Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson's disease through Mfn2-cGAS signaling.

BACKGROUND: Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson's disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined. METHODS: Long culture-induced replicative senescence model and 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature senescence model, and a mouse model of PD were used to investigate the effect of metformin on astrocyte senescence in vivo and in vitro. Immunofluorescence staining and flow cytometric analyses were performed to evaluate the mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA to mouse substantia nigra pars compacta regions to specifically reduce astrocytic cGAS expression to clarify the potential molecular mechanism by which metformin inhibited the astrocyte senescence in PD. RESULTS: We showed that metformin inhibited the astrocyte senescence in vitro and in PD mice. Mechanistically, metformin normalized mitochondrial function to reduce mitochondrial DNA release through mitofusin 2 (Mfn2), leading to inactivation of cGAS-STING, which delayed astrocyte senescence and prevented neurodegeneration. Mfn2 overexpression in astrocytes reversed the inhibitory role of metformin in cGAS-STING activation and astrocyte senescence. More importantly, metformin ameliorated dopamine neuron injury and behavioral deficits in mice by reducing the accumulation of senescent astrocytes via inhibition of astrocytic cGAS activation. Deletion of astrocytic cGAS abolished the suppressive effects of metformin on astrocyte senescence and neurodegeneration. CONCLUSIONS: This work reveals that metformin delays astrocyte senescence via inhibiting astrocytic Mfn2-cGAS activation and suggest that metformin is a promising therapeutic agent for age-associated neurodegenerative diseases.

Individualized intensive insulin therapy of diabetes: Not only the goal, but also the time.

Intensive insulin therapy has been extensively used to control blood glucose levels because of its ability to reduce the risk of chronic complications of diabetes. According to current guidelines, intensive glycemic control requires individualized glucose goals rather than as low as possible. During intensive therapy, rapid blood glucose reduction can aggravate microvascular and macrovascular complications, and prolonged overuse of insulin can lead to treatment-induced neuropathy and retinopathy, hypoglycemia, obesity, lipodystrophy, and insulin antibody syndrome. Therefore, we need to develop individualized hypoglycemic plans for patients with diabetes, including the time required for blood glucose normalization and the duration of intensive insulin therapy, which deserves further study.

[Soil Heavy Metal Contamination, Sources, and Health Risk of Typical Drinking Water Sources in the Suspended Reach of the Lower Yellow River].

With the implementation of ecological protection and a high-quality development strategy in the Yellow River Basin, the environmental conditions around the Yellow River have attracted wide attention from scholars. In this study, the soil of drinking water sources(Heichi and Liuchi) in the typical suspended reach of the lower reaches of the Yellow River was selected as the research object. The geo-accumulation index and pollution load index were used to analyze the pollution characteristics of seven heavy metals(Cr, Ni, Cu, Zn, Cd, Pb, and As), and correlation analysis, principal component analysis, and absolute factor score-multiple linear regression(APCS-MLR) were employed to reveal the sources of soil heavy metals from both qualitative and quantitative perspectives. The health risk assessment model recommended by the United States Environmental Protection Agency(USEPA) was used to analyze the impact of soil heavy metals on human health, and the contribution rate of pollution sources to health risks was analyzed by combining the APCS-MLR model. The results showed that the average values of ω(Cr), ω(Ni), ω(Cu), ω(Zn), ω(Cd), ω(Pb), and ω(As) in the soil around the water source were 60.27, 30.00, 35.14, 77.75, 0.38, 21.74, and 9.70 mg·kg-1, respectively. Except for As, the contents of Cr, Ni, Cu, Zn, Cd, and Pb were higher than the background values of soil elements in the fluvo-aquic soil area of the lower Yellow River, whereas the contents of Cu and Zn in the soil around Liuchi were significantly higher than those in Heichi. Both the geo-accumulation index and the single-factor index showed that the black pond and the willow pond were slightly polluted by heavy metals, and Cd was the main pollution factor. The pollution load index model showed that the number of non-polluted and mildly polluted samples in the study area accounted for 5% and 95% of the total samples, respectively, indicating that the study area was at a mild pollution level. The source apportionment showed that Cr, Ni, Cu, and As were mainly affected by parent materials. The analysis results of the APCS-MLR model showed that the soil pollutants in the study area were mainly from natural sources, traffic sources, agricultural sources, and unknown sources, and their contribution rates were 42.95%, 23.39%, 16.95%, and 16.71%, respectively. The health risk assessment showed that As was the main non-carcinogenic factor, and Ni was the main carcinogenic factor. The non-carcinogenic risk of heavy metals to adults and children was negligible, and there was a tolerable carcinogenic risk to the human body. For both adults and children, the non-carcinogenic and carcinogenic risk contribution rates of the four pollution sources were:natural sources>unknown sources>traffic sources>agricultural sources, among which natural sources contributed the most to non-carcinogenic and carcinogenic risks. Therefore, it is of great significance to study the characteristics, sources, and effects of soil pollution on human health around the water source area of the suspended reach of the lower reaches of the Yellow River, which is of great significance for the protection of water sources and provides theoretical support for the high-quality development of the ecological environment along the Yellow River.

[Pollution Characteristics and Source Analysis of Heavy Metals in Soils in Yellow River Cultural Park Based on APCS-MLR and PMF Receptor Model].

With open spaces and good ecological environments, urban parks have become the first choice for the leisure and entertainment of many people. Therefore, the quality of park soil environments has gradually attracted the extensive attention of scholars. In this study, we take the Yellow River Cultural Park, a typical human disturbance area in the lower reaches of the Yellow River, as the research area to discuss the characteristics and sources of heavy metal pollution in the soil. Thirty-three soil surface samples were collected from the Yellow River Cultural Park, and the contents of seven heavy metals (Cr, Ni, Cu, Zn, Cd, Pb, and As) were determined using an inductively coupled plasma emission spectrometer (ICP-AES) and an inductively coupled plasma mass spectrometer (ICP-MS). The geo-accumulation index and geo-statistics method were used. Meanwhile, the absolute factor analysis-multiple linear regression (APCS-MLR) receptor model and positive matrix factorization (PMF) analysis model were employed to reveal the sources of soil heavy metals. The results showed that the average contents of heavy metals (Cd, Zn, Cu, Pb, and As) in the surface soil of the study area were 4.62, 1.78, 1.41, 1.08, and 1.03 times higher than the background values of soil elements in the tidal soil area of the lower reaches of the Yellow River, respectively. Except for Zn, the contents of other elements were lower than the corresponding values of soil elements in different regions along the Yellow River Basin. Among the seven heavy metal elements, the coefficients of variation of Cd and As were greater than 50%, showing obvious spatial variability. The decreasing trend of the accumulation index of the seven elements was Cd>Zn>Cu>Ni>Pb>As=Cr, and the element Cd belonged to the middle pollution category, which was obviously accumulated in the surface soil. The spatial distribution of heavy metals in the soil differed:the high contents of Cr, Cu, and Ni were distributed in the southwest and northeast, and the high-value areas of Cd and Pb were consistent with the areas of human activity intensity. The high-value areas of Zn and As were located in the center of lacustrine sediments. The combined results of the APCS-MLR and PMF models suggested that the first pollution source of soil heavy metal elements in the Yellow River Cultural Park could have been a natural source, the second pollution source may have been a transportation source, and the third source of pollution was judged as a mixed source. Human activities such as transportation sources and mixed sources were the main sources of heavy metal soil pollution, and Cr, Cu, and Ni were affected by natural factors. The contribution rates of APCS-MLR were 46.67%, 24.11%, 16.12%, and 13.10%, respectively, and the contribution rates of PMF were 35.50%, 35.48%, and 29.02%, respectively. This research can provide a basis for improving the ecological environment quality of the park and improving the health level of the population and can also provide support for the ecological environment risk management and comprehensive management along the Yellow River.

Low Total Testosterone Levels in Men with Newly Diagnosed Early-Onset Type 2 Diabetes: A Cross-Sectional Study in China.

Objective: There is a bidirectional interaction between circulating testosterone and blood glucose levels. We aim to investigate the testosterone levels in men with early-onset type 2 diabetes (T2DM). Methods: A total of 153 drug naive men with T2DM were enrolled in the study. Early- (n = 63) and late-onset (n = 90) T2DM was classified according to age 40 years old. Clinical characteristics and plasma for biochemical criterions were collected. Gonadal hormones were measured using chemiluminescent immunometric assay. The concentrations of 3ß- and 17ß-HSD were determined using ELISA. Results: Compared with men with late-onset T2DM, those with early-onset T2DM had lower serum total testosterone (TT), sex hormone-binding globulin (SHBG), and FSH, but higher dehydroepiandrosterone sulfate (DHEA-S) level (p < 0.05). The mediating effect analysis showed that the decreased TT levels in patients with early-onset T2DM were associated with the higher HbA1c, BMI, and triglyceride in these patients (both p < 0.05). The early-onset of T2DM directly correlated with increased DHEA-S (both p < 0.01). The 3ß-HSD concentration in the early-onset T2DM group was lower than that in the late-onset T2DM group (11.07 ± 3.05 vs. 12.40 ± 2.72 pg/mL, p = 0.048) and was positively correlated with fasting C-peptide, while negatively correlated with HbA1c and fasting glucagon (p all < 0.05). Conclusions: Patients with early-onset T2DM showed inhibition of conversion from DHEA to testosterone, which may attribute to the low level of 3ß-HSD and high blood glucose in these patients.

Short-time intensive insulin therapy upregulates 3 beta- and 17 beta-hydroxysteroid dehydrogenase levels in men with newly diagnosed T2DM.

Objective: Our previous study has found that short-term intensive insulin therapy in patients with newly diagnosed type 2 diabetes mellitus (T2DM) increased serum testosterone levels, but the underlying mechanisms remain unclear. Design and methods: In this self-controlled study, 43 men with newly diagnosed drug naïve T2DM, aged 18-60 years, with HbA1c >9.0% were treated with continuous subcutaneous insulin infusion (CSII) to normalize blood glucose within one week. Venous blood specimens were collected for measuring of serum total testosterone, dehydroepiandrosterone sulfate (DHEA-S), 3ß- and 17ß-hydroxysteroid dehydrogenase (3ß- and 17ß-HSD) concentrations before and after insulin therapy. Results: Testosterone increased from 13.0 (11.3, 14.6) nmol/L to 15.7 (13.9, 17.5) nmol/L after intensive insulin therapy (p<0.001), while the levels of DHEA-S decreased significantly after treatment (from 6.5 (5.7, 7.3) µmol/L to 6.0 (5.3, 6.7) µmol/L, p=0.001). The ratio of testosterone/DHEA-S increased significantly (2.4 (2.0, 2.8) vs. 3.1 (2.6, 3.7) nmol/µmol, p<0.001). After blood glucose normalization with the short-term CSII therapy, 3ß-HSD increased from 11.0 (9.5, 12.5) pg/mL to 14.6 (13.5, 15.7) pg/mL, p=0.001, and 17ß-HSD increased from 20.7 (16.3, 25.2) pg/mL to 28.2 (23.8, 32.5) pg/mL, p=0.009. Conclusions: Blood glucose normalization via short-term intensive insulin therapy increases plasma total testosterone levels in men with newly diagnosed type 2 diabetes, associated with a decreased level of DHEA-S, probably because of the enhanced conversion from DHEA to testosterone catalyzed by 3ß-HSD and 17ß-HSD.

Response of blood glucose and GLP-1 to different food temperature in normal subject and patients with type 2 diabetes.

BACKGROUND: Eating behavior is a major factor in type 2 diabetes. We investigated the different responses of glucose-regulating hormones to cold and hot glucose solutions in normal subjects and patients with type 2 diabetes. METHODS: In this crossover, self-controlled study, normal subjects (N = 19) and patients with type 2 diabetes (N = 22) were recruited and randomly assigned to a hot (50 °C) or a cold (8 °C) oral glucose-tolerance test (OGTT). The subsequent day, they were switched to the OGTT at the other temperature. Blood glucose, insulin, GIP, glucagon-like peptide-1 (GLP-1), and cortisol were measured at 0, 5, 10, 30, 60, and 120 min during each OGTT. After the hot OGTT, all subjects ingested hot (>42 °C) food and water for that day, and ingested food and water at room temperature (≤24 °C) for the day after cold OGTT. All participants had continuous glucose monitoring (CGM) throughout the study. RESULTS: Compared to cold OGTT, blood glucose was significantly higher with hot OGTT in both groups (both P < 0.05). However, insulin and GLP-1 levels were significantly higher in hot OGTT in normal subjects only (both P < 0.05). The GIP and cortisol responses did not differ with temperature in both groups. CGM showed that normal subjects had significantly higher 24-h mean glucose (MBG) (6.11 ± 0.13 vs. 5.84 ± 0.11 mmol/L, P = 0.021), and standard deviation of MBG with hot meals (0.59 ± 0.06 vs. 0.48 ± 0.05 mmol/L, P = 0.043), T2DM patients had higher MBG only (8.46 ± 0.38 vs. 8.88 ± 0.39 mmol/L, P = 0.022). CONCLUSIONS: Food temperature is an important factor in glucose absorption and GLP-1 response. These food temperatures elicited differences are lost in type 2 diabetes.

Real-Time Flash Glucose Monitoring Had Better Effects on Daily Glycemic Control Compared With Retrospective Flash Glucose Monitoring in Patients With Type 2 Diabetes on Premix Insulin Therapy.

Background and Aims: To compare the effects of real-time and retrospective flash glucose monitoring (FGM) on daily glycemic control and lifestyle in patients with type 2 diabetes on premix insulin therapy. Methods and Results: A total of 172 patients using premix insulin, with HbA1c ≥ 7.0% (56 mmol/mol), or the time below the target (TBR) ≥ 4%, or the coefficient of variation (CV) ≥36% during the screening period, were randomly assigned to retrospective FGM (n = 89) or real-time FGM group (n = 83). Another two retrospective or real-time 14-day FGMs were performed respectively, 1 month apart. Both groups received educations and medication adjustment after each FGM. Time in range (3.9~10.0 mmol/l, TIR) increased significantly after 3 months in the real-time FGM group (6.5%) compared with the retrospective FGM group (-1.1%) (p = 0.014). HbA1c decreased in both groups (both p < 0.01). Real-time FGMs increased daily exercise time compared with the retrospective group (p = 0.002). Conclusions: Real-time FGM with visible blood glucose improves daily glycemic control and diabetes self-care behaviors better than retrospective FGM in patients with type 2 diabetes on premix insulin therapy. Clinical Trial Registration: https://clinicaltrials.gov/NCT04847219.

Effects of Pacemaker Implantation on Sudden Cardiac Death Rate and Quality of Life in Atrial Fibrillation Patients With Ventricular Pauses.

Ventricular arrest is a rare arrhythmic disease in the clinic; 35% to 55% of cases are associated with atrial fibrillation (AF). It is well known that ventricular arrest for ≥3 seconds can lead to brain symptoms such as dizziness and even syncope, but it is not clear whether ventricular pauses (≥3 seconds) with AF will lead to sudden cardiac death. If the implantation of a pacemaker can improve the quality of life of patients with permanent AF with ventricular arrest and whether it has a long-term protective effect on sudden cardiac death. To this end, we conducted a prospective follow-up observation study, which was conducted through telephone interviews and clinical hospital observation to obtain information on the quality of life, survival rate, and other details. The results show that for patients with permanent AF with ventricular arrest, pacemaker implantation cannot reduce sudden cardiac death, cardiovascular events, and stroke nor can it improve the cumulative survival rate. Fortunately, the implantation of pacemakers can improve the quality of life of patients.

Association of Acarbose with Decreased Muscle Mass and Function in Patients with Type 2 Diabetes: A Retrospective, Cross-Sectional Study.

INTRODUCTION: Prevalence of sarcopenia has increased in patients with type 2 diabetes. The influence of glucose-lowering drugs on muscles in these patients remains unclear. We aimed to investigate the association between muscle mass/function and glucose-lowering drugs. METHODS: Data of 1042 hospitalized patients with type 2 diabetes were included in this retrospective, cross-sectional study. All the patients had stable hypoglycemic therapy in the last 3 months, and performed bioelectrical impedance analysis, grip strength, and gait speed tests on admission. RESULTS: Skeletal muscle index [6.81 (95% CI 6.67, 6.94) vs. 7.17 (7.09, 7.24) kg/m2], handgrip strength [23.41 (22.24, 24.58) vs. 26.93 (26.33, 27.54) kg], and gait speed [1.19 (1.15, 1.22) vs. 1.27 (1.25, 1.28) m/s] decreased in patients using acarbose compared with the others (all p < 0.001). Gait speed and skeletal muscle index remained lower in patients using acarbose compared to their matched patients in propensity score matching (p = 0.036 and 0.010, respectively). Among drug-naïve patients and patients using insulin, metformin, sulfonylureas, or acarbose monotherapy, the acarbose group had lowest skeletal muscle index and handgrip strength [6.81 (6.52, 7.11) kg/m2 and 22.54 (19.28, 25.79) kg, p = 0.028 and 0.001, respectively]. CONCLUSION: Acarbose treatment was associated with decreased muscle mass and strength. Assessment and exercise of muscles in patients with long-term acarbose treatment should be considered.

Effects of GLP-1 Receptor Agonists on Bone Mineral Density in Patients with Type 2 Diabetes Mellitus: A 52-Week Clinical Study.

INTRODUCTION: Hypoglycemic drugs affect the bone quality and the risk of fractures in patients with type 2 diabetes mellitus (T2DM). We aimed to investigate the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and insulin on bone mineral density (BMD) in T2DM. METHODS: In this single-blinded study, a total of 65 patients with T2DM were randomly assigned into four groups for 52 weeks: the exenatide group (n = 19), dulaglutide group (n = 19), insulin glargine group (n = 10), and placebo (n = 17). General clinical data were collected, and BMD was measured by dual-energy X-ray absorptiometry. RESULTS: Compared with baseline, the glycosylated hemoglobin (HbA1c) decreased significantly in the exenatide (8.11 ± 0.24% vs. 7.40 ± 0.16%, P = 0.007), dulaglutide (8.77 ± 0.37% vs. 7.06 ± 0.28%, P < 0.001), and insulin glargine (8.57 ± 0.24% vs. 7.23 ± 0.25%, P < 0.001) groups after treatment. In the exenatide group, the BMD of the total hip increased. In the dulaglutide group, only the BMD of the femoral neck decreased (P = 0.027), but the magnitude of decrease was less than that in the placebo group; the BMD of L1-L4, femoral neck, and total hip decreased significantly (P < 0.05) in the placebo group, while in the insulin glargine group, the BMD of L2, L4, and L1-4 increased (P < 0.05). Compared with the placebo group, the BMD of the femoral neck and total hip in the exenatide group and the insulin glargine group were increased significantly (P < 0.05); compared with the exenatide group, the BMD of L4 in the insulin glargine group was also increased (P = 0.001). CONCLUSIONS: Compared with the placebo, GLP-1RAs demonstrated an increase of BMD at multiple sites of the body after treatment, which may not exacerbate the consequences of bone fragility. Therefore, GLP-1RAs might be considered for patients with T2DM. This trial is registered with ClinicalTrials.gov NCT01648582.

Effects of Dapagliflozin Adjunct to Insulin on Glycemic Variations in Patients with Newly Diagnosed Type 2 Diabetes: A Randomized, Controlled, Open-Labeled Trial.

BACKGROUND: This study is aimed at investigating whether dapagliflozin adjunct to insulin therapy further improves glycemic control compared to insulin therapy alone in patients with newly diagnosed type 2 diabetes (T2D). METHODS: This single-centre, randomized, controlled, open-labeled trial recruited newly diagnosed T2D patients. Subjects were randomized 1 : 1 to the dapagliflozin add-on to continuous subcutaneous insulin infusion (CSII) group (DAPA) or the CSII therapy group for 5 weeks. Standard meal tests were performed 3 times at days -3, 7, and 35 for glucose, C-peptide, and insulin level determination. Two-time continuous glucose monitoring (CGM) was performed at baseline and at the end of the study. The primary endpoint was the difference in the mean amplitude of glycemic excursions (MAGEs) between the groups. RESULTS: A total of 66 subjects completed the study, with 34 and 32 patients in the DAPA and CSII groups, respectively. Patients in the DAPA group exhibited significant decreases in MAGE levels at the endpoint. We also observed that patients in the DAPA group had a lower homoeostasis model assessment insulin resistance (HOMA-IR) and a higher homoeostasis model assessment B (HOMA-B) value at 1 week and 5 weeks compared to those with insulin therapy, respectively. In addition, our data showed that patients in the DAPA group showed a significantly lower insulin dose (0.07 U/kg) and weighed less than those in the CSII group. CONCLUSION: Our data indicate that dapagliflozin adjunct to insulin is a safe and effective therapy for improving glycemic variations, insulin sensitivity, and weight loss in newly diagnosed T2D patients.

Effectiveness of beinaglutide in a patient with late dumping syndrome after gastrectomy: A case report.

RATIONALE: Dumping syndrome is a frequent and potentially severe complication after gastric surgery. Beinaglutide, a recombinant human glucagon-like peptide-1 (GLP-1) which shares 100% homology with human GLP-1(7-36), has never been reported in the treatment of dumping syndrome before. PATIENT CONCERNS: The patient had undergone distal gastrectomy for gastric signet ring cell carcinoma 16 months ago. He presented with symptoms of paroxysmal palpitation, sweating, and dizziness for 4 months. DIAGNOSIS: He was diagnosed with late dumping syndrome. INTERVENTIONS AND OUTCOMES: The patient was treated with dietary changes and acarbose for 4 months before admitted to our hospital. The treatment with dietary changes and acarbose did not prevent postprandial hyperinsulinemia and hypoglycemia according to the 75 g oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM) on admission.Therefore, the patient was treated with beinaglutide 0.1 mg before breakfast and lunch instead of acarbose. After the treatment of beinaglutide for 1 month, OGTT showed a reduction in postprandial hyperinsulinemia compared with before starting treatment, and the time in the range of 3.9 to 10 mmol/L became 100% in CGM. No side effect was observed in this patient during beinaglutide treatment. LESSONS: These findings suggest that beinaglutide may be effective for treating post-gastrectomy late dumping syndrome.

Serum stromal cell-derived factor-1 levels are associated with diabetic kidney disease in type 2 diabetic patients.

The present study was designed to explore whether serum stromal cell-derived factor-1 (SDF-1) levels were associated with diabetic kidney disease (DKD). Serum SDF-1 levels were measured by sandwich ELISA. Patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or a urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g for 3 months were identified as having DKD. Among the recruited type 2 diabetic patients, 18.71% (n = 32) were found to have DKD, and the serum SDF-1 levels of these patients were higher than those of patients without DKD (p < 0.05). Serum SDF-1 levels were positively correlated with cystatin C levels, the UACR and DKD incidence (r = 0.330, 0.183 and 0.186, respectively, p < 0.05) and inversely related to eGFR (r = -0.368, p < 0.001). After adjusting for other clinical covariates by multivariate logistic regression analyses, serum SDF-1 levels were found to be an independent contributor to DKD, and the odds ratio (95% confidence interval) was 1.438 (1.041-1.986). Furthermore, receiver operating characteristic analysis revealed that the optimal SDF-1 cutoff value for indicating DKD was 5.609 ng/mL (its corresponding sensitivity was 82.00%, and specificity was 46.90%). Our results demonstrated that serum SDF-1 levels were closely associated with DKD and could be considered a potent indicator for DKD in patients with T2D.

Rapid Changes in Serum Testosterone in Men With Newly Diagnosed Type 2 Diabetes With Intensive Insulin and Metformin.

OBJECTIVE: To investigate the effect of metformin on testosterone levels in men with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: Seventy men with newly diagnosed drug-naive T2DM and HbA1c >9.0% (75 mmol/mol) were treated with intensive insulin pump therapy for 5 days to achieve glucose normalization. They were randomized to control (continued on intensive insulin only) and metformin (plus metformin) groups (1:1) for 1 month. Testosterone was measured at baseline, randomization, and after 1-month treatment. RESULTS: Total, free, and bioavailable testosterone increased significantly within 5 days (all P < 0.001). After 1 month, compared with the control group, the metformin group had lower total (12.7 vs. 15.3 nmol/L), free (0.20 vs. 0.24 nmol/L), and bioavailable (4.56 vs. 5.31 nmol/L) testosterone (all P < 0.05). CONCLUSIONS: In men with T2DM, 1-month oral metformin may decrease serum testosterone levels independent of blood glucose control. The effects of long-term metformin on testosterone in men need further study.

Whole-Brain Radiotherapy Can Improve the Survival of Patients with Multiple Brain Metastases from Non-Small Cell Lung Cancer Treated by Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors.

OBJECTIVE: To observe whether whole-brain radiotherapy (WBRT) can bring survival benefits to patients with multiple brain metastases (BM) from non-small cell lung cancer (NSCLC) treated by epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and determine the best time for WBRT intervention. METHODS: A retrospective analysis was performed on 148 patients diagnosed with EGFR gene-mutated NSCLC. All patients had multiple BM and received EGFR-TKI targeted therapy, which was performed to observe whether WBRT can bring survival benefits, and whether the choice of WBRT timing affects the survival of patients. RESULTS: Among the 148 patients with NSCLC treated with EGFR-TKI, 76 received WBRT; 72 were without WBRT. WBRT can reduce the intracranial progression rate in the patients (19.7% vs 33.3%, P=0.040), thus improving the intracranial progression-free survival (iPFS) (median iPFS: 11.9 months versus 10.2 months, P=0.039) and overall survival (OS) (median OS: 21.0 months versus 16.7 months, P=0.043). Multivariate analysis showed that WBRT (HR=0.606; 95% CI: 0.403-0.912, P=0.016) and the low Eastern Cooperative Oncology Group performance status (HR=1.884; 95% CI: 1.120-3.170, P=0.017) are independent prognostic factors in all patients. Further subgroup analysis showed that the choice of WBRT time had no effect on patient survival. CONCLUSION: WBRT can improve the survival of patients with multiple BM from NSCLC receiving EGFR-TKI targeted therapy and is an independent prognostic factor. The choice of RT time has no effect on patient survival.

Men with Latent Autoimmune Diabetes and Type 2 Diabetes May Have Different Change Patterns in Free Testosterone.

OBJECTIVE: Type 2 diabetic (T2D) male patients with low total testosterone (TT) levels are at an increasing risk of all-cause mortality. However, the levels of TT in male patients with latent autoimmune diabetes in adults (LADA) remain largely unknown. Research Design and Methods. This was a single-center, open, observational study. The inclusion criteria were male patients who were diagnosed with LADA, and sex, body mass index, C-peptide, and glycated hemoglobin (HbA1c) levels matched with those of T2D patients. Islet function/sensitivity and sex hormone concentrations were determined at baseline and 1-year follow-up. The primary endpoint was the changes in androgen levels from baseline to 1-year follow-up in patients with LADA. RESULTS: Our data showed that TT and Bio-T levels remained unchanged, while FT levels significantly decreased from baseline to 1-year follow-up in patients with T2D. However, TT, Bio-T, and FT concentrations dramatically increased in the LADA group from baseline to 1-year follow-up. Furthermore, a Spearman analysis showed that changes of TT, FT, and Bio-T levels from baseline to endpoint were significantly negatively correlated with Δ homeostasis model assessment-2 IR (ΔHOMA2-IR), respectively. CONCLUSIONS: The FT change patterns in patients with LADA may differ from those in patients with T2D. Our data also indicated the significant negative correlation between insulin sensitivity and changes of TT, FT, and Bio-T levels along with the diabetic duration in patients with T2D and LADA.

Sexual Differences in response to Mid- or Low-Premixed Insulin Analogue in Patients with Type 2 Diabetes.

OBJECTIVE: To observe whether there are sexual-related differences in response to mid- or low-premixed insulin in type 2 diabetic patients. METHODS: This was an analysis of CGM data of a previous study. After screening, patients with longstanding T2D receive a 7-day continuous subcutaneous insulin infusion (CSII) therapy, and then subjects were randomly assigned 1 : 1 into two groups receiving Novo Mix 30 or Humalog Mix 50 regimen for a 2-day phage, followed by a 4-day cross-over period. A 4-day continuous glucose monitoring (CGM) was performed during the cross-over period. The primary endpoint was the differences in glycemic control between male and female patients receiving mid- or low-premixed insulin therapy. RESULTS: A total of 102 patients (52 men and 50 women) completed the study. Our data showed that male patients had significant decrease in mean glucose levels monitored by CGM after three meals during Humalog Mix 50 treatment period compared to those received Novo Mix 30 regimen (0900: 11.0 ± 2.5 vs. 12.2 ± 2.8, 1000: 9.9 ± 2.9 vs. 11.3 ± 3.1, 1200: 8.0 ± 1.9 vs. 9.1 ± 2.5, 1400: 9.2 ± 2.3 vs. 10.3 ± 2.5, and 2000: 7.3 ± 2.1 vs. 8.2 ± 2.4 mmol/L, p < 0.05, respectively). In addition, male patients receiving Novo Mix 30 experienced a significantly increased hypoglycemic duration compared to those of receiving Humalog Mix 50 (0 (0, 4.8) vs. 0 (0, 0), p < 0.05, respectively). In addition, male patients receiving Novo Mix 30 experienced a significantly increased hypoglycemic duration compared to those of receiving Humalog Mix 50 (0 (0, 4.8) vs. 0 (0, 0). CONCLUSION: Our data indicate that male patients with T2D receiving mid-premixed insulin analogue regimen may have a potential benefit of improvement in glycemic control compared to female patients. This trial is registered with ClinicalTrials.gov ChiCTR-IPR-15007340.

Efficacy and safety of dulaglutide monotherapy compared with glimepiride in Chinese patients with type 2 diabetes: Post-hoc analyses of a randomized, double-blind, phase III study.

AIMS/INTRODUCTION: To investigate the efficacy/safety of dulaglutide once-weekly monotherapy versus glimepiride in Chinese patients with type 2 diabetes. MATERIALS AND METHODS: This was a post-hoc analysis of a Chinese randomized, double-blind, non-inferiority, phase III study. Patients (n = 572) with inadequate glycemic control received dulaglutide 1.5 mg (n = 189) or 0.75 mg (n = 194) once-weekly or glimepiride (1-3 mg/day; n = 189) for 26 weeks. The primary objective of the study was to investigate the non-inferiority of dulaglutide 1.5 mg versus glimepiride by the change from baseline to week 26 in glycated hemoglobin (non-inferiority margin 0.4%). RESULTS: Dulaglutide 1.5 mg and 0.75 mg were non-inferior (P < 0.001) and superior (P ≤ 0.002) versus glimepiride for the change in glycated hemoglobin from baseline to week 26. The least-squares mean differences (95% confidence interval) versus glimepiride were dulaglutide 1.5 mg, -0.53% (-0.74, -0.32) and dulaglutide 0.75 mg, -0.32% (-0.53, -0.12). Significantly more patients attained glycated hemoglobin <7.0% at week 26 in the dulaglutide 1.5 mg (71.7%) versus the glimepiride (57.5%; P = 0.005) group. The decrease from baseline to week 26 in fasting blood glucose was significantly more pronounced in both the dulaglutide groups versus the glimepiride group (P < 0.01). The overall incidence and rate of hypoglycemia were lower in both of the dulaglutide groups versus the glimepiride group. At week 26, bodyweight had increased from baseline in the glimepiride group and decreased from baseline in both dulaglutide groups. The most frequent gastrointestinal drug-related adverse events with dulaglutide were diarrhea, abdominal distension, nausea and vomiting. CONCLUSIONS: These findings support once-weekly dulaglutide monotherapy as a treatment for Chinese patients with early stage type 2 diabetes.

Association of Higher Circulating Insulin Antibody with Increased Mean Amplitude Glycemic Excursion in Patients with Type 2 Diabetes Mellitus: A Cross-Sectional, Retrospective Case-Control Study.

Insulin antibody (IA) may potentially affect a patient's glycemic control due to its variability in both binding and/or releasing insulin. However, the association between IA titer and daily glycemic variability (GV) is still unknown. We thus performed this cross-sectional, retrospective case-control study to assess the relationship between IA titer and mean amplitude glycemic excursion (MAGE) in type 2 diabetes mellitus (T2DM) patients using a continuous glucose monitoring (CGM) system. We recruited 100 eligible patients (IA > 5%, IA positive) and divided them into two groups-a low (L) group and a high (H) group-based on their IA titer. The control (C) group consisted of 47 patients (IA ≤ 5%, IA negative) matched for age, BMI, gender, and glycosylated hemoglobin A1c (HbA1c). The CGM determined the GV of enrolled patients. The primary outcome was the relationship between the IA titer and the MAGE, and the secondary outcome was the differences of GV among the three groups. We found that patients in the H group had higher levels of blood glucose fluctuation parameters than those in the L and C groups. The Ln(IA) was positively correlated with Ln(MAGE) even after adjusting for age, gender, BMI, HbA1c, and fasting and postprandial C-peptide(r = 0.423, p < 0.001). Multiple linear stepwise regression analysis revealed that Ln(IA) was an independent factor of Ln(MAGE) (beta = 0.405, p < 0.001). In conclusion, the higher circulating IA titer was associated with increased MAGE in T2DM patients, indicating that those patients with elevated IA titer should receive GV assessment and individualized treatment.