Tag Archives: #glucose

Millet-based Diet Can Lower Risk of Type 2 Diabetes And Help Manage Blood Glucose Levels (Food)

A new study has shown that eating millets can reduce the risk of developing type 2 diabetes and helps manage blood glucose levels in people with diabetes, indicating the potential to design appropriate meals with millets for diabetic and pre-diabetic people as well as for non-diabetic people as a preventive approach.

Drawing on research from 11 countries, the study published in Frontiers in Nutrition shows that diabetic people who consumed millet as part of their daily diet saw their blood glucose levels drop 12-15% (fasting and post-meal), and blood glucose levels went from diabetic to pre-diabetes levels. The HbA1c (blood glucose bound to hemoglobin) levels lowered on average 17% for pre-diabetic individuals, and the levels went from pre-diabetic to normal status. These findings affirm that eating millets can lead to a better glycemic response.

The authors reviewed 80 published studies on humans of which 65 were eligible for a meta-analysis involving about 1,000 human subjects, making this analysis the largest systematic review on the topic to date.

Dr. S Anitha, the study’s lead author and a Senior Nutrition Scientist at ICRISAT said:

“No one knew there were so many scientific studies undertaken on millets’ effect on diabetes and these benefits were often contested. This systematic review of the studies published in scientific journals has proven that millets can keep blood glucose levels in check and reduce the risk of diabetes. It has also shown just how well these smart foods do it.”

Millets, including sorghum, were consumed as staple cereals in many parts of the world until half a century ago. Investments in a few crops such as rice, wheat and maize, have edged nutritious and climate-smart crops like millets out of the plate.

Professor Ian Givens, a co-author of the study and Director at University of Reading’s Institute of Food, Nutrition and Health (IFNH) said:

“Awareness of this ancient grain is just starting to spread globally, and our review shows millets having a promising role in managing and preventing type 2 diabetes. In the largest review and analysis of research into different types of millet compared to other grains such as refined rice, maize and wheat we found that millets outperform their comparison crops with lower GI and lower blood glucose levels in participants.”  

According to the International Diabetes Association, diabetes is increasing in all regions of the world. India, China and the USA have the highest numbers of people with diabetes. Africa has the largest forecasted increase of 143% from 2019 to 2045, the Middle East and North Africa 96% and South East Asia 74%. The authors urge the diversification of staples with millets to keep diabetes in check, especially across Asia and Africa.

Strengthening the case for reintroducing millets as staples, the study found that millets have a low average glycemic index (GI) of 52.7, about 36% lower GI than milled rice and refined wheat, and about 14-37 GI points lower compared to maize. All 11 types of millets studied could be defined as either low (<55) or medium (55-69) GI, with the GI as an indicator of how much and how soon a food increases blood sugar level. The review concluded that even after boiling, baking and steaming (most common ways of cooking grains) millets had lower GI than rice, wheat and maize.

Dr. Jacqueline Hughes, Director General, ICRISAT said:

“The global health crisis of undernutrition and over-nutrition coexisting is a sign that our food systems need fixing. Greater diversity both on-farm and on-plate is the key to transforming food systems. On-farm diversity is a risk mitigating strategy for farmers in the face of climate change while on-plate diversity helps counter lifestyle diseases such as diabetes. Millets are part of the solution to mitigate the challenges associated with malnutrition, human health, natural resource degradation, and climate change. Trans-disciplinary research involving multiple stakeholders is required to create resilient, sustainable and nutritious food systems.” 

Professor Paul Inman, Pro-Vice-Chancellor (International) of the University of Reading, said:

“The rapidly accelerating threats of climate change and global health crises, including obesity and diabetes, require everyone to pull together in action. The partnership between ICRISAT and the University of Reading is doing exactly this, bringing together our world leading expertise in human nutrition with ICRISAT’s long established role as a leader in agricultural research for rural development.”

The study also identified information gaps and highlighted a need for collaborations to have one major diabetes study covering all types of millets and all major ways of processing with consistent testing methodologies. Structured comprehensive information will be highly valuable globally, taking the scientific knowledge in this area to the highest level.

Ms. Joanna Kane-Potaka, a co-author from ICRISAT and Executive Director of the Smart Food initiative said:

“This study is first in a series of studies that has been worked on for the last four years as a part of the Smart Food initiative led by ICRISAT that will be progressively released in 2021. Included are systematic reviews with meta-analyses of the impacts of millets on: diabetes, anemia and iron requirements, cholesterol and cardiovascular diseases and calcium deficiencies as well as a review on zinc levels. As part of this, ICRISAT and the Institute for Food Nutrition and Health at the University of Reading have formed a strategic partnership to research and promote the Smart Food vision of making our diets healthier, more sustainable on the environment and good for those who produce it.”

This research is part of a special edition and theme section in the Frontiers journal – Smart Food for Healthy, Sustainable and Resilient Food System. 

Full citation:

Anitha S, Kane-Potaka J, Tsusaka TW, Botha R, Rajendran A, Givens DI, Parasannanavar DJ, Subramaniam K, Prasad KDV, Vetriventhan M and Bhandari RK (2021) A Systematic Review and Meta-Analysis of the Potential of Millets for Managing and Reducing the Risk of Developing Diabetes Mellitus. Front. Nutr. 8:687428. doi: 10.3389/fnut.2021.687428


Provided by University of Reading

Loss Of Circadian Regulation Allows For Increase in Glucose Production During Lung Cancer Progression (Medicine)

New study identifies possible therapeutic target to suppress cancer cell growth

New research from the University of California, Irvine reveals how the circadian regulation of glucose production in the liver is lost during lung cancer progression, and how the resulting increase in glucose production may fuel cancer cell growth.

The new study titled, “Glucagon regulates the stability of REV-ERBα to modulate hepatic glucose production in a model of lung cancer-associated cachexia,” published today in Science Advancesillustrates how the circadian clock is regulated under conditions of stress such as during lung cancer progression and cancer-associated tissue wasting disease called cachexia.

“Our research shows that a critical circadian protein, REV-ERBa, controls glucose production in the liver. During lung cancer progression and specifically under conditions of cachexia, this circadian regulation is lost, resulting in increased glucose production from the liver,” said senior author Selma Masri, PhD, assistant professor in the Department of Biological Chemistry at UCI School of Medicine. “Based on our findings, we identified that lung tumors are able to provide instructive cues to the liver to increase glucose production, a major fuel source for cancer cells.”

This research places the circadian clock as a central regulator of glucose production during lung cancer progression and provides important insight toward the development of novel therapeutics to target REV-ERBa to suppress cancer cell growth.

“We are continuing to investigate the consequence of increased glucose production during lung cancer progression by tracing the metabolic fate of this newly generated glucose to determine if this fuel source can drive the heightened metabolic demand of lung cancer cells,” said Amandine Verlande, PhD, and Sung Kook Chun, PhD, postdoctoral scholars in the Masri Laboratory.

The circadian clock is our intrinsic biological pacemaker that maintains physiological homeostasis in all tissues of the body. Under conditions of stress, the biological clock is rewired as an adaptive mechanism to maintain synchrony and equilibrium throughout the body.

This research was supported in part by the National Institutes of Health, Concern Foundation, V Foundation for Cancer Research, Cancer Research Coordinating Committee, and shared resources supported through the UCI Chao Family Comprehensive Cancer Center.

Featured image: During lung cancer progression and the corresponding development of cachexia, circadian control of glucose production is disrupted, resulting in increased levels of glucose from the liver. These findings illustrate a tissue-tissue crosstalk whereby a lung tumor can disrupt the circadian metabolism of a distal tissue, potentially for its own growth advantage. © UCI School of Medicine


Provided by UCI School of Medicine

Lung Cancer Resistance: the Key is Glucose (Biology)

Lung tumors are home to immune cells that affect their growth and resistance to treatment. Looking at neutrophils, scientists led by EPFL have discovered that the key might lie in the cells’ ability to metabolize glucose, opening an entirely new target for improving radiotherapy.

Cancers are not only made of tumor cells. In fact, as they grow, they develop an entire cellular ecosystem within and around them. This “tumor microenvironment” is made up of multiple cell types, including cells of the immune system, like T lymphocytes and neutrophils.

The tumor microenvironment has predictably drawn a lot of interest from cancer researchers, who are constantly searching for potential therapeutic targets. When it comes to the immune cells, most research focuses on T lymphocytes, which have become primary targets of cancer immunotherapy – a cancer therapy that turns the patient’s own immune system against the tumor.

But there is another type of immune cell in the tumor microenvironment whose importance in cancer development has been overlooked: neutrophils, which form part of the body’s immediate or “innate” immune response to microbes. The question, currently debated among scientists, is whether neutrophils help or inhibit the tumor’s growth.

Now, a team of researchers led by Etienne Meylan at EPFL’s School of Life Sciences has discovered that the metabolism of neutrophils determines their tumor-supportive behavior in lung cancer development. The study is published in Cancer Research, a journal of the American Association for Cancer Research.

What intrigued the scientists was that cell metabolism in cancer becomes deregulated. Being neutrophil specialists, they considered the possibility that when these cells reside within the tumor microenvironment, their metabolism may also change, and that could affect how they contribute to the cancer’s growth.

Focusing on glucose metabolism in a genetically-engineered mouse model of lung adenocarcinoma, the scientists isolated tumor-associated neutrophils (TANs) and compared them to neutrophils from healthy lungs.

What they found was surprising: the TANs take-up and metabolize glucose much more efficiently than neutrophils from healthy lungs. The researchers also found that TANs express a higher amount of a protein called Glut1, which sits on the cell’s surface and enables increased glucose uptake and use.

To understand the importance of Glut1 in neutrophils during lung tumor development in vivo, we used a sophisticated system to remove Glut1 specifically from neutrophils,” says Pierre-Benoit Ancey, the study’s first author. “Using this approach, we identified that Glut1 is essential to prolong neutrophil lifespan in tumors; in the absence of Glut1, we found younger TANs in the microenvironment.”

Using X-ray microtomography to monitor adenocarcinomas, the researchers found that removing Glut1 from TANs led to lower tumor growth rate but also increased the efficacy of radiotherapy, a common treatment for lung cancer. In other words, the ability of TANs to metabolize glucose efficiently seems to bestow the tumor with the ability to resist treatment – at least in lung cancer.

Tumor-associated neutrophils taking up glucose, represented by the donut. This enables neutrophils to become older in lung tumors, and be tumor-supportive. Credit: Liloon (Julie de Meyer)

The scientists think that, because Glut1 loss diminishes the lifespan of TANs, their “age” determines whether they play a pro- or anti-tumor role. “Usually, we don’t know how to target neutrophils, because they are so important in innate immunity,” says Etienne Meylan. “Our study shows that their altered metabolism in cancer could be a new Achilles heel to consider in future treatment strategies. Undoubtedly, we are only beginning to learn about these fascinating cells in cancer.”

Other contributors

  • Swiss Cancer Center Léman
  • Lausanne University Hospital (CHUV)
  • University of Lausanne (UniL)
  • Swiss Institute of Bioinformatics
  • University of Iowa
  • Duke University Medical Center
  • Vanderbilt University Medical Center

Funding: Swiss Cancer Research Foundation, Swiss National Science Foundation, Emma Muschamp Foundation and US National Cancer Institute

Featured image: Histological staining of a lung adenocarcinoma, which is made of tumor cells as well as cells of the immune microenvironment including tumor-associated neutrophils. Credit: Caroline Contat (EPFL).


References

Pierre-Benoit Ancey, Caroline Contat, Gael Boivin, Silvia Sabatino, Justine Pascual, Nadine Zangger, Jean Yannis Perentes, Solange Peters, E. Dale Abel, David G. Kirsch, Jeffrey C. Rathmell, Marie-Catherine Vozenin, Etienne Meylan. Glut1 expression in tumor-associated neutrophils promotes lung cancer growth and resistance to radiotherapy. Cancer Research 22 March 2021. DOI: 10.1158/0008-5472.CAN-20-2870


Provided by EPFL

Artificial Pancreas System Upgraded with AI Algorithm (Medicine)

POSTECH professor Sung-Min Park’s research team is developing a fully automated glucose management system that goes beyond the limits

Diabetes is on the rise worldwide. It is a permanent condition that requires care over a life time. To help manage it, an artificial pancreas system, which automatically measures blood sugar levels to infuse the appropriate amount of insulin into the blood, has now become smarter thanks to AI learning.

A research team, led by Professor Sung-Min Park and Ph.D. candidate Seunghyun Lee and M.S. candidate Jiwon Kim of POSTECH’s Department of Convergence IT Engineering and Electrical Engineering, has newly developed a reinforcement learning (RL) based AI algorithm that calculates the amount of insulin needed for a diabetic patient and injects it automatically. These findings were published as a feature article in the latest issue of IEEE Journal of Biomedical and Health Informatics, an international journal on medical information science.

Patients with type 1 diabetes must inject insulin daily. One must check the amount of carbohydrates in the food ingested each time, calculate the proper amount of insulin, then inject the correct dosage before each meal. Though artificial pancreas systems on the market help with this process, there is still the hassle of having to input the meal intake in advance each time.

© POSTECH

To eliminate this inconvenience, the research team added a pharmacological concept to reinforcement learning, widely known as the algorithm of AlphaGo. This method of AI algorithm achieved a mean glucose of 124.72 mg/dL and percentage time in the normal range of 89.56%. Even without inputting the meal intake, the policy showed performance comparable to that of conventional artificial pancreas.

“The fully automated artificial pancreas is like autonomous driving for the medical industry,” explained Professor Sung-Min Park. “The newly developed AI algorithm enables fully automated blood sugar control without the hassle of inputting meal or exercise information.” He added, “We expect this algorithm to be extended to other drug-based treatments.”

This study was conducted with the support from the Mid-career Researcher Program in Basic Research in Science and Engineering of the National Research Foundation of Korea.


Reference: S. Lee, J. Kim, S. W. Park, S. -M. Jin and S. -M. Park, “Toward a Fully Automated Artificial Pancreas System Using a Bioinspired Reinforcement Learning Design: In Silico Validation,” in IEEE Journal of Biomedical and Health Informatics, vol. 25, no. 2, pp. 536-546, Feb. 2021. URL: http://ieeexplore.ieee.org/stamp/stamp.jsp?tp=&arnumber=9115809&isnumber=9348958
doi: 10.1109/JBHI.2020.3002022


Provided by POSTECH

Use of Goldenseal May Compromise Glucose Control in Diabetics on Metformin (Medicine)

Diabetic patients taking the natural product goldenseal while taking the prescription drug metformin may be unwittingly sabotaging their efforts to maintain healthy blood glucose levels. This concern arose from a recent study published in the journal Clinical Pharmacology & Therapeutics.

Metformin—the world’s most-prescribed oral glucose-lowering medication—was included in a cocktail of selected drugs given to participants in a clinical study led by scientists at Washington State University’s College of Pharmacy and Pharmaceutical Sciences. The study sought to determine the impact of goldenseal on specific drug transporters, proteins that facilitate absorption or expulsion of drug molecules in different tissues such as the intestine, liver and kidney.

“After six days of taking goldenseal, participants had about 25 percent less metformin in their bodies, a statistically significant change that could potentially impact glucose control in patients with type 2 diabetes,” said the study’s first author James Nguyen, a Ph.D. candidate in pharmaceutical sciences and recent Doctor of Pharmacy graduate. He said the finding serves as a caution to health care providers and patients that over-the-counter natural product use can lead to unwanted drug interactions, which may lead to negative health outcomes.

James Nguyen

Unstable glucose levels increase patients’ risk of serious health complications, such as heart disease, kidney disease and infections. Adding to that concern, Nguyen said there are reports that diabetic patients are increasingly using goldenseal and berberine—a substance found in goldenseal—to self-treat their condition, likely based on claims that berberine helps lower glucose levels.

A perennial herb native to North America, goldenseal is often combined with Echinacea, a top-selling botanical product, in herbal remedies used to self-treat the common cold and other respiratory tract infections. Goldenseal is also commonly used to self-treat digestive issues such as diarrhea and constipation as well as rashes and other skin problems.

Establishing Best Practices

Goldenseal is one of several natural products being studied by the researchers as part of the National Institutes of Health-funded Center of Excellence for Natural Product Drug Interaction Research, a WSU-led, multidisciplinary effort to develop standardized approaches for studying interactions between natural products and pharmaceutical drugs.

Senior author and center principal investigator Mary Paine—a professor in the WSU College of Pharmacy & Pharmaceutical Sciences—noted that while the Food and Drug Administration and other regulatory agencies have well-established guidelines for studying potential interactions between drugs, no such guidelines exist for natural product-drug interactions. This gap exists because, unlike drugs, natural products are not required to be tested for potential drug interaction risks prior to entering the market.

Mary Paine © WSU

“Our work in this goldenseal study helps lay the foundation for establishing best practices for studying these interactions, with a particular niche in transporter-mediated interactions,” Paine said.

Study Tests Model Predictions

One of the overarching goals of this recently published study was to determine whether established FDA basic mathematical models for predicting transporter-mediated drug-drug interactions could be used to successfully predict natural product-drug interactions. To find out, the researchers partnered with a contract research organization to conduct test tube experiments to determine whether a goldenseal extract inhibited any of 15 different transporters. Data from those experiments were then incorporated into the models to predict whether goldenseal interacts with any of the drugs included in a drug cocktail slated to be used in the subsequent clinical study. The cocktail included low doses of three different drugs known to be transported by various transporters: furosemide (a diuretic), rosuvastatin (an anti-cholesterol drug), and metformin. The drug midazolam (a short-acting sedative) was included in the cocktail as a positive control, or a drug known to interact with goldenseal. Goldenseal inhibits the metabolic enzyme that breaks down midazolam, leading to increased midazolam in the body.

Finally, they conducted a clinical study with 16 healthy participants to see if their predictions held up. Participants were given just the drug cocktail during the baseline phase. In the goldenseal exposure phase, participants took goldenseal three times daily for five days before being given the drug cocktail and another dose of goldenseal on day six, followed by two more doses later that day. Blood and urine samples were collected at regular intervals after participants took the drug cocktail and analyzed by the researchers to compare how each drug moved through the body with or without exposure to goldenseal.

Based on their model predictions, the researchers expected to find an interaction between goldenseal and rosuvastatin in the clinical study, but it did not materialize. Surprisingly, the clinical data showed that taking goldenseal along with metformin decreased metformin blood concentrations, which the model predictions did not reveal.

These findings will help the researchers refine these models to increase prediction accuracy of future natural product-drug interaction studies. As follow-up to the research, Nguyen plans to conduct studies to determine the mechanism by which goldenseal alters metformin absorption. Based on the data, he said that this appears to happen in the intestine and may be driven by the transporter OCT1. This research could eventually lead to the discovery of other natural product-drug interactions involving goldenseal and drugs transported by OCT1.

In addition to researchers at WSU, the team includes scientists from the University of North Carolina at Greensboro, the University of Washington, the University of Pittsburgh and SOLVO Biotechnology.

The study was funded by the National Center for Complementary and Integrative Health U54 Center Grant for Natural Product-Drug Interaction Research, U54-AT008909.

Featured image: Golden seal plant © Judith Van Dongen, WSU Health Sciences Spokane Office of Research


Reference: Nguyen, J.T., Tian, D.‐D., Tanna, R.S., Hadi, D.L., Bansal, S., Calamia, J.C., Arian, C.M., Shireman, L.M., Molnár, B., Horváth, M., Kellogg, J.J., Layton, M.E., White, J.R., Cech, N.B., Boyce, R.D., Unadkat, J.D., Thummel, K.E. and Paine, M.F. (2020), Assessing Transporter‐Mediated Natural Product‐Drug Interactions Via In vitro‐In Vivo Extrapolation: Clinical Evaluation With a Probe Cocktail. Clin Pharmacol Ther. https://doi.org/10.1002/cpt.2107


Provided by Washington State University

A Compound That Slows Bone Loss, and a Resource for Developing Treatments to Slow Aging (Biology)

A compound that extends lifespan in a tiny nematode worm slows bone loss in aging mice. That surprising result comes from a longitudinal and functional study of 700 aging mice at the Buck Institute, a project that provides a treasure trove of data for researchers aiming to develop therapeutics to slow aging and age-related diseases.  The study is currently online in the Journal of Bone and Mineral Research Plus.

The project, which involved five Buck labs and took several years to complete, involved serially profiling the individual mice as they aged while testing several therapeutics that extended lifespan in simple model organisms or reduced neurological disease in mice. Researchers established rates of change for clinically significant parameters in untreated mice including kyphosis, blood glucose, body composition, activity, metabolic measures and detailed parameters of skeletal aging in bone.  The study involved collecting and analyzing terabytes of data over several years.

The online application is available at https://danielevanslab.shinyapps.io/buckMouseAging/

Simon Belov © Buck Institute

“This is a unique resource that comes from a study of multiple phenotypes of aging that had never been looked at before,” said Buck professor Simon Melov, PhD, senior author of the paper. “Our hope is that our data will enable those working on pre-clinical studies to essentially model experiments virtually, in order to provide a starting point for testing other interventions in mice.” 

Benzoxazole, the compound that slowed bone aging by up to 31% over the course of a year’s treatment in the mice, was first identified as one of five compounds that extended nematode lifespan in the Lithgow lab in a study that appeared in Nature in 2011.  “If you have a therapeutic that extends lifespan in a simple animal that has no bone whatsoever, you certainly wouldn’t predict that it would slow the rate of bone aging in a mammal,” said Gordon Lithgow, PhD, Buck professor and Vice President. “It’s obvious that aging-related pathways have been conserved during evolution. This new finding is a great example of the utility of screening compounds in simple animals as the starting point to look for unexpected and surprising benefits in mammals.” In the Nature article, benzoxazole appeared to suppress age-related protein aggregation.  The mechanism of action in mouse bone is still under study, although researchers say the compound appears to slow the reabsorption of osteoclasts, bone cells that are active during growth and healing.

Gordon Lithgow © Buck Institute

Melov says the findings in the large study are relevant to humans, especially in regards to pre-clinical phenotypes. “The metrics we used are all directly applicable to aging in humans. They literally have direct clinical correlates to the types of things you would measure in humans.” For example, for the first time researchers witnessed spontaneous fractures in aging mouse femurs.  Melov says they occurred in 2.5% of the mouse population, not dissimilar to the 1 -2.7% incidence of hip fractures in people over the age of 65.  He also notes that they developed a new unbiased method for evaluating kyphosis, an age-related curvature of the spine, and may pave the way for testing new interventions.

“We think using this new database could save substantial resources for those wanting to do pre-clinical studies of interventions,” said Melov.  “If someone wants to test a compound against a particular aging phenotype this database could provide information about how many mice are needed for the experiments and how long it would likely take to see results.”

This work was supported by grants from the Larry L. Hillblom Foundation; The American Foundation for Aging Research; NIH Grants U19AG023122,  U24AG051129, AG055822, AG061879, AG051129, UL1DE019608, AG038688 & AG045835, and AR56679; the Glenn Foundation for Medical Research; the Ellison Medical Foundation; and family and friends of Catherine Munson.

Featured image: Kyphosis: Green = Young mice; Red = Old mice


Reference: Evans, D.S., O’Leary, M.N., Murphy, R., Schmidt, M., Koenig, K., Presley, M., Garrett, B., Kim, H.‐N., Han, L., Academia, E.C., Laye, M.J., Edgar, D., Zambataro, C.A., Barhydt, T., Dewey, C.M., Mayfield, J., Wilson, J., Alavez, S., Lucanic, M., Kennedy, B.K., Almeida, M., Andersen, J.K., Kapahi, P., Lithgow, G.J. and Melov, S. (2021), Longitudinal Functional Study of Murine Aging: A Resource for Future Study Designs. JBMR Plus. Accepted Author Manuscript e10466. https://doi.org/10.1002/jbm4.10466


Provided by Buck Institute

Sloan Kettering Institute Scientists Solve a 100-year-old Mystery About Cancer (Medicine)

A long-standing mystery is why fast-growing cells, like cancer cells and immune cells, rely on a seemingly inefficient form of metabolizing glucose to power their activities. In a new study, scientists at the Sloan Kettering Institute offer a compelling solution.

The year 2021 marks the 100th anniversary of a fundamental discovery that’s taught in every biochemistry textbook. In 1921, German physician Otto Warburg observed that cancer cells harvest energy from glucose sugar in a strangely inefficient manner: rather than “burn” it using oxygen, cancer cells do what yeast do — they ferment it. This oxygen-independent process occurs quickly, but leaves much of the energy in glucose untapped.

MSK immunologist Ming Li

Various hypotheses to explain the Warburg effect have been proposed over the years, including the idea that cancer cells have defective mitochondria — their “energy factories” — and therefore cannot perform the controlled burning of glucose. But none of these explanations has withstood the test of time. (Cancer cells’ mitochondria work just fine, for example.)

Now a research team at the Sloan Kettering Institute led by immunologist Ming Li offers a new answer, based on a hefty set of genetic and biochemical experiments and published January 21 in the journal Science.

It comes down to a previously unappreciated link between Warburg metabolism and the activity of a powerhouse enzyme in the cell called PI3 kinase.

“PI3 kinase is a key signaling molecule that functions almost like a commander-in-chief of cell metabolism,” Dr. Li says. “Most of the energy-costly cellular events in cells, including cell division, occur only when PI3 kinase gives the cue.”

As cells shift to Warburg metabolism, the activity of PI3 kinase is increased, and in turn, the cells’ commitment to divide is strengthened. It’s a bit like giving the commander-in-chief a megaphone.

The findings revise the commonly accepted view among biochemists that sees metabolism as secondary to cell signaling. They also suggest that targeting metabolism could be an effective way to thwart cancer growth.

Challenging the Textbook View

Dr. Li and his team, including graduate student Ke Xu, studied Warburg metabolism in immune cells, which also rely on this seemingly inefficient form of metabolism. When immune cells are alerted to the presence of an infection, a certain type called T cells shift from the typical oxygen-burning form of metabolism to Warburg metabolism as they grow in number and ramp up infection-fighting machinery.

The key switch that controls this shift is an enzyme called lactate dehydrogenase A (LDHA), which is made in response to PI3 kinase signaling. As a result of this switch, glucose remains only partially broken down and the cell’s energy currency, called ATP, is quickly generated in the cell’s cytosol. (In contrast, when cells use oxygen to burn glucose, the partially broken down molecules travel to the mitochondria and are further broken down there to make ATP on a delay.)

Dr. Li and his team found that in mice, T cells lacking LDHA could not sustain their PI3 kinase activity, and as a result could not effectively fight infections. To Dr. Li and his team, this implied that this metabolic enzyme was controlling a cell’s signaling activity.

“The field has worked under the assumption that metabolism is secondary to growth factor signaling,” Dr. Li says. “In other words, growth factor signaling drives metabolism, and metabolism supports cell growth and proliferation. So the observation that a metabolic enzyme like LDHA could impact growth factor signaling through PI3 kinase really caught our attention.”

Like other kinases, PI3 kinase relies on ATP to do its work. Since ATP is the net product of Warburg metabolism, a positive feedback loop is set up between Warburg metabolism and PI3 kinase activity, securing PI3 kinase’s continued activity — and therefore cell division.

As for why activated immune cells would preferentially resort to this form of metabolism, Dr. Li suspects it has to do with the cells’ need to produce ATP quickly to ramp up their cell division and infection-fighting machinery. The positive feedback loop ensures that once this program is engaged, it will be sustained until the infection is eradicated.

The Cancer Connection

Though the team made their discoveries in immune cells, there are clear parallels to cancer.

“PI3 kinase is a very, very critical kinase in the context of cancer,” Dr. Li says. “It’s what sends the growth signal for cancer cells to divide, and is one of the most overly active signaling pathways in cancer.”

As with immune cells, cancer cells may employ Warburg metabolism as a way to sustain the activity of this signaling pathway and therefore ensure their continued growth and division. The results raise the intriguing possibility that doctors could curb cancer growth by blocking the activity of LDHA — the Warburg “switch.”

This study received financial support from the National Institutes of Health (grant R01 AI 102888), the Howard Hughes Medical Institute, and the Memorial Sloan Kettering Cancer Center Support Grant/Core Grant P30 CA08748. The study authors declare no competing interests.

Reference: Ke Xu, Na Yin, Min Peng, Efstathios G. Stamatiades, Amy Shyu, Peng Li, Xian Zhang, Mytrang H. Do, Zhaoquan Wang, Kristelle J. Capistrano, Chun Chou, Andrew G. Levine, Alexander Y. Rudensky, Ming O. Li, “Glycolysis fuels phosphoinositide 3-kinase signaling to bolster T cell immunity”, Science  22 Jan 2021: Vol. 371, Issue 6527, pp. 405-410 DOI: 10.1126/science.abb2683 https://science.sciencemag.org/content/371/6527/405

Provided by MSKCC

Better Diet and Glucose Uptake in the Brain Lead to Longer Life in Fruit Flies (Neuroscience)

Improved neuronal glucose uptake plus healthier eating might have anti-aging effects.

Researchers from Tokyo Metropolitan University have discovered that fruit flies with genetic modifications to enhance glucose uptake have significantly longer lifespans. Looking at the brain cells of aging flies, they found that better glucose uptake compensates for age-related deterioration in motor functions, and led to longer life. The effect was more pronounced when coupled with dietary restrictions. This suggests healthier eating plus improved glucose uptake in the brain might lead to enhanced lifespans.

Glucose uptake in brain neurons decreases with age (left), Increasing glucose uptake in brain neurons counteracts aging (middle), Increasing glucose uptake in brain neurons plus dietary restriction further extends lifespan (light). © Tokyo Metropolitan University

The brain is a particularly power-hungry part of our bodies, consuming 20% of the oxygen we take in and 25% of the glucose. That’s why it’s so important that it can stay powered, using the glucose to produce adenosine triphosphate (ATP), the “energy courier” of the body. This chemical process, known as glycolysis, happens in both the intracellular fluid and a part of cells known as the mitochondria. But as we get older, our brain cells become less adept at making ATP, something that broadly correlates with less glucose availability. That might suggest that more food for more glucose might actually be a good thing. On the other hand, it is known that a healthier diet actually leads to longer life. Unravelling the mystery surrounding these two contradictory pieces of knowledge might lead to a better understanding of healthier, longer lifespans.

A team led by Associate Professor Kanae Ando studied this problem using Drosophila fruit flies. Firstly, they confirmed that brain cells in older flies tended to have lower levels of ATP, and lower uptake of glucose. They specifically tied this down to lower amounts of the enzymes needed for glycolysis. To counteract this effect, they genetically modified flies to produce more of a glucose-transporting protein called hGut3. Amazingly, this increase in glucose uptake was all that was required to significantly improve the amount of ATP in cells. More specifically, they found that more hGut3 led to less decrease in the production of the enzymes, counteracting the decline with age. Though this did not lead to an improvement in age-related damage to mitochondria, they also suffered less deterioration in locomotor functions.

Graphical abstract by Ando et al.

But that’s not all. In a further twist, the team put the flies with enhanced glucose uptake under dietary restrictions, to see how the effects interact. Now, the flies had even longer lifespans. Curiously, the increased glucose uptake did not actually improve the levels of glucose in brain cells. The results point to the importance of not just how much glucose there is, but how efficiently it is used once taken into cells to make the energy the brain needs.

Though the anti-aging benefits of a restricted diet have been shown in many species, the team were able to combine this with improved glucose uptake to leverage the benefits of both for even longer lifespans in a model organism. Further study may provide vital clues to how we might keep our brains healthier for longer.

This work was supported by a research award from the Japan Foundation for Aging and Health, a JSPS KAKENHI Grant-in-Aid for Scientific Research on Challenging Research (Exploratory) (19K21593), NIG-JOINT (71A2018, 25A2019), a Grant-in-Aid for JSPS Research Fellows (18J21936) and Research Funding for Longevity Science (19-7) from the National Center for Geriatrics and Gerontology, Japan.

Reference: Mikiko Oka, Emiko Suzuki, Akiko Asada, Taro Saito, Koichi M. Iijima, Kanae Ando, “Increasing neuronal glucose uptake attenuates brain aging and promotes life span under dietary restriction in Drosophila”, iScience, 24(1), 2021. https://www.cell.com/iscience/fulltext/S2589-0042(20)31176-7?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2589004220311767%3Fshowall%3Dtrue# https://doi.org/10.1016/j.isci.2020.101979

Provided by Tokyo Metropolitan University

Prediabetes Subtypes Identified (Medicine)

All prediabetes is not the same: in people in the preliminary stages of type 2 diabetes, there are six clearly distinguishable subtypes, which differ in the development of the disease, diabetes risk, and the development of secondary diseases. This is shown in a study by the Institute for Diabetes Research and Metabolic Diseases (IDM) of Helmholtz Zentrum München at the University of Tübingen, Tübingen University Hospital and the German Center for Diabetes Research (DZD). The results have now been published in Nature Medicine. The new classification can help in the future to prevent the manifestation of diabetes or the development of diabetes complications through targeted prevention.

Diabetes is a worldwide pandemic. Since 1980, the number of people with diabetes has quadrupled worldwide. In Germany alone, 7 million people suffer from it. And the trend is still rising. By 2040, the number of people with type 2 diabetes could increase to as many as 12 million. But type 2 diabetes does not develop from one day to the next. People often go through a longer preliminary stage of diabetes, in which blood glucose levels are already elevated but people are not yet ill. “For people with prediabetes it has not been possible until now to predict whether they would develop diabetes and be at risk for serious complications such as kidney failure, or whether they would only have a harmless form with slightly higher blood glucose levels but without significant risk,” said Professor Hans-Ulrich Häring, who initiated the study 25 years ago. However, such a distinction is important for the targeted prevention of the metabolic disease and thus for counteracting the diabetes pandemic. Researchers from Tübingen have now achieved an important breakthrough. Using cluster analysis* in people with prediabetes, they have discovered six distinct subtypes with different diabetes risk. A differentiated classification of prediabetes and diabetes makes it possible to carry out individual and early prevention and therapy of diabetes and its secondary diseases in a way that is adapted to the development of the disease.

Prediabetes: Six different clusters identified

The research group led by Professor Häring and Professor Fritsche at the University Hospital in Tübingen has conducted detailed studies of the metabolism of people with prediabetes who are still considered healthy. The test persons (n=899) are from the Tübingen Family Study and the study of the Tübingen Lifestyle Program. They have repeatedly undergone intensive clinical, laboratory chemical, magnetic resonance imaging and genetic examinations in Tübingen over the past 25 years. Based on key metabolic parameters such as blood glucose levels, liver fat, body fat distribution, blood lipid levels and genetic risk, the researchers were able to identify six subtypes of prediabetes. “As in manifest diabetes, there are also different disease types in the preliminary stage of diabetes, which differ in blood glucose levels, insulin action and insulin secretion, body fat distribution, liver fat and genetic risk,” said first author Professor Robert Wagner from the DZD Institute for Diabetes Research and Metabolic Diseases (IDM) of Helmholtz Zentrum München at the University of Tübingen, summarizing the results of the study.

In people with prediabetes, there are six clearly distinguishable subtypes (clusters), which differ in development of the diseases, risk for diabetes, and development of complications. Image source: IDM, DZD

Three of these groups (clusters 1, 2 and 4) are characterized by a low diabetes risk. The study participants in clusters 1 and 2 were healthy. Slim people are the main members of cluster 2. They have a particularly low risk of developing complications. Cluster 4 consists of overweight people, whose metabolism is still relatively healthy. The three remaining subtypes (clusters 3, 5 and 6) are associated with an increased risk of diabetes and/or secondary diseases. People who belong to subtype 3 produce too little insulin and have a high risk of developing diabetes. People in cluster 5 have a pronounced fatty liver and a very high risk of diabetes because their bodies are resistant to the blood glucose lowering effect of insulin. In subtype 6, damage to the kidneys occurs even before diabetes is diagnosed. Here, mortality is also particularly high.

But can the classification into six prediabetes subtypes also be confirmed in other cohorts? To investigate this, the researchers extended the analysis to include almost 7000 subjects in the Whitehall II Cohort in London and there, too, identified the six prediabetes subtypes.

More targeted prevention measures

The researchers are already making further plans. “Next, in prospective studies, we will first seek to determine to what extent the new findings are applicable for the classification of individual persons into risk groups,” said Professor Andreas Fritsche of Tübingen University Hospital. If this is the case, people with a high risk profile could be identified early on and receive specific treatment.

These results are based on research conducted by the Diabetes Research Department at Tübingen University Hospital over the past 25 years to characterize people with an increased risk of diabetes. The study was funded by the German Research Foundation, the Federal Ministry of Education and Research and the State of Baden-Württemberg.

“One of the DZD’s goals is to develop precise prevention and therapy measures, i.e. the appropriate prevention or treatment for the right group of people at the right time. The combination of in-depth clinical and molecular research with state-of-the-art bioinformatics has made this internationally important result possible. The identification of subtypes in the preliminary stages of type 2 diabetes is an important step towards precision medicine in the prevention of diabetes and its complications,” says DZD Executive Director Prof. Martin Hrab? de Angelis.

Note:

  • Cluster analysis:

Cluster analysis is a method through which the objects of investigation (e.g. persons) can be grouped on the basis of given criteria and characteristics. The groups found in this way – also called clusters – then contain cases that are similar to each other. A formed cluster should be maximally homogeneous in itself, but at the same time it should differ as much as possible from the other clusters. Here, six different clusters could be identified in test persons with pre-diabetes on the basis of eight core parameters important for metabolism (including blood glucose levels, liver fat, body fat distribution, blood lipid levels and genetic risk).

Reference: Robert Wagner et al: Pathophysiology-based subphenotyping of individuals at elevated risk for type 2 diabetes. Nature Medicine. DOI: https://doi.org/10.1101/2020.10.12.20210062

Provided by German Center for Diabetes Research