What was most impressive in your study was the size and diversity of the cohort involved – some 15,000 women.
The Women’s Health Initiative [created by the National Institutes of Health and the National Heart, Lung, and Blood Institute in 1993] is a long-term national health study begun more than 20 years ago. It is a major national observational study as well as home to several clinical trials.

ConvergenceRI: Can you describe why the use of material from the Women’s Health Initiative was so critical to your study?
Precisely because of the 20-year follow on; this is not just some database linkage. First of all, [there were] some very careful phenotyping – [detailing] what [the women] ate, their family history, [including levels] of physical activity.

Also, biological samples [were collected] from all these women, at the time when they were apparently healthy women. It enabled us to document what kinds of diseases they got, and to look at it in a much more controlled environment.

That’s been the general nature of the Women’s Health Initiative for the past 20 years. The overall cohort of women, in observational study alone, is about 93,000. There are more than 40,000 involved in clinical trials, from all across different ethnicities.

It allowed us to look at them and compare, according to classical risk assessment, comparing diets in relation to physical activity – important factors in predicting the future development of a whole host of diseases, including cardiovascular disease and diabetes.

ConvergenceRI: Heart disease is still the number one killer in the United States, for both men and women…
…and, in the world. Type 2 diabetes, it’s an emerging epidemic, but it’s already outdated to call it “emerging.”

I would argue that diabetes is the key epidemic of our time, especially if you look at it from a global perspective. Ultimately, 70-to-80 percent of the people who have diabetes die from heart disease. And they have a greater receptivity to a number of cancers.

We can identify the similarities across ethnicities, at the population level, in terms of the risk factors.

For our particular work, we thought: let’s look at the two diseases, cardiovascular disease and Type 2 diabetes, both as a common thing and as a distinct phenotype, to look at them together and see whether or not we could identify some shared molecular pathways, across populations. It would allow us to help understand the pathogenesis of both diseases.

At the same time, it would offer the potential for a more individualized prediction of the risk clinically, potentially identifying targets that pharmaceutical companies could use to develop new drugs.

ConvergenceRI: Are there environmental factors that could be triggering the diseases, changing the biology, increasing the incidence of both diseases, such as endocrine disruption or too much sugar in the diet?
The increase in obesity and diabetes in the last 50 to 60 years, this type of epidemic didn’t exist previously. Your question is excellent, but you’re jumping ahead.

Endocrine disrupting chemicals are indeed a very exciting area of research and study. Unfortunately, for the past two years, our research group has been banging its head against a brick wall in finding federal dollars to look at this set of hypotheses. We have not been able to get funding, despite [scoring high in reviews.]

We hoped to look at some of the more persistent disruptive chemicals in the environment, chemicals that are persistent in our body and our diet, to evaluate them, and see if there were correlations with our diseases of interest, in the metabolism, for diabetes, incorporating some of our genomic approaches.

Such research may allow us to investigate the interactive effects of all these genetic and environmental risk factors, in a comprehensive, in-depth fashion, [in order to] remove some of the potential confounding factors. 

We feel this would be the best way to move forward in the science, but unfortunately, it’s been somewhat frustrating [not to be funded.]

ConvergenceRI: Beyond environmental disruptors, is work going on specifically related to the over-abundance of sugar in the diet and the way it may change the biological pathways?
You are asking some very probing questions. The short answer is yes. Indeed, our prior work has associated some important dietary factors with cardiovascular disease and Type 2 diabetes, in several cohorts of men and women in the U.S. Our recent work in China also confirms these findings.

[But here in this paper], the focus is still trying to look at the genetic network that governs the pathogenesis, as the nutritional factors are ultimately regulated genetically in their intakes, digestion, absorption and excretion. 

We wanted to find the genetic similarities and the distinct variants in relation to the phenotypes. 

Not only the similarities, but also the potential disparities. There might be one gene for multiple effects, or multiple genes that serve the same kind of function, that would ripple across the whole genome. That’s the goal.

At the population level, our human genome has changed little during the last five or six decades in the genomic mutations we inherited from our parents.

So, obviously, what’s happening in the environment, in our way of life, such as diet, physical activity, energy balance, those have indeed changed quite significantly, no doubt about it.

At a global level, with countries like India and China, there have been tremendous economic and what we call epidemiological transitions in a short time span of only three decades.

Particularly in the case of China. They now have a 100 million people with Type 2 diabetes in China; 100 million people. [The scale of the epidemic] has coincided with their transition to reform and major revolution moving toward a market economy. The Westernization that accompanied that kind of economic transition, there’s no doubt in my mind, at the population level, can explain [the epidemic].

Back at the individual level. I think our kind of research is trying precisely to make the link all the way from the population level to the molecular level.

Which is very difficult to do, and not many research groups in the world can do that. That’s the concept behind our idea to pursue this, to understand, at a population, international and national level, and then bring it down to the individual level, at the molecular level, to see whether or not we can identify some of the significant paths.

The ways that the genetic gun is already loaded, so to speak. We want to identify what the critical drivers are, the ones that would respond to modifiable triggers from the environment.

ConvergenceRI: Have you thought about potential connections between diabetes and Alzheimers’ disease, given the potential connection between insulin and Alzheimers?
That’s a very provocative hypothesis. Yes, I think that needs to be followed up in our future work.


No comments on this story | Please log in to comment by clicking here
Please log in or register to add your comment

© | subscribe | contact us | report problem | About | Advertise

powered by creative circle media solutions

Join the conversation

Want to get ConvergenceRI
in your inbox every Monday?

Type of subscription (choose one):

We will contact you with subscription details.

Thank you for subscribing!

We will contact you shortly with subscription details.