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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


Fundamental Knowledge of Microbes Shedding New Light on Human Health

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A laboratory researching the human microbiome
Caption: Human microbiome research requires teamwork. Kimberly Jefferson (second from left), a leader of the Multi-Omic Microbiome Study—Pregnancy Initiative, joins some of the team at Virginia Commonwealth University, Richmond. Credit: Courtesy of Kimberly Jefferson

Basic research in biology generates fundamental knowledge about the nature and behavior of living systems. It is generally impossible to predict exactly where this line of scientific inquiry might lead, but history shows that basic science almost always serves as the foundation for dramatic breakthroughs that advance human health. Indeed, many important medical advances can be traced back to basic research that, at least at the outset, had no clear link at all to human health.

One exciting example of NIH-supported basic research is the Human Microbiome Project (HMP), which began 12 years ago as a quest to use DNA sequencing to identify and characterize the diverse collection of microbes—including trillions of bacteria, fungi, and viruses—that live on and in the healthy human body.

The HMP researchers have subsequently been using those vast troves of fundamental data as a tool to explore how microbial communities interact with human cells to influence health and disease. Today, these explorers are reporting their latest findings in a landmark set of papers in the Nature family of journals. Among other things, these findings shed new light on the microbiome’s role in prediabetes, inflammatory bowel disease, and preterm birth. The studies are part of the Integrative Human Microbiome Project.

If you’d like to keep up on the microbiome and other basic research journeys, here’s a good way to do so. Consider signing up for basic research updates from the NIH Director’s Blog and NIH Research Matters. Here’s how to do it: Go to Email Updates, type in your email address, and enter. That’s it. If you’d like to see other update possibilities, including clinical and translational research, hit the “Finish” button to access Subscriber Preferences.

As for the recent microbiome findings, let’s start with the prediabetes study [1]. An estimated 1 in 3 American adults has prediabetes, detected by the presence of higher than normal fasting blood glucose levels. If uncontrolled and untreated, prediabetes can lead to the more-severe type 2 diabetes (T2D) and its many potentially serious side effects [2].

George Weinstock, The Jackson Laboratory for Genomic Medicine, Farmington, CT, Michael Snyder, Stanford University, Palo Alto, CA, and colleagues report that they have assembled a rich new data set covering the complex biology of prediabetes. That includes a comprehensive analysis of the human microbiome in prediabetes.

The data come from monitoring the health of 106 people with and without prediabetes for nearly four years. The researchers met with participants every three months, drawing blood, assessing the gut microbiome, and performing 51 laboratory tests. All this work generated millions of molecular and microbial measurements that provided a unique biological picture of prediabetes.

The picture showed specific interactions between cells and microbes that were different for people who are sensitive to insulin and those whose cells are resistant to it (as is true of many of those with prediabetes). The data also pointed to extensive changes in the microbiome during respiratory viral infections. Those changes showed clear differences in people with and without prediabetes. Some aspects of the immune response also appeared abnormal in people who were prediabetic.

As demonstrated in a landmark NIH study several years ago [2], people with prediabetes can do a lot to reduce their chances of developing T2D, such as exercising, eating healthy, and losing a modest amount of body weight. But this study offers some new leads to define the biological underpinnings of T2D in its earliest stages. These insights potentially point to high value targets for slowing or perhaps stopping the systemic changes that drive the transition from prediabetes to T2D.

The second study features the work of the Inflammatory Bowel Disease Multi’omics Data team. It’s led by Ramnik Xavier and Curtis Huttenhower, Broad Institute of MIT and Harvard, Cambridge, MA. [4]

Inflammatory bowel disease (IBD) is an umbrella term for chronic inflammations of the body’s digestive tract, such as Crohn’s disease and ulcerative colitis. These disorders are characterized by remissions and relapses, and the most severe flares can be life-threatening. Xavier, Huttenhower, and team followed 132 people with and without IBD for a year, collecting samples of their gut microbiomes every other week along with biopsies and blood samples for a total of nearly 3,000 samples.

By integrating DNA, RNA, protein, and metabolic analyses, they followed precisely which microbial species were present. They could also track which biochemical functions those microbes were capable of performing, and which functions they actually were performing over the course of the study.

These data now offer the most comprehensive view yet of functional imbalances associated with changes in the microbiome during IBD flares. These data also show how those imbalances may be altered when a person with IBD goes into remission. It’s also noteworthy that participants completed questionnaires on their diet. This dataset is the first to capture associations between diet and the gut microbiome in a relatively large group of people over time.

The evidence showed that the gut microbiomes of people with IBD were significantly less stable than the microbiomes of those without IBD. During IBD activity, the researchers observed increases in certain groups of microbes at the expense of others. Those changes in the microbiome also came with other telltale metabolic and biochemical disruptions along with shifts in the functioning of an individual’s immune system. The shifts, however, were not significantly associated with people taking medications or their social status.

By presenting this comprehensive, “multi-omic” view on the microbiome in IBD, the researchers were able to single out a variety of new host and microbial features that now warrant further study. For example, people with IBD had dramatically lower levels of an unclassified Subdoligranulum species of bacteria compared to people without the condition.

The third study features the work of The Vaginal Microbiome Consortium (VMC). The study represents a collaboration between Virginia Commonwealth University, Richmond, and Global Alliance to Prevent Prematurity and Stillbirth (GAPPS). The VMC study is led by Gregory Buck, Jennifer Fettweis, Jerome Strauss,and Kimberly Jefferson of Virginia Commonwealth and colleagues.

In this study, part of the Multi-Omic Microbiome Study: Pregnancy Initiative, the team followed up on previous research that suggested a potential link between the composition of the vaginal microbiome and the risk of preterm birth [5]. The team collected various samples from more than 1,500 pregnant women at multiple time points in their pregnancies. The researchers sequenced the complete microbiomes from the vaginal samples of 45 study participants, who gave birth prematurely and 90 case-matched controls who gave birth to full-term babies. Both cases and controls were primarily of African ancestry.

Those data reveal unique microbial signatures early in pregnancy in women who went on to experience a preterm birth. Specifically, women who delivered their babies earlier showed lower levels of Lactobacillus crispatus, a bacterium long associated with health in the female reproductive tract. Those women also had higher levels of several other microbes. The preterm birth-associated signatures also were associated with other inflammatory molecules.

The findings suggest a link between the vaginal microbiome and preterm birth, and raise the possibility that a microbiome test, conducted early in pregnancy, might help to predict a woman’s risk for preterm birth. Even more exciting, this might suggest a possible way to modify the vaginal microbiome to reduce the risk of prematurity in susceptible individuals.

Overall, these landmark HMP studies add to evidence that our microbial inhabitants have important implications for many aspects of our health. We are truly a “superorganism.” In terms of the implications for biomedicine, this is still just the beginning of what is sure to be a very exciting journey.

References:

[1] Longitudinal multi-omics of host-microbe dynamics in prediabetes. Zhou W, Sailani MR, Contrepois K, Sodergren E, Weinstock GM, Snyder M, et. al. Nature. 2019 May 29.

[2] National Diabetes Statistics Report, 2017, Center for Disease Control and Prevention (Atlanta, GA)

[3] Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Diabetes Prevention Program Research Group.Lancet Diabetes Endocrinol.2015 Nov;3(11):866-875.

[4] Multi-omics of the gut microbial ecosystem in inflammatory bowel disease. Lloyd-Price J, Arze C. Ananthakrishnan AN, Vlamakis H, Xavier RJ, Huttenhower C, et. al. Nature. 2019 May 29.

[5] The vaginal microbiome and preterm birth. Fettweis JM, Serrano MG, Brooks, JP, Jefferson KK, Strauss JF, Buck GA, et al. Nature Med. 2019 May 29.

Links:

Insulin Resistance & Prediabetes (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Crohn’s Disease (NIDDK/NIH)

Ulcerative colitis (NIDDK/NIH)

Preterm Labor and Birth: Condition Information (Eunice Kennedy Shriver National Institute of Child Health and Human Development/NIH)

Global Alliance to Prevent Prematurity and Stillbirth (Seattle, WA)

NIH Integrative Human Microbiome Project

NIH Human Microbiome Project

NIH Support:

Prediabetes Study: Common Fund; National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Human Genome Research; National Center for Advancing Translational Sciences

Inflammatory Bowel Disease Study: Common Fund; National Institute of Diabetes and Digestive and Kidney Diseases; National Center for Advancing Translational Sciences; National Institute of Human Genome Research; National Institute of Dental and Craniofacial Research

Preterm Birth Study: Common Fund; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development


Oral Insulin Delivery: Can the Tortoise Win the Race?

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Turtle shape compared to capsule shape
Caption: The African leopard tortoise’s shape inspired a new insulin-injecting “pill” (right). Credit: Alex Abramson

People with diabetes often must inject insulin multiple times a day to keep their blood glucose levels under control. So, I was intrigued to learn that NIH-funded bioengineers have designed a new kind of “pill” that may someday reduce the need for those uncomfortable shots. The inspiration for their design? A tortoise!

The new “pill”—actually, a swallowable device containing a tiny injection system—is shaped like the shell of an African leopard tortoise. In much the same way that the animal’s highly curved shell enables it to quickly right itself when flipped on its back, the shape of the new device is intended to help it land in the right position to inject insulin or other medicines into the stomach wall.

The hunt for a means to deliver insulin in pill form has been on ever since insulin injections first were introduced, nearly a century ago. The challenge in oral delivery of insulin and other “biologic” drugs—including therapeutic proteins, peptides, or nucleic acids—is how to get these large biomolecules through the highly acidic stomach and duodenum, where multiple powerful digestive enzymes reside, and into the bloodstream unscathed. Past efforts to address this challenge have met with only limited success.

In a study published in the journal Science, a team, led by Robert Langer at Massachusetts Institute of Technology, Cambridge, and Giovanni Traverso, Brigham and Women’s Hospital, Harvard Medical School, Boston, took a new approach to the problem by developing a tiny, ingestible injection system [1]. They call their pea-sized device SOMA, short for “self-orienting millimeter-scale applicator.”

In designing SOMA, the researchers knew they had to come up with a design that would orient the injection apparatus correctly. So they looked to the African leopard tortoise. They knew that, much like a child’s “weeble-wobble” toy, this tortoise can easily right its body if tipped over due to its low center of gravity and highly curved shell. With the shape of the tortoise shell as a starting point, the researchers used computer modeling to perfect their design. The final result features a partially hollowed-out, polymer-and-steel capsule that houses a tiny, spring-loaded needle tipped with compressed, freeze-dried insulin. There is also a dissolvable sugar disk to hold the needle in place until the time is right.

Here’s how it works: once a SOMA is swallowed and reaches the stomach, it quickly orients itself in a way that its needle-side rests against the stomach wall. After the protective sugar disk dissolves in stomach acid, the spring-loaded needle tipped with insulin is released, injecting its load of insulin into the stomach wall, from which it enters the bloodstream. Meanwhile, the spent SOMA device passes on through the digestive system.

The researchers’ tests in pigs have shown that a single SOMA can successfully deliver insulin doses of up to 3 milligrams, comparable to the amount a human with diabetes might need to inject. The tests also showed that the device’s microinjection did not damage the animals’ stomach tissue or the muscles surrounding the stomach. Because the stomach is known for being insensitive to pain, researchers expect that people receiving insulin via SOMA wouldn’t feel a thing, but much more research is needed to confirm both the safety and efficacy of the new device for human use.

Meanwhile, this fascinating work serves as a reminder that when it comes to biomedical science, inspiration sometimes can come from the most unexpected places.

Reference:

[1] An ingestible self-orienting system for oral delivery of macromolecules. Abramson A, Caffarel-Salvador E, Khang M, Dellal D, Silverstein D, Gao Y, Frederiksen MR, Vegge A, Hubálek F, Water JJ, Friderichsen AV, Fels J, Kirk RK, Cleveland C, Collins J, Tamang S, Hayward A, Landh T, Buckley ST, Roxhed N, Rahbek U, Langer R, Traverso G. Science. 2019 Feb 8;363(6427):611-615.

Links:

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

Langer Lab (MIT, Cambridge)

Giovanni Traverso (Brigham and Women’s Hospital, Harvard Medical School, Boston)

NIH Support: National Institute of Biomedical Imaging and Bioengineering


The Actin Superhighway

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Actin Superhighway

Credit: Andrew Lombardo and David Warshaw, University of Vermont, Burlington

What looks like a traffic grid filled with roundabouts is nothing of the sort: It’s actually a peek inside a tiny microchamber that models a complex system operating in many of our cells. The system is a molecular transportation network made of the protein actin, and researchers have reconstructed it in the lab to study its rules of the road and, when things go wrong, how it can lead to molecular traffic accidents.

This 3D super-resolution image shows the model’s silicone beads (circles) positioned in a tiny microfluidic-chamber. Suspended from the beads are actin filaments that form some of the main cytoskeletal roadways in our cells. Interestingly, a single dye creates the photo’s beautiful colors, which arise from the different vertical dimensions of a microscopic image: 300 nanometers below the focus (red), at focus (green), and 300 nanometers above the focus (blue). When a component spans multiple dimensions—such as the spherical beads—all the colors of the rainbow are visible. The technique is called 3D stochastic optical reconstruction microscopy, or STORM [1].


Building a Smarter Bandage

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Smart Bandage

Credit: Tufts University, Medford, MA

Smartphones, smartwatches, and smart electrocardiograms. How about a smart bandage?

This image features a prototype of a smart bandage equipped with temperature and pH sensors (lower right) printed directly onto the surface of a thin, flexible medical tape. You also see the “brains” of the operation: a microprocessor (upper left). When the sensors prompt the microprocessor, it heats up a hydrogel heating element in the bandage, releasing drugs and/or other healing substances on demand. It can also wirelessly transmit messages directly to a smartphone to keep patients and doctors updated.

While the smart bandage might help mend everyday cuts and scrapes, it was designed with the intent of helping people with hard-to-heal chronic wounds, such as leg and foot ulcers. Chronic wounds affect millions of Americans, including many seniors [1]. Such wounds are often treated at home and, if managed incorrectly, can lead to infections and potentially serious health problems.


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