This study examined the effects of exercise on islet fibrosis in mice with type 2 diabetes and investigated the role of irisin in the regulation of islet stellate cell (ISC) activation. Following the 16-week moderate-intensity exercise intervention, db/db mice showed reduced body weight and improved glucose tolerance and insulin sensitivity. This exercise intervention also decreased collagen-I (Col-I), fibronectin (FN), and α-smooth muscle actin (α-SMA); reduced islet fibrosis area (assessed by Masson staining); and lowered the numbers of α-SMA-positive ISCs in the pancreas. Serum irisin was increased after a single bout of moderate-intensity exercise but decreased following the 16-week exercise intervention. In vitro experiments showed that irisin suppressed ISC activation by delaying lipid droplet loss, inhibiting migration, and reducing expression of α-SMA, Col-I, and FN. Irisin also attenuated advanced glycation end products-or transforming growth factor-β (TGF-β)-induced ISC activation and extracellular matrix production and competitively bound to TGF-β receptor 2 (TGFBR2), inhibiting TGF-β/Smad pathway phosphorylation. These findings suggest that exercise may help to alleviate diabetes-related islet fibrosis, in part by suppressing ISC activation via irisin-mediated inhibition of TGF-β/Smad signaling.

Importance Oral small-molecule glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may address limitations of injectable and peptide-based agents for type 2 diabetes. Objective To evaluate the efficacy and safety of HRS-7535, an oral nonpeptide GLP-1 RA, as add-on therapy among adults with type 2 diabetes inadequately controlled with metformin. Design, Setting, and Participants This 16-week, phase 2, double-blind, placebo-controlled randomized clinical trial was conducted at 44 centers in China. Adults aged 18 to 75 years with type 2 diabetes, hemoglobin A 1c (HbA 1c ) levels ranging from 7.5% to 11.0%, and receiving stable metformin therapy were enrolled between May 10 and December 18, 2023. Data were analyzed from May 8 to 22, 2024. Interventions Participants were randomized (1:1:1:1:1) to once-daily oral HRS-7535 (15, 30, 60, or 90 mg) or matching placebo. The 60- and 90-mg treatment groups used dose-escalation regimens. Main Outcomes and Measures The primary outcome was change in HbA 1c level from baseline to week 16. Secondary outcomes included changes in fasting plasma glucose level, 2-hour postprandial glucose level, body weight, and the proportion of patients achieving HbA 1c levels less than 7.0%. Safety outcomes included adverse events (AEs), hypoglycemia, and AEs of special interest. Results Of 194 randomized patients (mean [SD] age, 52.3 [11.0] years; 115 [59.3%] men; mean [SD] HbA 1c level, 8.5% [0.7]), 177 (91.2%) completed treatment. The mean changes in HbA 1c level at week 16 were −1.19% (95% CI, −1.54% to −0.84%) with the 15-mg dose, −1.59% (95% CI, −1.94% to −1.24%) with the 30-mg dose, −1.82% (95% CI, −2.16% to −1.48%) with the 60-mg dose, and −1.64% (95% CI, −1.97% to −1.30%) with the 90-mg dose compared with −0.25% (95% CI, −0.60% to 0.09%) with placebo; placebo-adjusted differences ranged from −0.94% (95% CI, −1.43% to −0.45%) to −1.57% (95% CI, −2.05% to −1.08%) (all P < .001). HbA 1c level less than 7.0% was achieved in proportions ranging from 48.7% (95% CI, 32.4%-65.2%) to 63.2% (95% CI, 46.0%-78.2%) of HRS-7535–treated patients vs 15.4% (95% CI, 5.9%-30.5%) with placebo. The 90-mg group had greater body weight reduction than placebo (−2.63% [95% CI, −3.72% to −1.54%] vs −1.30% [95% CI, −2.46% to −0.15%]). AEs occurred in 28 of 39 (71.8%) to 33 of 39 (84.6%) HRS-7535–treated patients and 28 of 39 (71.8%) placebo-treated patients and were predominantly mild to moderate gastrointestinal events. Level 1 hypoglycemia occurred in 9 HRS-7535–treated patients; no level 2 or 3 hypoglycemia, pancreatitis, or elevations of alanine aminotransferase or aspartate aminotransferase levels greater than 3 times the upper limit of normal occurred. Conclusions and Relevance In this randomized clinical trial of adults with type 2 diabetes inadequately controlled with metformin, oral HRS-7535 improved glycemic control and was associated with modest weight reduction, with a safety profile consistent with that of GLP-1 RAs. Because HRS-7535 is a nonpeptide oral GLP-1 RA that does not require fasting administration or injection, it may be a viable treatment option, pending confirmation in phase 3 trials. Trial Registration ClinicalTrials.gov Identifier: NCT05759897

Microvascular disease has traditionally been regarded as a defining complication of diabetes, responsible for major clinical outcomes including retinopathy, nephropathy, neuropathy, and limb amputation. Existing frameworks have largely attributed microvascular injury to chronic hyperglycaemia, mediated through pathways such as advanced glycation end product formation, protein kinase C activation, and oxidative stress. While these mechanisms are well established, a predominantly glucose-centric paradigm may incompletely capture the complexity of microvascular pathology. Accumulating evidence indicates that microvascular abnormalities are also prevalent in individuals without diabetes and may arise across a continuum of metabolic dysfunction. Epidemiological studies and clinical trials further suggest that intensive glucose lowering alone does not fully eliminate the risk of microvascular complications, highlighting the importance of non-glycaemic contributors, including hypertension, dyslipidaemia, insulin resistance, adiposity, and chronic inflammation. Notably, these metabolic disturbances may precede overt hyperglycaemia and provide earlier signals of vascular vulnerability. These observations have direct clinical relevance for diabetologists, as they suggest that microvascular injury may develop during prediabetes or earlier stages of metabolic dysfunction, with important implications for early screening and risk stratification in diabetes-oriented clinical practice. In this review, we propose the concept of metabolic microvascular disease (MMD), which reframes microvascular pathology as a systemic consequence of metabolic dysregulation rather than a complication confined to diabetes. We synthesise evidence of microvascular disease across populations with and without diabetes, summarise shared and distinct pathogenic mechanisms, and outline a pragmatic framework to support early clinical recognition and research stratification. Finally, we discuss the clinical and public health implications of adopting a metabolic perspective, emphasising the need for prevention strategies that extend beyond glucose-lowering to include comprehensive metabolic risk management.

Case numbers of metabolic diseases such as diabetes and hyperlipidaemia are increasing worldwide and show geographic heterogeneity, but the role of environmental geography in shaping this pattern is poorly defined. Here we integrate large multi-region cohorts in China (n = 3,648 cross-sectional; n = 1,547 prospective) with high-resolution soil trace-element data to test whether geography shapes levels of dietary ions and risk of metabolic disease. We observe geographic variations in levels of serum and urinary trace elements, with selenium, zinc and chromium linked to metabolic outcomes. Soil selenium was a predictor of serum selenium in participants even after incorporating regional dietary, socioeconomic and air-quality indicators. In a prospective cohort, participants in the highest serum selenium tertile (107.2–162.8 µg l−1) had a 35% higher risk of incident diabetes than those in the lowest tertile (relative risk (RR) = 1.35; 95% confidence interval (CI) = 1.02–1.77) after multivariable and dietary adjustment; the association was significant in men (RR = 1.96; 95% CI = 1.21–3.17), but not in women (RR = 1.10; 95% CI = 0.77–1.58). Globally, an estimated 14% of land area—home to approximately 1 billion people—has high soil selenium, with residents projected to have serum selenium levels above 110 µg l−1, a range in which selenium supplementation could increase diabetes risk. In a prospective multi-centre cohort in China, people living in areas of high soil selenium had a 35% increased risk of incident diabetes over a 3-year study period, with a stronger effect seen for men.

Importance:Oral small-molecule glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may address limitations of injectable and peptide-based agents for type 2 diabetes. Objective:To evaluate the efficacy and safety of HRS-7535, an oral nonpeptide GLP-1 RA, as add-on therapy among adults with type 2 diabetes inadequately controlled with metformin. Design, Setting, and Participants:This 16-week, phase 2, double-blind, placebo-controlled randomized clinical trial was conducted at 44 centers in China. Adults aged 18 to 75 years with type 2 diabetes, hemoglobin A1c (HbA1c) levels ranging from 7.5% to 11.0%, and receiving stable metformin therapy were enrolled between May 10 and December 18, 2023. Data were analyzed from May 8 to 22, 2024. Interventions:Participants were randomized (1:1:1:1:1) to once-daily oral HRS-7535 (15, 30, 60, or 90 mg) or matching placebo. The 60- and 90-mg treatment groups used dose-escalation regimens. Main Outcomes and Measures:The primary outcome was change in HbA1c level from baseline to week 16. Secondary outcomes included changes in fasting plasma glucose level, 2-hour postprandial glucose level, body weight, and the proportion of patients achieving HbA1c levels less than 7.0%. Safety outcomes included adverse events (AEs), hypoglycemia, and AEs of special interest. Results:Of 194 randomized patients (mean [SD] age, 52.3 [11.0] years; 115 [59.3%] men; mean [SD] HbA1c level, 8.5% [0.7]), 177 (91.2%) completed treatment. The mean changes in HbA1c level at week 16 were -1.19% (95% CI, -1.54% to -0.84%) with the 15-mg dose, -1.59% (95% CI, -1.94% to -1.24%) with the 30-mg dose, -1.82% (95% CI, -2.16% to -1.48%) with the 60-mg dose, and -1.64% (95% CI, -1.97% to -1.30%) with the 90-mg dose compared with -0.25% (95% CI, -0.60% to 0.09%) with placebo; placebo-adjusted differences ranged from -0.94% (95% CI, -1.43% to -0.45%) to -1.57% (95% CI, -2.05% to -1.08%) (all P < .001). HbA1c level less than 7.0% was achieved in proportions ranging from 48.7% (95% CI, 32.4%-65.2%) to 63.2% (95% CI, 46.0%-78.2%) of HRS-7535-treated patients vs 15.4% (95% CI, 5.9%-30.5%) with placebo. The 90-mg group had greater body weight reduction than placebo (-2.63% [95% CI, -3.72% to -1.54%] vs -1.30% [95% CI, -2.46% to -0.15%]). AEs occurred in 28 of 39 (71.8%) to 33 of 39 (84.6%) HRS-7535-treated patients and 28 of 39 (71.8%) placebo-treated patients and were predominantly mild to moderate gastrointestinal events. Level 1 hypoglycemia occurred in 9 HRS-7535-treated patients; no level 2 or 3 hypoglycemia, pancreatitis, or elevations of alanine aminotransferase or aspartate aminotransferase levels greater than 3 times the upper limit of normal occurred. Conclusions and Relevance:In this randomized clinical trial of adults with type 2 diabetes inadequately controlled with metformin, oral HRS-7535 improved glycemic control and was associated with modest weight reduction, with a safety profile consistent with that of GLP-1 RAs. Because HRS-7535 is a nonpeptide oral GLP-1 RA that does not require fasting administration or injection, it may be a viable treatment option, pending confirmation in phase 3 trials. Trial Registration:ClinicalTrials.gov Identifier: NCT05759897.

BACKGROUND:Pancreatic cancer (PC) is among the most aggressive and lethal malignancies, characterized by development within a complex tumor microenvironment (TME) that includes a desmoplastic stroma composed of extracellular matrix (ECM) and various cellular components. OBJECTIVES:This study aims to elucidate the cellular and molecular mechanisms regulating PC progression through an integrated analysis of single-cell pseudotime trajectories and intercellular communication. MATERIAL AND METHODS:We constructed pseudotime trajectories using single-cell RNA sequencing (scRNA-seq) data from PC tissues to trace the developmental progression of cancer cells. Transitional cell states and critical genes involved in the shift from early-to-advanced disease stages were identified. Through a comprehensive analysis, we pinpointed key transcription factors and signaling pathways implicated in tumor progression. Expression of stemness-associated genes in pancreatic stellate cells (PSC) was validated using immunofluorescence and transmission electron microscopy (TEM). Additionally, cell-cell communication analysis was performed to examine interactions within the TME, with particular emphasis on ligand-receptor pairings. RESULTS:Our analysis identified key transcription factors and signaling pathways that drive the cellular transitions associated with cancer progression. The findings revealed extensive intercellular crosstalk between cancer cells, stromal fibroblasts, and diverse immune cell subpopulations. Notably, the study underscored the distinct functional contributions of these cell populations to tumor development, immune evasion and metastatic dissemination. CONCLUSIONS:The study uncovers the complex cellular diversity and intercellular crosstalk in PC, providing novel avenues for therapeutic interventions and early predictive markers in diagnosis. These findings support the potential for more targeted, personalized treatment strategies in combating PC.

Introduction and Objective: Obesity is highly prevalent in heart failure with preserved ejection fraction (HFpEF). Impaired branched-chain amino acid (BCAA) catabolism has been implicated in HFpEF, and systemic inhibition of branched-chain ketoacid dehydrogenase kinase (BCKDK), a key negative regulator of BCAA oxidation, improves cardiac function. However, whether cardiomyocyte-specific manipulation of BCAA catabolism is sufficient to confer cardioprotection remains unknown. Methods: Cardiomyocyte-specific BCKDK knockout and overexpression mouse models were generated and subjected to echocardiography, transcriptomic, metabolomic, and molecular analyses in vivo and in vitro. Results: Despite reduced myocardial BCAA levels, cardiomyocyte-specific BCKDK deletion unexpectedly exacerbated cardiac dysfunction and ventricular remodelling in obese HFpEF. Notably, cardiac BCKDK expression is reduced in obese HFpEF. In contrast, cardiomyocyte-specific BCKDK overexpression markedly improved cardiac function and remodelling, accompanied by enhanced mitochondrial respiratory capacity and suppression of MAPK-driven inflammatory signalling, despite further reductions in myocardial BCAA levels. Mechanistically, mitochondrial ROS scavenging with mitoTEMPO rescued mitochondrial dysfunction and inflammatory activation induced by BCKDK deficiency. Conclusion: These findings reveal an unexpected BCAA-independent role of BCKDK in preserving cardiomyocyte mitochondrial function and restraining inflammatory signalling in obese HFpEF. Our study identifies cardiac BCKDK as a potential therapeutic target, while cautioning that systemic BCKDK inhibition may exert unanticipated adverse cardiac effects and overestimate cardioprotection driven primarily by extracardiac mechanisms. Disclosure Y. Liu: None. Y. Guo: None. H. Wang: None. Y. Fan: None. Z. Sun: None. Funding National Natural Science Foundation of China (82000334; 82270848), China Postdoctoral Science Foundation (2023M730571), Medical Research Project of Jiangsu Provincial Health Commission (MQ2024041), Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX22_0298)

Background: Prediabetes comprises three heterogeneous glucometabolic phenotypes and is associated with an increased risk of metabolic dysfunction-associated fatty liver disease (MAFLD). However, the association of different prediabetes phenotypes with the presence of MAFLD and liver fibrosis remains underexplored. Objectives: To examine the association of different prediabetes phenotypes with MAFLD and liver fibrosis. Design: Population-based cross-sectional study. Methods: Prediabetes was stratified as an isolated defect (impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or impaired hemoglobin A1c (IA1c)), two defects (IFG + IGT, IFG + IA1c, or IGT + IA1c), or all three defects (IFG + IGT + IA1c). Hepatic steatosis and liver fibrosis were assessed by vibration-controlled transient elastography. Multivariate logistic regression analysis was conducted to estimate the odds ratio (OR) and 95% confidence interval (CI) for different prediabetes phenotypes associated with MAFLD and liver fibrosis. Results: A total of 1599 subjects (394 with normal glucose tolerance (NGT) and 1205 with prediabetes) were included. The prevalence of MAFLD and liver fibrosis was higher in prediabetes than in NGT. The odds of MAFLD in prediabetes with two or three glucometabolic defects were increased compared with those with a single glucometabolic defect, with insulin resistance as a possible mediator. Compared with isolated IA1c, isolated IGT had an increased prevalence of MAFLD ( p < 0.05). Moreover, glucose-defined prediabetes had higher odds of MAFLD than HbA1c-defined prediabetes (OR 1.72, 95% CI 1.00–2.96). However, there was no significant difference in the odds of liver fibrosis across different prediabetes phenotypes ( p = 0.58). Conclusion: The odds of MAFLD but not liver fibrosis were increased with the increasing number of glucometabolic defects in participants with prediabetes. Trial registration: Not applicable.

Background:Increased physical activity and reduced sedentary time are associated with lower risks of diabetes. However, their association with diabetic kidney disease (DKD) is unclear. This study aimed to assess this issue in the Chinese adults with diabetes. Methods:This multicenter, cross-sectional study included adults with diabetes from 40 hospitals across 26 diverse Chinese cities. Leisure-time physical activity (LTPA), housework physical activity (HPA), occupational physical activity (OPA), and sedentary time were assessed using a validated questionnaire. DKD was defined according to the NKF-K/DOQI guidelines. Associations between activity domains and DKD were examined using multivariable logistic regression, with subgroup, interaction, and sensitivity analyses to assess robustness. Results:A total of 4,979 patients with diabetes were included. After multivariable adjustment, those meeting the guideline-recommended amount of LTPA had lower odds of DKD (OR 0.79, 95% CI 0.68-0.91 for aerobic exercise; OR 0.69, 95% CI 0.50-0.96 for resistance exercise) compared with those not meeting recommendations. However, heavier HPA and larger OPA were associated with higher odds of DKD (OR 1.51 and 1.66, respectively). Moreover, longer daily sedentary time was associated with increased odds of DKD only in women (OR 2.10), but not in men. Further stratified analysis suggested that the association between LTPA and lower odds of DKD may be modified by HPA, OPA, or sedentary time. Conclusions:Among Chinese adults with diabetes, LTPA was associated with lower odds of DKD, whereas higher occupational and household physical activity showed positive associations, underscoring the differences in domain-specific physical activity in DKD prevention.

Physical function declines with ageing; however, the changes in the prevalence of impaired physical function during ageing and how the changes would be affected by physical activity are not well investigated. This study aimed to address the issues. We included participants aged ≥ 65 years in the 2008–2010 wave, who were followed-up in the 2012–2014 and the 2016–2018 waves of the Health and Retirement Study. Types of impaired physical function included weak grip strength, slow walking speed, and poor standing balance. Their prevalence in each wave was calculated and their changes over time were estimated using the mixed-effects logistic regression model. A total of 6,537 older adults were included. The prevalence of slow walking speed ranked the highest in all the types of impaired physical function in all the 3 individual waves (all Pcomparison <0.001). During follow-up, participants were increasingly being older and the prevalences of all the types of impaired physical function were gradually increased after multivariate-adjustment (all Ptrend <0.001). These increases were unlikely to be significantly moderated by weight status, drinking history or the presence of diabetes (all Pinteraction ≥0.19). However, the increases in the prevalences of weak grip strength and slow walking speed were nonsignificant in participants with regular physical activity, but was significant in those without (Pinteraction = 0.009 and 0.01, respectively). Despite gradual increases in the prevalence of impaired physical function during ageing, regular physical activity may help to preserve physical function in older adults. Not applicable.

INTRODUCTION:Pancreatic stellate cells (PSCs) play a central role in pancreatic physiology and disease, and the transition between their quiescent and activated states influences processes such as fibrosis and regeneration. However, the stem cell-like properties of PSCs remain unclear. This study aims to clarify the stem cell characteristics of PSCs and establish a method to maintain their quiescent state, thereby providing a new perspective on pancreatic regeneration. METHODS:PSCs from Lrat-cre; Rosa26-tdTomato mice were fate-traced, and immunofluorescence was used to assess Lrat, Oct4, and Nanog co-localization. Primary PSCs from C57BL/6 mice were cultured in mesenchymal stem cell (MSC) or DMEM/F12 medium. Lipid droplets, morphology, activation markers (α-SMA, collagen-I, fibronectin), and stemness-associated markers were analysed via qRT-PCR and immunofluorescence. RESULTS:Lrat co-localized with Oct4/Nanog in mice. MSC-cultured PSCs had more lipid droplets, a quiescent morphology, and lower levels of activation markers than DMEM/F12-cultured cells. They also expressed stemness-associated markers (Pdx1, Oct4, Nkx6.1, Ngn3, Sox2, Pax6). DISCUSSION:These results indicate that PSCs possess stemness and can be preserved under specific culture conditions. The ability of MSC medium to maintain PSCs in a quiescent and stem-like state provides a valuable model for studying their biology. CONCLUSION:PSCs exhibit stemness, and MSC medium maintains their quiescence, offering a novel experimental platform to study PSC biology and lineage plasticity.

AIMS:Impaired branched-chain amino acid (BCAA) catabolism has been implicated in obesity cardiomyopathy (OCM), and systemic inhibition of branched-chain ketoacid dehydrogenase kinase (BCKDK), a key negative regulator of BCAA oxidation, improves cardiac function. However, whether cardiomyocyte-specific manipulation of BCAA catabolism is sufficient to confer cardioprotection remains unknown. METHODS AND RESULTS:Cardiomyocyte-specific BCKDK knockout and overexpression mouse models were generated and subjected to high-fat diet feeding, followed by echocardiography, transcriptomic, metabolomic, and molecular analyses. The mechanistic findings were further validated using in vitro experiments. Despite reduced myocardial BCAA levels, cardiomyocyte-specific BCKDK deletion unexpectedly exacerbated cardiac dysfunction and ventricular remodelling in OCM. Consistently, cardiac BCKDK expression was reduced in OCM. In contrast, cardiomyocyte-specific BCKDK overexpression improved cardiac function and remodelling, accompanied by a further reduction in myocardial BCAA levels, attenuation of mitochondrial oxidative stress, and suppression of MAPK-driven inflammatory signalling. Mechanistically, BCKDK reprogrammed mitochondrial metabolism to restrain oxidative stress. Moreover, mitochondrial ROS scavenging with MitoTEMPO alleviated mitochondrial dysfunction, and reversed the MAPK activation induced by BCKDK deficiency in vitro. CONCLUSION:These findings reveal an unexpected BCAA-independent role of BCKDK in preserving cardiomyocyte mitochondrial function and restraining inflammatory signalling in OCM. Our study identifies cardiomyocyte-intrinsic BCKDK as a potential therapeutic target, while cautioning against overestimating the cardioprotective effects of systemic BCKDK inhibition, which may be driven primarily by extracardiac mechanisms.

BackgroundThe pathogenesis of type 2 diabetes (T2DM) remained to be fully understood. Meanwhile, exosome have shown its potential to further advance diabetes research as a rich source of biomarkers. This study aims to explore the proteomic profiles of circulating plasma exosomes in individuals with varying glucose statuses and offer potentially new perspective on the pathogenesis of T2DM.MethodsParticipants with different glucose status were recruited according to the diagnostic criteria of the American diabetes association. Plasma exosomes were collected and went through data independent acquisition mass spectrometry quantitative proteomics analysis. Differential proteins identified through pairwise group comparisons underwent further analysis like protein-protein interaction (PPI) and gene ontology (GO) to reveal their functions and interactions.ResultsA total of 75 participants (25 euglycemia; 25 prediabetes; 25 diabetes) were included in this study. Principal coordinates analysis showed that the proteomic patterns of exosomes in groups with prediabetes and diabetes exhibited certain similarities, contrasting with those in euglycemic individuals. From pairwise differential protein comparison, 32 proteins were selected for PPI and functional analysis, of which 7 were deemed significant within the network. GO annotations highlighted a close link between immunity and T2DM. Local STRING clustering, Reactome and KEGG pathway analysis all indicated great significance of complement and coagulation cascades.ConclusionThe proteomic patterns of exosomes in groups with different glucose levels exhibited that even before overt diabetes manifests, the circulating exosome cargo signals immune and coagulatory activation distinct from normal physiology.

BACKGROUND:Cardiorespiratory fitness (CRF) is inversely associated with the risk of cardiovascular disease, which is related to impaired vascular function. However, its relationship with vascular function remains unknown in patients with type 2 diabetes. AIM:To assess the relationship of CRF with vascular function in type 2 diabetes. METHODS:Patients with type 2 diabetes who were aged ≥ 18 years and underwent an incremental and symptom-limited exercise test were included. Vascular function was assessed by the construction of the vascular health index (VHI), which is defined as a composite score of ankle-brachial index, transcutaneous oxygen pressure, pulse wave velocity, and carotid intima-media thickness. Impaired vascular function is defined as a VHI of < 8 points. Linear and logistic regression analyses were used to assess the associations. RESULTS:We included 343 patients with type 2 diabetes. CRF was positively correlated with VHI (β = 0.10, P = 0.047), particularly with ankle-brachial index and pulse wave velocity. The odds ratio (OR) of impaired vascular function was 0.44 [95% confidence interval (CI): 0.20-0.96] for the highest vs the lowest CRF category. For each one metabolic equivalent increase in CRF, the OR of impaired vascular function was 0.73 (95%CI: 0.57-0.93). CONCLUSION:Higher CRF was associated with better vascular function and lower odds of impaired vascular function in patients with type 2 diabetes.

The activation of islet stellate cells (ISCs) plays an important role in islet fibrosis, which leads to impaired islet function. While our previous work showed that the expression of the Pdpn gene was significantly increased in activated ISCs, it remains unknown whether Pdpn is responsible for islet fibrosis. This study was aimed at elucidating its function on islet fibrosis, along with the exploration of the underlying mechanisms. Then, diabetic mice were used for in vivo studies, while primary ISCs were used for in vitro experiments. Podoplanin (PDPN) expression was manipulated using gene knockdown and overexpression techniques. Beta-cell function was assessed by insulin secretion and glucose tolerance tests. Islet fibrosis was evaluated by quantifying extracellular matrix deposition and ISCs activation markers using histological staining and immunohistochemistry, respectively. The effects of advanced glycation end products (AGEs) and TGF-β1 on PDPN expression and the corresponding mechanisms of ISCs activation were investigated. Finally, it was found that knocking down PDPN in diabetic mice led to reduced ISCs activation and islet fibrosis, accompanied by improved insulin expression and lower fasting blood glucose. AGEs were found to induce PDPN expression in ISCs. The overexpression of PDPN triggers the activation of ISCs via cell deformation and TGF-β1 secretion. Interestingly, TGF-β1 in turn activates the TGF-β1/SMAD2/3 pathway by binding to TGF-βRI, inducing the expression of PDPN and the activation of ISCs. In summary, PDPN regulates the activation of ISCs through a mechanism involving cell deformation and a PDPN-TGF-β1 autocrine feedback loop, thereby significantly contributing to islet fibrosis in diabetes.

AIMS:Current hypertension guidelines fail to discriminate between fasting and postprandial blood pressure (BP) measurements. Meal ingestion often triggers a marked increase in splanchnic blood flow, potentially inducing a sustained fall in systolic BP of ≥20 mmHg, termed postprandial hypotension (PPH). This study aimed to evaluate BP responses to a 75 g glucose drink and its implications for detecting hypertension and PPH in community-dwelling adults. METHODS AND RESULTS:A stratified multi-stage random sampling method was used to obtain a nationally representative sample of n = 4429 adult residents between April 2020 and January 2021 in China. BP and heart rate (HR) were measured before, and 1 and 2 h after, a 75 g glucose drink. When fasting, 38.4% of the study population had high BP (BP ≥140/90 mmHg). Following the glucose drink, SBP and DBP decreased (SBP by 6.2 [95% CI: 5.8, 6.6] mmHg and 8.1 [7.7, 8.5] mmHg, DBP by 4.7 [4.4, 4.9] mmHg and 6.1 [5.8, 6.4] mmHg), and HR increased (by 4.3 [4.0, 4.5] bpm and 2.6 [2.4, 2.9] bpm) at 1 and 2 h (P < 0.001 for all), with only 30.9% and 27.0% of the study population having high BP at 1 and 2 h, respectively. After adjustment for age and sex distribution, 19.9% of the general population was estimated to have PPH. Postprandial hypotension was associated with an increased risk of combined cardiovascular disease and stroke. CONCLUSION:Ingestion of a 75 g glucose drink often lowers BP, frequently leading to PPH and influencing the detection of hypertension. Accordingly, guidelines for measurements of BP and interpretation of outcomes should consider the potential impact of meal ingestion on BP.