Efficacy and safety of oral semaglutide vs sitagliptin in a predominantly Chinese population with type 2 diabetes uncontrolled with metformin: PIONEER 12, a double-blind, Phase IIIa, randomised trial.

AIMS/HYPOTHESIS: The aim of this study was to assess the efficacy and safety of oral semaglutide vs sitagliptin in a predominantly Chinese population with type 2 diabetes inadequately controlled with metformin treatment. METHODS: The Peptide Innovation for Early Diabetes Treatment (PIONEER) 12 trial was a randomised, double-dummy, active-controlled, parallel-group, Phase IIIa trial conducted over 26 weeks at 90 sites across the China region (including mainland China, Taiwan and Hong Kong) and five other countries. Adults aged ≥18 years (≥20 years in Taiwan) with a diagnosis of type 2 diabetes, HbA1c between 53 and 91 mmol/mol (inclusive) and treated with a stable daily dose of metformin were eligible for inclusion. Participants were randomised (1:1:1:1) using a web-based randomisation system to either once-daily oral semaglutide (3 mg, 7 mg or 14 mg) or once-daily oral sitagliptin 100 mg. Treatment allocation was masked to both participants and investigators. Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary endpoint was change in HbA1c from baseline to week 26. The confirmatory secondary endpoint was change in body weight (kg) from baseline to week 26. All randomised participants were included in the full analysis set (FAS). All participants exposed to at least one dose of trial product were included in the safety analysis (SAS). RESULTS: Of 1839 participants screened, 1441 were randomly assigned to oral semaglutide 3 mg (n=361), 7 mg (n=360), 14 mg (n=361) or sitagliptin 100 mg (n=359) and included in the FAS. A total of 1438 participants were included in the SAS. In total, 75.2% of participants were from the China region. A total of 1372 (95.2%) participants completed the trial and 130 participants prematurely discontinued treatment (8.3%, 8.6% and 15.0% for oral semaglutide 3 mg, 7 mg and 14 mg, respectively; 4.2% for sitagliptin 100 mg). Significantly greater reductions in HbA1c from baseline to week 26 were reported for all doses of oral semaglutide vs sitagliptin 100 mg. For oral semaglutide 3 mg, 7 mg and 14 mg vs sitagliptin 100 mg, the estimated treatment differences (ETDs [95% CI]) were -2 (-4, -1) mmol/mol, -8 (-9, -6) mmol/mol and -11 (-12, -9) mmol/mol, respectively. The corresponding ETDs (95% CI) in percentage points vs sitagliptin 100 mg were -0.2 (-0.3, -0.1), -0.7 (-0.8, -0.6) and -1.0 (-1.1, -0.8), respectively. Reductions in body weight were significantly greater for all doses of oral semaglutide vs sitagliptin 100 mg (ETD [95% CI] -0.9 [-1.4, -0.4] kg, -2.3 [-2.8, -1.8] kg and -3.3 [-3.8, -2.8] kg for 3 mg, 7 mg and 14 mg, respectively). In the subpopulation of participants from the China region (75.2% of trial participants), reductions in HbA1c and body weight from baseline to week 26 were similar to those seen in the overall population. The most frequent adverse events in the semaglutide treatment arms were gastrointestinal, although these were mostly transient and mild/moderate in severity. CONCLUSIONS/INTERPRETATION: Significantly greater reductions in both HbA1c and body weight over 26 weeks were seen with oral semaglutide 3 mg, 7 mg and 14 mg than with sitagliptin 100 mg in a predominantly Chinese population with type 2 diabetes inadequately controlled with metformin treatment. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04017832. FUNDING: This trial was funded by Novo Nordisk A/S, Søborg, Denmark.

Duodenal-jejunal bypass improves hypothalamic oxidative stress and inflammation in diabetic rats via glucagon-like peptide 1-mediated Nrf2/HO-1 signaling.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is often accompanied by impaired glucose utilization in the brain, leading to oxidative stress, neuronal cell injury and infla-mmation. Previous studies have shown that duodenal jejunal bypass (DJB) surgery significantly improves brain glucose metabolism in T2DM rats, the role and the metabolism of DJB in improving brain oxidative stress and inflammation condition in T2DM rats remain unclear. AIM: To investigate the role and metabolism of DJB in improving hypothalamic oxidative stress and inflammation condition in T2DM rats. METHODS: A T2DM rat model was induced via a high-glucose and high-fat diet, combined with a low-dose streptozotocin injection. T2DM rats were divided into DJB operation and Sham operation groups. DJB surgical intervention was carried out on T2DM rats. The differential expression of hypothalamic proteins was analyzed using quantitative proteomics analysis. Proteins related to oxidative stress, inflammation, and neuronal injury in the hypothalamus of T2DM rats were analyzed by flow cytometry, quantitative real-time PCR, Western blotting, and immunofluorescence. RESULTS: Quantitative proteomics analysis showed significant differences in proteins related to oxidative stress, inflammation, and neuronal injury in the hypothalamus of rats with T2DM-DJB after DJB surgery, compared to the T2DM-Sham groups of rats. Oxidative stress-related proteins (glucagon-like peptide 1 receptor, Nrf2, and HO-1) were significantly increased (P < 0.05) in the hypothalamus of rats with T2DM after DJB surgery. DJB surgery significantly reduced (P < 0.05) hypothalamic inflammation in T2DM rats by inhibiting the activation of NF-κB and decreasing the expression of interleukin (IL)-1ß and IL-6. DJB surgery significantly reduced (P < 0.05) the expression of factors related to neuronal injury (glial fibrillary acidic protein and Caspase-3) in the hypothalamus of T2DM rats and upregulated (P < 0.05) the expression of neuroprotective factors (C-fos, Ki67, Bcl-2, and BDNF), thereby reducing hypothalamic injury in T2DM rats. CONCLUSION: DJB surgery improve oxidative stress and inflammation in the hypothalamus of T2DM rats and reduce neuronal cell injury by activating the glucagon-like peptide 1 receptor-mediated Nrf2/HO-1 signaling pathway.

Evaluation of the effects of vitamin D deficiency and cigarette smoking on insulin resistance in type 2 diabetes mellitus: A meta-analysis of randomized controlled trials.

There are contradictory findings regarding the effects of vitamin D supplementation and cigarette smoking on glucose metabolism in individuals with type 2 diabetes mellitus (T2DM). Consequently, this meta-analysis focused on the association between vitamin D interventions and smoking cessation on glycemic control in T2DM patients. This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Cochrane Library, EMBASE and PubMed databases were used for a language-inclusive literature search until November 2022. The primary outcomes of this meta-analysis were changes in glycated hemoglobin (HbA1c) level, vitamin D concentration and body mass index (BMI) values. This meta-analysis included 14 randomized controlled trials (RCTs) with a total of 23,289 individuals with T2DM. Nine RCTs were related to vitamin D supplementation interventions, and 5 RCTs were related to smoking cessation interventions. The studies on vitamin D supplementation showed a substantial change in the intervention group, with a risk ratio (RR) of 0.72 (95% confidence interval (95% CI): 0.58, 0.88; p = 0.001) and an odds ratio (OR) of 0.52 (95% CI: 0.34, 0.78; p = 0.002); high heterogeneity was observed (I2 ≥ 95%). Similarly, the smoking cessation studies showed a substantial change in the intervention group, with a RR of 0.92 (95% CI: 0.86, 0.99; p = 0.04) and an OR of 0.86 (95% CI: 0.74, 0.99; p = 0.04); high heterogeneity was observed (I2 = 87%). In conclusion, both vitamin D supplementation and smoking cessation are associated with moderate BMI decline and an improvement of insulin sensitivity in people with T2DM.

Inverse correlation between serum adiponectin and 8-iso-prostaglandin F2α in newly diagnosed type 2 diabetes patients.

This study was set out to determine the association of serum adiponectin and oxidative stress in newly diagnosed type 2 diabetes patients. 106 patients with newly diagnosed type 2 diabetes were recruited. Simultaneously scanning of the extracranial carotid arteries, common iliac arteries and femoral arteries were performed for measurement of intima media thickness (IMT) in all subjects. Atherosclerotic plaque was defined as IMT value >1.3 mm. The serum levels of adiponectin and 8-iso-prostaglandin F2α (8-iso-PGF2α), a marker of oxidative stress, were examined by enzyme-linked immunosorbent assay. Metabolic parameters were detected by clinical chemistry. According to the results, all of 106 patients with type 2 diabetes were newly diagnosed within 12 months, and aged 60.68±4.32 years. The level of serum adiponectin in newly diagnosed type 2 diabetes patients was lower than that in healthy subjects. Furthermore, type 2 diabetes patients with atherosclerotic plaques had lower serum adiponectin level than those without atherosclerotic plaques. Serum 8-iso-PGF2α level in newly diagnosed type 2 diabetes patients was higher than that in healthy subjects. Further analyses showed that serum adiponectin level was reversely associated with serum 8-iso-PGF2α in newly diagnosed type 2 diabetes patients. Additionally, the atherosclerotic plaques in newly diagnosed type 2 diabetes patients were positively correlated with total cholesterol, but negatively correlated with serum adiponectin level. Taken together, this study suggests that in newly diagnosed type 2 diabetes, serum adiponectin levels are probably associated with oxidative stress and also with the severity of atherosclerosis.

Bioinformatic analysis of specific genes in diabetic nephropathy.

OBJECTIVE: We attempt to explore the pathogenesis and specific genes with aberrant expression in diabetic nephropathy (DN). METHODS: The gene expression profile of GSE1009 was downloaded from Gene Expression Omnibus database, including 3 normal function glomeruli and DN glomeruli from cadaveric donor kidneys. The differentially expressed genes (DEGs) were analyzed and the aberrant gene-related functions were predicted by informatics methods. The protein-protein interaction (PPI) networks for DEGs were constructed and the functional sub-network was screened. RESULTS: A total of 416 DEGs were found to be differentially expressed in DN samples comparing with normal controls, including 404 up-regulated genes and 12 down-regulated genes. DEGs were involved in the process of combination to saccharides and the decline of tissue repairing ability of the organisms. The genes of VEGFA, ACTG1, HSP90AA1 had high degree in the PPI network. The main biological process of genes in the sub-network was related with cell proliferation and signal transmitting of cell membrane receptor. CONCLUSION: Significant nodes in PPI network provide new insights to understand the mechanism of DN. VEGFA, ACTG1 and HSP90AA1 may be the potential targets in the DN treatment.

An insight into the key genes and biological functions associated with insulin resistance in adipose tissue with microarray technology.

In the present study, the key genes and biological functions associated with insulin resistance were investigated by comparing the gene expression profiles of adipose tissue obtained from insulin­sensitive and insulin­resistant patients. The gene expression data set GSE20950 was downloaded from the Gene Expression Omnibus, including 39 adipose tissue samples obtained from insulin­sensitive and insulin­resistant patients undergoing gastric bypass surgery. Adipose samples were divided into two groups (the insulin­sensitive and insulin­resistant groups) and the differentially expressed genes (DEGs) were screened out with packages of R. The interactions among DEGs were retrieved with Osprey and functional enrichment analysis was performed with the WebGestalt system. Information regarding the interaction network and enriched biological functions was combined to construct a functional interaction network. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was then conducted using the Database for Annotation, Visualization and Integrated Discovery. A total of 170 DEGs were detected in the insulin­sensitive group, 8 downregulated and 162 upregulated. Response to glucose stimulus was the most significantly over­represented functional term. The focal adhesion pathway was identified to be significant in the genes of the functional interaction network. The present study revealed key biological functions and DEGs in adipose tissues associated with insulin resistance, which may facilitate the development of novel therapies for insulin resistance and diabetes.

Age- and sex-specific prevalence of diabetes and impaired glucose regulation in 11 Asian cohorts.

OBJECTIVE: To report the age- and sex-specific prevalence of diabetes and impaired glucose regulation (IGR) according to revised World Health Organization criteria for diabetes in Asian populations. RESEARCH DESIGN AND METHODS: We performed 11 studies of 4 countries, comprising 24,335 subjects (10,851 men and 13,484 women) aged 30-89 years who attended the 2-h oral glucose tolerance test and met the inclusion criteria for data analysis. RESULTS: The prevalence of diabetes increased with age and reached the peak at 70-89 years of age in Chinese and Japanese subjects but peaked at 60-69 years of age followed by a decline at the 70 years of age in Indian subjects. At 30-79 years of age, the 10-year age-specific prevalence of diabetes was higher in Indian than in Chinese and Japanese subjects. Indian subjects also had a higher prevalence of IGR in the younger age-groups (30-49 years) compared with that for Chinese and Japanese subjects. Impaired glucose tolerance was more prevalent than impaired fasting glycemia in all Asian populations studied for all age-groups. CONCLUSIONS: Indians had the highest prevalence of diabetes among Asian countries. The age at which the peak prevalence of diabetes was reached was approximately 10 years younger in Indian compared with Chinese and Japanese subjects. Diabetes and IGR will be underestimated in Asians based on the fasting glucose testing alone.