OBJECTIVES

In Asia, younger individuals (below age 45) are diagnosed to have type 2 diabetes with increased rates of obesity defined by lower BMI yet with greater visceral adiposity (waist circumference and waisthip ratios). The prevalence data on type 1 diabetes is not well established, considered to be low, but is seen to be increasing as well. This changing phenotype therefore, presents a clinical dilemma in terms of correctly classifying diabetes and deciding on the consequent appropriate treatment. Distinguishing type 1 from type 2 diabetes has become more difficult with type 2 diabetes dramatically increasing in young adults and children. This study aims to define the characteristics of diabetes among young adults in the Philippines to provide a basis for appropriate management amidst changes in diabetes phenotypes seen globally.

METHODS

In this cross-sectional analytic study, we characterized the demographic, metabolic, and autoimmune features of diabetes among young adult Filipinos aged 18 to 45 years old consulting at a tertiary referral center in Manila, Philippines. Baseline serum A1c, FBS, 75-g oral glucose tolerance test, insulin, serum C-peptide, insulin autoantibodies, leptin, adiponectin, lipid profile, and thyroid function tests were obtained from the participants and analyzed. The homeostasis model assessment (HOMA) was used to estimate the insulin sensitivity.

RESULTS

A total of 348 patients with diabetes were included, with females comprising two-thirds of the participants. The mean age at diagnosis of diabetes was 35.9±7.22 years. The mean BMI was 28.12 kg/m2, with median waist to hip ratio (WHR) of 0·93. Metabolic syndrome was found in 60% of participants and 67.82% were obese by body mass index. The mean A1c was 9.07±2.52%. Good glucose control (A1c less than 7.0%) was seen in 23% of participants  while nearly half (48%) had HbA1c which was >9.0%. The median levels of fasting insulin and C-peptide were 12.62 (range 1.33–90.42) mIU/L and 0.78 ng/mL (range 0–16.2), respectively. 

Included participants were diagnosed with diabetes within a year and as such, majority did not have any micro- or macrovascular complications. The most common diabetes complication was sensory neuropathy detected by monofilament testing, which was found in 28% of participants, followed by non-proliferative diabetic retinopathy in 13%. A history of previous diabetic ketoacidosis was found in 10 patients (2.87%). Glutamic acid decarboxylase (GAD) and insulin auto-antibodies were found in 3.2% and 19.3% of participants, respectively. Approximately half (51.73%) of the participants were insulin resistant by HOMA-IR.

CONCLUSION

In contrast with Caucasians and other Asians, diabetes among young Filipino adults is associated with lower BMI but with a similarly high visceral adiposity as shown by an elevated WHR. Metabolic syndrome with insulin resistance as defined by a variety of indices is predominant. Type 1 diabetes with autoantibodies occur in only a small fraction of this population. Data derived from this work can provide a framework for cluster analysis towards personalized management specific to this population.

Human ; Acids ; Adiponectin ; Adiposity ; Adult ; Aged ; Antibodies ; Asia ; Asian ; Asian Continental Ancestry Group ; Autoantibodies ; Body Mass Index ; C-peptide ; Carboxy-lyases ; Child ; Cluster Analysis ; Demography ; Diabetes Complications ; Diabetes Mellitus ; Diabetes Mellitus, Type 1 ; Diabetes Mellitus, Type 2 ; Diabetic Ketoacidosis ; Diabetic Retinopathy ; Diagnosis ; Fasting ; Female ; Glucose ; Glucose Tolerance Test ; Glutamate Decarboxylase ; Glutamic Acid ; Insulin ; Insulin Resistance ; Ketosis ; Leptin ; Lipids ; Metabolic Syndrome ; Obesity ; Patients ; Peptides ; Phenotype ; Philippines ; Population ; Prevalence ; Serum ; Therapeutics ; Thyroid Gland ; Thyroid Function Tests ; Young Adult

OBJECTIVE: To elucidate the clinical and genetic characteristics of familial cases with Glucose transporter type 1 deficiency syndrome (Glut1DS). METHODS: A survey of family history was conducted on children (proband) with Glut1DS who had visited Peking University First Hospital between November 2008 and April 2024 by focusing on the clinical manifestations of family members. Peripheral venous blood (2 mL) was collected from the pediatric patients and their parents. Genomic DNA was extracted and sequenced subsequently. Sanger sequencing was performed to validate the identified variant sites of the SLC2A1 gene in the probands and their family members. The pathogenicity of suspected variants was analyzed according to the 2015 American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Interpretation of Sequence Variants. The clinical features, auxiliary examinations, and mutational characteristics of family members with SLC2A1 variants were analyzed. This study has been approved by the Clinical Research Ethics Committee of Peking University First Hospital (Ethics No. 2021 Research 332). RESULTS: Among 87 cases with Glut1DS, 10 families with autosomal dominate inherited cases were identified, accounting for 11.0% of the cases. Of the 11 children, 8 were boys and 3 were girls. The onset of the disease had ranged from 3 months to 120 months (median 6 months), with 4 cases of early-onset classic type, 2 cases of late-onset classic type, and 5 cases of non-classic type. Six children had seizures, and 7 exhibited movement disorders. Seven children underwent developmental assessment, of which 3 had mild developmental delay, 2 were borderline, and 2 were normal. Nine children underwent lumbar puncture. The cerebrospinal fluid glucose levels ranged from 1.45 to 2.25 mmol/L (median 1.86 mmol/L), and the cerebrospinal fluid to blood glucose ratios ranged from 0.29 to 0.44 (median 0.35). Among the 8 fathers with SLC2A1 gene variants, 4 were asymptomatic, 2 developed paroxysmal exercise-induced movement disorders (PED) in childhood and adulthood, respectively. 1 had poor memory since childhood, 1 developed migraines during adolescence, and his sister was an asymptomatic carrier. The father with childhood-onset PED had a cerebrospinal fluid test with CSF glucose of 1.85 mmol/L. Of the 3 mothers with SLC2A1 gene mutations, 1 was an asymptomatic carrier; 2 developed PED in childhood and after the age of 20, respectively. The mother who developed PED in childhood also had psychomotor developmental delay. Genetic testing results revealed that among 10 families, 8 carried missense variants, 1 carried a nonsense variant, and 1 carried a small fragment insertion leading to a frameshift variant. Among the 11 cases, SLC2A1 gene variants in 8 children were inherited from their fathers, while in 3 cases, the variants were inherited from their mothers. The pathogenicity of the genetic variants was evaluated according to the Standards and Guidelines for the Interpretation of Sequence Variants published by the ACMG. Among the 8 variants identified in the 10 families, 4 were classified as pathogenic variants, 1 as likely pathogenic, and 3 as variants of uncertain significance (VUS). Four variant sites, including c.204_205insTCTC (p.V69fs), c.412G>C (p.G138R), c.431T>G (p.V144G), and c.875A>G (p.Y292C), were not previously reported in the literature. Among these, the latter three were categorized as VUS. CONCLUSION Familial Glut1DS account for 11.0% of the cases in China, with the majority of SLC2A1 gene variants inherited from the fathers, predominantly missense mutations, and with an autosomal dominant inheritance pattern. Probands tend to have earlier onset and more severe symptoms than their parents, who often present with mild or no symptoms.
Humans ; Male ; Female ; Glucose Transporter Type 1/deficiency* ; Monosaccharide Transport Proteins/deficiency* ; Child ; Child, Preschool ; Carbohydrate Metabolism, Inborn Errors/genetics* ; Mutation ; Infant ; Pedigree ; Adolescent ; Adult

OBJECTIVE: To observe the effects of moxibustion at different temperatures on cognitive function and blood glucose levels in patients with cognitive impairment associated with type 2 diabetes mellitus (T2DM). METHODS: A total of 66 T2DM patients with cognitive impairment were randomly assigned to a high-temperature group (22 cases, 1 case dropped out, 1 case was eliminated), a medium-temperature group (22 cases, 2 cases were eliminated), and a low-temperature group (22 cases, 2 cases were eliminated). All groups received moxibustion at Baihui (GV20), Dazhui (GV14), and Shenting (GV24) based on their existing glycemic control treatment. Moxibustion temperatures were maintained at 44-46 ℃ (high-temperature group), 41-43 ℃ (medium-temperature group), and 38-40 ℃ (low-temperature group), respectively, for 20 min per session, every other day, 3 times a week for 3 months. The Montreal cognitive assessment (MoCA) score, mini-mental state examination (MMSE) score, short-term memory (STM) accuracy and average reaction time, Rey-Osterrieth complex figure (ROCF) score, fasting plasma glucose (FPG), and glycated hemoglobin (HbA1c) were assessed before and after treatment. Clinical efficacy was evaluated after treatment. RESULTS: After treatment, MMSE scores in all three groups were higher than those before treatment (P<0.05). In the high-temperature group, the total MoCA score and the scores of visuospatial and executive function, memory and delayed recall, attention, naming, language, and abstraction were higher than those before treatment (P<0.05); the scores of ROCF copy, immediate recall, and delayed recall were higher than those before treatment (P<0.05); the HbA1c level was lower than that before treatment (P<0.05). In the medium-temperature group, the total MoCA score and the scores of memory and delayed recall, attention, and language were higher than those before treatment (P<0.05). STM accuracy was higher than before treatment (P<0.05), and STM average reaction time was shorter than before treatment (P<0.05) in both the high-temperature and medium-temperature groups. After treatment, the total MoCA score and the scores of visuospatial and executive function, memory and delayed recall, attention, and language in the high-temperature group were higher than those in the medium- and low-temperature groups (P<0.05); MMSE score, STM accuracy, and ROCF immediate recall and delayed recall scores were higher than those in the medium- and low-temperature groups (P<0.05); STM average reaction time was shorter than that in the medium- and low-temperature groups (P<0.05); HbA1c level was lower than that in the low-temperature group (P<0.05). The total MoCA score, attention score, and MMSE score in the medium-temperature group were higher than those in the low-temperature group (P<0.05), and STM average reaction time was shorter than that in the low-temperature group (P<0.05). There were no statistically significant differences in FPG within or between the three groups before and after treatment (P>0.05). The total effective rates were 75.0% (15/20) in the high-temperature group, 50.0% (10/20) in the medium-temperature group, and 15.0% (3/20) in the low-temperature group; the total effective rate in the high-temperature group was significantly higher than that in the low-temperature group (P<0.05). CONCLUSION Moxibustion at different temperatures has a dose-effect relationship in treating cognitive impairment in T2DM patients. A temperature range of 44-46 ℃ is more effective in improving cognitive function and stabilizing average blood glucose levels over 2-3 months.
Humans ; Diabetes Mellitus, Type 2/therapy* ; Male ; Female ; Moxibustion ; Middle Aged ; Aged ; Cognitive Dysfunction/psychology* ; Cognition ; Temperature ; Blood Glucose/metabolism* ; Adult ; Acupuncture Points

BACKGROUND: Angiotensin receptor neprilysin inhibitors (ARNIs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers (BBs), and mineralocorticoid receptor antagonists (MRAs) are the cornerstones in treating heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) are included in HFrEF treatment guidelines. However, the effect of SGLT-2i and the five drugs on HFrEF have not yet been systematically evaluated. METHODS: PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) from inception dates to September 23, 2022. Additional trials from previous relevant reviews and references were also included. The primary outcomes were changes in left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter/dimension (LVEDD), left ventricular end-systolic diameter/dimension (LVESD), left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV), left ventricular end-systolic volume index (LVESVI), and left ventricular end-diastolic volume index (LVEDVI). Secondary outcomes were New York Heart Association (NYHA) class, 6-min walking distance (6MWD), B-type natriuretic peptide (BNP) level, and N-terminal pro-BNP (NT-proBNP) level. The effect sizes were presented as the mean difference (MD) with 95% confidence interval (CI). RESULTS: We included 68 RCTs involving 16,425 patients. Compared with placebo, ARNI + BB + MRA + SGLT-2i was the most effective combination to improve LVEF (15.63%, 95% CI: 9.91% to 21.68%). ARNI + BB + MRA + SGLT-2i (5.83%, 95% CI: 0.53% to 11.14%) and ARNI + BB + MRA (3.83%, 95% CI: 0.72% to 6.90%) were superior to the traditional golden triangle ACEI + BB + MRA in improving LVEF. ACEI + BB + MRA + SGLT-2i was better than ACEI + BB + MRA (-8.05 mL/m 2 , 95% CI: -14.88 to -1.23 mL/m 2 ) and ACEI + BB + SGLT-2i (-18.94 mL/m 2 , 95% CI: -36.97 to -0.61 mL/m 2 ) in improving LVEDVI. ACEI + BB + MRA + SGLT-2i (-3254.21 pg/mL, 95% CI: -6242.19 to -560.47 pg/mL) was superior to ARB + BB + MRA in reducing NT-proBNP. CONCLUSIONS: Adding SGLT-2i to ARNI/ACEI + BB + MRA is beneficial for reversing cardiac remodeling. The new quadruple drug "ARNI + BB + MRA + SGLT-2i" is superior to the golden triangle "ACEI + BB + MRA" in improving LVEF. REGISTRATION PROSPERO; No. CRD42022354792.
Humans ; Heart Failure/physiopathology* ; Stroke Volume/physiology* ; Angiotensin Receptor Antagonists/therapeutic use* ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use* ; Sodium-Glucose Transporter 2 Inhibitors/therapeutic use* ; Randomized Controlled Trials as Topic ; Mineralocorticoid Receptor Antagonists/therapeutic use* ; Adrenergic beta-Antagonists/therapeutic use*

BACKGROUND: The role of inflammation in the development of gestational diabetes mellitus (GDM) has recently become a focus of research. The systemic immune-inflammation index (SII) and systemic inflammation response index (SIRI), novel indices, reflect the body's chronic immune-inflammatory state. This study aimed to investigate the associations between the SII or SIRI and GDM. METHODS: A prospective birth cohort study was conducted at Beijing Obstetrics and Gynecology Hospital from February 2018 to December 2020, recruiting participants in their first trimester of pregnancy. Baseline SII and SIRI values were derived from routine clinical blood results, calculated as follows: SII = neutrophil (Neut) count × platelet (PLT) count/lymphocyte (Lymph) count, SIRI = Neut count × monocyte (Mono) count/Lymph count, with participants being grouped by quartiles of their SII or SIRI values. Participants were followed up for GDM with a 75-g, 2-h oral glucose tolerance test (OGTT) at 24-28 weeks of gestation using the glucose thresholds of the International Association of Diabetes and Pregnancy Study Groups (IADPSG). Logistic regression was used to analyze the odds ratios (ORs) (95% confidence intervals [CIs]) for the the associations between SII, SIRI, and the risk of GDM. RESULTS: Among the 28,124 women included in the study, the average age was 31.8 ± 3.8 years, and 15.76% (4432/28,124) developed GDM. Higher SII and SIRI quartiles were correlated with increased GDM rates, with rates ranging from 12.26% (862/7031) in the lowest quartile to 20.10% (1413/7031) in the highest quartile for the SII ( Ptrend <0.001) and 11.92-19.31% for the SIRI ( Ptrend <0.001). The ORs (95% CIs) of the second, third, and fourth SII quartiles were 1.09 (0.98-1.21), 1.21 (1.09-1.34), and 1.39 (1.26-1.54), respectively. The SIRI findings paralleled the SII outcomes. For the second through fourth quartiles, the ORs (95% CIs) were 1.24 (1.12-1.38), 1.41 (1.27-1.57), and 1.64 (1.48-1.82), respectively. These associations were maintained in subgroup and sensitivity analyses. CONCLUSION The SII and SIRI are potential independent risk factors contributing to the onset of GDM.
Humans ; Female ; Pregnancy ; Diabetes, Gestational/immunology* ; Prospective Studies ; Adult ; Inflammation/immunology* ; Glucose Tolerance Test ; Birth Cohort

BACKGROUND: Alpha-glucosidase inhibitors or dipeptidyl peptidase-4 inhibitors are both hypoglycemia agents that specifically impact on postprandial hyperglycemia. We compared the effects of acarbose and sitagliptin add on to metformin on time in range (TIR) and glycemic variability (GV) in Chinese patients with type 2 diabetes mellitus through continuous glucose monitoring (CGM). METHODS: This study was a randomized, open-label, active-con-trolled, parallel-group trial conducted at 15 centers in China from January 2020 to August 2022. We recruited patients with type 2 diabetes aged 18-65 years with body mass index (BMI) within 19-40 kg/m 2 and hemoglobin A1c (HbA1c) between 6.5% and 9.0%. Eligible patients were randomized to receive either metformin combined with acarbose 100 mg three times daily or metformin combined with sitagliptin 100 mg once daily for 28 days. After the first 14-day treatment period, patients wore CGM and entered another 14-day treatment period. The primary outcome was the level of TIR after treatment between groups. We also performed time series decomposition, dimensionality reduction, and clustering using the CGM data. RESULTS: A total of 701 participants received either acarbose or sitagliptin treatment in combination with metformin. There was no statistically significant difference in TIR between the two groups. Time below range (TBR) and coefficient of variation (CV) levels in acarbose users were significantly lower than those in sitagliptin users. Median (25th percentile, 75th percentile) of TBR below target level <3.9 mmol/L (TBR 3.9 ): Acarbose: 0.45% (0, 2.13%) vs . Sitagliptin: 0.78% (0, 3.12%), P = 0.042; Median (25th percentile, 75th percentile) of TBR below target level <3.0 mmol/L (TBR 3.0 ): Acarbose: 0 (0, 0.22%) vs . Sitagliptin: 0 (0, 0.63%), P = 0.033; CV: Acarbose: 22.44 ± 5.08% vs . Sitagliptin: 23.96 ± 5.19%, P <0.001. By using time series analysis and clustering, we distinguished three groups of patients with representative metabolism characteristics, especially in GV (group with small wave, moderate wave and big wave). No significant difference was found in the complexity of glucose time series index (CGI) between acarbose users and sitagliptin users. By using time series analysis and clustering, we distinguished three groups of patients with representative metabolism characteristics, especially in GV. CONCLUSIONS: Acarbose had slight advantages over sitagliptin in improving GV and reducing the risk of hypoglycemia. Time series analysis of CGM data may predict GV and the risk of hypoglycemia. TRIAL REGISTRATION Chinese Clinical Trial Registry: ChiCTR2000039424.
Humans ; Metformin/therapeutic use* ; Sitagliptin Phosphate/therapeutic use* ; Acarbose/therapeutic use* ; Diabetes Mellitus, Type 2/blood* ; Middle Aged ; Male ; Female ; Adult ; Blood Glucose/drug effects* ; Hypoglycemic Agents/therapeutic use* ; Aged ; Glycated Hemoglobin/metabolism* ; Adolescent ; Young Adult ; China ; East Asian People

BACKGROUND: Studies on the impact of blood glucose indicators on metabolism remain relatively scarce. The aim of this study was to investigate the associations between blood glucose indicators and metabolic disorders in China. METHODS: Data were from the Thyroid disorders, Iodine status and Diabetes Epidemiological survey (TIDE survey), which randomly selected 31 cities from 31 provinces in the Chinese mainland. A total of 68,383 participants without preexisting diabetes and have complete data on blood glucose, lipids, and blood pressure were included in the analysis. The diabetic population was divided into seven groups based on different types of elevated blood glucose levels, including fasting plasma glucose (FPG), postprandial glucose (PPG), and hemoglobin A1c (HbA1c): FPG ≥7 mmol/L; PPG ≥11.1 mmol/L; HbA1c ≥6.5%; FPG ≥7 mmol/L and PPG ≥11.1 mmol/L; FPG ≥7 mmol/L and HbA1c ≥6.5%; PPG ≥11.1 mmol/L and HbA1c ≥6.5%; FPG ≥7 mmol/L, PPG ≥11.1 mmol/L, and HbA1c ≥6.5%. The effects of each blood glucose indicator on metabolism were investigated separately. Weighted calculation was applied during the analysis, with the weighting coefficient based on the number of people corresponding to the population characteristics of each sample in the 2010 Chinese Census. A logistic regression model with restricted cubic splines (RCS) was employed to characterize the nonlinear associations of age and body mass index (BMI) with the risk of diabetes subtypes defined by distinct blood glucose indicators elevations, as well as the relationships between different blood glucose indicators (FPG, PPG, HbA1c) and the risk of metabolic disorders such as hypertension, hypertriglyceridemia, hypercholesterolemia, high low-density lipoprotein cholesterol (high LDL-C) and low high-density lipoprotein cholesterol (low HDL-C). RESULTS: Among individuals with diabetes, elevated PPG alone was the most common abnormality, affecting 26.96% (1382/5127) of the population. Among the seven groups with only one elevated blood glucose indicator, individuals with elevated PPG alone exhibited the highest mean levels of triglycerides (TG) at 2.11 mmol/L (95% confidence interval [CI]: 1.97-2.25 mmol/L, P = 0.004), total cholesterol (TC) at 5.26 mmol/L (95% CI: 5.18-5.33 mmol/L, P <0.001), and low-density lipoprotein cholesterol (LDL-C) at 3.12 mmol/L, (95% CI: 3.06-3.19 mmol/L, P = 0.001). Individuals with elevated PPG alone showed a high prevalence of hypertension (806/1382, 58.32%), hypertriglyceridemia (676/1382, 48.91%), hypercholesterolemia (694/1382, 50.22%), High LDL-C (525/1382, 37.94%), and Low HDL-C (364/1382, 26.34%). The association of age and BMI with the risk of diabetes revealed that the older the patient, the steeper the RCS curve for the odds ratio (OR) of diabetes with elevated PPG alone (age = 60, OR = 2.79, 95% CI [2.49-3.12], P <0.01). Similarly, as BMI increased, the RCS curve for the OR of diabetes with elevated HbA1c alone also steepened (BMI = 35, OR = 3.75, 95% CI [3.23-4.35], P <0.001). Additionally, the RCS yielded a positive association between blood glucose indicators and metabolic diseases risk. In individuals with diabetes, RCS for both the ORs of metabolic diseases (hypertension, hypertriglyceridemia, hypercholesterolemia, high LDL-C, low HDL-C) and the levels of metabolic indicators (TG, TC, LDL-C, HDL-C) revealed some inflection points within the ranges of FPG 5-6 mmol/L, PPG 6-8 mmol/L, and HbA1c 5.5-6.0%. CONCLUSIONS PPG is more closely related to metabolic disorders than FPG and HbA1c in people with diabetes. For patients with diabetes and metabolic disorders, it may be necessary to monitor blood glucose fluctuations within specific ranges (FPG 5-6 mmol/L, PPG 6-8 mmol/L, and HbA1c 5.5-6.0%).
Humans ; Female ; Cross-Sectional Studies ; Male ; Blood Glucose/metabolism* ; Middle Aged ; Glycated Hemoglobin/metabolism* ; Adult ; Metabolic Diseases/epidemiology* ; Aged ; China ; Diabetes Mellitus/blood* ; East Asian People

OBJECTIVES: To investigate the effect of Didang Decoction-medicated serum on autophagy in high glucose (HG)-induced rat glomerular endothelial cells (RGECs) and explore the pathway that mediates its effect. METHODS: Primary RGECs were isolated and cultured using sequential sieving combined with collagenase digestion, followed by identification using immunofluorescence assay for factor VIII. High glucose medium was used to induce RGECs to simulate a diabetic environment, and the effects of Didang Decoction-medicated serum and 3-MA (an autophagy inhibitor), either alone or in combination, on autophagy of HG-exposed cells were evaluated by observing autophagic vacuoles using monodansylcadaverine (MDC) staining. RT-qPCR and Western blotting were employed to measure mRNA and protein expression levels of Beclin-1, p62, LC3B, p-PI3K, p-Akt, and p-mTOR. RESULTS: Compared with the control cells, the HG-exposed RGECs showed significantly reduced autophagic fluorescence intensity, decreased Beclin-1 mRNA expression, increased p62 mRNA expression, downregulated Beclin-1 protein and LC3-II/I ratio, and upregulated p62, p-PI3K, p-Akt, and p-mTOR protein levels. Didang Decoction-medicated serum significantly enhanced autophagic fluorescence intensity in HG-exposed cells, increased Beclin-1 mRNA expression, decreased p62 mRNA expression, upregulated Beclin-1 protein, and downregulated p62, p-PI3K, p-Akt, and p-mTOR protein levels. CONCLUSIONS Didang Decoction-medicated serum enhances autophagy in HG-exposed RGECs by regulating the PI3K/Akt/mTOR signaling pathway, which sheds light on a new therapeutic strategy for diabetic nephropathy.
Animals ; Autophagy/drug effects* ; Signal Transduction/drug effects* ; Rats ; TOR Serine-Threonine Kinases/metabolism* ; Drugs, Chinese Herbal/pharmacology* ; Proto-Oncogene Proteins c-akt/metabolism* ; Endothelial Cells/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Glucose ; Cells, Cultured ; Kidney Glomerulus/cytology* ; Rats, Sprague-Dawley

OBJECTIVES: To investigate the mechanism through which salidroside inhibits proliferation of gastric cancer (GC) cells focusing on glucose metabolic reprogramming pathways. METHODS: High-throughput sequencing combined with bioinformatics analysis was employed to identify the potential targets of salidroside in human GC MGC-803 cells. Liposome-mediated transfection experiments were carried out to validate the functional and mechanistic roles of these targets. CCK-8 and colony formation assays were used to assess the effects of salidroside on GC cell viability and clonogenic ability. qRT-PCR, Western blotting, and biochemical assay kits were used to analyze the regulatory effects of salidroside on the miR-1343-3p-OGDHL/PDHB enzyme complex-pyruvate metabolic pathway in GC cells. RESULTS: Bioinformatics analysis suggested that the tumor-suppressive factor miR-1343-3p negatively regulated the key glycolytic enzyme gene oxoglutarate dehydrogenase-like (OGDHL) in GC cells, and OGDHL and pyruvate dehydrogenase E1 subunit beta (PDHB) were both significantly upregulated in GC tissues, which was close by correlated with reduced survival rates of GC patients. In MGC-803 cells, salidroside treatment significantly enhanced the expression level of miR-1343-3p and downregulated OGDHL expression, resulting in disruption of the stability of PDHB, reduced pyruvate oxidative decarboxylation, and consequently decreased production of acetyl-CoA and ATP. CONCLUSIONS Salidroside inhibits GC cell proliferation possibly by regulating the miR-1343-3p-OGDHL/PDHB enzyme complex-pyruvate metabolic pathway, which provides new insights into its anti-tumor mechanisms and suggests new strategies for targeted therapy for GC.
Humans ; Stomach Neoplasms/pathology* ; MicroRNAs/genetics* ; Cell Proliferation/drug effects* ; Glucosides/pharmacology* ; Phenols/pharmacology* ; Cell Line, Tumor ; Glucose/metabolism* ; Pyruvate Dehydrogenase (Lipoamide)/metabolism*

OBJECTIVES: To investigate the role of sphingosine-1-phosphate receptor 5 (S1PR5) in modulating barrier function of mouse brain microvascular endothelial cells with oxygen-glucose deprivation and reoxygenation (OGD/R). METHODS: Mouse brain microvascular endothelial cells (bEnd.3) were exposed to OGD/R to induce barrier dysfunction following treatment with S1PR5-specific agonist A971432 or lentivirus-mediated transfection with a S1PR5-specific siRNA, a S1PR5-overexpressing plasmid, or their respective negative control sequences. The changes in viability and endothelial barrier permeability of the treated cells were evaluated with CCK-8 assay and FITC-dextran permeability assay; the levels of intracellular reactive oxygen species (ROS) and localization and expression levels of the proteins related with barrier function and oxidative stress were detected using immunofluorescence staining, DCFH-DA probe and Western blotting. RESULTS: S1PR5 activation obviously enhanced viability of bEnd.3 cells exposed to OGD/R (P<0.0001). Both activation and overexpression of S1PR5 reduced FITC-dextran leakage, while S1PR5 knockdown significantly increased FITC-dextran leakage in the exposed bEnd.3 cells. Activation and overexpression of S1PR5 both increased the cellular expressions of the barrier proteins ZO-1 and occludin, while S1PR5 knockdown produced the opposite effect. In cells exposed to OGD/R, ROS production was significantly reduced by S1PR5 activation and overexpression but increased following S1PR5 knockdown. Overexpression of S1PR5 obviously increased the expressions of the antioxidant proteins Nrf2, HO-1 and SOD2 in the exposed cells. CONCLUSIONS S1PR5 activation and overexpression significantly improve cell viability and reduce permeability of a mouse brain microvascular endothelial cell model of OGD/R, the mechanism of which may involve the reduction in ROS production and upregulation of the antioxidant proteins.
Animals ; Mice ; Oxidative Stress ; Endothelial Cells/cytology* ; Brain/blood supply* ; Reactive Oxygen Species/metabolism* ; Receptors, Lysosphingolipid/metabolism* ; Sphingosine-1-Phosphate Receptors ; Blood-Brain Barrier/metabolism* ; Glucose ; Cell Line ; Oxygen/metabolism* ; NF-E2-Related Factor 2/metabolism*