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

Background: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of non-Hodgkin lymphoma (NHL), but the underlying mechanisms remain unclear. This study aimed to identify potential biomarkers and elucidate the molecular mechanisms underlying the co-pathogenesis of T2DM and NHL.

Methods: Microarray datasets of T2DM and NHL were downloaded from the Gene Expression Omnibus database. Subsequently, a protein-protein interaction network was constructed based on the common differentially expressed genes (DEGs) between T2DM and NHL to explore regulatory interactions. Functional analyses were performed to explore underlying mechanisms. Topological analysis and machine learning algorithms were applied to refine hub gene selection. Finally, quantitative real-time polymerase chain reaction was performed to validate hub genes in clinical samples.

Results: Intersection analysis of DEGs from the T2DM and NHL datasets identified 81 shared genes. Functional analyses suggested that immune-related pathways played a significant role in the co-pathogenesis of T2DM and NHL. Topological analysis and machine learning identified three hub genes: GZMM, HSPG2, and SERPING1. Correlation analysis revealed significant correlations between these hub genes and immune cells, underscoring the importance of immune dysregulation in shared pathogenesis. The expression of these genes was successfully validated in clinical samples.

Conclusion: This study suggested the pivotal role of immune dysregulation in the co-pathogenesis of T2DM and NHL and identified and validated three hub genes as key contributors. These findings provide insight into the complex interplay between T2DM and NHL.

Background: Reactive oxygen species (ROS) is known to play a significant role in the activation of chronic inflammatory processes in diabetic retinopathy. This study was aimed to evaluate activated growth factor (AGF) from platelet for diabetic retinopathy treatment, utilizing an in vivo investigation to regulate the antioxidant-oxidative stress pathway.

Methods: The activated growth factor was initially derived by extracting intravenous blood from the rats. Advanced glycation end products (AGEs), p38 mitogen activated protein kinase (p38 MAPK), nuclear factor-κβ (NF-κβ), reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), superoxide dismutase (SOD) and vascular endothelial growth factor (VEGF) was assessed using enzyme linked immunoassay (ELISA). In vivo, diabetic retinopathy rat models were induced by streptozotocin injection and were evaluated by retinal funduscopy.

Results: The mean diameter of the retinal artery was significantly reduced when activated growth factor with transforming growth factor-β concentration of 10 ng/mL or 100 ng/mL was administered (p<0.05). The retinal tissue of diabetic rats showed a decline in antioxidant activity due to oxidative stress. AGF containing TGF-β (10 ng/mL and 100 ng/mL) significantly increased SOD activity (p<0.05). AGF administration effectively decreased proinflammatory cytokines like TNF-α and IL-1β.

Conclusion: The study shows that AGF, with TGF-β concentrations of 10 ng/mL and 100 ng/mL, can reduce AGEs, p38MAPK, Nf-κβ, ROS, TNF-α, IL-1β, VCAM-1, ICAM-1, and VEGF in diabetic retinopathy rats' retinal tissue, while increasing antioxidant SOD concentration, suggesting AGF may help treat diabetic retinopathy by reducing inflammation and oxidative stress.

Purpose: Obesity is a complex disease caused by a combination of genetic, environmental, and epigenetic factors, and is associated with an increased risk of chronic diseases. The leptin-melanocortin pathway integrates peripheral signals about the body's energy stores with a central neuronal circuit in the hypothalamus. This pathway has been extensively studied over the years, as genetic variations in genes related to it may play a crucial role in determining an individual's susceptibility to obesity. Therefore, we analyzed the association between obesity and specific polymorphisms in leptin-melanocortin-related genes such as LEPR rs1137101, POMC rs1042571, LEP rs7799039, BDNF rs6265, FTO rs17817449, CART rs121909065, and NPY rs16147/rs5574.

Patients and methods: The study enrolled 501 participants from Rio de Janeiro, Brazil, with obesity class II or greater (BMI ≥ 35 kg/m2) and normal weight controls (18.5≤ BMI ≤24.9 kg/m2). We collected demographic, body composition, biochemical, and genotyping data by real-time PCR, and performed logistic and linear regression analyses to investigate the association of polymorphisms with severe obesity status and obesity-related quantitative parameters.

Results: Individuals with severe obesity had significantly higher anthropometric measures, blood pressure, and biochemical levels. The FTO rs17817449 TT genotype was associated with a significantly higher risk of developing severe obesity, and distinct cytokine expression was observed across the FTO rs17817449 genotypes. The BDNF rs6265 dominant-model and NPY rs16147 CC genotypes were associated with triglyceride levels and childhood obesity, respectively. Finally, individuals with obesity were more likely to carry a greater number of risk alleles than those without obesity.

Conclusion: Our study observed an important association between FTO rs17817449 polymorphism with obesity and obesity-related traits. Additionally, BDNF rs6265 dominant-model was associated with triglyceride serum levels, and NPY rs16147 may have a role in obesity onset.

Tirzepatide is a GLP1/GIP receptor agonist that is used to treat type 2 diabetes and promote weight loss. Common side effects of Tirzepatide include nausea, vomiting, and diarrhea. More severe side effects include pancreatitis, cholelithiasis, thyroid cancer, and cholecystitis. With the increased use of these medications, additional side effects are being discovered. Delayed gastric emptying associated with GLP1/GIP receptor agonists can increase the risk of developing appendicitis due to changes in gastrointestinal motility. There is minimal data on the risk of developing appendicitis with Tirzepatide. This novel case report presents a 73-year-old female patient, without typical risk factors or obvious triggers, who developed appendicitis one week following the initiation of Tirzepatide. Once Tirzepatide was stopped, the patient's symptoms dramatically improved and there was improvement also demonstrated on CT imaging. The patient eventually got an outpatient appendectomy. Appendicitis is not frequently reported as a GLP1/GIP receptor agonist side effect in clinical studies. There seems to be a temporal association between Tirzepatide and the onset of appendicitis. This case report highlights the importance of considering appendicitis as a potential adverse effect of Tirzepatide, a GLP1/GIP receptor agonist.

Introductions: Diabetic foot ulcers (DFU) are notoriously difficult to heal, however, its underlying molecular mechanisms are unknown. MicroRNA-139-5p participates in various biological processes, including cancer and vascular endothelial injury, while its role in diabetic wound healing has not been reported.

Methods: Sprague-Dawley (SD) rats were intraperitoneally injected with streptozotocin and a 1.0 cm full-layer dorsal skin wound was made to establish a diabetic wound model. On days 1, 4, 7, and 10 after the wound was made, a solution containing microRNA-139-5p antagomir or control was injected along the dorsal edge of the wound. Wound healing was analyzed using Image J, histological analysis and molecular analysis. Skin tissues from 4 diabetic and 4 matched non-diabetic ulcer patients were obtained to detect microRNA-139-5p expression. In vitro, human skin fibroblasts were transfected with microRNA-139-5p inhibitors/mimics, the function of the fibroblasts was evaluated by CCK-8 assay and scratch assay, and AP-1 (c-Fos/c-Jun) was detected.

Results: Obviously elevated microRNA-139-5p expression was detected in the wound tissue of the rats with diabetes and patients with DFUs, and the microRNA-139-5p antagonist-treated diabetic wounds had faster healing rates. The pace of diabetic wound re-epithelialization and angiogenesis was accelerated, and the expression of AP-1 family members (c-Fos/c-Jun), and VEGF, PDGF was upregulated in the wound tissue of diabetic rats treated with topical microRNA-139-5p antagomir. In vitro, the expression of microRNA-139-5p was up-regulated in human skin fibroblasts induced by high glucose treatment, while the function of the cell proliferation and migration was promoted and the level of AP-1 (c-Fos/c-Jun) was increased after transfected with the microRNA-139-5p inhibitor, and vice versa. Our study further verified that microRNA-139-5p regulated the migration of human skin fibroblasts by modulating c-Fos.

Conclusion: Inhibiting microRNA-139-5p improves fibroblasts viability and promotes diabetic wound healing, suggesting that this may be a therapeutic strategy for diabetic foot ulcer.

Introduction: While the benefits of metabolic bariatric surgery (MBS) are well described, only few studies have been published from the Gulf region, where the impact of regional patient characteristics on outcomes remains poorly understood.

Methods: Data were reviewed for patients attending metabolic follow-up three or more months after primary MBS at our center in the UAE from 2016 to 2022. Total weight loss (TWL), status of type 2 diabetes (T2D), hyperlipidemia, and hypertension were assessed following sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB).

Results: Of 2851 included patients, 62.6% were female and 94.0% Emirati. Pre-operatively, mean age was 34.2 ±0.2 years, median BMI was 41.0 (IQR 37.8-45.2) kg/m²; 92.5% had SG and 7.5% RYGB. %TWL (95% confidence interval) for RYGB was 31.2% (30.0-32.5), 30.9% (29.0-32.9) and 28.4% (23.0-33.8) at 1, 3 and 5 years. Following SG, %TWL was 29.9% (29.5-30.3), 25.8% (25.0-26.7) and 23.4% (21.6-25.2) for the same intervals. The proportion of total operated patients included was 60.2%, 43.7% and 33.8% respectively. Men lost more weight than women 12 months after SG, with mean %TWL of 32.5% (31.8-33.2) vs 28.4% (27.9-28.9) respectively. T2D remission (HbA1c <6.5% without diabetes medications) after SG was 61.9% (179/289) at 1 year and 40.9% (18/44) at 5 years. RYGB favored T2D remission over SG at 12 months, OR=2.272 (1.152-4.65). There was no difference between procedures for hypertension status, although remission from hyperlipidemia was higher 1 year after RYGB at 41.8% (23/55) compared to SG 16.4% (78/475) (p<0.001).

Conclusion: In this young Emirati cohort, RYGB was associated with more weight loss and favored T2D and hyperlipidemia remission over SG. Women lost less weight than men after SG. Weight recurrence from 1 to 5 years after SG was greater than the international average. Further research is required to explain these differences and improve outcomes.

Purpose: Klinefelter's syndrome (KS) is the most common sex chromosome disorder in the male population and is characterized by the presence of one or more X chromosomes. Studies have reported that the proportion of KS patients with diabetes is not low. It is also not uncommon for diabetes patients with poorly controlled blood glucose to have a transient mild increase in their carcinoembryonic antigen (CEA) levels. This study reports the case of Diabetic ketoacidosis (DKA) concurrently with a significant increase in CEA levels (reaching 40.8 ng/mL) in patients with KS.

Methods: This middle-aged KS patient was immediately treated for DKA upon admission. A series of exams were performed to exclude the possibility of malignant tumors, and the patient's glucose and CEA levels were closely monitored.

Results: After excluding the possibility of malignant tumors, the patient's CEA level gradually decreased to normal after good glycemic control.

Conclusion: This is the first report describing significant increases in CEA levels in KS patients with diabetes, which is of great clinical significance for the treatment of diabetes patients.

Background: Early alterations in cardiac energy metabolism and lipotoxicity are crucial factors in the pathogenesis and progression of diabetic cardiomyopathy (DCM). The excessive accumulation of lipid metabolic intermediates within the myocardium can lead to increased production of reactive oxygen species (ROS) and promote apoptosis. Pigment epithelium-derived factor (PEDF) has been shown to regulate cardiac energy metabolism; however, its role in modulating energy metabolism, ROS generation, and apoptosis in the context of DCM requires further investigation.

Methods: PEDF was overexpressed in db/db mice via tail vein injection of adeno-associated virus 9(AAV9)-PEDF. At week 24, assessments were conducted on cardiac hypertrophy, fibrosis, cardiac function, and alterations in energy metabolism. Additionally, H9c2 cells were transfected with a PEDF plasmid and cultured under HG+PA conditions (33 mm glucose + 250 μM palmitic acid) for 24 hours. Subsequent analyses focused on changes in energy metabolism, ROS levels, and apoptosis.

Results: At 24 weeks, db/db mice exhibited hallmark features of DCM, including hyperglycemia, hyperlipidemia, cardiac hypertrophy, fibrosis, and diastolic dysfunction. Overexpression of PEDF reversed cardiac remodeling in these mice. In both db/db mice and HG+PA-treated H9c2 cells, PEDF overexpression modulated cardiac energy metabolism, mitigated lipotoxicity, and promoted the expression of adipose triglyceride lipase(ATGL) and glucose transporter type 4(Glut4) while inhibiting the expression of peroxisome proliferator-activated receptor alpha (PPARα), carnitine palmitoyltransferase 1 alpha (CPT1α), and scavenger receptor B2 (CD36). Additionally, PEDF overexpression reduced ROS generation and apoptosis in db/db mice myocardium and HG+PA-treated h9c2 cells.

Conclusion: PEDF can effectively prevent cardiac hypertrophy, fibrosis remodeling, and the deterioration of diastolic dysfunction in DCM by modulating cardiac energy metabolism and mitigating ROS production and apoptosis induced by lipotoxicity.

Purpose: This study aims to identify key genes that may be involved in the pathogenesis of gestational diabetes mellitus and to preliminarily elucidate the underlying mechanisms.

Methods: High-throughput transcriptome sequencing was employed to identify Differentially expressed genes (DEGs) in placental tissue samples of GDM and normal pregnant women. Functional and pathway analyses of these DEGs were conducted using bioinformatics databases. Significant DEGs were validated through real-time quantitative PCR in conjunction with relevant literature.

Results: In comparison to the normal pregnancy group, 435 DEGs were identified in the GDM group, comprising 128 upregulated and 307 downregulated genes. GO enrichment analysis revealed that DEGs were primarily associated with biological processes, such as cellular processes, biological regulation, regulation of biological processes, and response to stimuli. Cell component enrichment analysis indicated their association with cellular anatomical entities and protein-containing complexes. Molecular function enrichment analysis highlighted their roles in binding and catalytic activities. KEGG pathway enrichment analysis indicated the involvement of DEGs in signalling pathways related to PI3K-Akt signaling pathway and ECM-receptor interaction. qRT-PCR validation of five randomly selected DEGs confirmed consistent expression trends with RNA-Seq quantification.

Conclusion: YWHAB, LEP, CCL21, PAPPA2, and SFN may be potential biological markers for the diagnosis of GDM, involved in the occurrence and development of GDM, and have certain value for disease prediction and diagnosis.

Objective: To investigate the allelic genotypes of the adiponectin (APN) gene polymorphisms (rs1501299) and its association with APN level among Mets patients.

Methods: A total of 410 patients with Mets and 203 healthy subjects were included in the study. The serum APN levels of the subjects were detected using enzyme-linked immunosorbent assay. The polymorphisms of the G/T gene at the rs1501299 locus of the APN gene were detected using restriction fragment length polymorphism polymerase chain reaction technology.

Results: The serum APN levels were significantly lower in Mets patients than in the control group (15.0 ± 4.9 mg/L vs 27.2 ± 6.5 mg/L, p < 0.05). The distribution of the three genotypes at the rs1501299 locus was statistically different between the Mets patients and the control group (GG, GT, and TT, p < 0.05), and the frequencies of the T alleles were higher in the Mets patients than in control group (GT and TT, p < 0.05). Logistic regression analysis showed that the study subjects with the T allele had a higher risk of Mets than those with the G allele (OR = 1.85, p < 0.05). The risk of Mets was higher in GT and TT genotypes compared to in GG genotypes (OR = 1.43; OR = 2.14 vs OR = 1.00 ref). Similarly, it increased after combining GT and GG genotypes (OR = 1.73, p < 0.05). The APN levels in the GT (14.3 ± 5.3 mg/L) and TT (13.4 ± 5.4 mg/L) genotypes of the study subjects were lower than those of the GG genotype (15.5 ± 4.8 mg/L, p < 0.05).

Conclusion: The occurrence of Mets may be associated with genetic variants at the rs1501299 locus, especially for individuals with G to T variants that reduce APN levels and lead to a higher risk of developing Mets.