American journal of physiology. Endocrinology and metabolism最新文献

{"title":"Effect of <i>in utero</i> Metformin Exposure in Gestational Diabetes Mellitus on Infant Mesenchymal Stem Cell Metabolism.","authors":"Ericka M Biagioni, John C Rowe, Sripallavi Yendamuri, Breanna L Wisseman, Donghai Zheng, Guo-Fang Zhang, Deborah Muoio, James E DeVente, Kelsey Fisher-Wellman, Peter Darrell Neufer, Linda E May, Nicholas T Broskey","doi":"10.1152/ajpendo.00428.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00428.2024","url":null,"abstract":"<p><p>Offspring exposed to metformin treatment for gestational diabetes mellitus (GDM) experience altered growth patterns that increase the risk for developing cardiometabolic diseases later in life. The adaptive cellular mechanisms underlying these patterns remain unclear. Therefore, the objective of this study was to determine if chronic <i>in utero</i> metformin exposure associated with GDM treatment elicits infant cellular metabolic adaptations. In a cross-sectional design, 22 pregnant women diagnosed with GDM and treated exclusively with metformin (Met; n=12) or diet (A1DM; n=10) were compared. Umbilical cord derived mesenchymal stem cells (MSCs) were used as a model to study infant metabolism <i>in vitro</i>. OXPHOS and citrate synthase content were assessed by Western blot and intracellular lipid content was measured by Oil Red-O staining. Substrate oxidation and insulin action were measured with ¹⁴C radiolabeled glucose and oleate at baseline and following a 24-hour lipid challenge. Mitochondrial respiration was assessed by high-resolution respirometry. While no differences in infant birth measures were observed between groups, MSC outcomes revealed lower oleate oxidation rates (p=0.03) and lower mitochondrial capacity (p=0.009) among Met-MSCs. These findings suggest differences in energy metabolism may be present at birth among infants exposed to metformin <i>in utero</i>. Lower oleate oxidation and mitochondrial capacity in infant MSC may contribute to altered growth patterns that have been reported among offspring of metformin treated pregnant women with GDM.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vertical sleeve gastrectomy and semaglutide have distinct effects on skeletal health and heart function in obese male mice.","authors":"Caroline de Carvalho Picoli, Sergey Tsibulnikov, Mavy Ho, Victoria Demambro, Tiange Feng, May Eltahir, Phuong T Le, Carolyn Chlebek, Clifford J Rosen, Sergey Ryzhov, Ziru Li","doi":"10.1152/ajpendo.00521.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00521.2024","url":null,"abstract":"<p><p>Obesity is a global health challenge associated with significant metabolic and cardiovascular risks. Bariatric surgery and GLP-1 receptor agonists (GLP-1RAs) are effective interventions for weight loss and metabolic improvement, yet their comparative effects on systemic metabolism-particularly energy metabolism, bone health, and heart function-remain unclear. In this study, obese male mice underwent vertical sleeve gastrectomy (VSG), 6 weeks of GLP-1RA (semaglutide) treatment, or sham procedure with saline injection as controls. Dynamic changes in body weight, food intake, fat mass, lean mass and bone mineral density were monitored. Energy metabolism was assessed using indirect calorimetry. Bone parameters and heart function were evaluated by micro-computed tomography or echocardiography, respectively. Compared to obese controls, VSG and semaglutide treatment comparably reduced body weight and improved glucose metabolism. However, VSG decreased energy expenditure, whereas both treatments similarly promoted lipid utilization. Semaglutide treatment increased ambulatory activity during nighttime. VSG led to significant bone loss, while 6 weeks of semaglutide treatment had no significant effects on the skeleton. Cardiovascular outcomes also differed: VSG increased stroke volume without altering heart mass, whereas semaglutide reduced heart mass and transiently elevated heart rate. These findings underscore the importance of carefully weighing the benefits and potential risks of different weight loss treatments when addressing obesity and its systemic complications.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Central FGF19 signaling enhances energy homeostasis and adipose tissue thermogenesis through sympathetic activation in obese mice.","authors":"Lucas Zangerolamo, Marina Carvalho, Carina Solon, Davi Sidarta-Oliveira, Gabriela M Soares, Carine Marmentini, Antonio C Boschero, Yu-Hua Tseng, Licio A Velloso, Helena C L Barbosa","doi":"10.1152/ajpendo.00488.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00488.2024","url":null,"abstract":"<p><p>Fibroblast growth factor 19 (FGF19) signaling in the brain is associated with body weight loss, reduced food intake, and improved glycemic control in obese mice through unclear mechanisms. Here, we investigated the effects of central FGF19 administration on peripheral tissues, focusing on adipose tissue, and its contributions to body weight loss. Using single-cell RNA sequencing of the adult murine hypothalamus, we found that FGF19 has the potential to target multiple cell populations, including astrocytes-tanycytes, microglia, neurons, and oligodendrocytes. Central delivery of FGF19 decreased body weight gain and ameliorated glucose-insulin homeostasis in diet-induced obese (DIO) mice. These results were accompanied by increased energy expenditure and reduced peripheric inflammation. Notably, these effects were attributable to the increased activity of thermogenic adipocytes, as up-regulated thermogenic markers in brown and inguinal adipose tissue and improved cold tolerance were induced by central FGF19. However, under blunted sympathetic activity, the described effects were abolished. Moreover, cold exposure induced upregulation of FGF19 receptors and coreceptors specifically in the hypothalamus, suggesting a critical metabolic adaptation for thermoregulation and energy homeostasis. Our findings indicate that central FGF19 signaling improves energy homeostasis in DIO mice, at least in part, by stimulating sympathetic activity and adipose tissue thermogenesis. These findings highlight FGF19's potential as a therapeutic target for obesity and metabolic disorders.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of A Novel Regulator, 3β-Sulfate-5-Cholestenoic Acid, of Lipid Metabolism and Inflammation.","authors":"Yaping Wang, Arun J Sanyal, Phillip Hylemon, Shunlin Ren","doi":"10.1152/ajpendo.00426.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00426.2024","url":null,"abstract":"<p><p>Mitochondrial oxysterols, cholestenoic acid (CA), 25-hydroxycholesterol (25HC), and 27-hydroxycholesterol (27HC), are potent regulators involved in many important biological events. This study aimed to investigate the metabolic pathways of these oxysterols and their roles between hepatocytes and macrophages. LC-MS-MS analysis showed a novel regulatory molecule, 3β-sulfate-5-cholestenoic acid (3SCA), following addition of CA in media culturing hepatocytes. Further study showed that 3SCA could also derived from 27HC. As comparison, 25HC was converted to 25HC3S, of which mostly remained in the cells and nuclei. Functional study showed that 3SCA significantly downregulated the expression of genes involved in lipid metabolism in hepatocytes and suppressed gene expression of pro-inflammatory cytokines induced by LPS in human macrophages. Based on the results, we conclude that 3SCA acts as a secretory regulator for the regulation of lipid metabolism and inflammatory responses in hepatocytes and macrophages. These findings shed light on understanding the unique metabolic pathways of these oxysterols and their possible roles in liver tissues.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypothalamus and brainstem circuits in the regulation of glucose homeostasis.","authors":"Zitian Lin, Yunxin Xuan, Yingshi Zhang, Qirui Zhou, Weiwei Qiu","doi":"10.1152/ajpendo.00474.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00474.2024","url":null,"abstract":"<p><p>The central nervous system (CNS) senses and integrates blood glucose status, regulating its levels through communication with peripheral organs. While traditional wisdom holds that the hypothalamus primarily controls glucose homeostasis, the brainstem, although less studied, has been emerging as a key player in blood glucose metabolism. While the brainstem is reciprocally wired with the hypothalamus, their interactions are crucial for glucose control. Here, we focus on classic discoveries and recent advancements of hypothalamic and brainstem nodes that regulate glucose homeostasis. Based on the current progress and development for central regulation of blood sugar, we propose that the circuitry and cellular mechanisms for how hypothalamus and brainstem coordinate in blood sugar regulation are crucial, hence, a deeper understanding of both nuclei could shed light on a future cure for diabetes.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma complement system markers and their association with cardiometabolic risk factors: an ethnic comparison of White European and Black African men.","authors":"Reuben M Reed, Wioleta M Zelek, B Paul Morgan, Gráinne Whelehan, Sam Lockhart, Stephen O'Rahilly, Oliver C Witard, Martin B Whyte, Louise M Goff","doi":"10.1152/ajpendo.00419.2024","DOIUrl":"https://doi.org/10.1152/ajpendo.00419.2024","url":null,"abstract":"<p><p>Populations of Black African (BA) ancestry are disproportionately affected by cardiometabolic diseases, possibly due to dysregulation of the complement system. This study aimed to determine 1) relationships between fasting complement markers and cardiometabolic risk in BA and White European (WE) men, and 2) whether postprandial complement response differs by ethnicity. Eighty-eight BA and 97 WE men (age=44.4 [42.0-47.6] years, BMI=29.2±4.5 kg/m²) were assessed for fasting plasma complement markers and cardiometabolic risk factors. A second cohort (<i>n</i>=20 men, 10 BA) (age=31.0±1.1 years, BMI=27.1 [26.0-28.6] kg/m²) men underwent a moderate-to-high-fat feeding protocol to measure postprandial plasma complement, serum insulin, plasma glucose, TAG and non-esterified fatty acids. C4 and Factor D were lower, and iC3b was higher, in BA compared with WE men. C3 and C4 were strongly associated with all adiposity markers in both ethnicities, but the WE cohort showed stronger associations between C3 and subcutaneous adipose tissue, C5 and WC, and iC3b and visceral adipose tissue compared with BA. C3 was associated with all cardiometabolic risk factors in both ethnicities. Associations between C5 and cholesterol, C4 and TAG, and TCC and (both total and LDL)-cholesterol were only observed in the WE cohort. There was a trend towards ethnic differences in postprandial Factor D (<i>P</i>=0.097) and iC3b (<i>P</i>=0.085). The weaker associations between the complement system markers with adiposity and lipid profiles in BA compared with WE men suggest ethnic differences in the determinants of complement production and activation, whereby adipose tissue may play a less important role in BA men.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise alters molecular profiles of inflammation and substrate metabolism in human white adipose tissue.","authors":"Maria F Pino, Pieter Dijkstra, Katie L Whytock, Cheehoon Ahn, Gongxin Yu, James A Sanford, Josh Hansen, Chelsea Hutchinson, Marina Gritsenko, Paul Piehowski, Joshua N Adkins, Elvis A Carnero, Stuart Sealfon, Elena Zaslavsky, Venugopalan Nair, Steve R Smith, Lauren M Sparks","doi":"10.1152/ajpendo.00339.2024","DOIUrl":"10.1152/ajpendo.00339.2024","url":null,"abstract":"<p><p>White adipose tissue (WAT) plays a significant role in whole body energy homeostasis, and its excess typifies obesity. In addition to WAT quantity, perturbations in the basic cellular processes of WAT (i.e., quality) are also associated with obesity and metabolic disease. Exercise training alleviates metabolic perturbations associated with obesity; however, the underlying molecular mechanisms that drive these metabolic adaptations in WAT are not well described. Abdominal subcutaneous WAT biopsies were collected after an acute bout of exercise (1 day after) at baseline and following 3 wk of supervised aerobic training in sedentary overweight women (<i>n</i> = 6) without alterations in body weight and fat mass. RNA-seq, global proteomics, and phosphoproteomics in WAT revealed training-induced changes in 1,527 transcripts, 154 proteins, and 144 phosphosites, respectively. Training decreased abundance of transcripts and proteins involved in inflammation and components of the extracellular matrix and increased abundance of transcripts and proteins related to fatty acid esterification and lipolysis. In summary, short-term aerobic training significantly reduces local inflammation and increases lipid metabolism in WAT of sedentary overweight women-independent of alterations in body and fat mass. As such, some of the health benefits of aerobic training may occur through molecular alterations in WAT (i.e., enhanced quality) rather than a sheer reduction in WAT quantity.<b>NEW & NOTEWORTHY</b> This is the first study to utilize a multiomic (RNAseq, proteomics, and phosphoproteomics) approach to investigate molecular adaptations in WAT after a short-term intervention in sedentary overweight women. We show that supervised aerobic training reduces molecular markers of inflammation and proteins regulating ECM and increases abundance of transcripts and proteins involved in lipolysis and fatty acid re-esterification, indicating that molecular adaptations in WAT occur independent of alterations in body weight or fat mass.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E478-E492"},"PeriodicalIF":4.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single incretin receptor knockout mice do not compensate by increasing glucose-stimulated secretion of the remaining incretin hormone.","authors":"Katrine D Galsgaard, Jon Vergara, Sara L Jepsen, Alice Bazzichi, Hannelouise Kissow, Mark M Smits, Jens J Holst","doi":"10.1152/ajpendo.00437.2024","DOIUrl":"10.1152/ajpendo.00437.2024","url":null,"abstract":"<p><p>Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones. Lack of GLP-1 receptor signaling has been reported to be compensated for by increased GIP secretion and action. Conversely, GLP-1 sensitivity has been reported to be increased in GIP receptor knockout (<i>Gipr</i>^-/-) mice. This suggests a compensatory adaptation to the loss of incretin signaling via increased action/secretion of the remaining incretin hormone. We assessed glucose-stimulated GIP and GLP-1 secretion during oral glucose tolerance tests (OGTTs) and in isolated perfused intestines of GLP-1 receptor knockout (<i>Glp-1r</i>^-/-) mice and their wild-type littermates (<i>Glp-1r</i>^+/+) and in <i>Gipr</i>^-/- mice and their wild-type littermates (<i>Gipr</i>^+/+). Sensitivity to GIP and GLP-1 was assessed in isolated perfused pancreases of <i>Glp-1r</i>^-/- and <i>Glp-1r</i>^+/+ mice and <i>Gipr</i>^-/- and <i>Gipr</i>^+/+ mice, respectively. We found similar GIP responses in <i>Glp-1r</i>^-/- and <i>Glp-1r</i>^+/+ mice and similar GLP-1 responses in <i>Gipr</i>^-/- and <i>Gipr</i>^+/+ mice during the OGTTs and in the isolated perfused intestines. Insulin responses to GIP and GLP-1 were similar in <i>Glp-1r</i>^-/- and <i>Glp-1r</i>^+/+ mice and in <i>Gipr</i>^-/- and <i>Gipr</i>^+/+ mice, respectively. Our results do not support the existence of a compensatory adaptation to the loss of single incretin signaling via increased glucose-stimulated secretion of, or sensitivity to, the remaining incretin hormone.<b>NEW & NOTEWORTHY</b> We show that mice lacking the GLP-1 receptor do not compensate by increased glucose-stimulated GIP secretion or sensitivity, nor do mice lacking the GIP receptor compensate by increased glucose-stimulated GLP-1 secretion or sensitivity. The notion of a compensatory adaptation to the loss of single incretin signaling via increased action/secretion of the remaining incretin hormone was thus not supported using single incretin receptor knockout mice.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E435-E446"},"PeriodicalIF":4.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"VPS41 deletion triggers progressive loss of insulin stores and downregulation of β-cell identity.","authors":"Belinda Yau, Yousun An, Mark Germanos, Patricia Schwarzkopf, A Gabrielle van der Kraan, Mark Larance, Hayley Webster, Christian Burns, Cedric S Asensio, Melkam A Kebede","doi":"10.1152/ajpendo.00389.2024","DOIUrl":"10.1152/ajpendo.00389.2024","url":null,"abstract":"<p><p>Vacuolar protein sorting-associated protein 41 (VPS41) has been established as a requirement for normal insulin secretory function in pancreatic β cells. Genetic deletion of <i>VPS41</i> in mouse pancreatic β cells results in diabetes, although the mechanisms are not understood. Presently, we show that <i>VPS41</i> deletion results in rapid mature insulin degradation and downregulation of β-cell identity. This phenotype is observed in vivo, with <i>VPS41</i>KO mice displaying progressive loss of insulin content and β-cell function with age. In acute <i>VPS41</i> depletion in vitro, the loss of insulin is associated with increased degradative pathway activity, increased Adapter Protein 3 complex colocalization with lysosomes, increased nuclear localization of transcription factor E3, and downregulation of <i>PDX1</i> and <i>INS</i> mRNA expression. Inhibition of lysosomal degradation rescues the rapidly depleted insulin content. These data evidence a VPS41-dependent mechanism for both insulin content degradation and loss of β-cell identity in β cells.<b>NEW & NOTEWORTHY</b> In this study, we show that acute <i>VPS41</i> deletion results in rapid degradation of insulin, whereas chronic <i>VPS41</i> deletion results in downregulation of β-cell identity. In acute <i>VPS41</i> depletion in vitro, the loss of insulin is associated with increased degradative pathway activity, increased Adapter Protein 3 complex colocalization with lysosomes, increased nuclear localization of transcription factor E3, and downregulation of <i>PDX1</i> and <i>INS</i> mRNA expression. Inhibition of lysosomal degradation rescues the rapidly depleted insulin content.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E457-E469"},"PeriodicalIF":4.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel soluble guanylate cyclase activator, avenciguat, in combination with empagliflozin, protects against renal and hepatic injury in diabetic <i>db/db</i> mice.","authors":"Nisha Sharma, Wenjin Liu, Xiao-Qing E Tsai, Zhou Wang, Connor Outtrim, Anna Tang, Michael P Pieper, Glenn A Reinhart, Yufeng Huang","doi":"10.1152/ajpendo.00254.2024","DOIUrl":"10.1152/ajpendo.00254.2024","url":null,"abstract":"<p><p>Diabetic complications are linked to oxidative stress, which hampers the cyclic guanosine monophosphate production by inhibiting nitric oxide/soluble guanylate cyclase (sGC) signaling. This study aimed to determine whether the administration of a novel sGC activator avenciguat alone or in combination with an SGLT2 inhibitor could slow the progression of renal and liver fibrosis in the type 2 diabetic and uninephrectomized <i>db/db</i> mouse model. Experiment groups included normal controls, untreated <i>db/db</i> mice terminated at 12 and 18 wk of age, and <i>db/db</i> mice treated with either one of two doses of avenciguat alone, empagliflozin (Empa) alone, or a combination of both from <i>weeks 12</i> to <i>18</i> of age. Untreated <i>db/db</i> mice exhibited obesity, hyperglycemia, elevated levels of HbA1c and triglycerides (TG), and developed progressive albuminuria, glomerulosclerosis, fatty liver, and liver fibrosis between <i>weeks 12</i> and <i>18</i> of age, accompanied by increased renal and liver production of fibronectin, type-IV collagen, laminin, and increased oxidative stress markers. Avenciguat had no effect on body weight but reduced both blood HbA1c and TG levels, whereas Empa reduced HbA1c but not TG levels as compared with untreated <i>db/db</i>. Both avenciguat and Empa alone effectively slowed the progression of diabetes-associated glomerulosclerosis and liver fibrosis. Importantly, avenciguat, especially at high doses in combination with Empa, further lowered these progression markers compared with baseline measurements. These results suggested that either avenciguat alone or in combination with Empa is therapeutic. Avenciguat in combination with Empa shows promise in halting the progression of diabetic complications.<b>NEW & NOTEWORTHY</b> Whether combining an sGC activator with an SGLT2 inhibitor could better control diabetes-associated oxidative stress and NO-cGMP signal deficiency has not yet been explored. Using the type 2 diabetic <i>db/db</i> mouse model, this study underscores the sGC activator avenciguat as a novel therapy for diabetic nephropathy and liver injury beyond sGLT2 inhibitors. It also highlights the need for further investigation into the combined effects of these two treatments in managing diabetic complications.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":"E362-E376"},"PeriodicalIF":4.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}