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Study in Africa Yields New Diabetes Gene

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Francis Collins Volunteering in Nigeria
Caption: Volunteering my medical services in Nigeria three decades ago inspired me to learn more about type 2 diabetes in Africa and beyond. Credit: Margaret Collins

When I volunteered to serve as a physician at a hospital in rural Nigeria more than 25 years ago, I expected to treat a lot of folks with infectious diseases, such as malaria and tuberculosis. And that certainly happened. What I didn’t expect was how many people needed care for type 2 diabetes (T2D) and the health problems it causes. Surprisingly, these individuals were generally not overweight, and the course of their illness seemed different than in the West.

The experience inspired me to join with other colleagues at Howard University, Washington, DC, to help found the Africa America Diabetes Mellitus (AADM) study. It aims to uncover genomic risk factors for T2D in Africa and, using that information, improve understanding of the condition around the world.

So, I’m pleased to report that, using genomic data from more than 5,000 volunteers, our AADM team recently discovered a new gene, called ZRANB3, that harbors a variant associated with T2D in sub-Saharan Africa [1]. Using sophisticated laboratory models, the team showed that a malfunctioning ZRANB3 gene impairs insulin production to control glucose levels in the bloodstream.

Since my first trip to Nigeria, the number of people with T2D has continued to rise. It’s now estimated that about 8 to 10 percent of Nigerians have some form of diabetes [2]. In Africa, diabetes affects more than 7 percent of the population, more than twice the incidence in 1980 [3].

The causes of T2D involve a complex interplay of genetic, environmental, and lifestyle factors. I was particularly interested in finding out whether the genetic factors for T2D might be different in sub-Saharan Africa than in the West. But at the time, there was a dearth of genomic information about T2D in Africa, the cradle of humanity. To understand complex diseases like T2D fully, we need all peoples and continents represented in the research.

To begin to fill this research gap, the AADM team got underway and hasn’t looked back. In the latest study, led by Charles Rotimi at NIH’s National Human Genome Research Institute, in partnership with multiple African diabetes experts, the AADM team enlisted 5,231 volunteers from Nigeria, Ghana, and Kenya. About half of the study’s participants had T2D and half did not.

As reported in Nature Communications, their genome-wide search for T2D gene variants turned up three interesting finds. Two were in genes previously linked to T2D risk in other human populations. The third involved a gene that codes for ZRANB3, an enzyme associated with DNA replication and repair that had never been reported in association with T2D.

To understand how ZRANB3 might influence a person’s risk for developing T2D, the researchers turned to zebrafish (Danio rerio), an excellent vertebrate model for its rapid development. The researchers found that the ZRANB3 gene is active in insulin-producing beta cells of the pancreas. That was important to know because people with T2D frequently have reduced numbers of beta cells, which compromises their ability to produce enough insulin.

The team next used CRISPR/Cas9 gene-editing tools either to “knock out” or reduce the expression of ZRANB3 in young zebrafish. In both cases, it led to increased loss of beta cells.

Additional study in the beta cells of mice provided more details. While normal beta cells released insulin in response to high levels of glucose, those with suppressed ZRANB3 activity couldn’t. Together, the findings show that ZRANB3 is important for beta cells to survive and function normally. It stands to reason, then, that people with a lower functioning variant of ZRANB3 would be more susceptible to T2D.

In many cases, T2D can be managed with some combination of diet, exercise, and oral medications. But some people require insulin to manage the disease. The new findings suggest, particularly for people of African ancestry, that the variant of the ZRANB3 gene that one inherits might help to explain those differences. People carrying particular variants of this gene also may benefit from beginning insulin treatment earlier, before their beta cells have been depleted.

So why wasn’t ZRANB3 discovered in the many studies on T2D carried out in the United States, Europe, and Asia? It turns out that the variant that predisposes Africans to this disease is extremely rare in these other populations. Only by studying Africans could this insight be uncovered.

More than 20 years ago, I helped to start the AADM project to learn more about the genetic factors driving T2D in sub-Saharan Africa. Other dedicated AADM leaders have continued to build the research project, taking advantage of new technologies as they came along. It’s profoundly gratifying that this project has uncovered such an impressive new lead, revealing important aspects of human biology that otherwise would have been missed. The AADM team continues to enroll volunteers, and the coming years should bring even more discoveries about the genetic factors that contribute to T2D.

References:

[1] ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response. Adeyemo AA, Zaghloul NA, Chen G, Doumatey AP, Leitch CC, Hostelley TL, Nesmith JE, Zhou J, Bentley AR, Shriner D, Fasanmade O, Okafor G, Eghan B Jr, Agyenim-Boateng K, Chandrasekharappa S, Adeleye J, Balogun W, Owusu S, Amoah A, Acheampong J, Johnson T, Oli J, Adebamowo C; South Africa Zulu Type 2 Diabetes Case-Control Study, Collins F, Dunston G, Rotimi CN. Nat Commun. 2019 Jul 19;10(1):3195.

[2] Diabetes mellitus in Nigeria: The past, present and future. Ogbera AO, Ekpebegh C. World J Diabetes. 2014 Dec 15;5(6):905-911.

[3] Global report on diabetes. Geneva: World Health Organization, 2016. World Health Organization.

Links:

Diabetes (National Institute of Diabetes ad Digestive and Kidney Diseases/NIH)

Diabetes and African Americans (Department of Health and Human Services)

Why Use Zebrafish to Study Human Diseases (Intramural Research Program/NIH)

Charles Rotimi (National Human Genome Research Institute/NIH)

NIH Support: National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Minority Health and Health Disparities


Can Artificial Cells Take Over for Lost Insulin-Secreting Cells?

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artificial beta cells

Caption: Artificial beta cell, made of a lipid bubble (purple) carrying smaller, insulin-filled vesicles (green). Imaged with cryo-scanning electron microscope (cryo-SEM) and colorized.
Credit: Zhen Gu Lab

People with diabetes have benefited tremendously from advances in monitoring and controlling blood sugar, but they’re still waiting and hoping for a cure. Some of the most exciting possibilities aim to replace the function of the insulin-secreting pancreatic beta cells that is deficient in diabetes. The latest strategy of this kind is called AβCs, short for artificial beta cells.

As you see in the cryo-SEM image above, AβCs are specially designed lipid bubbles, each of which contains hundreds of smaller, ball-like vesicles filled with insulin. The AβCs are engineered to “sense” a rise in blood glucose, triggering biochemical changes in the vesicle and the automatic release of some of its insulin load until blood glucose levels return to normal.

In recent studies of mice with type 1 diabetes, researchers partially supported by NIH found that a single injection of AβCs under the skin could control blood glucose levels for up to five days. With additional optimization and testing, the hope is that people with diabetes may someday be able to receive AβCs through patches that painlessly stick on their skin.


Creative Minds: Potential Diabetes Lessons from Binge-Eating Snakes

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Secor with a snake

Stephen Secor/Credit: Secor Lab

Many people would do just about anything to avoid an encounter with a snake. Not Stephen Secor. Growing up in central New York State, Secor was drawn to them. He’d spend hours frolicking through forest and field, flipping rocks and hoping to find one. His animal-loving mother encouraged him to keep looking, and she even let him keep a terrarium full of garter snakes in his bedroom. Their agreement: He must take good care of them—and please make sure they don’t get loose.

As a teen, Secor considered a career as a large-animal veterinarian. But a college zoology course led him right back to his fascination with snakes. Now a professor at the University of Alabama, Tuscaloosa, he’s spent 25 years trying to understand how some snakes, such as the Burmese python shown above, can fast for weeks or even months, and then go on a sudden food binge. Secor’s interest in the feast-or-famine digestive abilities of these snakes has now taken an unexpected turn that he never saw coming: a potential treatment to help people with diabetes.


Snapshots of Life: A Van Gogh Moment for Pancreatic Cancer

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Pancreatic Cancer

Credit: Nathan Krah, University of Utah,
Salt Lake City

Last year, Nathan Krah sat down at his microscope to view a thin section of pre-cancerous pancreatic tissue from mice. Krah, an MD/PhD student in the NIH-supported lab of Charles Murtaugh at the University of Utah, Salt Lake City, had stained the tissue with three dyes, each labelling a different target of interest. As Krah leaned forward to look through the viewfinder, he fully expected to see the usual scattershot of color. Instead, he saw enchanting swirls reminiscent of the famous van Gogh painting, The Starry Night.

In this eye-catching image featured in the University of Utah’s 2016 Research as Art exhibition, red indicates a keratin protein found in the cytoskeleton of precancerous cells; green, a cell adhesion protein called E-cadherin; and yellow, areas where both proteins are present. Finally, blue marks the cell nuclei of the abundant immune cells and fibroblasts that have expanded and infiltrated the organ as a tumor is forming. Together, they paint a fascinating new portrait of pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer.


Progress Toward Stem Cell Treatment for Diabetes

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patient-derived pancreatic beta cells

Caption: Insulin-containing pancreatic beta cells (green) derived from human stem cells. The red cells are producing another metabolic hormone, glucagon, that regulates blood glucose levels. Blue indicates cell nuclei.
Credit: The Salk Institute for Biological Studies, La Jolla, CA

In people with type 1 diabetes, the immune system kills off insulin-producing beta cells of the pancreas needed to control the amount of glucose in their bloodstream. As a result, they must monitor their blood glucose often and take replacement doses of insulin to keep it under control. Transplantation of donated pancreatic islets—tissue that contains beta cells—holds some promise as a therapy or even a cure for type 1 diabetes. However, such donor islets are in notoriously short supply [1]. Recent advances in stem cell research have raised hopes of one day generating an essentially unlimited supply of replacement beta cells perfectly matched to the patient to avoid transplant rejection.

A couple of years ago, researchers took a major step toward this goal by coaxing induced pluripotent stem cells (iPSCs), which are made from mature human cells, to differentiate into cells that closely resembled beta cells. But a few things were troublesome. The process was long and difficult, and the iPSC-derived cells were not quite as good at sensing glucose and secreting insulin as cells in a healthy person. They also looked and, in some ways, acted like beta cells, but were unable to mature fully in the lab. Now, an NIH-funded team has succeeded in finding an additional switch that enables iPSC-derived beta cells to mature and produce insulin in a dish—a significant step toward moving this work closer to the clinical applications that many diabetics have wanted.


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