glucose
Chipping Away at the Causes of Polycystic Kidney Disease
Posted on by Lawrence Tabak, D.D.S., Ph.D.
It’s often said that two is better than one. That’s true whether driving across the country, renovating a kitchen, or looking for a misplaced set of car keys. But a recent study shows this old saying also applies for modeling a kidney disease with two very complementary, cutting-edge technologies: an organoid, a living miniaturized organ grown in a laboratory dish; and an “organ-on-a-chip,” silicon chips specially engineered to mimic the 3D tissue structure and basic biology of a human body organ.
Using this one-two approach at the lab bench, the researchers modeled in just a few weeks different aspects of the fluid-filled cysts that form in polycystic kidney disease (PKD), a common cause of kidney failure. This is impossible to do in real-time in humans for a variety of technical reasons.
These powerful technologies revealed that blood glucose plays a role in causing the cysts. They also showed the cysts form via a different biological mechanism than previously thought. These new leads, if confirmed, offer a whole new way of thinking about PKD cysts, and more exciting, how to prevent or slow the disease in millions of people worldwide.
These latest findings, published in the journal Nature Communications, come from Benjamin Freedman and colleagues at the University of Washington School of Medicine, Seattle [1]. While much is known about the genetic causes of PKD, Freedman and team realized there’s much still much to learn about the basics of how cysts form in the kidney’s tiny tubes, or tubules, that help to filter toxins out of the bloodstream.
Each human kidney has millions of tubules, and in people with PKD, some of them expand gradually and abnormally to form sacs of fluid that researchers liken to water balloons. These sacs, or cysts, crowd out healthy tissue, leading over time to reduced kidney function and, in some instances, complete kidney failure.
To understand cyst formation better, Freedman’s team and others have invented methods to grow human kidney organoids, complete with a system of internal tubules. Impressively, organoids made from cells carrying mutations known to cause PKD develop cysts, just as people with these same mutations do. When suspended in fluid, the organoids also develop telltale signs of PKD even more dramatically, showing they are sensitive to changes in their environments.
At any given moment, about a quarter of all the fluids in the body pass through the kidneys, and this constant flow was missing from the organoid. That’s when Freedman and colleagues turned to their other modeling tool: a kidney-on-a-chip.
These more complex 3D models, containing living kidney cells, aim to mimic more fully the kidney and its environment. They also contain a network of microfluidic channels to replicate the natural flow of fluids in a living kidney. Combining PKD organoids with kidney-on-a-chip technology provided the best of both worlds.
Their studies found that exposing PKD organoid-on-a-chip models to a solution including water, glucose, amino acids, and other nutrients caused cysts to expand more quickly than they otherwise would. However, the cysts don’t develop from fluids that the kidneys outwardly secrete, as long thought. The new findings reveal just the opposite. The PKD cysts arise and grow as the kidney tissue works to retain most of the fluids that constantly pass through them.
They also found out why: the cysts were absorbing glucose and taking in water from the fluid passing over them, causing the cysts to expand. Although scientists had known that kidneys absorb glucose, they’d never connected this process to the formation of cysts in PKD.
In further studies, the scientists gave fluorescently labeled glucose to mice with PKD and could see that kidney cysts in the animals also took up glucose. The researchers think that the tubules are taking in fluid in the mice just as they do in the organoids.
Understanding the mechanisms of PKD can point to new ways to treat it. Indeed, the research team showed adding compounds that block the transport of glucose also prevented cyst growth. Freedman notes that glucose transport inhibitors (flozins), a class of oral drugs now used to treat diabetes, are in development for other types of kidney disease. He said the new findings suggest glucose transport inhibitors might have benefits for treating PKD, too.
There’s much more work to do. But the hope is that these new insights into PKD biology will lead to promising ways to prevent or treat this genetic condition that now threatens the lives of far too many loved ones in so many families.
This two-is-better-than-one approach is just an example of the ways in which NIH-supported efforts in tissue chips are evolving to better model human disease. That includes NIH’s National Center for Advancing Translational Science’s Tissue Chip for Drug Screening program, which is enabling promising new approaches to study human diseases affecting organ systems throughout the body.
Reference:
[1] Glucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease. Li SR, Gulieva RE, Helms L, Cruz NM, Vincent T, Fu H, Himmelfarb J, Freedman BS. Nat Commun. 2022 Dec 23;13(1):7918.
Links:
Polycystic Kidney Disease (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)
Your Kidneys & How They Work (NIDDK)
Freedman Lab (University of Washington, Seattle)
Tissue Chip for Drug Screening (National Center for Advancing Translational Sciences/NIH)
NIH Support: National Center for Advancing Translational Sciences; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute
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
Can Artificial Cells Take Over for Lost Insulin-Secreting Cells?
Posted on by Dr. Francis Collins
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.
Feed a Virus, Starve a Bacterium?
Posted on by Dr. Francis Collins
Thinkstock/Stockbyte
Yes, the season of colds and flu is coming. You’ve probably heard the old saying “feed a cold and starve a fever.” But is that sound advice? According to new evidence from mouse studies, there really may be a scientific basis for “feeding” diseases like colds and flu that are caused by viruses, as well as for “starving” certain fever-inducing conditions caused by bacteria.
In the latest work, an NIH-funded research team found that providing nutrition to mice infected with the influenza virus significantly improved their survival. In contrast, the exact opposite proved true in mice infected with Listeria, a fever-inducing bacterium. When researchers forced Listeria-infected mice to consume even a small amount of food, they all died.
Taking a New Look at Artificial Sweeteners
Posted on by Dr. Francis Collins
Diet sodas and other treats sweetened with artificial sweeteners are often viewed as guilt-free pleasures. Because such foods are usually lower in calories than those containing natural sugars, many have considered them a good option for people who are trying to lose weight or keep their blood glucose levels in check. But some surprising new research suggests that artificial sweeteners might actually do the opposite, by changing the microbes living in our intestines [1].
To explore the impact of various kinds of sweeteners on the zillions of microbes living in the human intestine (referred to as the gut microbiome), an Israeli research team first turned to mice. One group of mice was given water that contained one of two natural sugars: glucose or sucrose; the other group received water that contained one of three artificial sweeteners: saccharin (the main ingredient in Sweet’N Low®), sucralose (Splenda®), or aspartame (Equal®, Nutrasweet®). Both groups ate a diet of normal mouse chow.
Next Page
