Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy最新文献

Background: Type 2 diabetes mellitus (T2DM) increases major adverse cardiovascular event (MACE) risk, requiring effective interventions. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce MACE, but the impact of baseline characteristics on their efficacy is unclear from previous analyses.

Methods: This PRISMA-guided systematic review and meta-analysis included randomised controlled trials (RCTs) comparing GLP-1RAs with placebo in patients with T2DM, sourced from PubMed and Google Scholar. We extracted MACE hazard ratios (HR), 95% confidence intervals (CI), and baseline characteristics (age, BMI, SBP, HbA1c, eGFR, male proportion, diabetes duration, CVD prevalence). A random-effects model estimated pooled HR, with heterogeneity assessed via prediction intervals. Meta-regression identified moderators. Sensitivity analyses and the RoB 2 Tool assessed bias; GRADE evaluated the certainty of evidence.

Results: Across 11 RCTs (83,536 participants), the pooled HR for MACE was 0.87 (95% CI: 0.81-0.93), indicating a 13% risk reduction with moderate heterogeneity (prediction interval: 0.79-0.96). After excluding T2DM duration due to multicollinearity, multivariate meta-regression identified age (p = 0.02) and HbA1c (p = 0.03) as significant moderators, which persisted after excluding FREEDOM-CVO (age, p = 0.03; HbA1c, p = 0.04). Baseline CVD prevalence did not moderate outcomes (p = 0.892). Bias was low; evidence certainty was moderate.

Conclusion: GLP-1RAs reduce MACE in T2DM, particularly in older patients with lower baseline HbA1c. This fills a critical gap in prior meta-analyses by identifying actionable pre-treatment predictors that support personalised therapy.

Protocol registration: Ghosal et al INPLASY protocol 202580045. doi:10.37766/inplasy2025.8.0045 INPLASY202580045.

Background: Diabetes peripheral neuropathy (DPN) is closely related to the occurrence and development of sarcopenia. However, the relevant early biological metabolites and their pathophysiological mechanism is unclear.

Aim: To explore the underlying mechanisms of Diabetic Peripheral Neuropathy with Sarcopenia (DPNS) by integrating metabolomics and 16S rRNA sequencing.

Methods: A total of 151 diabetic neuropathy patients were enrolled in the study. Untargeted metabolomics was performed using ultra-high-performance liquid. Chromatography-mass spectrometry, andgut microbiota was assessed through 16S rRNA sequencing. Differential metabolites and microbial taxa were identified, and theirassociations were explored using correlation analysis.

Results: A total of 376 differential metabolites were identified. Compared with the DPN group, the contents of glycerophosphocholine(GPC), taurine, and succinic acid in the DPNS group were significantly decreased, while that of 2-amino-1-methyl-6-phenylimidazo(4, 5-b)pyridine(PhIP), Sphingosine were increased. Gutmicrobiota analysis revealed reduced diversity in DPNS, with decreased beneficial genera (Faecalibacterium, Bacteroides) and increased pathogenic taxa (Streptococcus). Additionally, KEGG enrichment analysis showed that the mammalian target of necroptosis, sphingolipid metabolism, the mTOR signaling pathway, ABC transporters, and bile secretion pathways are closely related to DPNS.

Conclusion: We systematically explored the biomarkers and potential therapeutic targets in the patients with DPNS, which may provide new insights that may advance the treatment of sarcopenia.

Aim: The mechanisms governing dynamic regulation of counterregulatory hormones in type 1 diabetes (T1DM) remain incompletely understood. To eliminate potential confounding effects of female sex hormones and menstrual cycle variations on insulin sensitivity and counter-regulatory hormone secretion, this study investigated the correlation between counter-regulatory hormone levels and insulin resistance in male patients with T1DM.

Research design and methods: From March 2022 to December 2022, 34 male patients with newly diagnosed T1DM and 8 male normal people without DM were included. Counter-regulatory hormone levels and clinical characteristics were collected. All the included T1DM subjects were treated with intensive insulin therapy by insulin pump for 1 week to achieve glycemic control, followed by using the hyperinsulinemic-hypoglycemic clamp to determine the steady-state glucose infusion rate, an indicator of insulin sensitivity. The chemiluminescent immunometric assay was also used to measure circulating counter-regulatory hormones, such as glucagon (GCG), insulin-like growth factor-1 (IGF-1), adrenocorticotropic hormone (ACTH), growth hormone (GH), and cortisol (Cor) at 0min and 30min during hyperinsulinemic-hypoglycemic test. Correlation analysis was conducted to investigate the relationship between insulin-stimulated glucose disposal rates (M value) and counter-regulatory hormone levels.

Results: The T1DM group exhibited lower fasting C-peptide levels than the normal group (p<0.050). During the hypoglycemic clamp test and in the hypoglycemic state, the T1DM group showed a greater magnitude of increase in Cor and GH levels than the control group, whereas GCG displayed an opposite trend. Moreover, the M value was negatively correlated with ACTH, COR, and GH, and positively correlated with IGF-1 in male patients with newly diagnosed T1DM.

Conclusion: The current study demonstrates that inhibiting the upregulation of insulin counter-regulatory hormone levels contributes to impaired insulin regurgitator response during hypoglycaemia in newly man diagnosed T1DM patients. This study provides insight into the glycaemic control benefits of insulin counter-regulatory hormones, and insulin counter-regulatory hormone levels may serve as a potential biomarker for assessing the blood glucose control risk of T1DM.

Trial registration: This trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT05290207).

Background: Type-2 diabetes mellitus (T2DM) is a chronic disorder marked by insulin resistance, beta (β)-cell dysfunction, and persistent hyperglycemia, often leading to diabetic kidney disease. There is growing recognition that inflammation exacerbates diabetes. Human umbilical cord mesenchymal stem cells (hUC-MSCs) have shown promising immunomodulatory effects in the treatment of T2DM; however, the optimal dosing remains inconclusive.

Objective: This study evaluates the effectiveness of early, late, and repeated doses of Cytopeutics^® hUC-MSCs in a T2DM rat model.

Methods: Male Sprague Dawley (SD) rats were allocated into five groups: normal control group and diabetic control group receiving saline, and three diabetic treatment groups receiving hUC-MSCs at different time points-early, late, and repeated. The male rats were fed a high-fat diet (HFD), followed by diabetes induction via a single intraperitoneal injection of streptozotocin (STZ) at 35 mg/kg body weight (BW). Each treatment group received 3.5 × 10⁶ cells/rat intravenously. At the end of the study, blood and tissue were collected before termination for glycemic control (hemoglobin A1C (HbA1c), fasting serum glucose (FSG), and fasting urine glucose (FUG) levels), pro-inflammatory factor high sensitivity C Reactive Protein (hs-CRP), and histopathological analyses.

Results: The diabetic control group exhibited significantly poorer glycemic control along with extensive pancreatic and kidney damage compared to the normal control group. The early dose group showed limited glycemic control, but reduced hs-CRP sustainably compared to the diabetic control group. The late dose group demonstrated glycemic control partially, and preserved pancreatic β-cells and kidney from damage but did not reduce hs-CRP. The repeated dose group reduced HbA1c, FSG, FUG and hs-CRP up to the end of the study and is also associated with fewer pancreatic β-cells and renal tissue damage.

Conclusion: Repeated hUC-MSCs administration demonstrated better glycemic control, modulated inflammatory responses, protected β-cells and kidneys from damage in a T2DM rat model.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is highly prevalent condition, with gut microbiota dysbiosis playing a contributory role in its pathogenesis and progression. Fecal microbiota transplantation (FMT) has emerged as a potential therapeutic approach for MAFLD. This report describes two patients diagnosed with MAFLD who underwent FMT in combination with lifestyle intervention. Post treatment findings demonstrated notable improvements in body mass index (decreased by 20.7% and 3%, respectively), serum transaminases levels (decreased by 51% and 27.2%, respectively), lipid profiles, uric acid concentrations, and liver stiffness measurements (decreased by 22.2% and 24.2%, respectively). Additionally, microbiome analysis showed increased diversity, improved anti-inflammatory and colonization resistance capacity, reduced pathogens, and enriched probiotics. A review of seven Chinese and international randomized controlled trials (RCTs) investigating the application of FMT in MAFLD was conducted. Among these, four trials reported improvement in liver function post-treatment. Two trials reported reductions in small intestinal or gastric permeability, one trial demonstrated a decrease in homeostasis model assessment of insulin resistance (HOMA-IR), one trial noted a reduction in blood lipid levels, and one trial documented a decrease in fat attenuation index (FAI). Only one trial included histological evaluation of liver tissue before and after FMT, which did not demonstrate significant pathological improvement. The combination of FMT and lifestyle intervention has achieved quite satisfactory therapeutic effects in the treatment of MAFLD, providing new ideas and potential therapeutic targets for the management of MAFLD. This approach holds broad application prospects. However, further confirmation through large-scale RCTs is still needed.

Background: Diabetic nephropathy (DN) is a common chronic microvascular complication of diabetes mellitus (DM). Circular RNAs (circRNAs) have emerged as ideal biomarkers for various diseases. Recent studies have shown that circXPNPEP3 is upregulated in high glucose-induced human umbilical vein endothelial cells. In this study, we aimed to examine the expression levels of circXPNPEP3 in the serum of patients with DN and to evaluate its diagnostic potential for this condition.

Methods: The expression levels of circXPNPEP3 in DN tissues and serum were detected using quantitative real-time polymerase chain reaction (qRT-PCR). DN was confirmed by biopsy or clinically defined as a urine albumin/creatinine ratio (uACR) > 30 mg/g or an estimated glomerular filtration rate (eGFR) < 60 mL/min per 1.73 m². The association between circXPNPEP3 expression levels and the clinical features of patients with DN was investigated. Using healthy individuals as controls, the diagnostic value of circXPNPEP3 for DN was evaluated by receiver operating characteristic (ROC) curve analysis. Finally, a potential RNA-interaction-network involving circXPNPEP3 was constructed using bioinformatics approaches.

Results: The expression levels of circXPNPEP3 were significantly upregulated in both DN tissues and serum compared to those in non-DN tissues and serum from healthy controls. The dysregulation of circXPNPEP3 was significantly correlated with albuminuria categories and glomerular filtration rate (GFR) categories. Serum expression of circXPNPEP3 distinguished patients with DN from controls, yielding an area under the ROC curve (AUC) of 0.8389, with a sensitivity of 70.59% and a specificity of 86.27%. Finally, hsa-miR-135b-5p, hsa-miR-135a-3p, and hsa-miR-1237-3p were predicted to be potential targets of circXPNPEP3 in DN, and a competing endogenous RNA (ceRNA) network involving circXPNPEP3 was constructed based on bioinformatic predictions.

Conclusion: CircXPNPEP3 is upregulated in DN tissues and serum. Its elevated expression in serum shows promise as a non-invasive diagnostic biomarker for DN.

Background and objectives: To investigate the associations of C-peptide-based insulin resistance index (HOMA2 IR-CP) and triglyceride-glucose-body mass index (TyG-BMI) with metabolic dysfunction-associated steatotic liver disease (MASLD) in patients with type 2 diabetes mellitus (T2DM), identify independent risk factors for MASLD, construct a clinical predictive model, and evaluate its predictive performance.

Methods: A total of 311 T2DM patients were enrolled and randomly assigned to a derivation cohort (218 cases) and a validation cohort (93 cases) at a 7:3 ratio. Predictive factors were screened via LASSO regression, with results integrated with those from logistic regression analysis. A nomogram was developed, and model performance was assessed using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). Restricted cubic spline (RCS) regression was used to explore dose-response relationships, and stratified analyses and interaction analyses were performed.

Results: HOMA2 IR-CP and TyG-BMI as independent risk factors for MASLD in T2DM patients. The area under the curve (AUC) was 0.805 in the derivation cohort and 0.730 in the validation cohort. Calibration curves showed good agreement between predicted probabilities and actual outcomes, and DCA verified the model's substantial clinical net benefit. RCS analysis revealed a non-linear association between HOMA2 IR-CP and MASLD (P for non-linearity < 0.05), whereas TyG-BMI exhibited a linear association with MASLD (P for non-linearity = 0.139). No significant interaction effects were observed across subgroups stratified by gender, age, BMI, or HbA1c level; however, the associations were more prominent in patients with BMI < 28 kg/m² and those with HbA1c ≥ 7%.

Conclusion: HOMA2 IR-CP and TyG-BMI are independent risk factors for MASLD in T2DM patients. The nomogram model constructed based on these two factors exhibits good predictive performance and can provide a reference for MASLD risk assessment in T2DM patients.

Background: We aimed to investigate the association and causality between blood pressure (BP) during pregnancy and gestational diabetes mellitus (GDM).

Methods: In a Chinese birth cohort study, 5,952 participants with repeated measurements of BP were included. Logistic regression models were used to estimate the associations between BP and BP trajectories with the risk of GDM. Polygenic risk scores (PRS) were used in a one-sample Mendelian randomization (MR) analysis conducted on a subset of the cohort. Linkage disequilibrium score regression and a two-sample MR analysis were performed to explore genetic correlation and causal relationship between BP and GDM in both Europeans and East Asians.

Results: Elevated first and mean systolic blood pressure (SBP) during pregnancy were both associated with an increased risk of GDM. Individuals with a High-stable SBP trajectory throughout pregnancy had a higher risk of GDM (OR, 1.43[95% CI, 1.07-1.88]) compared to those with a low-stable SBP trajectory. The top quintile of genetically predicted SBP was associated with an increased risk of GDM compared to the lowest quintile (OR, 1.54[95% CI, 1.05-2.27]). A modest genetic correlation between SBP and GDM was observed in Europeans (r _g=0.12, p=0.0002). The MR analysis provided consistent evidence for a causal effect of SBP on GDM in Europeans (OR, 1.42[95% CI, 1.12-1.82]).

Conclusion: Our findings highlight the crucial role of elevated SBP in the development of GDM. Further genetic correlation and MR studies provide compelling evidence suggesting a potential causal relationship, thereby enhancing our understanding of the etiology of GDM.

Purpose: To investigate the correlation between α-glycosidase inhibitors (AGIs) and bone mineral density (BMD) in patients with type 2 diabetes mellitus (T2DM).

Patients and methods: A total of 251 patients with T2DM admitted to the Zhongshan Hospital, Fudan University (Xiamen Branch) from September 2018 to September 2020 were enrolled. Baseline information of patients was analyzed according to different BMD subgroups. Clinical characteristics and BMD were compared between AGIs Group (n = 58) and non-AGIs group (n = 193). Multiple linear regression model was used to examine the relationship between AGIs application and BMD.

Results: The lower BMD group showed the characteristics of older age, longer duration of diabetes, lower body mass index (BMI) and estradiol (E2). In the AGIs group, the proportion of females, duration of diabetes, incidence of diabetic peripheral vascular disease and the use of sulfonylureas were significantly higher than those in the non-AGIs group (p < 0.05), the results of HbA1c, TC, TG, LDL, FT3, FT4 were opposite (p < 0.05). Compared with the non-AGIs group, the BMD of femoral neck and lumbar spine in the AGIs group was significantly decreased, FRAX score and the prevalence of osteoporosis were remarkably increased, accompanied by a decrease in β-CTX and P1NP level. Multivariate linear regression analysis showed a significant negative correlation between AGIs and lumbar BMD after adjustment for potential confounding variables (β = -0.053, 95% CI -0.100~0.006, P = 0.029).

Conclusion: This study indicates that the use of AGIs in patients with T2DM is significantly associated with an increased risk of BMD decline, osteoporosis, and fracture.

Background: The pathogenesis of diabetic nephropathy (DKD) remains unclear; however, existing literature suggests that ectopic fat deposition and metabolic reprogramming contribute to the development of diabetic renal fibrosis. Our previous studies have demonstrated that pigment epithelium-derived factor (PEDF) can alleviate diabetic renal fibrosis.

Methods: In this study, db/db mice were utilized as animal models to simulate type 2 diabetic nephropathy, and human proximal tubular epithelial cells (HK-2) cultured under conditions of high glucose and high palmitic acid were employed for in vitro analysis to investigate the mechanism through which PEDF improves diabetic renal fibrosis.

Results: The results revealed that implanting the PEDF gene via AAV9 effectively improved renal function and blood lipid levels in db/db mice, and alleviated renal tubular injury, urinary albumin excretion, renal ectopic fat accumulation, and renal fibrosis in these mice. The protein expressions in renal peroxisomes and mitochondria could be up-regulated by PEDF, leading to enhanced β-oxidation of fatty acids in db/db mice. This effect was associated with the up-regulation of the ATGL-PPARα pathway and the down-regulation of the HIF-1α-HK2 pathway. It was observed that PEDF effectively mitigated lipid deposition and transdifferentiation of HK-2 cells by activating the ATGL-PPARα pathway, while concurrently inhibiting HIF-1α-HK2 pathway and glycolysis. Furthermore, PEDF facilitated fatty acid β-oxidation in both mitochondria and peroxisomes of HK-2 cells through the ATGL-PPARα pathway.

Conclusion: PEDF can reduce abnormal renal fat accumulation and regulate metabolic reprogramming of renal tubular epithelial cells, thereby alleviating diabetic renal fibrosis.