Research Updates
Acid build-up in the body is linked to metabolic alterations
NIDDK researchers found that acid accumulation in healthy participants was correlated with altered metabolic characteristics, including increased waist and thigh circumferences; body fat percentage; fat mass; triglycerides, a type of body fat that can increase risk of heart disease; and lower HDL cholesterol, often referred to as “good” cholesterol. In addition, acid accumulation, which occurs when too much acid builds up in a person’s body fluids, was associated with higher intake of calories, protein, and fat, as well as increased energy expenditure. Previous research has also linked acid build-up to adverse health outcomes, such as obesity, kidney disease, and hypertension.
The study examined common markers of acid accumulation, including low bicarbonate, a form of carbon dioxide in the blood that helps stabilize the body’s acid levels, and anion gap, which reflects the difference between the negatively and positively charged electrolytes in the blood. Low bicarbonate and high anion gap are indicators of acid accumulation. In addition, animal protein is the largest source of dietary acid and may contribute to acid retention. Published in June in Obesity, the research suggests that using acid accumulation measurements, which are routinely available in clinical practice, may be beneficial in identifying markers of early obesity, metabolic dysfunction, and acid-promoting eating habits.
Behavioral intervention decreases how much pain affects daily activities in people with kidney failure receiving dialysis treatment
An NIH-funded clinical trial found that, among people with dialysis-dependent kidney failure, pain coping skills training (PCST) reduced how much pain affected their work and social activities, mood, and relationships, also known as pain interference.
The PCST comprised 12 weeks of virtual, one-on-one, coach-led sessions to teach coping skills for chronic pain and enhance self-efficacy (the belief in one’s ability to achieve goals), followed by 12 weeks of automated, interactive voice response sessions to refresh the newly acquired skills. At 12 weeks, 51% of people in the PCST group reported a reduction in pain interference vs. 37% in group who received no trial-based intervention, and the benefit continued throughout the 24-week intervention period. PCST also improved other effects of pain, including pain severity, depression, anxiety, and quality of life.
Although the effect of PCST on the overall cohort was modest, its high acceptability, tolerability, and safety support further research on developing nonpharmacologic, non-invasive strategies for managing pain in dialysis populations, especially since opioid side effects can be more pronounced for people with dialysis-dependent kidney failure. The study, conducted by the Hemodialysis Opioid Prescription Effort (HOPE) Consortium Trial to Reduce Pain and Opioid Use in Hemodialysis, published in JAMA Internal Medicine in December and was funded by NIDDK through the NIH Helping to End Addiction Long-term (HEAL) Initiative.
Inhibiting immune cell growth may improve inflammation in people with rheumatoid arthritis
Recent NIDDK-funded research showed inhibiting cyclin-dependent kinase 7 (CDK7), a key protein involved in immune cell growth, reduced disease severity in mouse models of inflammatory arthritis. Macrophages, a type of immune cell that can stimulate immune activity, are key contributors to chronic inflammation found in rheumatoid arthritis and other autoimmune conditions. By targeting the CDK7 protein, which is known to stop gene activity in macrophages, researchers aimed to prevent abnormal macrophage function without causing toxicity in patients by only suppressing pro-inflammatory genes in the cells.
Mice with inflammatory arthritis who were treated with the CDK7 inhibitor showed reduced ankle thickness, arthritis clinical scores, and time to remission versus non-treated counterparts. Applying the same treatment to synovial fluid, the connective tissue that lines the inside of joints, from patients with rheumatoid arthritis, the researchers observed decreased activity of inflammation-associated genes, proving a possible anti-inflammatory effect of CDK7 inhibition in humans. The findings, which were published in Science Translational Medicine in November, offer a new potential therapeutic approach for rheumatoid arthritis and other autoimmune diseases.
New chemical reporter for understudied N-glycan structures
NIDDK researchers created the first metabolic chemical reporter, 1,3-Pr2-6-OTs GlcNAlk (MM-JH-1), to exclusively label a poorly understood N-glycan structure, hybrid N-Glycans, that can alter viral entry, immune recognition, and cell signaling. Found on the surface of cells, surface glycans are components of the immune system, which pathogens can manipulate to evade detection.
Building on previous literature, researchers created the reporter by converting a commercially available amino sugar, D-glucosamine hydrochloride, to MM-JH-1. To prove the reporter could label hybrid N-glycan structures specifically and enzymatically, researchers interfered with the function of a Golgi enzyme, MGAT1, which produces hybrid N-glycan structures. Reporter levels decreased when the enzyme was inhibited or deleted, demonstrating that MM-JH-1 was selectively incorporated into hybrid N-glycan structures.
While characterizing MM-JH-1, researchers also observed MM-JH-1 appeared in the nucleus and nucleolus of cells, implying the presence of hybrid N-glycan on proteins in these compartments. Using antibodies and MM-JH-1, the researchers found that fibrillarin, a nucleolar protein and methyltransferase, was modified by hybrid N-linked glycosylation, a novel finding with broad implications. Broadly, N-glycan structures and their hybrid forms are essential to cell processes necessary for cancer onset and progression, such as epithelial-mesenchymal transition. The N-glycan hybrid specific marker created in this study, which was published in Nature Chemical Biology in October, could be used to target early-stage cancer and explore its role in other diseases, such as viral infection and immune cell activation.
Celebrating 40 years of DCCT/EDIC
Credit: Diabetes Care, American Diabetes Association
Celebrating the 40th anniversary of the NIDDK-supported Diabetes Control and Complications Trial (DCCT) and its long-term outcome study, the Epidemiology of Diabetes Interventions and Complications (EDIC), Diabetes Care featured a five-article collection in September 2024, highlighting new type 1 diabetes research from DCCT/EDIC. In its initial findings, the DCCT proved that people who kept their blood glucose levels close to normal greatly reduced their chances of having diabetes-related eye, kidney, and nerve disease. The EDIC has shown the long-term benefits of early and intensive blood glucose control on the future development of diabetes-related complications, and that early and intensive blood glucose control also lengthens life.
These landmark studies continue to provide new knowledge on the positive effects of intensive glycemic management. In these new reports, investigators evaluated the DCCT/EDIC cohort to look at diabetes-associated retinal structure abnormalities, bone microarchitecture, neuropathic pain, and plasma biomarkers of brain injury and kidney tubular function. The findings, particularly the decreased risk of retinal layer disorganization, neuropathic pain, and bone fractures, continue to demonstrate the benefits that intensive glucose control offers over time.
In the article collection, NIDDK Director Dr. Griffin Rodgers and Division of Diabetes, Endocrinology, and Metabolic Diseases Director Dr. William Cefalu discussed the importance of long-term investment in research and its benefit on public health, stating that longitudinal studies like DCCT/EDIC can answer clinical questions that shorter studies cannot answer, such as how chronic poor glycemic control affects bone mineral density and how well specific biomarkers may serve as early indicators of cognitive decline or progressive kidney damage.
Age-related metabolic and molecular changes spike at age 44 and 60 in humans
In an NIDDK-supported study on human aging, researchers found most metabolic pathways and microbiomes are not constant over the lifetime, but tend to change rapidly throughout the body at specific age ranges, most notably around ages 44 and 60. The findings, published in Nature Aging in August, suggest aging does not progress gradually over time but, instead, major changes may occur in humans at specific points during their lives.
Following 108 healthy participants between 25 and 75 years old for a median of 1.7 years, researchers collected blood, stool, skin, oral, and nasal samples every 3-6 months. This allowed them to characterize changes to the molecules and microbiomes of each person over a fraction of their lifetime. Researchers observed rapid molecular changes taking place across all participants around 44 and 60 years of age. The changes were found in cellular and metabolic pathways necessary for skin, heart, and kidney function, among others, demonstrating a possible link between the observed alterations and risk of age-related diseases, such as cardiovascular disease. The findings support previous research on the non-linear nature of aging, and future work is planned to explore the uncovered molecular patterns.
Editor’s note: corresponding author of this paper, Dr. Michael P. Snyder was an NIDDK Advisory Council member from 2020-2023.
View full-sized image Credit: Nature Aging
Accessible Image Description
A schematic depicting the types of samples collected from the 108 study participants (plasma, stool, skin, oral, and nasal) and the data gathered from each sample type (transcriptomics, proteomics, metabolomics, cytokines, clinical lab tests, lipidomics, gut microbiomes, skin microbiomes, oral microbiomes, and nasal microbiomes).
| Sample collection | Data acquisition | Participant number | Sample number | Variable number |
|---|---|---|---|---|
| Sample collection Plasma | Data acquisition Transcriptomics | Participant number 100 | Sample number 879 | Variable number 8,556 |
| Sample collection Plasma | Data acquisition Proteomics | Participant number 104 | Sample number 947 | Variable number 302 |
| Sample collection Plasma | Data acquisition Metabolomics | Participant number 99 | Sample number 919 | Variable number 814 |
| Sample collection Plasma | Data acquisition Cytokines | Participant number 91 | Sample number 962 | Variable number 62 |
| Sample collection Plasma | Data acquisition Clinical lab test | Participant number 102 | Sample number 967 | Variable number 51 |
| Sample collection Plasma | Data acquisition Lipidomics | Participant number 100 | Sample number 933 | Variable number 846 |
| Sample collection Stool | Data acquisition Gut microbiome | Participant number 78 | Sample number 729 | Variable number 1,230 genera |
| Sample collection Skin | Data acquisition Skin microbiome | Participant number 85 | Sample number 630 | Variable number 1,129 genera |
| Sample collection Oral | Data acquisition Oral microbiome | Participant number 86 | Sample number 786 | Variable number 1,129 genera |
| Sample collection Nasal | Data acquisition Nasal microbiome | Participant number 84 | Sample number 740 | Variable number 1,230 genera |
Nearly one-third of people from West Africa have gene variants that increase chronic kidney disease risk
A study partially funded by NIDDK has identified an additional genetic risk factor for kidney disease in people of African ancestry. In the study, which was conducted by the Human Heredity and Health in Africa (H3Africa) Kidney Disease Research Network, researchers found that a single variant in the apolipoprotein L1 gene (APOL1) significantly increases the risk of chronic kidney disease in West African populations. In participants from Ghana and Nigeria, a variant in one APOL1 copy increased their risk of chronic kidney disease by 18%, while variants in both APOL1 copies increased their risk by 25%. Past studies suggested variants in both copies of APOL1 were needed to increase the overall risk.
APOL1 variants are seen most often in people of West African descent, nearly one-third of whom carry APOL1 variants. However, studies have also found APOL1 variants in people from Europe, Asia, and South America. The results, which were published in October in the New England Journal of Medicine, suggest more studies are needed on APOL1 variants and kidney outcomes in specific populations.
Semaglutide may help people feel full even before eating
An NIDDK-funded study has located a region of the brain affected by semaglutide and similar GLP-1 receptor-stimulating weight-loss drugs, shedding new light on the neural pathways associated with satiation. Researchers identified neurons that express GLP-1 receptors in the dorsomedial hypothalamus (DMH) of mice and humans, which reduce the drive to eat in response to seeing food or during anticipation of a meal. The DMH is associated with feeding, drinking, body-weight regulation, and circadian activity.
When researchers artificially stimulated the GLP-1 receptor expressing neurons in mice during a meal, the mice stopped eating immediately. When these neurons were chronically activated, the mice ate less. When the neurons were chronically inhibited, the mice ate more. This finding suggests that GLP-1 receptor-stimulating drugs may activate DMH neurons, which heightens satiation.
The researchers observed similar effects in people. For example, people with obesity who received semaglutide had increased feelings of fullness before and while consuming food compared to those who received placebo. The findings, which appeared in Science in November, provide insight into previously unexplored neural targets for treating obesity and metabolic diseases.
Synthetic immunology shows potential as a treatment for type 1 diabetes
In an NIDDK-funded study, a team led by scientists at the University of California San Francisco (UCSF) designed synthetic suppressor T cells that blocked autoimmune attacks in targeted tissues. Since many treatments for autoimmune or inflammatory conditions weaken the body’s entire immune system, the scientists developed cells that could be programmed to suppress immunity in specific tissues or transplants – similar to how engineered CAR T cells are used to treat certain cancers. In a mouse model, these synthetic cells were able to protect transplanted pancreatic islets from autoimmune attacks, which shows the potential of synthetic immunology as a novel treatment for type 1 diabetes (T1D). The study, which was published in Science in December, demonstrates how engineered immune suppressor cells could suppress autoimmunity in a variety of contexts, including transplant rejection, cancer treatment, and auto-immune diseases.
The NIDDK-funded Human Islet Research Network (HIRN) supports this research through initiatives funded by the Special Statutory Funding Program for Type 1 Diabetes Research, or Special Diabetes Program. This congressionally-funded program aims to promote progress in T1D research and has led to the creation of unique, innovative, and collaborative research consortia and clinical trials networks.
Editor’s Note: The HIRN is celebrating its 10th Anniversary in 2025 and held a 10-year anniversary symposium entitled “Changing the Course in Type 1 Diabetes” on January 13-14, 2025.
View full-sized image Credit: Science
The Urologic Diseases in America project highlights key findings from 2024
The 2024 Annual Data Reports from the Urologic Diseases in America project are now available. Drawing primarily from claim form data related to various urologic diseases and disorders, the report provides detailed urologic disease analyses and highlights notable trends. Funded by NIDDK, these annual reports have been essential in understanding the epidemiology of urologic diseases in the United States since the original report was published in 2012.
The 2024 reports highlight findings from 19 different topics. Some key findings include:
- The annual prevalence of benign prostatic hyperplasia and associated lower urinary tract symptoms (BPH/LUTS) from 2012 to 2021 was 29-35% among men ages 65 and older, significantly higher than the 5-6% prevalence among men ages 40-64. While transurethral resection of the prostate remains the most common procedure, data showed a shift towards minimally invasive treatments.
- About 17% of patients newly diagnosed with urinary stone disease (USD) had an emergency department visit within a year; 10% had multiple visits.
- Opioid prescriptions decreased from 71% to 56% among USD patients ages 18-64 and from 56% to 40% among those ages 65 and older.
- Although the reported prevalence of urinary incontinence (UI) between 2012 and 2021 was 6-8% among people ages 65 and older, data suggested an underreporting by patients and health care providers.
- Urodynamic tests were used in only 7% of patients newly diagnosed with UI from 2015 to 2020.
- About 40% of patients with urologic chronic pelvic pain syndrome filled an opioid prescription in 2021. Though use declined from 2012 to 2021, the high use rate remains concerning.
- The prevalence of Fournier’s gangrene (FG), a rare, life-threatening urologic disease, was higher in patients ages 65-69 compared to other age groups above 65. In 2021, 66% of older adults with FG also had diabetes. Mortality remains high among people with FG.
Read the reports and listen to a podcast featuring key findings on the NIDDK website.
Heat causes enhanced T cell activity and mitochondrial damage in immune cells
Researchers from Vanderbilt University Medical Center have discovered how heat affects T cells, which are among the body’s most critical immune cells to fight infection and mediate inflammation. The study, funded in part by NIDDK, found that various types of T cells proliferated more at higher temperatures, but not all the results boosted immune responses to infection. Regulatory T cells, which suppress part of the immune response, were less effective at the higher temperature, for example.
In mouse T cells cultured at fever temperature (39° C), compared to those cultured at body temperature (37° C), the researchers observed a boost in metabolism, proliferation, and activity. But the higher temperatures also led to mitochondrial stress and dysfunction, DNA damage, and death among a subset of helper T cells called TH1 cells. In addition, the higher temperatures impaired the protein ETC1 in TH1 cells, setting off signaling that raised their mutation potential.
Researchers also examined sequencing data from people with two inflammatory diseases, Crohn’s disease and rheumatoid arthritis, and saw similarities with the cultured mouse cells, indicating damaged DNA and ETC1 impairment in TH1 cells. The research, published in Science in September and highlighted in NIH Research Matters, may explain how chronic inflammation increases cancer risk.
View full-sized image Credit: Science Immunology
Accessible Image Description
Six electron microscope images of six different mitochondria split into two rows labelled “Naïve” (top), which represent mitochondria from naïve T cells, and “TH1” (bottom), which represent mitochondria from TH1 T cells, and three columns labelled “37°C,” “39°C,” and “39°C,” which are the temperatures the T cells were cultured at for 3 days.
Each image portrays differences in mitochondrial mass, density, and cristae formation caused by the naïve and TH1 T cells being cultured at non-fever (37°C ) and fever-range (39°C) heat for 3 days.
Gut hormone, GIP, stabilizes blood glucose levels in mouse models of obesity and type 2 diabetes
A collaborative NIDDK study in mice showed how glucose-dependent insulinotropic polypeptide (GIP), a gut hormone known to promote insulin release, plays a role in stabilizing blood glucose levels. The researchers discovered that stimulating the continuous release of GIP helped maintain normal blood glucose levels under different experimental conditions. Generating a mutant mouse model allowed the researchers to selectively stimulate GIP release from intestinal K-cells using a drug designed to activate a signaling molecule known as Gs. Activating Gs signaling promotes hormone release in K-cells and other hormone-secreting cells.
The researchers observed stimulating acute and chronic GIP release improved glucose tolerance and reduced high blood glucose levels in mouse models of obesity and type 2 diabetes. These findings, published by the Journal of Clinical Investigation in December, demonstrate that stimulation of Gs signaling in K-cells may represent a new avenue for the treatment of type 2 diabetes and other metabolic disorders.