Newly identified hormone may be a critical driver of type 1 and type 2 diabetes

A newly discovered hormone named fabkin helps regulate metabolism and may play an important role in the development of both type 1 and type 2 diabetes, according to research led by the Sabri Ülker Center for Metabolic Research at Harvard T.H. Chan School of Public Health.

The study showed blood levels of fabkin were abnormally high in mice and human patients with either type 1 or type 2 diabetes. The researchers found that blocking the activity of fabkin prevented the development of both forms of diabetes in the animals. Fabkin likely plays a similar role in humans and the hormone complex could be a promising therapeutic target, according to the researchers.

“For many decades, we have been searching for the signal that communicates the status of energy reserves in adipocytes to generate appropriate endocrine responses, such as the insulin production from pancreatic beta cells,” said senior author Gökhan S. Hotamisligil, director of the Sabri Ülker Center. “We now have identified fabkin as a novel hormone that controls this critical function through a very unusual molecular mechanism.”

The findings were published online in Nature on December 8, 2021.

Many hormones are involved in the regulation of metabolism, such as insulin and leptin. Fabkin is different from traditional hormones in that it is not a single molecule with a single defined receptor. Instead, fabkin is composed of a functional protein complex consisting of multiple proteins, including fatty acid binding protein 4 (FABP4), adenosine kinase (ADK) and nucleoside diphosphate kinase (NDPK). Through a series of experiments, the researchers determined that fabkin regulates energy signals outside of cells. These signals then act through a family of receptors to control target cell function. In the case of diabetes, fabkin controls the function of beta cells in the pancreas that are responsible for insulin production.

More than a decade ago, Hotamisligil and colleagues discovered that a protein known as FABP4 is secreted from fat cells during lipolysis, the process in which lipids stored within fat cells are broken down, typically in response to starvation. Numerous studies have since shown correlations between circulating FABP4 and metabolic diseases including obesity, diabetes, cardiovascular disease, and cancer. However, the mechanism of action was unknown.

In the new study, the researchers showed that when FABP4 is secreted from fat cells and enters the blood stream, it binds with the enzymes NDPK and ADK to form the protein complex now identified as fabkin. In this protein complex, FABP4 modifies the activity of NDPK and ADK to regulate levels of molecules known as ATP and ADP, which are the essential units of energy in biology. The researchers discovered that surface receptors on nearby cells sense the changing ratio of ATP to ADP, triggering the cells to respond to the changing energy status. As such, fabkin is able to regulate the function of these target cells.

The authors showed that the insulin-producing beta cells of the pancreas are a target of fabkin and that the hormone is a driving force behind the development of diabetes. When the researchers used an antibody to neutralize fabkin in mice, the animals did not develop diabetes. When the antibody was given to obese, diabetic mice, they reverted to a healthy state.

“The discovery of fabkin required us to take a step back and reconsider our fundamental understanding of how hormones work.” said lead author Kacey Prentice, research associate in the Sabri Ülker Center and Department of Molecular Metabolism. “I am extremely excited to find a new hormone, but even more so about seeing the long-term implications of this discovery.”

SARS-CoV-2 can cause type 1 diabetes by killing beta cells

Researchers have identified that SARS-CoV-2 can cause type 1 diabetes by killing beta cells, making them less productive, and reprogramming them.

People who have type 1 diabetes don’t make insulin, a hormone that breaks down glucose from food. They require daily shots of insulin to control glucose, also known as blood sugar. While type 1 diabetes can be managed, it cannot be cured.

Recent studies have found that people who don’t already have type 1 diabetes can develop it after an acute COVID-19 infection. Two studies — both conducted in part at the National Human Genome Research Institute — found out how SARS-CoV-2 could cause diabetes.

After looking at autopsy samples from people who died of COVID-19, the researchers confirmed that SARS-CoV-2 seemed to target beta cells more than other pancreatic cells. When SARS-CoV-2 was blocked from interacting with neuropilin, the virus was unable to infect the beta cells. Blocking that interaction could prevent people with COVID-19 from developing diabetes.

In one study, researchers examined lab-grown beta cells infected with COVID-19 and found that they made less insulin when infected with the virus. Some of the cells died outright.

In the other study, researchers found that infection effectively reprogrammed some of those lab-grown cells. Instead of producing insulin, which breaks down blood sugar, they started producing glucagon, which increases blood sugar. The scientists then tested almost 400 drugs approved by the U.S. Food and Drug Administration to see if one might prevent the reprogramming. They zeroed in on a chemical called trans-ISRIB, which prevented reprogramming but not infection.

Article published courtesy of National Institute of Health

Researchers propose that humidity from masks may lessen severity of COVID-19

Masks help protect the people wearing them from getting or spreading SARS-CoV-2, the virus that causes COVID-19, but now researchers from the National Institutes of Health have added evidence for yet another potential benefit for wearers: The humidity created inside the mask may help combat respiratory diseases such as COVID-19.

The study, led by researchers in the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), found that face masks substantially increase the humidity in the air that the mask-wearer breathes in. This higher level of humidity in inhaled air, the researchers suggest, could help explain why wearing masks has been linked to lower disease severity in people infected with SARS-CoV-2, because hydration of the respiratory tract is known to benefit the immune system. The study published in the Biophysical Journal(link is external).

“We found that face masks strongly increase the humidity in inhaled air and propose that the resulting hydration of the respiratory tract could be responsible for the documented finding that links lower COVID-19 disease severity to wearing a mask,” said the study’s lead author, Adriaan Bax, Ph.D., NIH Distinguished Investigator. “High levels of humidity have been shown to mitigate severity of the flu, and it may be applicable to severity of COVID-19 through a similar mechanism.”

High levels of humidity can limit the spread of a virus to the lungs by promoting mucociliary clearance (MCC), a defense mechanism that removes mucus − and potentially harmful particles within the mucus − from the lungs. High levels of humidity can also bolster the immune system by producing special proteins, called interferons, that fight against viruses − a process known as the interferon response. Low levels of humidity have been shown to impair both MCC and the interferon response, which may be one reason why people are likelier to get respiratory infections in cold weather.

Dr. Adriaan Bax sits in front of lab equipment.NIDDK

The study tested four common types of masks: an N95 mask, a three-ply disposable surgical mask, a two-ply cotton-polyester mask, and a heavy cotton mask. The researchers measured the level of humidity by having a volunteer breathe into a sealed steel box. When the person wore no mask, the water vapor of the exhaled breath filled the box, leading to a rapid increase in humidity inside the box.

When the person wore a mask, the buildup of humidity inside the box greatly decreased, due to most of the water vapor remaining in the mask, becoming condensed, and being re-inhaled. To ensure no leakage, the masks were tightly fitted against the volunteer’s face using high-density foam rubber. Measurements were taken at three different air temperatures, ranging from about 46 to 98 degrees Fahrenheit.

The results showed that all four masks increased the level of humidity of inhaled air, but to varying degrees. At lower temperatures, the humidifying effects of all masks greatly increased. At all temperatures, the thick cotton mask led to the most increased level of humidity.

“The increased level of humidity is something most mask-wearers probably felt without being able to recognize, and without realizing that this humidity might actually be good for them,” Bax said.

Kidney transplantation between people with HIV is safe, NIH study finds

Kidney transplantation from deceased donors with HIV to people living with both HIV and end-stage kidney disease is feasible and safe, investigators supported by the National Institutes of Health have found.

Their study demonstrates that the pool of available kidneys for people with HIV can be expanded by including donors with HIV, making more kidneys available for all who are awaiting a transplant. 

The new findings build on research from 2019, when scientists from the University of Cape Town and NIH reported that people living with HIV who received kidney transplants from deceased donors with HIV had high overall survival and kidney graft survival after five years.

People living with HIV have a growing prevalence of end-stage kidney disease and are nearly three times more likely to die while on kidney dialysis than people without HIV. Kidney transplantation extends the lives of people with HIV and end-stage kidney disease, but these individuals face a shortage of donors and limited access to donor kidneys. The HIV Organ Policy Equity (HOPE) Act, passed by the U.S. Congress and signed into law in 2013, allows organ transplants from donors with HIV to recipients with HIV in approved research studies in the United States. Experts concurred that kidney transplantation between people with HIV would expand the pool of available organs and save lives. Consequently, investigators sought to explore the safety of this innovative transplantation practice.

The multicenter study was conducted by the HOPE in Action team led by Christine M. Durand, M.D., associate professor of medicine, and Dorry Segev, M.D., professor of surgery at Johns Hopkins University in Baltimore. NIH’s National Institute of Allergy and Infectious Diseases (NIAID) funded the study with additional support from the National Cancer Institute, also part of NIH.

Between March 2016 and July 2019, investigators at 14 clinical research sites enrolled 75 adults with end-stage kidney disease and HIV whose virus was reliably suppressed by anti-HIV therapy. Twenty-five participants received kidney transplants from deceased donors with HIV, and 50 participants received kidney transplants from deceased donors without HIV. The latter group included 22 donors who had false-positive HIV tests, another new organ source that has been an unexpected benefit of the HOPE Act.

All participants survived transplantation at a median follow-up of 1.4 years for recipients of HIV-positive kidneys and 1.8 years for recipients of HIV-negative kidneys. One year after transplantation, overall graft survival was excellent and comparable between recipients of HIV-positive kidneys (91%) and HIV-negative kidneys (92%). In addition, there were no differences in the rates of infections requiring hospitalization, serious adverse events (1.1 per person year) or HIV-related complications, which were rare.

Dr. Durand also is leading the HOPE in Action Multicenter Kidney Study, a large-scale, NIAID-sponsored clinical trial to further study the safety of kidney transplantation between people with HIV.

WHO receives first-ever donation of insulin

Fifty low- and middle-income countries are soon to receive insulin for people with diabetes, thanks to a donation by global health-care company, Novo Nordisk. 

The donation, of insulin and glucagon, to the value of US$ 1.3 million, comes at a time when many people with noncommunicable diseases such as diabetes are facing challenges with access to life-saving treatment as a result of the COVID-19 pandemic. 

“For many people living with diabetes these are difficult times,” said Professor Andrew Boulton, President of the International Diabetes Federation. “They are both vulnerable to the severe effects of COVID-19 and struggling with day-to-day problems managing their diabetes, such as disrupted access to medication, equipment and health care. Initiatives to secure the supply of essential diabetes medicines, and of insulin in particular, are very welcome.” 

“We are very grateful for this timely donation of insulin,” said Dr Bente Mikkelsen, Director of the Department of Noncommunicable Diseases at WHO. “It is the first donation of a medicine for a noncommunicable disease to WHO and it comes at a critical point.“ 

The selection of countries to receive this donation was based on their income group and information provided to WHO by ministries of health on the capacity of their health systems to manage storage and supply at a time when transport systems have been disrupted and health-care systems are stretched. 

In order to meet the long-term needs of people with diabetes, however, a sustainable supply of insulin, provided at prices that countries can afford, is needed. 

“We must not forget that as we approach the centenary of the discovery of insulin many people globally still face multiple hurdles in accessing insulin on a daily basis in normal circumstances,” said Dr Kaushik Ramaiya, Chair of the International Insulin Foundation. 

The donation comes several months after the inclusion of insulin in WHO’s prequalification programme, which accelerates and increases access to critical medical products that are quality-assured, affordable and adapted for markets in low- and middle-income countries. 

The effort to ensure a regular, affordable supply of insulin is just one of a number of strategies implemented by WHO to improve treatment of diabetes. In April, the Organization launched updated guidance on diagnosis, classification and management of type 2 diabetes intended for all those involved in planning and delivery of diabetes care. WHO also works with countries to promote healthy diets and physical activity to lower people’s risk of developing type 2 diabetes.

Countries are addressing diabetes as part of the Sustainable Development Goals, committing to cut premature death from diabetes and other noncommunicable diseases by one third by 2030.

NIH publishes the largest genomic study on type 2 diabetes in sub-Saharan African populations

National Institute of Health researchers have reported the largest genomic study of type 2 diabetes (T2D) in sub-Saharan Africans, with data from more than 5,000 individuals from Nigeria, Ghana and Kenya.

About 422 million people worldwide have diabetes, a number likely to more than double in the next 20 years. Photo credit: WHO

Researchers confirmed known genomic variants and identified a novel gene ZRANB3, which may influence susceptibility to the disease in sub-Saharan African populations. The gene could also influence the development of T2D in other populations and inform further research.

In a study published in the journal Nature Communications, researchers analyzed genomic data available on participants through the Africa America Diabetes Mellitus study, the single largest diabetes genomic association study conducted on the continent. Using the information available from 5,231 people, they found many genomic variants to be significantly associated with T2D.

The findings replicate results for many of the variants which other research studies have already implicated in T2D in mostly European ancestry populations. The work was funded by the National Human Genome Research Institute (NHGRI), the National Institute of Diabetes and Digestive and Kidney Diseases and the Office of the Director at the National Institutes of Health.

“Africa is the original cradle of all humanity, to which all humans can trace their genetic origin,” said Francis S. Collins, M.D., Ph.D., co-author of the paper and senior investigator with the NHGRI Medical Genomics and Metabolic Genetics Branch. “Thus, studying the genomes of Africans offers important opportunities to understand genetic variation across all human populations.”

To better understand how ZRANB3 was involved in T2D, the researchers studied its effects on zebrafish pancreas. The pancreas is one of the key organs involved in T2D, because their β-cells release insulin as a response to rising glucose in the bloodstream.

“In the early days of large-scale genomic studies, we did not know the effect of genes we found through our statistical tests,” said Dr. Adebowale Adeyemo, NHGRI researcher and first author of the paper. “But with the availability of new genomic tools, our next step was to ask: What does ZRANB3 do? How does it confer risk for T2D, and by what mechanisms does it act? That is the knowledge that will help the results become actionable for patients.”

Working with Dr. Norann Zaghloul of the University of Maryland, the researchers used a CRISPR-Cas9 DNA editing system to make the ZRANB3 gene inoperative in zebrafish (called a ‘knockout’). They also used biological tools to reduce the expression of the ZRANB3 gene in different zebrafish. In both cases, researchers observed a reduction in β-cell numbers in the developing zebrafish embryo. They realized it was because the β-cells were being destroyed when the ZRANB3 gene was inactive.

To follow up on these results and identify the consequence of such β-cell death, the researchers took β-cell cells from mice and performed a similar knockdown of the ZRANB3 gene as in the zebrafish model. They found that cells with ZRANB3 knockdown released much less insulin in the presence of high glucose than normal mouse β-cells.

Although the role of ZRANB3 in T2D was discovered in African populations (which have been vastly underrepresented in genomics research), it is possible that the same gene may also influence the development of T2D in other populations as scientists study the biology of this gene further, according to the researchers.

This is because the function of genes is, for the most part, universally same. However, differences in sequence variations in a gene as well as how they interact with lifestyle, behavior and other factors may influence the impact of a gene on disease in a given population. 

“The findings of this study further demonstrate why it is important to study all human populations. By doing so, we have the opportunity to make novel discoveries that will not only help the specific population but also people all around the globe,” said Dr. Charles Rotimi, senior author of the paper. “The biology then becomes generalizable, and that much more impactful.”

The next steps for the researchers will be to return to the human participants who have T2D as well as the variant for ZRANB3. The question is: could the presence of the ZRANB3 variant in T2D patients help predict whether these individuals will require insulin early in the course of their diabetes treatment? Providing insulin to such people early may be advantageous because that could help delay the exhaustion of their β-cells over time. This could someday be a simple, yet vastly effective way of treating T2D in a personalized manner.      

Could a popular food ingredient raise the risk for diabetes and obesity?

Consumption of propionate, a food ingredient that’s widely used in baked goods, animal feeds, and artificial flavorings, appears to increase levels of several hormones that are associated with risk of obesity and diabetes, according to new research led by Harvard T.H. Chan School of Public Health in collaboration with researchers from Brigham and Women’s Hospital and Sheba Medical Center in Israel.

The study, which combined data from a randomized placebo-controlled trial in humans and mouse studies, indicated that propionate can trigger a cascade of metabolic events that leads to insulin resistance and hyperinsulinemia—a condition marked by excessive levels of insulin. The findings also showed that in mice, chronic exposure to propionate resulted in weight gain and insulin resistance.

The study was published online in Science Translational Medicine on April 24, 2019.

“Understanding how ingredients in food affect the body’s metabolism at the molecular and cellular level could help us develop simple but effective measures to tackle the dual epidemics of obesity and diabetes,” said Gökhan S. Hotamışlıgil, James Stevens Simmons Professor of Genetics and Metabolism and Director of the Sabri Ülker Center for Metabolic Research at Harvard Chan School.

More than 400 million people worldwide suffer from diabetes, and the rate of diabetes incidence is projected to increase 40% by 2040 despite extensive efforts to curb the disease. The surging rates of diabetes, as well as obesity, in the last 50 years indicate that environmental and dietary factors must be influencing the growth of this epidemic. Researchers have suggested that dietary components including ingredients used for preparation or preservation of food may be a contributing factor, but there is little research evaluating these molecules.

For this study, the researchers focused on propionate, a naturally occurring short-chain fatty acid that helps prevents mold from forming on foods. They first administered this short chain fatty acid to mice and found that it rapidly activated the sympathetic nervous system, which led to a surge in hormones, including glucagon, norepinephrine, and a newly discovered gluconeogenic hormone called fatty acid-binding protein 4 (FABP4). This in turn led the mice to produce more glucose from their liver cells, leading to hyperglycemia—a defining trait of diabetes. Moreover, the researchers found that chronic treatment of mice with a dose of propionate that was equivalent to the amount typically consumed by humans led to significant weight gain in the mice, as well as insulin resistance.

To determine how the findings in mice may translate to humans, the researchers established a double-blinded placebo-controlled study that included 14 healthy participants. The participants were randomized into two groups: One group received a meal that contained one gram of propionate as an additive and the other group was given a meal that contained a placebo. Blood samples were collected before the meal, within 15 minutes of eating the meal, and every 30 minutes thereafter for four hours.

The researchers found that people who consumed the meal containing propionate had significant increases in norepinephrine as well as increases in glucagon and FABP4 soon after eating the meal. The findings indicate that propionate may act as a “metabolic disruptor” that potentially increases the risk for diabetes and obesity in humans. The researchers noted that while propionate is generally recognized as safe by the U.S. Food and Drug Administration, these new findings warrant further investigation into propionate and potential alternatives that could be used in food preparation.

“The dramatic increase in the incidence of obesity and diabetes over the past 50 years suggests the involvement of contributing environmental and dietary factors. One such factor that warrants attention is the ingredients in common foods. We are exposed to hundreds of these chemicals on a daily basis, and most have not been tested in detail for their potential long-term metabolic effects,” said Amir Tirosh, associate professor of medicine at Tel-Aviv University’s Sackler School of Medicine, director of the Division of Endocrinology at Sheba Medical Center in Israel, and research fellow at Harvard Chan School.

Other Harvard Chan School authors included Ediz Calay, Gurol Tuncman, Kathryn Claiborn, Karen Inouye, Kosei Eguchi, and Michael Alcala.

Funding for this study came from National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases grant K08 DK097145, as well as the Nutrition Obesity Research Center at Harvard grant P30-DK040561, the Cardiovascular, Diabetes and Metabolic Disorder Research Center of the Brigham Research Institute, and the Israeli Ministry of Health Research and Fellowship Fund.