OBJECTIVES: Resistance training (RT) is recommended for type 2 diabetes (T2D), but secondary evidence is voluminous and heterogeneous. We conducted an umbrella review to map, appraise, and grade the certainty of RT effec...OBJECTIVES: Resistance training (RT) is recommended for type 2 diabetes (T2D), but secondary evidence is voluminous and heterogeneous. We conducted an umbrella review to map, appraise, and grade the certainty of RT effects on glycaemic and cardiometabolic outcomes in adults with T2D. METHODS: We searched PubMed, Scopus, and Web of Science for systematic reviews/meta-analyses of RT in adults with T2D. The studies were screened, extracted, mapped primary-study overlap (corrected covered area, CCA), and appraised review quality (AMSTAR-2). Certainty was judged at the overview level using a GRADE-style framework integrating review methods (AMSTAR-2). RESULTS: Forty-three reviews met inclusion. Overlap was moderate to very high across outcomes (e.g. , CCA: HbA1c 9.8%, fasting glucose 21.3%, blood pressure 33.4%, strength 35.3%, HRQoL 56.5%). RT versus non-exercise was associated with small-to-moderate improvements in HbA1c (~-0.3 to -0.6%-points), fasting glucose (~-0.5-1.4 mmol/L), and systolic blood pressure (~-4-7 mmHg); small reductions in triglycerides and LDL/total cholesterol; mixed HDL findings; and large gains in muscle strength, although the relevant evidence base showed substantial overlap across reviews. Effects on body weight/BMI were small or null; fat% and waist circumference tended to decrease modestly; physical HRQoL showed small benefits. Heterogeneity was substantial for several outcomes. AMSTAR-2 flagged frequent critical issues (e.g., use of quality scales instead of domain-based risk-of-bias; infrequent small-study bias assessment). GRADE certainty was moderate for HbA1c, LDL-C, triglycerides, and systolic BP; low-moderate for fasting glucose, diastolic blood pressure; and low for fasting insulin, HDLC, and mental/overall HRQoL. CONCLUSIONS: RT likely confers small-to-moderate metabolic and vascular benefits and large strength improvements in adults with T2D, but certainty is tempered by heterogeneity, trial overlap, and recurrent methodological shortcomings. Well-reported, prospectively registered syntheses and trials with standardized RT dose and domain-based bias assessment are needed.
MitoNEET is a protein localized to the mitochondrial outer membrane and is recognized as an important regulator of mitochondrial activity, participating in redox signaling, iron-sulfur cluster trafficking, and trace elem...MitoNEET is a protein localized to the mitochondrial outer membrane and is recognized as an important regulator of mitochondrial activity, participating in redox signaling, iron-sulfur cluster trafficking, and trace element homeostasis. The heart is an organ with exceptionally high energy demands and relies critically on tightly coordinated mitochondrial processes to sustain continuous contractile activity. Accumulating evidence indicates that mitoNEET influences multiple aspects of cardiac mitochondrial biology, including mitochondrial dynamics, energy production, redox balance, ion homeostasis, and metabolic regulation of fatty acid and glucose utilization, all of which are essential for normal cardiac contraction and relaxation. Alterations in mitoNEET expression or activity are closely associated with mitochondrial dysfunction in cardiovascular diseases, including ischemic heart disease and heart failure, in which it regulates mitochondrial oxidative stress, ion homeostasis, and metabolic flexibility. In this review, we outline the molecular mechanisms through which mitoNEET affects cardiac mitochondrial function, providing a perspective on its therapeutic potential for the prevention and treatment of cardiovascular disease through modulation of mitochondrial function.
STAU1, an RNA-binding protein central to the STAU1-mediated mRNA decay (SMD) pathway, promotes adipogenesis. This study reveals that STAU1 protein levels positively correlate with obesity severity. Adipose specific STAU1...STAU1, an RNA-binding protein central to the STAU1-mediated mRNA decay (SMD) pathway, promotes adipogenesis. This study reveals that STAU1 protein levels positively correlate with obesity severity. Adipose specific STAU1 deficient mice on a high-fat diet showed reduced weight, enhanced thermogenesis, and improved glucose tolerance. Deleting Stau1 gene in brown adipose tissue upregulated UCP1 protein. We further identified that STAU1 binds to the 3' UTR of Ucp1 mRNA. The β adrenergic receptor pathway enhances SMD activity, while inhibiting the cAMP-PKA pathway downregulates STAU1. Our findings establish STAU1 as a modulatory factor that adjusts thermogenic output in response to diverse thermogenic stimuli, providing insight into post-transcriptional regulation of energy balance and potential therapeutic targets for metabolic disease.
BACKGROUND & AIMS: Hepatic steatosis, a hallmark of many liver diseases, is primarily driven by metabolic dysfunction; however, the extrahepatic regulatory mechanisms remain poorly understood. This study aimed to investi...BACKGROUND & AIMS: Hepatic steatosis, a hallmark of many liver diseases, is primarily driven by metabolic dysfunction; however, the extrahepatic regulatory mechanisms remain poorly understood. This study aimed to investigate muscle-liver crosstalk and to identify the underlying mechanisms of hepatic steatosis in patients with muscular dystrophy. METHODS: We used mouse models of muscular dystrophy, fibroadipogenic progenitor (FAP)-specific annexin A2 (ANXA2) knockout mice, and muscle biopsy samples from patients with muscular dystrophy. The correlation between serum ANXA2 levels and lipid accumulation was evaluated in both human patients and mouse models of muscular dystrophy. RNA sequencing, mass spectrometry, and peptide library analyses were performed to investigate the mechanisms underlying hepatic steatosis associated with muscular dystrophy. RESULTS: We identified hepatic steatosis and hyperlipidemia in both patients and mouse models of muscular dystrophy. Using multiomic analyses, we found that muscle-resident FAPs secrete ANXA2, which functions as a key myokine driving hepatic steatosis. Muscle-specific overexpression of ANXA2 and manipulation of primary cells further confirmed this finding. In vivo FAP-specific ANXA2 ablation significantly alleviated systemic metabolic disturbances and hepatic steatosis in muscular dystrophy mouse models and high-fat diet-treated mice. Mechanistically, ANXA2 secreted by FAPs acts on hepatocyte-specific ANXA2R, promoting liver de novo lipogenesis through activation of the sterol regulatory element-binding protein 1c (SREBP1c) signaling pathway. Moreover, neutralizing ANXA2 suppressed hepatic steatosis and insulin resistance in mice. Collectively, our results demonstrate that ANXA2 derived from muscle FAPs promotes hepatic steatosis by activating SREBP1c-mediated de novo lipogenesis. CONCLUSION: Our findings identify the ANXA2-SREBP1c axis as a novel mechanism underlying muscle-liver metabolic crosstalk, and suggest that ANXA2 may represent a potential therapeutic target for hepatic steatosis in metabolic dysfunction-associated steatotic liver disease.
AIMS/HYPOTHESIS: Obesity is associated with insulin resistance, a major risk factor for type 2 diabetes (T2D), yet the underlying mechanisms remain incompletely defined. We hypothesized that elevated transforming growth...AIMS/HYPOTHESIS: Obesity is associated with insulin resistance, a major risk factor for type 2 diabetes (T2D), yet the underlying mechanisms remain incompletely defined. We hypothesized that elevated transforming growth factor beta 1 (TGFβ1) level is associated with impaired insulin sensitivity. METHODS: Using primary hepatocytes, and mouse models with hepatic TGFβ1 overexpression or hepatic TGFβ1 signaling disruption, we examined the impact of TGFβ1 signaling on hepatic insulin signaling and glucose metabolism. We performed bulk RNA sequencing of liver samples identify potential mediator of obesity-induced insulin resistance. Immunoprecipitation, in vitro kinase assay, and mass-spec assay were used to explore the mechanisms underlying TGFβ1-induced insulin receptor substrate (IRS1) degradation. We further evaluated the therapeutic potential of targeting TGFβ1 signaling to improve glycemic control using the TGFβ1 signaling inhibitor LY2157299. RESULTS: Prolonged TGFβ1 exposure markedly reduced IRS1 protein abundance and impaired insulin-stimulated Akt activation in hepatocytes. Hepatic TGFβ1 overexpression exacerbated insulin resistance, whereas hepatic TGFβ1 signaling disruption improved insulin sensitivity by increasing IRS1 protein abundance. Mechanistically, TGFβ1 signaling increased Cullin 7 (CUL7) expression and promoted IRS1 phosphorylation at serine 685, leading to ubiquitin-dependent IRS1 degradation. Pharmacological inhibition of TGFβ1 signaling by LY2157299 improved insulin sensitivity in both lean and diabetic db/db mice. CONCLUSIONS/INTERPRETATION: These findings identify TGFβ1 as a key driver of hepatic insulin resistance by promoting CUL7-dependent IRS1 degradation, establishing a mechanistic link between obesity-associated cytokine signaling and impaired insulin action and highlighting the TGFβ1-CUL7-IRS1 axis as a potential therapeutic target for T2D.
BACKGROUND: Exposure to fine particulate matter (PM) and its constituents has been linked to increased risk of cardiovascular diseases (CVD), yet the metabolic mechanisms underlying this association remain unclear. METHO...BACKGROUND: Exposure to fine particulate matter (PM) and its constituents has been linked to increased risk of cardiovascular diseases (CVD), yet the metabolic mechanisms underlying this association remain unclear. METHODS: This study included 236,549 adults free of CVD at baseline from a large prospective cohort. Long-term exposure to PM and its constituents were estimated, including elemental carbon, organic matter, ammonium, nitrate, and sulfate. Constituent-related metabolites were identified via elastic net regression, and metabolic scores were constructed. Biological age acceleration was estimated using the PhenoAge algorithm. Associations of PM constituents and metabolic scores with incident CVD were examined using Cox models, and serial mediation analyses assessed pathways involving metabolic alterations and biological aging. RESULTS: During a median follow-up of 12.38 years, 30,885 participants developed CVD. Higher exposures to PM and its constituents were associated with elevated CVD risks (hazard ratios per standard deviation: 1.02-1.04). Constituent-specific metabolic signatures were identified, including 63 metabolites for PM, 82 for elemental carbon, 85 for organic matter, 28 for sulfate, 30 for nitrate, and 12 for ammonium. The PM-related metabolic signature was positively associated with CVD risk (hazard ratio: 1.04), while most constituent-specific signatures showed consistent directions of association with CVD risk. Mediation analyses indicated that metabolic signatures explained 5.18-10.08% of PM constituents-CVD association, while serial mediation through biological aging accounted for an additional 0.30-1.19%. CONCLUSIONS: Long-term exposure to PM constituents was associated with increased cardiovascular risk, while metabolomic signatures and biological aging were potential intermediate factors underlying these associations.
Late meal timing has been linked to increased body mass, although the physiological mechanisms are unknown. While previous research has suggested that identical meals consumed in the morning produce greater thermogenic r...Late meal timing has been linked to increased body mass, although the physiological mechanisms are unknown. While previous research has suggested that identical meals consumed in the morning produce greater thermogenic responses than evening meals, it is unclear whether this is due to endogenous circadian control or due to behavioral and environmental factors. Therefore, this mechanistic randomized trial tested whether the endogenous circadian system, thus independently of sleep/wake, rest/activity, body posture, dark/light, and fasting/eating cycles, modulates diet-induced thermogenesis (DIT). To unmask endogenous circadian effects from environmental and behavioral confounds, 16 healthy adults with overweight or obesity (12 males; mean ± SD age, 36 ± 11 years; BMI, 28.8 ± 2.4 kg·m; HbA1c, 5.4 ± 0.3%) completed a gold-standard Constant Routine (CR) protocol, consisting of 36 h of continuous wakefulness, rest, semi-recumbent posture, dim light, and identical test meals every 6 h. The data demonstrated a significant endogenous circadian rhythm in DIT, with a peak-to-trough amplitude of 44% (∼10 kcal/4 h), a peak during the biological morning and a trough in the evening (p = 0.005; equivalent to ∼8 am/∼8 pm, respectively). After adjusting for the circadian rhythm in fasting energy expenditure, the circadian rhythm in DIT remained significant with similar circadian timing, although with slightly reduced amplitude (∼7 am/∼7 pm; ∼29%; ∼7 kcal/4 h; p = 0.026). In exploratory analyses using an experimental within-subject design, data revealed that this endogenous circadian rhythm in DIT was not affected by prior early versus late eating schedules. The endogenous circadian rhythm in DIT, with a peak in the biological morning, may be one of the mechanisms contributing to the reported link between late meal timing and increased body mass. TRIAL REGISTRATION: ClinicalTrials.gov; NCT02298790; clinicaltrials.gov; registered on November 20, 2014.
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic liver disease that can progress to metabolic dysfunction-associated steatohepatitis (MASH), a more severe form charact...BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic liver disease that can progress to metabolic dysfunction-associated steatohepatitis (MASH), a more severe form characterized by inflammation, hepatocyte injury, and fibrosis. Although the gut-liver axis is implicated in disease progression, stage-specific changes in gut-derived metabolites, lipids, and enteroendocrine signaling remain unclear. This study investigated metabolic, lipidomic, and enteroendocrine alterations during MASLD-to-MASH progression. METHODS: Male C57BL/6NTac mice were fed a modified Amylin liver NASH high-fat diet for 16 weeks to induce MASLD or 29 weeks to induce MASH, age-matched chow-fed mice served as controls. Liver, colon, and stool underwent untargeted metabolomics and lipidomics. Plasma hormones and cytokines were measured by multiplex assay and ELISA. Histology, immunofluorescence, disease-signature enrichment, cross-species network analysis, and organoid differentiation assays were used to assess tissue pathology and signaling pathways. RESULTS: The high-fat diet produced histologically confirmed MASLD and MASH at 16 and 29 weeks, respectively. Cholic acid was elevated across liver, colon, and stool in both stages. MASLD was associated with increased circulating glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and peptide YY, which correlated with colonic cholic acid as well as increased colonic TGR5 expression, whereas these changes were absent in MASH. MASH showed broader metabolic and lipid remodeling, elevated tumor necrosis factor and interleukin-6, impaired enteroendocrine differentiation markers, and increased hepatic serotonin colocalized with fibronectin. CONCLUSIONS: MASLD-to-MASH progression involves stage-specific gut-liver metabolic remodeling, loss of enteroendocrine responsiveness, and hepatic serotonergic-fibrotic signaling.
BACKGROUND: Type 2 diabetes (T2D) causes multisystem complications, but an integrated multi-omics framework for cross-system, multi-outcome analysis is lacking. We aimed to comprehensively construct the proteomic and met...BACKGROUND: Type 2 diabetes (T2D) causes multisystem complications, but an integrated multi-omics framework for cross-system, multi-outcome analysis is lacking. We aimed to comprehensively construct the proteomic and metabolomic atlas of major T2D outcomes and to identify predictive panels that balance performance and clinical feasibility. METHODS: Among UK Biobank participants with T2D, we established proteomic (n = 3104), metabolomic (n = 28,834), and multi-omics (n = 3059) subcohorts. Using cross-sectional and longitudinal analyses, we systematically evaluated the associations of plasma proteins and metabolites with 19 T2D-related outcomes. Predictive models were developed using machine learning-based molecular feature selection and were compared with the clinical risk model. RESULTS: The study identified molecular signals that consistently exhibited positive or negative associations across multiple T2D outcomes, revealing shared biological pathways. We also uncovered outcome-specific and heterogeneous molecular signatures. Furthermore, protein-based models substantially outperformed clinical models (median delta C-index = 0.108; range: 0.063-0.143), while combined models achieved the best performance (median delta C-index = 0.109; range: 0.080-0.150) with consistent improvements in reclassification metrics, whereas metabolites provided only modest incremental gains (median delta C-index = 0.027; range: 0.006-0.070). Evaluation across varying selection thresholds identified a simplified panel of 174 proteins that maintained robust predictive performance. CONCLUSION: This large-scale multi-omics study systematically constructs the molecular atlas of T2D complications, providing new insights into disease biology and potential therapeutic targets. It further defines the predictive value of proteomic and metabolomic profiles and proposes a clinically feasible and practical framework for risk prediction and precision intervention.
BACKGROUND: Subretinal fibrosis (SRF) is a critical end-stage feature of neovascular age-related macular degeneration (nAMD) with limited treatment options. However, the pathological mechanism during the transformation o...BACKGROUND: Subretinal fibrosis (SRF) is a critical end-stage feature of neovascular age-related macular degeneration (nAMD) with limited treatment options. However, the pathological mechanism during the transformation of choroidal neovascularization (CNV) into SRF remains unclear. METHODS: Bulk RNA-seq of mouse macrophages treated with succinate or lactate in acidic hypoxia identified Spp1 as a key fibrosis-associated gene. Dynamic Spp1 expression was tracked by single-cell RNA-seq in a CNV model, while laser-induced CNV and SRF models assessed the pro-fibrotic role of Spp1 in vivo. In vitro, the binding of SPP1 to RPE CD44 was identified through bioinformatics and Co-IP, and Western blotting examined downstream CD44/RhoA/YAP1 pathway proteins. qPCR quantified nine YAP1 isoforms to identify the predominant one after SPP1 intervention. The specific YAP1 isoform undergoing liquid-liquid phase separation (LLPS) was determined by visualizing intracellular localization and biomolecular condensates via EGFP-tagged plasmid transfection, with LLPS characteristics confirmed by live-cell imaging and fluorescence recovery after photobleaching (FRAP). ATAC-seq identified the transcription factors co-activated with YAP1 driving fibrosis, while EMT phenotypes were evaluated using pro-fibrotic gene expression, migration, and collagen contraction assays. RESULTS: Succinate and lactate upregulated Spp1 and activated correlated Ca influx pathways. An expanding Spp1 Mφ population was found in early-to-mid CNV. SRF mice showed elevated Spp1in Mφs, and intravitreal Spp1 worsened CNV fibrosis, which blocked by small interfering extracellular matrix receptor III (siCD44). In vitro, SPP1 bound to CD44 activated the RhoA/YAP1 pathway, characterized by a predominant isoform shift from YAP1-1α to YAP1-2α. The nuclear translocation and LLPS of YAP1-2α facilitated pro-fibrotic gene transcription by binding to TEAD4, thereby promoting EMT-like changes in RPE. CONCLUSIONS: Under accumulation of acidic metabolites, SPP1-overexpressing Mφs promote EMT in the RPE via CD44/RhoA-mediated YAP1-2α LLPS. This process involves binding to TEAD4 to co-activate pro-fibrotic gene transcription, revealing novel pathomechanisms involved in SRF progression.
BACKGROUND/AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) lacks effective pharmacotherapy. Although AMP-activated protein kinase (AMPK) is a central metabolic regulator with hepatoprotective effec...BACKGROUND/AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) lacks effective pharmacotherapy. Although AMP-activated protein kinase (AMPK) is a central metabolic regulator with hepatoprotective effects, the upstream mechanisms governing its degradation in MASLD remain poorly defined. Here, we identify potassium channel modulatory factor 1 (KCMF1) as a previously unrecognized E3 ubiquitin ligase targeting AMPKα and investigate its role in MASLD pathogenesis. METHODS: Protein interactions were characterized by co-immunoprecipitation and GST pull-down assays. Ubiquitin-linkage specificity and AMPKα stability were assessed biochemically. Hepatocyte-targeted gain-of-function and hepatocyte-specific KCMF1 ablation were evaluated across multiple mouse MASLD models (HFD, GAN, CDAHFD, and ob/ob), with AMPK dependency assessed by pharmacological modulation. An AI-guided virtual screen with biophysical validation was conducted to identify candidate KCMF1 inhibitors. RESULTS: KCMF1 expression was markedly upregulated in hepatocytes from murine and human MASLD livers. KCMF1 directly interacted with AMPKα and catalyzed its K48-linked polyubiquitination, promoting its degradation and suppressing hepatic AMPK signaling. Functionally, hepatic KCMF1 overexpression exacerbated steatosis, inflammation, and fibrosis, whereas its knockdown or hepatocyte-specific deletion conferred protection across MASLD models. Pharmacological modulation of AMPK in vivo and in primary hepatocytes demonstrated pathway dependency, as AMPK activation attenuated KCMF1-driven pathology. Furthermore, the flavonoid Rhoifolin was identified as a direct KCMF1 binder that stabilized AMPKα and ameliorated MASLD in mice. CONCLUSIONS: KCMF1 drives MASLD pathogenesis by promoting K48-linked ubiquitination and degradation of AMPKα. Targeting the KCMF1-AMPK axis restores hepatic metabolic homeostasis and represents a potential therapeutic strategy for MASLD.
BACKGROUND: Steatotic liver disease is associated with cardiovascular risk, yet the relevance of hepatic fibro-inflammatory activity to cerebral small vessel disease remains unclear. We investigated whether liver MRI phe...BACKGROUND: Steatotic liver disease is associated with cardiovascular risk, yet the relevance of hepatic fibro-inflammatory activity to cerebral small vessel disease remains unclear. We investigated whether liver MRI phenotypes, iron-corrected T1 (cT1; fibro-inflammatory injury) and proton density fat fraction (PDFF; hepatic fat), and brain MRI white matter hyperintensity (WMH; cerebral small-vessel disease burden) predict incident composite neuropsychiatric events and mortality. METHODS: This prospective study included 29,344 UK Biobank participants with liver and brain MRI. Participants were classified into four phenotypes based on liver imaging impairment (cT1 ≥ 800 ms) and high WMH burden (>80th percentile, age-adjusted). Cause-specific Cox models estimated risks for incident composite neuropsychiatric events (stroke, dementia, or late-life depression), liver events, and all-cause mortality, adjusting for prespecified covariates. RESULTS: Over a median follow-up of 5.7 years, 530 participants developed neuropsychiatric events. Higher cT1 was associated with neuropsychiatric events (per 100 ms, hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.04-1.65) and mortality (1.29, 1.04-1.60). Liver fat (PDFF) was not associated with composite neuropsychiatric events (1.00, 0.98-1.03) or mortality (1.00, 0.97-1.03). High WMH burden associated with neuropsychiatric events (1.26, 1.08-1.48) and mortality (1.17, 1.01-1.35). Participants with both elevated cT1 and high WMH had a higher risk of neuropsychiatric events (2.30, 1.00-5.29) and liver events (7.13, 3.32-15.33). CONCLUSIONS: Fibro-inflammatory liver injury, rather than steatosis, was the primary liver MRI correlate of incident composite neuropsychiatric events and mortality. Combined liver-brain MRI phenotyping identified a high-risk subgroup, consistent with shared microvascular vulnerability.
In this narrative translational review, we propose that obesity and aging are not merely parallel epidemics, but biologically convergent processes with shared metabolic and molecular substrates. We introduce the Obesity-...In this narrative translational review, we propose that obesity and aging are not merely parallel epidemics, but biologically convergent processes with shared metabolic and molecular substrates. We introduce the Obesity-Accelerated Aging (ObAGE) framework, arguing that excess adiposity functions as a clinically relevant accelerator of biological aging trajectories. Because much of the supporting human evidence is observational, we use acceleration to indicate earlier appearance or increases in aging-related biological signatures and clinical phenotypes, while recognizing that causal strength varies across aging pathways and study designs. By prematurely engaging core aging hallmarks, including dysregulated nutrient sensing, chronic low-grade inflammation, cellular senescence, and epigenetic drift, obesity may intensify aging-related decline without replacing the underlying aging process, progressively eroding physiological resilience before overt cardiometabolic disease becomes clinically manifest. This convergence helps explain why obesity does not simply increase risk for isolated non-communicable diseases but is associated with earlier multimorbidity and functional impairment. Importantly, this biological embedding begins during sensitive life-course windows. Yet, converging evidence from human studies (from lifestyle interventions to incretin-based pharmacotherapy) suggests that several aging-related signatures remain at least partially modifiable through metabolic optimization. Framing obesity within a geroscience paradigm positions metabolic treatment not only as disease management but also as a strategy to preserve physiological capacity and delay aging-related decline.
While the functional adaptation of β-cells during type 2 diabetes progression is well-established, the role of non-β islet cells remains largely unexplored. Utilizing single-cell RNA sequencing, we identified a substanti...While the functional adaptation of β-cells during type 2 diabetes progression is well-established, the role of non-β islet cells remains largely unexplored. Utilizing single-cell RNA sequencing, we identified a substantial expansion of the macrophage population and a concomitant reduction in the proportion of mesenchymal stem cells (MSCs) within the islets of diabetic mice transitioning from metabolic compensation to decompensation. Under conditions of metabolic stress, macrophages extensively infiltrated the islets and adopted a pronounced pro-inflammatory phenotype. This phenotypic shift impaired β-cell glucose-stimulated insulin secretion and induced β-cell apoptosis. Simultaneously, macrophage-derived inflammatory factors, notably TNF-α, suppressed MSC proliferation and downregulated Wntless (Wls), thereby reducing extracellular Wnt transport. The resultant loss of Wls diminished MSCs' capacity to provide trophic support to β-cells and hindered the transition of macrophages to an anti-inflammatory phenotype. This self-perpetuating cycle establishes a chronic pro-inflammatory environment within the islets, culminating in β-cell functional deterioration and the onset of diabetes. Experimental intervention involving macrophage elimination and MSC administration was shown to disrupt this detrimental cycle, restoring β-cell function and glycemic control. Collectively, our findings reveal that macrophages and MSCs jointly govern β-cell adaptation through intricate paracrine crosstalk. Modulating these macrophage-MSC interactions holds significant therapeutic implications for maintaining β-cell integrity and underscores the considerable potential of MSC-based therapies for type 2 diabetes treatment.
Yamazaki H, Tokgöz S, Tauchi S
… +14 more, Nakamura F, Dohke M, Hanawa N, Kodama Y, Katanuma A, Yamamoto Y, Fukuhara S, Prystupa K, Hummel J, Deden L, Boss M, Gotthardt M, Wagner R, Heni M
BACKGROUND: Individuals with type 2 diabetes (T2D) tend to have a smaller pancreas and lower beta-cell mass; however, whether this is cause or consequence of T2D is unclear. We investigated the connection between pancrea...BACKGROUND: Individuals with type 2 diabetes (T2D) tend to have a smaller pancreas and lower beta-cell mass; however, whether this is cause or consequence of T2D is unclear. We investigated the connection between pancreatic volume, beta-cell mass, beta-cell function, and T2D risk, and whether intrapancreatic fat deposition (IPFD) modifies these associations. METHODS: We conducted three complementary studies. In a PET/CT study (N = 52), beta-cell mass was estimated using [Ga]Ga-NODAGA-exendin-4 PET/CT imaging, and its correlations with CT-measured pancreatic volume, IPFD, and beta-cell function (HOMA2-%B) were evaluated. In a cross-sectional study using UK Biobank (N = 25,212), individuals were classified into four groups according to median pancreatic volume and IPFD on MRI, and the association with T2D prevalence was estimated. Finally, a case-cohort study with 6-year follow-up (N = 2168, subcohort of 658 and 146 incident T2D cases) used CT imaging to assess whether pancreatic volume and IPFD were associated with future T2D. RESULTS: In the PET/CT study, smaller pancreatic volume (r = 0.66 [95% CI: 0.47-0.80]) combined with higher IPFD (r = 0.29 [95% CI: 0.011-0.53]) was associated with reduced estimated beta-cell mass, which in turn was linked to lower insulin secretion (r = 0.48 [95% CI: 0.22-0.68]). In the UK Biobank, individuals with small pancreas that contained much fat (small/high-fat pancreas) had the highest T2D likelihood (adjusted-odds ratio: 1.71 [95% CI: 1.42-2.07]) compared to those with large/low-fat pancreas. Validation in the longitudinal study showed adjusted-hazard ratios for T2D of 3.12 (1.40-6.96) for small/high-fat, 0.99 (0.58-1.67) for large/high-fat, and 0.74 (0.26-2.14) for small/low-fat pancreas. CONCLUSION: The combination of a small pancreas and high IPFD is associated with increased T2D risk, supporting a structural phenotype linked to beta-cell failure.
Zhao W, Jiao X, Du K
… +19 more, Sun Q, Duan J, Cao Y, Shen X, Said Z, Karri SS, Ellsworth P, Hu W, Sargsyan A, Astapova I, Kim SY, Gonzalez J, Higgins-Chen AT, Perry RJ, Seki E, Herman MA, Andersen B, Nie Q, Yang Q
The liver is a major metabolic organ regulating systemic insulin sensitivity, which progressively declines with age. Due to the complexity of cellular components and spatial structures, how the liver regulates insulin re...The liver is a major metabolic organ regulating systemic insulin sensitivity, which progressively declines with age. Due to the complexity of cellular components and spatial structures, how the liver regulates insulin resistance during aging remains to be elucidated. Using single-cell RNA-seq, ATAC-seq, and spatial transcriptomics, we studied liver cellular composition and zonation in young, insulin-sensitive mice and old mice with varying degrees of insulin resistance. Aging reduced pericentral zone 3 hepatocyte population but increased mid-zone 2 hepatocytes and hepatic stellate cells (HSCs). The interaction of aging and insulin resistance led to further zone 3 contraction and zone 2 expansion. Cell-cell communication and spatial proximity analysis revealed reduced hepatocyte growth factor (HGF) signaling activity from HSCs to zone 3 hepatocytes in aging and insulin resistance. In HGF activator (HGFAC)-knockout mice, a significant reduction in the zone 3 hepatocyte proportion was observed. Treating insulin-resistant aged mice with HGF reversed zone 3 contraction and improved insulin sensitivity. These findings highlight the significance of liver zonation dynamics in aging-associated insulin resistance.