BackgroundGastrointestinal adverse events (GI AEs) are the main dose-limiting side effects of metformin in type 2 diabetes mellitus (T2DM), reducing adherence and compromising long-term glycaemic control. Current strategies (dose adjustment or combination therapy) seldom address both tolerability and sustained metabolic efficacy. Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation technique that may modulate gut–brain–metabolic pathways—vagal reflexes, inflammation, intestinal barrier function, and enteroendocrine signaling—and thus improve drug tolerance while preserving glycaemic control.MethodsThis single-center, randomized, sham-controlled pilot trial will enroll 60 T2DM patients with metformin-associated GI AEs, randomized 1:1 to either the taVNS group or the sham control group. The intervention lasts 2 weeks with a follow-up at week 4. Assessments at baseline and follow-up include a validated Metformin Symptom Severity Score (total score 0–50; primary outcome), Bristol Stool Form Scale, bowel urgency, glycaemic/metabolic indices [fasting blood glucose (FBG), 2-h postprandial glucose (PG2h), glycated albumin (GA), fasting C-peptide, fasting insulin, HOMA-IR, ISI], and mechanistic biomarkers (GLP-1, 5-HT, IL-6, IL-10, TNF-α, D-lactate, DAO, bile acids). Safety monitoring includes routine hematology, liver and renal function tests.DiscussionBy combining clinical outcomes with targeted biomarker analyses in a randomized design, this pilot study will assess whether taVNS alleviates metformin-associated GI intolerance without impairing glycaemic efficacy, and will provide feasibility data, effect-size estimates, and biomarker selection for future confirmatory trials.Clinical trial registrationTrial registration International Traditional Medicine Clinical Trial Registry (ITMCTR) http://itmctr.ccebtcm.org.cn/, Identifier: ITMCTR2025001086.
MiniMed flexes with next-gen insulin pump after spinning off from Medtronic
Within two weeks of MiniMed’s initial public offering in March, the Medtronic spinoff received FDA clearance for its latest-generation MiniMed Flex automated insulin delivery system. The smaller, screenless pump system is a major milestone for one of the world’s largest diabetes businesses. “We have a long history with durable pumps,” MiniMed EVP, Chief Product and…
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Advances in Stem Cell‑Derived Insulin‑Producing Cells for Type 1 Diabetes
Researchers at Karolinska Institutet and KTH Royal Institute of Technology have developed an improved method for creating insulin-producing cells from human stem cells. In a newly published study, the team demonstrated that these cells effectively regulate blood sugar levels in laboratory tests and can reverse diabetes in mice.
“We have developed a method that reliably produces high-quality insulin-producing cells from multiple human stem cell lines,” said Per-Olof Berggren, PhD, professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet. “This opens up opportunities for future patient-specific cell therapies, which could reduce immune rejection.” Berggren and Siqin Wu, PhD, researcher at Spiber Technologies AB (formerly at Karolinska Institutet), are co-corresponding authors of the researchers’ published paper in Stem Cell Reports, titled “An optimized protocol for efficient derivation of pancreatic islets from multiple human pluripotent stem cell lines.”
Type 1 diabetes (T1D) occurs when the immune system destroys insulin-producing cells in the pancreas, meaning the body can no longer absorb glucose from the blood and regulate blood sugar levels. “In type 1 diabetes (T1D), autoimmune destruction of β cells results in loss of glycemic control,” the authors wrote.
One possible treatment strategy is to replace these cells with new ones. However, previous methods of producing such cells from stem cells have often yielded mixed results. Stem cell therapy for type 1 diabetes is already being tested in several clinical trials. However, a challenge with previous methods is that the stem cells often develop into a combination of the desired and undesired cell types, increasing the risk of complications. Another challenge is that the insulin-producing cells created are often not mature enough to respond well to glucose.
“The success of cell therapy for type 1 diabetes (T1D) depends on reliable differentiation of stem cells into functional pancreatic islets,” the authors noted. They pointed out that previous protocols have exhibited variable efficiency across different human pluripotent stem cell (hPSC) lines. “Differentiation beyond the stage (S) 4 pancreatic progenitor (PP) stage frequently yields heterogeneous cultures containing proliferative non-endocrine cells and immature endocrine cells … increasing the risk of cyst or tumor formation,” the team further commented.
The newly optimized production process reported by Berggren and colleagues yields more mature and purer insulin-producing cells than previous methods. In a laboratory setting, the cells were able to secrete insulin and responded strongly to glucose. When the researchers transplanted these cells into streptozotocin (STZ)-induced diabetic mice, the animals gradually regained the ability to regulate their blood sugar. “By adjusting the culture steps and allowing the cells to form three-dimensional clusters themselves, many unwanted cell types are eliminated and the cells gain a better ability to respond to glucose, according to the researchers. “Single-cell analyses show that the SC-islets are free of non-endocrine cell populations before and after transplantation,” the team stated.
The transplantation was performed in the anterior chamber of the eye (ACE) which provides a transparent and accessible site for noninvasive monitoring of engrafted SC-islets through the cornea, the team pointed out. Transplantation into this compartment is also straightforward and minimally invasive. In their paper, the team noted, “Intraperitoneal glucose tolerance tests (IPGTT) at three, four, and six months post-transplantation showed improved glucose handling over time … SC-islet transplantation reversed hyperglycemia by three months, and by five–six months blood glucose levels fell slightly below pre-STZ baselines.”
Berggren commented, “This is a technique we use to monitor the development and function of the cells over time in a minimally invasive way. We observed that the cells gradually matured after transplantation, retaining their ability to regulate blood sugar for several months, which demonstrates their potential for future treatments.”
Fredrik Lanner, PhD, professor at the Department of Clinical Science, Intervention and Technology, Karolinska Institutet, and last author of the paper, added, “This could solve several of the problems that have previously hindered the development of stem cell-based treatments for type 1 diabetes. Building on this, we will work towards clinical translation aiming at treating type 1 diabetes.” In their report the authors concluded, “Our protocol generated glucose-responsive SC-islets from all eight hPSC lines tested … demonstrating potential for autologous applications … Our efficient differentiation protocol represents a key step toward autologous cell therapy, though further work is required to realize this goal.”
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STAT+: Researchers behind GLP-1 obesity drugs advance new approach: Drop GLP-1 as a target
The scientists whose work spurred the development of powerful obesity drugs like Eli Lilly’s Zepbound are now raising a provocative hypothesis: Perhaps targeting the GLP-1 hormone is actually not necessary to achieve effective weight loss.
A group of researchers led by Richard DiMarchi and Matthias Tschöp has created an experimental drug that activates receptors of the GIP and glucagon hormones. They propose — based on rodent and monkey studies — that this kind of molecule, when administered at high enough doses, may result in weight loss comparable to the weight loss seen with drugs that include GLP-1 as a target, and without the tolerability issues like nausea and vomiting that often come with the approved treatments, according to a peer-reviewed draft paper published this week.
The research, funded by a biotech called BlueWater Biosciences, would still need to be confirmed in humans; oftentimes results seen in animals don’t translate in the clinic. But the proposed approach, outlined in the journal Molecular Metabolism by some of the most well-known scientists in the field, is likely to stir controversy, as it challenges a central notion underpinning not just the development of approved obesity products but also next-generation versions.
Pregnancy Sickness Study Identifies New Genetic Links
The University of Southern California (USC) research team that identified the hormone-encoding gene GDF15 as a key driver of pregnancy sickness has identified nine additional genes linked to its most severe form, hyperemesis gravidarum (HG). Six of the identified genes had not been previously linked to the condition.
The Keck School of Medicine of USC team and international collaborators conducted a genome-wide association study (GWAS), scanning the entire genome for differences between women who developed HG during pregnancy and those who did not. They analyzed data from more than 10,000 women with the condition and more than 450,000 controls across European, Asian, African, and Latino ancestries. Their findings offer new clues about the condition and new hope for those affected.
Marlena Fejzo, PhD, a clinical assistant professor of population and public health sciences in the Center for Genetic Epidemiology at the Keck School of Medicine, led the present study and earlier research linking GDF15 to HG. Fejzo told GEN, “The study is much larger than previous studies and on a more diverse population allowing for identification of new genes associated with HG … The new genes give us new directions to explore for prediction, diagnosis, treatment, and response to therapies.”
Fejzo is first author of the team’s published report in Nature Genetics (“Multi-ancestry genome-wide association study of severe pregnancy nausea and vomiting”), in which the team stated, “Potential roles for candidate genes in appetite, insulin signaling, and brain plasticity provide pathways to explore etiological mechanisms and therapeutic avenues.”
HG, which affects about 2% of women, causes nausea and vomiting so severe that eating can become extremely difficult. “Most pregnancies are affected by nausea and vomiting (NVP), but in 0.3–10.8% of pregnancies the symptoms can be severe enough to cause maternal weight loss and adverse maternal and fetal outcomes,” the authors wrote. HG in its most severe form can even be life threatening.
HG was long misunderstood and often dismissed as psychological, growing evidence shows that it has a strong biological and genetic basis and can lead to severe malnourishment, putting both mother and baby at risk. Current treatments for HG are frequently ineffective in improving patient symptoms, the authors further pointed out, and so increase the risk of pregnancy termination, postpartum depression, and suicidal ideation, along with other maternal and offspring comorbidities. “Therefore, understanding of HG etiology is critical to begin to address the negative impact severe NVP has on maternal and child health.”
While historical hypotheses have previously centered around human chorionic gonadotropin (hCG), recent large-scale genetic studies have implicated the GDF15 gene encoding growth differentiation factor-15—a hormone associated with nausea and vomiting, the authors further pointed out. Earlier research by Fejzo and an international team had shown that the link between HG and GDF15 lies in women’s sensitivity to the hormone. They found that women exposed to lower levels of the hormone before pregnancy because of a mutation in the gene experience more severe symptoms, while women exposed to higher levels of the hormone before pregnancy have less severe nausea and vomiting symptoms.
“GDF15 was identified as the greatest genetic risk factor for HG in both a genome-wide and an exome-wide association study, and a rare mutation in GDF15 was associated with a greater than tenfold increased risk for HG,” the scientists noted in their newly reported study. Fejzo explained to GEN, “The mutation in GDF15 is rare. People who carry the mutation have abnormally low levels of GDF15 when they are not pregnant and that increases their risk of being hypersensitive to it during pregnancy when it is produced in massive amounts by the placenta.”
Commenting on their prior work implicating a role for GDF15 and HG, Fejzo further explained to GEN, “In our first GWAS study we found the association between the GDF15 gene and HG. Next, we published a whole-exome sequencing study that identified a mutation in GDF15 associated with HG. Then we published our study in Nature which provided strong evidence that hypersensitivity to the rise of GDF15 in pregnancy (due to low pre-pregnancy GDF15 in circulation) is the main driver of the condition.”
For their newly reported study the researchers carried out a multi-ancestry genome-wide association study of 10,974 HG/excessive vomiting in pregnancy cases and 461,461 controls across European, Asian, African, and Latino ancestries from nine contributing studies.
The results identified 10 genes that were linked to HG, including four that had previously been identified, and six new genes. “Because this is the largest study of HG ever conducted, we’ve been able to tease out important new details that were previously unknown,” said Fejzo. “The fact that we’ve studied women from multiple ancestry groups suggests that these results may be generalizable across a broad population.”
The four genes previously identified were growth differentiation factor 15 (GDF15), GFRAL, which produces the receptor for the GDF15 hormone of the same name, and IGFBP7 and PGR, both of which are involved in development of the placenta. The strongest link by far was to GDF15, which rises sharply during pregnancy. “We know that GDF15 and it’s receptor GFRAL are the main drivers and are in a signaling pathway that causes aversions, nausea, and vomiting,” Fejzo told GEN. “More work needs to be done to explore the other associations, but since studies suggest manipulating progesterone and/or IGFBP7 may not be safe in pregnancy, current studies are focusing on the GDF15 pathway.”
The six newly identified genes offer further clues that might help explain the basis of HG or point to new ways of treating it. They include FSHB, TCFL72 SLITRK1, SYN3, IGSF11, and CDH9. “Now that we’ve more than doubled the genes associated with HG, we can dig deeper into the biology behind this condition, as well as new possible pathways for treating it,” Fejzo said. Speaking to GEN, the researchers noted, “Because the new associations are novel, we need to understand the roles they may play in normal pregnancy and then compare that to pregnancies affected by HG.”
Of the newly identified genes, TCF7L2 stands out because it is one of the strongest genetic risk factors for type 2 diabetes and is also associated with gestational diabetes. “This is a brand-new target, and it’s not yet clear what it’s doing in pregnancy,” Fejzo said. In further commentary to GEN, Fejzo added, “The TCF7L2 gene is a type 2 diabetes-associated gene and a transcription factor that may control glucagon-like peptide-1 (GLP-1) expression and has been associated with liraglutide effects resulting in greater weight loss in obesity. So understanding its role in that rapidly evolving therapeutic arena has potential.”
Several of the other genes identified are involved in appetite and nausea, as well as brain plasticity, or how the brain learns and adapts to new information. Fejzo suggests the brain may learn to associate certain foods with feeling sick, leading to strong, lasting aversions during pregnancy. More research is needed to explore this possibility. “Other genes are associated with learning flexibility so we hypothesize that they may play a role in conditioned taste aversion and may provide new targets to alter or dampen learned aversions,” Fejzo told GEN. Historically, people believed the pregnancy hormone hCG was the cause, but we found no evidence to support that and instead, fascinatingly, we found a link to the follicle stimulating hormone receptor.”
Of the ten candidate genes six—GDF15, GFRAL, IGFBP7, PGR, TCF7L2 and SYN3—have been linked with cachexia—a wasting condition with similar symptoms to HG, including loss of appetite, weight loss and muscle wasting, the scientists noted. “Manipulation of GDF15, GFRAL, IGFBP7, PGR and TCF7L2 in animal models has shown effectiveness in reducing symptoms of cachexia. Thus, assuming analogous functions for these factors in HG, there is both genetic and biological support for causal and potentially reversible contributions for these genes in NVP.”
The researchers also found that some genes linked to HG were associated with other pregnancy outcomes. “This study also identified individual associations between risk genes and adverse outcomes including shorter pregnancy duration, pre-eclampsia, and birth weight,” they noted.
Several medications are available for treating HG, but even the most effective, Zofran, only partly relieves symptoms for about half of patients. The new findings reveal new potential treatment targets and could possibly also help match existing medications to patients based on their genetic profiles. “The ten genetic associations provide intriguing avenues to advance our understanding and pursue therapeutic pathways for a common pregnancy condition that in its most severe form is associated with substantial morbidity and even mortality for mothers and exposed offspring,” the scientists concluded.
Fejzo and her team just received approval to launch a clinical trial of metformin, a widely used diabetes medicine that increases GDF15 levels. The study will test whether taking metformin before pregnancy can desensitize women to the hormone, potentially reducing nausea and vomiting or preventing HG in women who have had it before. GEN was told, “We will be initiating a clinical trial to increase GDF15 prior to pregnancy in patients with a history of HG and planning to conceive to desensitize them to the hormone’s rapid rise in early pregnancy. We and others have shown preliminary evidence that this approach may work as in our retrospective study pre-pregnancy metformin use was associated with a significant reduction in HG risk.”
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DNA Tests to Predict GLP-1 Drug Response to Launch in 2026
PrecisionLife and Ovation.io have signed a commercialization agreement to bring GLP-1 response genetic tests to the market. Today, the partners announced plans to launch both direct-to-consumer and laboratory developed tests later this year.
The companies had entered a collaboration at the end of last year, leveraging Ovation’s multi-omics and longitudinal clinical data and PrecisionLife’s advanced analytics platform to uncover genetic mechanisms of response to GLP-1 medication. Earlier this year, they reported the identification of a series of biomarker signatures that can quantitatively predict which patients are most likely to respond to GLP-1 therapies and sustain that response over time.
The partners are now actively working on translating this discovery into noninvasive genetic tests for patients to make informed decisions about the likely risks and benefits of these increasingly popular drugs, as well as for drug developers to stratify patients in clinical trials.
“Our teams have generated the world’s most detailed insights into why patients respond differently to these medicines,” said Steve Gardner, chief executive officer of PrecisionLife. “We will make these insights clinically actionable via noninvasive DNA tests supported by our results reporting platform and CLIA lab partners.”
PrecisionLife stressed that their findings go beyond the GLP-1 genetic predictors reported last week by 23andMe. “While that study highlighted a handful of variants associated with modest differences in outcomes, this work identifies combinatorial biomarker signatures that stratify patients and quantitatively predict response—and is already being translated into tests designed for use in real treatment decisions,” a company representative told Inside Precision Medicine.
Over the course of the next six months, PrecisionLife will reproduce, refine, and validate their findings using additional datasets provided by Ovation, including studies to confirm the predicted response to GLP-1 drugs including semaglutide and tirzepatide in a real-world context.
The launch of a consumer DNA test is expected to enable patients to understand their individual safety, efficacy, and tolerability profile for GLP-1 drugs before starting treatment. This could also offer providers a clearer basis for selecting therapies and help payors make more sustainable coverage decisions. The collaborators have stated they will evaluate the opportunity of using these tests to inform reimbursement decisions and expand coverage of certain health plans based on an individual’s predicted response.
For drug developers, laboratory developed tests (LDT) could open up opportunities for more precise patient stratification, improving the probability of success in clinical trials evaluating the expansion of GLP-1 drugs into new indications. The companies are currently in discussions with various stakeholders and sponsors to deploy the LDTs as stratification tools in a clinical setting.
“We’re confident that together we can translate those insights into commercial outcomes and products in GLP-1s and other diseases with huge clinical impact,” said Curt Medeiros, chief executive officer of Ovation.io.
Going forward, the partners will continue to validate their findings and expand the scope of the studies, including identifying additional markers of safety and tolerability to GLP-1 drugs as well as pinpointing further efficacy and safety signals for individual molecules.
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Syncing Exercise to Body Clock Maximizes Cardiovascular Benefits
Timing exercise according to a person’s natural propensity towards being a “morning lark” or an “night owl” could maximize its cardiovascular benefits, a randomized trial suggests.
Matching exercise according to individual body clocks maximized the sleep quality and several parameters of cardiovascular health of middle-aged adults with preclinical risk factors.
The findings highlight the added value of incorporating circadian biology into exercise plans to optimize health outcomes.
Reporting their findings in Open Heart, the researchers suggest that assessing for chronotype—the predisposition towards morningness or eveningness—should be considered when prescribing exercise for those at risk of cardiometabolic disease.
“Our study shows that when you exercise may be just as important as how you exercise,” researcher Arsalan Tariq, PhD, from the University of Lahore, explained to Inside Precision Medicine.
“Aligning workouts with an individual’s biological clock significantly amplifies cardiovascular and metabolic benefits, offering a simple way to personalize prevention and improve adherence.”
A person’s chronotype affects their sleeping patterns, hormonal secretion, and energy levels during the day through an internal timing mechanism.
This is regulated by the circadian clock in a system that influences various physiological processes including blood pressure, heart rate, glucose metabolism, and vascular function.
Tariq and team examined how timing exercise affected key indicators of cardiovascular health among at-risk middle-aged adults.
Participants were aged 40 to 60 years and had at least one cardiovascular risk factor, such as high blood pressure, overweight, or obesity. The group also included those with a family history of premature cardiovascular disease.
Participants were randomly assigned to exercise at a time that either matched or did not match their chronotype, between 8am and 11am or between 6pm and 9pm.
This consisted of five, 40-minute sessions per week of supervised moderate intensity aerobic exercise such as brisk or treadmill walking for 12 weeks.
Of the 134 participants who completed the 60 sessions, 70 were larks—34 of whom had exercise matched with chronotype—and 64 were owls, with 30 matched to chronotype.
Measurements taken at the start of the trial and three days after it finished showed particular improvements in sleep and systolic blood pressure among those matched with chronotype.
Sleep quality improved by 3.4 points in matched participants versus 1.2 in the unmatched on the Pittsburgh Sleep quality Index. Systolic blood pressure dropped by 10.8 mmHg compared with 5.5mmHg in matched versus unmatched groups, respectively.
Chronotype-aligned exercise also led to significantly greater improvements in diastolic blood pressure, heart rate variability, peak oxygen consumption, low-density lipoprotein, and fasting glucose compared with misaligned exercise.
“Personalized, time-matched exercise interventions may become a practical strategy in clinical and public health settings, potentially leading to better outcomes and improved engagement,” the researchers reported.
“Future research and guidelines may consider circadian factors as a core component of lifestyle-based disease prevention.”
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STAT+: Pharmalittle: We’re reading about FDA seeking more data on a Lilly obesity pill, a pharma 340B win, and more
Top of the morning to you. The middle of the week is upon us and, since you made it this far, why not forge ahead? After all, there is always light at the end of the proverbial tunnel. You never know what you may accomplish. So please join us as we celebrate this notion with a cup or three of delicious stimulation. Our choice today is chocolate raspberry. Meanwhile, we have assembled the latest menu of tidbits to help you along. So please dig in. Have a smashing day, and please feel free to forward any secrets you come across. Our “in basket” is always open. …
The U.S. Food and Drug Administration asked Eli Lilly for more data on liver injury linked to its newly approved obesity pill, Reuters says, citing a letter posted on the agency website. The April 1 letter also said Lilly must conduct post-marketing trials to assess risks related to cardiovascular events and delayed gastric emptying. The drugmaker is required to also conduct a milk-only lactation study in lactating women who have received a dose of the pill to assess concentrations of the drug in breast milk using a validated assay. The weight loss pill, branded Foundayo, a once-daily oral medication that targets the GLP-1 hormone, won approval earlier this month under the Commissioner’s National Priority voucher program, which aims to speed FDA decisions on drugs deemed critical to public health or national security.
AbbVie, Novartis, AstraZeneca, and the Pharmaceutical Research & Manufacturers of America, the industry trade group, notched a victory after a U.S. appeals court vacated an order rejecting their request to block a Maryland drug discount law, remanding the decision for review, Bloomberg Law reports. The U.S. Court of Appeals for the Fourth Circuit ruled that a lower court erred when it denied a motion filed by the companies and the trade group for a preliminary injunction against a Maryland law. H.B. 1056, currently in effect, requires manufacturers to distribute discounted drugs to an unlimited number of pharmacies that contract with health providers under the 340B Drug Discount Program. They argued the law improperly forces drug companies to supply so-called contract pharmacies as part of the program, and that the law is illegal because it is preempted by federal law and also violates the U.S. Constitution.
Gut microbiota profiles in anorexia nervosa: associations with disease severity, BMI, and history of childhood trauma
Study objectivesEmerging evidence suggests a possible link between anorexia nervosa (AN) and alterations in the gut microbiota. This study aimed to characterize the gut microbiota profile in a cohort of Chinese female patients with AN.MethodA comparative analysis of the gut microbiota was conducted between 30 female patients with AN and 30 sex- and age-matched healthy controls (HCs). Fecal samples were collected for 16S rRNA gene sequencing analysis. All participants were assessed using the Eating Disorder Inventory (EDI) and the Childhood Trauma Questionnaire (CTQ). Bioinformatics analysis was performed using QIIME2, and statistical analyses were carried out with SPSS 26.0 and R software. Correlations between microbiota differences and body mass index (BMI), EDI, and CTQ were further investigated.ResultsThe analysis revealed differences in beta diversity and the abundances of specific microbial taxa between the two groups; however, no significant differences were observed in alpha diversity nor in the associations between gut microbiota and BMI, disease severity, or childhood trauma.ConclusionsThis study identified limited differences in the gut microbiota composition between patients with AN and HCs. Critically, no robust associations between gut microbiota and clinical features were found after rigorous multiple comparison correction. While nominal (uncorrected) correlations were observed between the specific microbiota and psychological traits, these results are exploratory and should be considered hypothesis-generating. They highlight a potential avenue for future research but require validation in larger, longitudinal cohorts to determine their reproducibility and biological significance.
GLP-1 Drug Improves Liver Health Independent of Weight Loss, Mouse Study Finds
Studying mice, researchers at Toronto’s Sinai Health have found that semaglutide—the active ingredient in popular weight loss drugs that mimic the gut hormone GLP-1—acts directly on a subset of liver cells to improve organ function, and does so independently of weight loss. The finding challenges long-held assumptions about how GLP-1 medicines work in the liver and could reshape how physicians treat metabolic liver disease.
Headed by Daniel Drucker, MD, a senior investigator at the Lunenfeld-Tanenbaum Research Institute, the team reported on their findings in Cell Metabolism, in a paper titled “The weight-loss-independent hepatoprotective benefits of semaglutide are orchestrated by intrahepatic sinusoidal endothelial GLP-1 receptors.”
For years, the liver benefits of semaglutide have puzzled scientists. “Glucagon-like peptide-1 (GLP-1) medicines improve metabolic liver disease through weight-loss-dependent and -independent actions,” the authors wrote. The drug was known to lower blood sugar and promote weight loss, but patients’ livers were improving in ways that those effects alone could not explain. And as the authors further noted, “The therapeutic scope of GLP-1 medicines extends beyond glycemic control and weight loss, with benefits evident in people with atherosclerotic heart disease, heart failure with preserved ejection fraction (HFpEF), peripheral artery disease, diabetic kidney disease, knee osteoarthritis, and obstructive sleep apnea (OSA).” However, as the team further pointed out, “… the mechanisms by which GLP-1 medicines improve organ dysfunction remain incompletely understood.”
Drucker has been at the forefront of GLP-1 research since the 1980s when his pioneering discoveries helped lay the groundwork for the development of GLP-1 medicines. After transforming treatment of type 2 diabetes and obesity, semaglutide and other GLP-1 medicines have been approved for other conditions including MASH (metabolic dysfunction-associated steatohepatitis). MASH is a severe form of fatty liver disease in which fat build-up, inflammation, and tissue scarring can lead to cirrhosis and liver failure. It affects about 25% Canadian adults and because it is closely linked with obesity and type 2 diabetes, treatment typically includes lifestyle interventions to reduce weight. “The approval of semaglutide for MASH highlights the importance of understanding the hepatoprotective mechanisms of GLP-1 action,” the investigators stated.
Drucker and colleagues have now found that semaglutide acts directly on the liver to reduce inflammation and scarring and improve organ function in a way that is independent of weight loss. Their finding overturns a prevailing assumption in the field that liver cells do not carry the receptor that semaglutide binds to, meaning the drug had no direct route to the organ.
Postdoctoral researcher Maria Gonzalez-Rellan, PhD, spearheaded the work that combined sophisticated mouse models of MASH with deep molecular analyses of liver cells. Her work identified two cell types carrying semaglutide receptors: liver sinusoidal endothelial cells (LSECs) and immune T cells. Although LSECs account for only about 3% of liver cell volume, they proved to be the key driver of semaglutide’s liver benefits.
![A pioneer in GLP-1 biology Dr. Daniel Drucker has dedicated his career to understanding how the GLP-1 hormone, and the therapies derived from it, function in the body. His early discovery that GLP-1 stimulates insulin secretion in a glucose-dependent manner paved the way for today's widely popular medications for type 2 diabetes and obesity. Dr. Drucker's ongoing research continues to shine light on the less understood aspects of GLP-1 biology including its effects on the liver and in regulating inflammation. [Colin Dewar, Sinai Health]](https://www.genengnews.com/wp-content/uploads/2026/04/Low-Res_Drucker_LTRI_Colin_Dewar-225x300.jpeg)
LSECs line the tiniest blood vessels in the liver and are studded with pores that allow them to act as a molecular sieve, filtering substances passing between the liver and the bloodstream. Gonzalez-Rellan showed that semaglutide reversed MASH in mice that lacked the brain receptors controlling appetite, demonstrating that weight loss is not required for liver benefits. “Unexpectedly. semaglutide improves hepatic inflammation, fibrosis, and immune remodeling through actions on Glp1r+ pericentral liver sinusoidal ECs (LSECs) independent of changes in body weight (BW),” the team reported. “… we leveraged a unique model of GLP-1R deficiency, Glp1rWnt1-/- mice, which are resistant to GLP-1RA-induced weight loss. Remarkably, semaglutide markedly improved hepatic steatosis, fibrosis, and immune remodeling in the absence of weight reduction.”
In a further test, mice lacking LSEC receptors showed no liver improvement on semaglutide even after losing 20% of their body weight. Detailed molecular analyses of liver cell types showed that semaglutide shifts gene activity in LSCEs, prompting them to release anti-inflammatory molecules that act on the broader liver environment, pushing it toward a state more closely resembling a healthy, disease-free liver. “Together, the data using mouse models of MASH reveal an EC-specific, weight-loss-independent, semaglutide-regulated, GLP-1R-dependent intrahepatic network for improving liver health,” the scientists said.
“It turns out that the receptor responsible for these benefits is in a very specialized population of liver cells,” commented Drucker, who is also a professor of medicine at the University of Toronto. “And this receptor orchestrates the production of molecules that talk to many different types of liver cells to calm down the inflammatory environment that is the problem in metabolic disease.”
The findings carry practical implications. GLP-1 medicines have become widely prescribed, yet their mechanism of action in the body, beyond appetite suppression and blood sugar control, have remained incompletely understood. Knowing that semaglutide improves liver health independently of weight loss could influence prescribing decisions. “We’ve seen in clinical trials that patients who lose very little weight see the same reductions in liver inflammation, scarring and enzyme levels as those who lose a great deal of weight. Now we know why,” Drucker pointed out. In their paper the team concluded “Hence, semaglutide produces a broad proteomic remodeling of the liver, enabling restoration of metabolic homeostasis and suppression of fibrogenic and inflammatory programs. The strong concordance between single-cell transcriptional changes, bulk tissue proteomics, and biomarker signatures underscores the breadth of GLP-1R-mediated hepatic reprogramming.”
Physicians may choose lower doses that avoid the side effects associated with the higher doses needed for significant weight loss, potentially also lowering costs for patients, Drucker suggested adding “We’re not saying weight loss isn’t important because many things improve when patients lose weight. But we now know that weight shouldn’t be the only measure of success, because GLP-1 medicines will improve liver health whether or not the patient loses weight.”
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