type 2 diabetes
Science, Serendipity, and Art
Posted on by Lawrence Tabak, D.D.S., Ph.D.
Fractals are complex geometric patterns repeated at progressively smaller scales. You’ll find them throughout nature. That includes in the 3D structures and shapes of tissues throughout our bodies, from the bones in our skulls down to the blood vessels in our feet. But the fractal pattern above isn’t from a precisely patterned human tissue. It comes from some unexpected biochemistry that formed the stunning pattern on its own.
In fact, the exact source for this fractal pattern reminiscent of peacock feathers isn’t known. It turned up out of the blue (and green) in a sample that had been sitting around on the shelf for some time. The original image appeared in black and white, but the colors added post-collection help to highlight the fractal pattern of a sample including an essential hormone produced in the pancreas. The hormone is called islet amyloid polypeptide (IAPP).
Also known as amylin, IAPP plays many important roles in our bodies, including the feeling of fullness after a meal. But the amino acid chains that make up IAPP also are prone to forming abnormal clumps of misfolded polypeptides (a long name for proteins) known as amyloids. Much like the amyloid plaques in the brains of people with Alzheimer’s disease, misfolded IAPP amyloids in people with type 2 diabetes also can damage insulin-producing beta cells in the pancreas and make controlling their blood sugar levels even more difficult.
This unusual image comes from graduate students Bryan Bogin and Matthew Steinsaltz. They study the biophysics and biochemistry of protein folding and misfolding in the lab of Zachary Levine, Yale School of Medicine, New Haven, CT. The Levine lab recently moved to the Altos Labs San Diego Institute. However, Bogin and Steinsaltz continue to conduct their studies at Yale.
The two conduct in-solution experiments and molecular simulations to elucidate the precise conditions and triggers that can lead otherwise normal polypeptide chains to fold up incorrectly and wreak havoc as they do in diabetes and other diseases. When Steinsaltz was learning how to use transmission electron microscopy (TEM), a technique in which an electron beam captures images including detailed molecular-level structures, Bogin handed over an assortment of IAPP samples in different solution conditions from some of his past experiments for a look.
In those microscopy images, they expected to see long, linear fibrils consisting of IAPP polypeptides. While that’s indeed what they saw in most of the samples, this one was the exception. It was such a remarkable image that they submitted it in the Biophysical Society’s 2022 Art of Science Image Contest, where it took the top prize.
Bogin and Steinsaltz say they still can’t explain the source or meaning behind these unusual fractal patterns. But they do continue to conduct experiments to understand how various polypeptides implicated in health and disease misfold to form destructive aggregates. This striking image may not hold the answers they seek, but it is an inspiring reminder that the path to making groundbreaking biomedical discoveries will have many beautiful surprises along the way.
Links:
Type 2 Diabetes (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)
Zachary Levine Lab (Yale School of Medicine, New Haven, CT)
Art of Science Image Contest (Biophysical Society, Rockville, MD)
NIH Support: National Institute on Aging
Large Study Reveals Prevalence, Health Benefits of Brown Fat
Posted on by Dr. Francis Collins
It’s pretty easy to spot differences between the two people on these positron emission tomography (PET) scans. In the scan of the male individual on the left, you see lots of small, dark spots around the neck and shoulders. But you can’t see any on the female on the right. What’s the explanation? Is this a sex difference? No! Brown fat!
This energy-burning type of fat happens to show up as small, dark spots in the neck and shoulder area on PET scan studies. So, as these scans reveal, the individual on the left possesses an abundance of brown fat, while the person on the right has essentially none. This wide range of difference in abundance is true for both men and women.
Researchers’ interest in brown fat began to heat up (sorry about that!) more than a decade ago when it was discovered that certain adults have persistently high levels of brown fat. It’s long been known that babies have brown fat, but it had been thought this fat generally vanished as children grew up. It turns out that adults who hold onto their brown fat are less likely to be overweight than adults who do not. That’s because brown fat actually burns extra calories, instead of storing it in the way the more familiar white fat does.
But are people with more brown fat actually any healthier? After studying about 130,000 PET scans from more than 52,000 people, researchers led by Paul Cohen, The Rockefeller University Hospital, New York, NY, say that the answer is “yes” in certain key areas. In a recent study in the journal Nature Medicine, they found that people with detectable brown fat had a lower incidence of many cardiovascular and metabolic conditions, including type 2 diabetes, congestive heart failure, and high blood pressure.
Studies to explore the health benefits of brown fat have been challenging to do. That’s because brown fat only shows up on PET scans, which measure how much glucose various tissues consume, an indication of their metabolic activity. What’s more, PET scans are quite costly and involve radiation exposure. So, researchers have been reluctant to ask healthy people to undergo a PET scan just to look at brown fat. But a solution occurred to the study’s first author Tobias Becher, who was aware that thousands of patients at nearby Memorial Sloan Kettering Cancer Center were undergoing PET scans each year as part of routine evaluation and care. In fact, cancer doctors often make note of brown fat on PET scans, if only to make sure it’s not mistaken for cancer.
So, the Cohen lab teamed up with Memorial Sloan Kettering Cancer Center radiologists Heiko Schöder and Andreas G. Wibmer to review many thousands of PET scans for the presence of brown fat. And they found it in about one of 10 people.
Next, they looked for health differences between the 10 percent of people with brown fat and the 90 percent who lack it. The differences turned out be striking. Type 2 diabetes was about half as prevalent in folks with detectable brown fat compared to those without. Individuals with brown fat also were less likely to have high cholesterol, high blood pressure, congestive heart failure, and coronary artery disease.
The findings suggest that brown fat may even help to offset the negative health effects of obesity. The researchers found that obese people with brown fat had a health profile that otherwise appeared more similar to individuals who weren’t obese. In fact, the benefits of brown fat were more pronounced in individuals who were overweight or obese than they were in people of normal weight.
Still, the researchers note that people with cancer might tend to show differences in brown fat compared to healthy adults. There’s some evidence also that prevalence may vary across cancer types and stages. The researchers took those variables into account in their studies. It’s also known that women are more likely to have brown fat than men and that the amount of brown fat tends to decline with age. What’s not yet well understood is whether differences in brown fat exist among people of different racial and ethnic backgrounds, and whether specific genetic factors are involved.
So, plenty of questions remain! Researchers not only want to figure out why some adults have so much more brown fat than others, they want to explore whether brown fat produces hormones that may add to its calorie-burning benefits. The hope is that these and other discoveries could eventually lead to new strategies for treating obesity, diabetes, and other metabolic conditions.
Reference:
[1] Brown adipose tissue is associated with cardiometabolic health. Becher T, Palanisamy S, Kramer DJ, Eljalby M, Marx SJ, Wibmer AG, Butler SD, Jiang CS, Vaughan R, Schöder H, Mark A, Cohen P. Nat Med. 2021 Jan;27(1):58-65.
Links:
Paul Cohen (The Rockefeller University, New York, NY)
Heiko Schöder (Memorial Sloan Kettering Cancer Center, NY)
Andreas Wibmer (Memorial Sloan Kettering Cancer Center, NY)
NIH Support: National Center for Advancing Translational Sciences
Study in Africa Yields New Diabetes Gene
Posted on by Dr. Francis 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
Posted on by Dr. Francis Collins
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 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
Does Gastric Bypass Reduce Cardiovascular Complications of Diabetes?
Posted on by Dr. Francis Collins
Thinkstock/IPGGutenbergUKLtd
For obese people with diabetes, doctors have increasingly been offering gastric bypass surgery as a way to lose weight and control blood glucose levels. Short-term results are often impressive, but questions have remained about the long-term benefits of such operations. Now, a large, international study has some answers.
Soon after gastric bypass surgery, about 50 percent of folks not only lost weight but they also showed well-controlled blood glucose, cholesterol, and blood pressure. The good news is that five years later about half of those who originally showed those broad benefits of surgery maintained that healthy profile. The not-so-good news is that the other half, while they generally continued to sustain weight loss and better glucose control, began to show signs of increasing risk for cardiovascular complications.
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