Immune Checkpoint Inhibitor-related New-onset Thyroid Dysfunction: A Retrospective Analysis Using the US FDA Adverse Event Reporting System.

OBJECTIVES: The study aimed to investigate the prevalence and demographic characteristics of an immune checkpoint inhibitor (ICI)-related thyroid dysfunction (ICI-TD), and to explore risk factors of poor clinical outcome using data from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). METHODS: This is a retrospective study. All cases, aged over 18-year olds, of new-onset or new-diagnosed thyroid dysfunction related to FDA-approved ICIs from January 1, 2011 to December 31, 2020 were identified using FAERS. Data of age, gender, other combined endocrinopathies related to ICIs besides ICI-TDs, and the prognosis was analyzed. RESULTS: In total, 2.60% (2971/114 121) cases of ICI-TDs were identified. Among them, 1842 (62.0%) developed hypothyroidism, 675 (22.7%) were hyperthyroidism, and 454 (15.3%) presented in thyroiditis without the mention of thyroid function. Patients on anti- programmed cell death protein-1 (PD-1) therapy displayed higher risk of hypothyroidism compared with other 3 regimens, respectively (P < .01 for all). The likelihood of other immune-related endocrinopathies in patients on the combination therapy of anti-cytotoxic T-cell-associated protein-4 (CTLA-4) and anti-PD-1 was significantly elevated than anti-PD-1 (odds ratio [OR] 2.362, 95% confidence interval [CI] [1.925-2.898], P < .001) and anti-programmed death-ligand 1 (PD-L1) regimens (OR 4.857, 95%CI [3.228-7.308], P < .001). The risk of severe cases was positively related to hypothyroidism in individuals on anti-PD-1 therapy (OR 1.587, 95%CI [1.146-2.197], P = .005) and those on anti-CTLA-4 therapy (OR 3.616, 95%CI [1.285-10.171], P = .015). The risk of severe cases was positively associated with the comorbidity with other endocrinopathies (anti-PD-1 group, OR 0.285, 95%CI [0.200-0.467], P < .001; anti-PD-1+anti-CTLA-4 group, OR 0.574, 95%CI [0.371-0.890], P = .013). CONCLUSIONS: Regular monitor of thyroid function is indispensable, since ICI-TDs manifested as hypothyroidism or hyperthyroidism, especially those on the combination therapy. Awareness among health care professionals is critical when hypothyroidism occurs, which might indicate poor clinical outcomes.

Foot Care Education Among Patients With Diabetes Mellitus in China: A Cross-sectional Study.

PURPOSE: To investigate the foot care knowledge and behavior of patients with diabetes to determine effect and current challenges of foot care education, as a basis to improve education and reduce diabetic foot complications. DESIGN: Quantitative, cross-sectional study. METHODS: A convenience sampling method was used to recruit 200 patients with diabetes from the endocrinology clinic of a tertiary general hospital in Beijing between September 2014 and January 2015. Demographic and disease-related data, foot care education, foot risk stratification status, and knowledge and behavior (K&B) scores were collected using investigator-designed questionnaires. RESULTS: Of the 200 patients, 128 (64.0%) patients received routine diabetes education, and 73 (36.5%) received foot care education. The mean ± standard deviation (SD) for K&B scores were 63.76 ± 14.85, and 59.78 ± 11.17, respectively. The K&B scores of patients who received foot care education (69.54 ± 14.32 and 65.27 ± 11.90) were significantly higher than those who received diabetic education only (60.75 ± 15.27 and 57.54 ± 10.25) and those with no diabetic education (60.21 ± 13.37 and 55.94 ± 8.74) (P < .01). The K&B scores did not differ for patients based on diabetic foot risk strata (P > .05). CONCLUSION: The foot care K&B scores of patients with diabetes were low to moderate levels, particularly on items that pertained to self-foot examination, prompt treatment of foot problems, and regular foot inspection by professionals. Individuals with high risk of developing foot complications did not score higher on the K&B questionnaire. These data suggest there is need for improvement in instruction and patient uptake and application of knowledge. We recommend further study on the effectiveness of the delivery of foot care education based on foot risk stratification, and the implications of foot ulcer prevention in community settings.

Immune checkpoint inhibitor-associated new-onset hypophysitis: a retrospective analysis using the FAERS.

BACKGROUND: Our study aimed to investigate the prevalence and demographic characteristics of immune checkpoint inhibitor-associated hypophysitis (ICI-hypophysitis) using data from the FAERS, and the risk factors of prognosis were explored. METHODS: In this retrospective study, all cases of newly-diagnosed hypophysitis associated with FDA approved ICIs from 1st January 2007 to 31st December 2022 were accumulated using FAERS. Demographic data including age, sex, body weight, the prognosis of cases, and other co-occurred endocrinopathies induced by ICIs were analyzed and compared between different subgroups of immunotherapy. RESULTS: The reporting frequency of ICI-hypophysitis was 1.46% (2343/160089). Patients on the combination therapy had higher risk of hypophysitis reporting, followed by anti-CTLA-4 agent compared with other monotherapies (p < 0.001). Male subjects displayed higher reporting risk of ICI-hypophysitis (p = 0.015). Patients on anti-PD-1 therapy or the combination therapy showed higher occurrence rate of type 1 diabetes (anti-PD-1 vs. anti-PD-L1 vs. anti-CTLA-4 vs. combination therapy, 4.2% vs. 0.7% vs. 0.3% vs. 8.4%, p < 0.001). The occurrence rate of new-onset thyroid diseases in patients receiving combination therapy was higher than anti-PD-1 monotherapy (12.3% vs. 8.4%, p = 0.010). Elder age, lung cancer, and renal cancer emerged to be positively associated with severe clinical outcomes [>65 years, OR 1.042, 95%CI (1.022-1.063), p < 0.001; lung cancer, OR 1.400, 95%CI (1.019-1.923), p = 0.038; renal cancer, OR 1.667, 95%CI (1.153-2.412), p = 0.007]. Anti-CTLA-4 monotherapy was discovered to be a protective factor of severe outcomes [OR 0.433, 95%CI (0.335-0.558), p < 0.001]. Female sex and co-occurrence of ICI-related diabetes exhibited lower risk of death [female, OR 0.571, 95%CI (0.361-0.903), p = 0.017; diabetes, OR 0.090, 95%CI (0.016-0.524), p = 0.007]. CONCLUSIONS: ICI-induced hypophysitis is male-predominant irAE, most commonly seen in patients on anti-CTLA-4 mono- or combination therapy. Awareness among clinicians is critical when patients with elder age, lung or renal cancer develop hypophysitis, which indicates poor clinical outcomes. Female sex, anti-CTLA-4 monotherapy and co-occurrence of ICI-related diabetes are protective risk factors for poor prognosis.

Exploration of predictive risk factors for diabetic foot in patients with diabetes in Beijing: analysis of 5-year follow-up data of patients with diabetes mellitus in a single center in Beijing.

Background: Large-scale prospective cohort studies on diabetic foot ulcers risk factor screening in China are limited. Therefore, this prospective cohort study aimed to explore the predictive risk factors for diabetic foot ulcers to provide clinicians with concise and effective clinical indicators for identifying a high-risk diabetic foot and guiding the prevention of diabetic foot ulcers. Methods: Patients with diabetes who visited the Department of Endocrinology of Peking University First Hospital from October 2017 to December 2018 were selected as research participants by convenience sampling. A total of 968 patients were included. After enrollment, a dedicated person collected and recorded all baseline data. A dedicated telephone follow-up was conducted every 12-24 months to evaluate whether the endpoint event had occurred. All patients were followed up for an average of 61 (57-71) months, with 95% of them followed up for more than 60 months. According to the occurrence of endpoint events, they were divided into the DFU and non-DFU groups. The data between the two groups were analyzed using independent-sample t-test, Wilcoxon rank sum test, and chi square test. We used univariate and multivariate logistic regression analysis to analyze the factors that affected the occurrence of diabetic foot ulcers. Results and conclusions: After the 5-year follow-up, the incidence of diabetic foot was 25.83%. Multivariate logistic regression analysis revealed that body mass index (odds ratio: 1.046; 95% confidence interval: 1.001-1.093), abnormal pinprick sensation (odds ratio: 4.138; 95% confidence interval: 1.292-13.255), history of fungal foot infection (odds ratio: 2.287; 95% confidence interval: 1.517-3.448), abnormal 128-Hz tuning fork test (odds ratio: 2.628; 95% confidence interval: 1.098-6.294), and HbA1c≥ 8% (odds ratio: 1.522; 95% confidence interval: 1.014-2.284) were independent predictors of diabetic foot. Our study highlights clinically relevant indicators that may help to prevent the occurrence of diabetic foot and guide timely interventions.

GABA Analogue HSK16149 in Chinese Patients With Diabetic Peripheral Neuropathic Pain: A Phase 3 Randomized Clinical Trial.

Importance: Many patients with diabetic peripheral neuropathic pain (DPNP) experience inadequate relief, despite best available medical treatments. There are no approved and effective therapies for patients with DPNP in China. Objective: To evaluate the efficacy and safety of capsules containing γ-aminobutyric acid (GABA) analogue HSK16149 in the treatment of Chinese patients with DPNP. Design, Setting, and Participants: This phase 2 to 3 adaptive randomized clinical trial was multicenter, double blind, and placebo and pregabalin controlled. The trial started on December 10, 2020, and concluded on July 8, 2022. In stage 1, various doses of HSK16149 were evaluated to determine safety and efficacy for stage 2. The second stage then validated the efficacy and safety of the recommended dose. Intervention: In stage 1, enrolled patients (n = 363) were randomized 1:1:1:1:1:1 to 4 HSK16149 doses (40, 80, 120, or 160 mg/d), pregabalin (300 mg/d), or placebo. In stage 2, patients (n = 362) were randomized 1:1:1 to receive HSK16149, 40 or 80 mg/d, or placebo. The final efficacy and safety analysis pooled data from patients receiving the same treatment. Main Outcomes and Measures: The primary efficacy end point in stage 1 was the change from baseline in average daily pain score (ADPS) at week 5. The primary efficacy end point in stage 2 was the change from baseline in ADPS at week 13. When the final statistical analysis was performed, the P values calculated from the independent data of each phase were combined using the weighted inverse normal method to make statistical inferences. Results: Of 725 randomized patients in the full-analysis set (393 men [54.2%]; mean [SD] age, 58.80 [9.53] years; 700 [96.6%] of Han Chinese ethnicity), 177 received placebo; 178, HSK16149, 40 mg/d; 179, HSK16149, 80 mg/d; 66, HSK16149, 120 mg/d; 63, HSK16149, 160 mg/d; and 62, pregabalin, 300 mg/d. A total of 644 patients (88.8%) completed the study. The 40- and 80-mg/d doses of HSK16149 were recommended in stage 2. At week 13, the ADPS mean (SD) change from baseline was -2.24 (1.55) for the 40-mg/d and -2.16 (1.79) for 80-mg/d groups and -1.23 (1.68) for the placebo group, showing statistical significance for both HSK16149 doses vs placebo (both P < .001). In a safety set (n = 726), 545 patients (75.1%) had adverse events, which were generally mild to moderate, with dizziness and somnolence being the most common. Conclusions and Relevance: Forty- and eighty-mg/d doses of HSK16149 were recommended for treating patients with DPNP in China. The efficacy of HSK16149 capsules was superior to placebo in all groups for relieving DPNP and appeared well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT04647773.

ßAR-mTOR-lipin1 pathway mediates PKA-RIIß deficiency-induced adipose browning.

Background: Enhancing white adipose tissue (WAT) browning combats obesity. The RIIß subunit of cAMP-dependent protein kinase (PKA) is primarily expressed in the brain and adipose tissue. Deletion of the hypothalamic RIIß gene centrally induces WAT browning, yet the peripheral mechanisms mediating this process remain unexplored. Methods: This study investigates the mechanisms underlying WAT browning in RIIß-KO mice. Genetic approaches such as ß3-adrenergic receptors (ß3ARs) deletion and sympathetic denervation of WAT were utilized. Genome-wide transcriptomic sequencing and bioinformatic analysis were employed to identify potential mediators of WAT browning. siRNA assays were employed to knock down mTOR and lipin1 in vitro, while AAV-shRNAs were used for the same purpose in vivo. Results: We found that WAT browning substantially contributes to the lean and obesity-resistant phenotypes of RIIß-KO mice. The WAT browning can be dampened by ß3ARs deletion or WAT sympathetic denervation. We identified that adipocytic mTOR and lipin1 may act as mediators of the WAT browning. Inhibition of mTOR or lipin1 abrogates WAT browning and hinders the lean phenotype of RIIß-KO mice. In human subcutaneous white adipocytes and mouse white adipocytes, ß3AR stimulation can activate mTOR and causes lipin1 nuclear translocation; knockdown of mTOR and Lipin1 mitigates WAT browning-associated gene expression, impedes mitochondrial activity. Moreover, mTOR knockdown reduces lipin1 level and nuclear translocation, indicating that lipin1 may act downstream of mTOR. Additionally, in vivo knockdown of mTOR and Lipin1 diminished WAT browning and increased adiposity. Conclusions: The ß3AR-activated mTOR-lipin1 axis mediates WAT browning, offering new insights into the molecular basis of PKA-regulated WAT browning. These findings provide potential adipose target candidates for the development of drugs to treat obesity.

Denosumab treatment for refractory hypercalcemia in a hemodialysis patient with tertiary hyperparathyroidism.

The most appropriate surgical procedure for tertiary hyperparathyroidism is still controversial. Medical management may be considered in those patients with failed previous surgical intervention. There are limited medical options for tertiary hyperparathyroidism with renal dysfunction. The monoclonal antibody denosumab has been used in patients with osteoporosis and hypercalcemia of malignancy. We report a case of medically refractory hypercalcemia caused by tertiary hyperparathyroidism treated with denosumab. A 46-year-old female was on hemodialysis for 10 years. She was diagnosed with tertiary hyperparathyroidism due to hypercalcemia with a high level of intact parathyroid hormone (iPTH, 1411 pg/ml). After right parathyroidectomy 6 weeks, her serum calcium remained persistently elevated (Ca, 3.17 mmoL/L). Denosumab (60 mg) was administered subcutaneously, and her serum calcium quickly decreased (from 3.43 to 2.04 mmoL/L within 8 days) and was slightly elevated (Ca, 2.8 mmoL/L) 3 months later. We conclude that denosumab has a significant effect on the reduction of serum calcium for tertiary hyperparathyroidism patients. The long-term treatment effect and safety warrant more studies in the future.

Clinical characteristics and the prognosis of diabetic foot in Tibet: A single center, retrospective study.

The objective of this study was to explore the clinical characteristics and prognosis of diabetic foot in hospitalized patients with diabetes in Tibet. To achieve that, patients hospitalized in People's Hospital of Tibet Autonomous Region and diagnosed with diabetic foot ulcer (DFU) from January 1, 2016 to December 31, 2020 were enrolled in the study, and DFU cases of Peking University First Hospital were collected as control group. Analysis and comparison of clinical characteristics of DFU in plateau and plain areas were conducted. Normal distribution data or non-normal distribution data between groups were analyzed by t-test analysis or the nonparametric Mann-Whitney U test, and categorical variants were compared by Chi-square of Pearson. A total of 54 DFU cases were enrolled in the study in the People's Hospital of Tibet Autonomous Region (Tibet group for short). Males accounted for 83.3% (45 cases) in Tibet group, which was higher than that of Peking University First Hospital (Beijing group for short), which accounted for 67.0%. Compared with the DFU patients in the Beijing group, the Tibet group was younger (58.11 ± 12.25 years vs 64.18 ± 11.37 years, P < 0.05), with a shorter disease duration (7.00 years vs 12.00 years, P < 0.05). In contrast, alcohol consumption was higher in the Tibet group (44.4 vs 27.4%, P < 0.05), and the number of patients with smoking habit was higher in the Beijing group (29.6 vs 43.7%, P < 0.05). The Tibet group had higher HbA1c (10.2 vs 8.7%, P < 0.05) and lower DFU proportion (22.2 vs 44.2%, P < 0.05). There was no statistically significant difference in the proportion of moderate to severe infections between the two groups (58.5 vs 59.6%, P = 0.887). Leukocytes (6.75 × 109/L vs 8.72 × 109/L, P < 0.05) and neutrophils (4.07 × 109/L vs 6.26 × 109/L, P < 0.05) in Tibet group were lower. Although the DFU amputation rate in the Tibet group was lower than that in the Beijing group (9.3 vs 29.8%, P < 0.05), there was no statistically significant difference between the two groups in terms of treatment cost, hospital stay, and mortality. In conclusion, patients with DFU in Tibet had a smaller age, shorter duration of diabetes, and more male predominance. The proportions of gangrene and amputation were lower in Tibet, with gangrene accounting for 80% of all amputees.

Incidence of Childhood Type 1 Diabetes in Beijing During 2011-2020 and Predicted Incidence for 2025-2035: A Multicenter, Hospitalization-Based Study.

INTRODUCTION: China has a low incidence of type 1 diabetes mellitus (T1DM); however, based on the large population, the absolute numbers are high. Our aim was to assess the incidence of childhood T1DM in Beijing during 2011-2020, predicted incidence for 2025-2035, and to determine the incidence of diabetic ketosis or diabetic ketoacidosis (DK/DKA) in this population. METHODS: Data on patients aged less than 15 years of age with newly diagnosed T1DM between January 1, 2011 and December 31, 2020 was obtained from five tertiary hospitals in Beijing and retrospectively analyzed. RESULTS: In all, 636 children aged less than 15 years were diagnosed with T1DM during 2011-2020. The incidence of T1DM was 3.11-5.46 per 100,000 per year, with an average increase of 5.10% per year. The age-specific incidence for ages 0-4 years, 5-9 years, and 10-14 years was 2.97, 4.69, and 4.68 per 100,000 per year, respectively. The highest average annual increase (7.07%) in incidence was for the youngest age group. DK or DKA was present at the time of diagnosis of T1DM in 84.6% of patients. The age-specific incidence of T1DM among children aged less than 15 years was predicted to be 7.32, 11.4, and 11.52 per 100,000 in 2035 for ages 0-4 years, 5-9 years, and 10-14 years, respectively. CONCLUSIONS: The was a gentle increase in the incidence of childhood T1DM during 2011-2020 in Beijing. This increase is expected to continue for the next 15 years.

Multiscale entropy and small-world network analysis in rs-fMRI - new tools to evaluate early basal ganglia dysfunction in diabetic peripheral neuropathy.

Objective: The risk of falling increases in diabetic peripheral neuropathy (DPN) patients. As a central part, Basal ganglia play an important role in motor and balance control, but whether its involvement in DPN is unclear. Methods: Ten patients with confirmed DPN, ten diabetes patients without DPN, and ten healthy age-matched controls(HC) were recruited to undergo magnetic resonance imaging(MRI) to assess brain structure and zone adaptability. Multiscale entropy and small-world network analysis were then used to assess the complexity of the hemodynamic response signal, reflecting the adaptability of the basal ganglia. Results: There was no significant difference in brain structure among the three groups, except the duration of diabetes in DPN patients was longer (p < 0.05). The complexity of basal ganglia was significantly decreased in the DPN group compared with the non-DPN and HC group (p < 0.05), which suggested their poor adaptability. Conclusion: In the sensorimotor loop, peripheral and early central nervous lesions exist simultaneously in DPN patients. Multiscale Entropy and Small-world Network Analysis could detect basal ganglia dysfunction prior to structural changes in MRI, potentially valuable tools for early non-invasive screening and follow-up.

Risk Factors for Diabetic Peripheral Neuropathy, Peripheral Artery Disease, and Foot Deformity Among the Population With Diabetes in Beijing, China: A Multicenter, Cross-Sectional Study.

Diabetic peripheral neuropathy (DPN), peripheral artery disease (PAD), and foot deformity are the most common causes of diabetic foot, which can considerably worsen the patient's quality of life. In this study, we aimed to investigate the prevalence and risk factors associated with DPN, PAD, and foot deformity among patients with diabetes living in Beijing, China. In total, 3,898 diabetes patients from 11 hospitals in Beijing were evaluated using questionnaires and physical examinations, and 3,758 patients were included in the analysis. We compared the demographic, clinical, biological characteristics, and comorbidities of patients with and without DPN, PAD, or foot deformity, and used binary logistic regression analysis to identify potential factors associated with these outcomes. Overall, 882 patients (23.5%) had DPN, 437 patients (11.6%) had PAD, and 1,117 patients (29.7%) had foot deformities, including callus. The risk factors for DPN included: age ≥40 years, a ≥10+year duration of diabetes, a body mass index of <18.5 kg/m2 or ≥24 kg/m2, a systolic blood pressure (SBP) of ≥140 mm Hg, a hemoglobin A1c (HbA1c) level of ≥7%, chronic kidney disease, and cerebrovascular disease. The risk factors for PAD included: a 15+ year diabetes duration, a body mass index of <18.5 kg/m2, a SBP of ≥140 mm Hg, a HbA1c level of ≥7%, chronic kidney disease, coronary heart disease, and cerebrovascular disease. The risk factors for skeletal foot deformities included: women, age ≥40 years, a SBP ≥140 mm Hg, and hyperlipidemia. The risk factors for callus formation included: women, a SBP ≥140 mm Hg, and hyperlipidemia. In conclusion, the prevalence of foot deformities was higher than DPN and PAD in patients with diabetes. Managing the risk factors for DPN, PAD, and foot deformity is important for reducing the risk of diabetic foot.

[Investigation of amylin level changes among obese patients at different glucose metabolic states and effects of rosiglitazone intervention].

OBJECTIVE: To measure the changes in plasma amylin level among obese patients at different glucose metabolic states, and to evaluate effects of rosiglitazone intervention on obese type 2 diabetes patients. METHODS: A total of 92 obese patients were categorized into normal glucose tolerance group (Group A, n=31), impaired glucose tolerance group (Group B, n=30), and type 2 diabetes group (Group C, n=31) according to oral glucose tolerance test (OGTT) results. Within the new type 2 diabetes group, patients were further randomized into 4 mg rosiglitazone treatment group and life style adjustment group. Body mass index (BMI) and waist circumference of all the patients were measured, and their plasma amylin and true insulin levels measured by radioimmunoassay and EIA. RESULTS: Compared with Group A, both fasting and 30 minute glucose load plasma amylin levels, and ΔAmylin30/ΔGlucose30 in Group B and C were lower. Compared with the life style adjustment group, both fasting and 30 minute plasma amylin levels, and homeostasis model assessment for B cell function (HOMA-B) were higher in the group that received rosiglitazone treatment, but still lower than those in the Group A. CONCLUSION: Pancreatic B cell function and amylin secretion were impaired in the abnormal metabolic states of impaired glucose tolerance and type 2 diabetes patients. Rosiglitazone intervention helped to improve B cell function and increase amylin level.

Resveratrol attenuates dapagliflozin-induced renal gluconeogenesis via activating the PI3K/Akt pathway and suppressing the FoxO1 pathway in type 2 diabetes.

Dapagliflozin alleviates hyperglycemia by increasing glycosuria, but it induces renal gluconeogenesis, thus neutralizing its efficacy. Resveratrol (Rsv), a natural polyphenolic chemical, improves insulin sensitivity in type 2 diabetes (T2D). Here, we investigated the regulatory effects and underlying mechanisms of Rsv on dapagliflozin-induced renal gluconeogenesis. Male ob/ob mice were given the vehicle (HF), dapagliflozin (1 mg kg-1), Rsv (10 mg kg-1), or dapagliflozin and Rsv combination for 10 weeks. Glucose metabolism was evaluated by glucose and pyruvate tolerance tests. HK-2 cells (human renal proximal tubule cells) were treated with dapagliflozin (1 µmol L-1) for 2 h and further incubated with Rsv (10 µmol L-1) for 12 h. The effects of Rsv on gluconeogenesis and insulin signaling were assessed. Dapagliflozin treatment increased glucose production in HK-2 cells and lowered blood glucose and induced gluconeogenesis in ob/ob mice. After Rsv treatment, the enhanced glucose production and gluconeogenesis were alleviated. The upregulated mRNA and protein expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) and the activation of the forkhead transcription factor O1 (FoxO1) protein in the dapagliflozin group were attenuated by Rsv administration. Rsv also improved renal insulin signaling by increasing PI3K and Akt phosphorylation. The PI3K inhibitor LY294002 dramatically decreased the p-Akt expression and activated FoxO1 by dephosphorylation, thus diminishing the inhibitory effects of Rsv on dapagliflozin-induced PEPCK and G6Pase expression. The data showed the mechanisms of Rsv in attenuating dapagliflozin-induced renal gluconeogenesis via activating the PI3K/Akt pathway and further suppressing FoxO1 activation, suggesting a potential intervention to achieve better glucose-lowering effects for SGLT2 inhibitors in T2D therapy.

Aberrant expression of miR-214 is associated with obesity-induced insulin resistance as a biomarker and therapeutic.

BACKGROUND: Insulin resistance (IR) in obesity is associated with the occurrence of metabolic and cardiovascular diseases. Dipepidyl peptidase 4 (DPP4) plays a pivotal role during the development of IR, and was found to be a target gene of microRNA-214 (miR-214) in our study. This study sought to assess the expression and clinical value of miR-214 in obese patients with IR, and investigate its therapeutic potential in obese rats and adipocytes with IR. METHODS: Serum expression of miR-214 in obese patients with or without IR was estimated by quantitative real-time-PCR. A receiver operating characteristic curve was plotted to evaluate the diagnostic value of miR-214 in the patients. Obesity-induced IR animal and cell models were constructed, and the therapeutic ability of miR-214 was explored. RESULTS: Serum expression of miR-214 was decreased in obese patients compared with the healthy controls, and the lowest expression was observed in the cases with IR. Downregulation of miR-214 was significantly correlated with the serum DPP4 levels and HOMA-IR of the patients upon IR conditions, and was demonstrated to perform diagnostic accuracy for distinguishing obese patients with IR from those without IR. In obesity-associated IR animal and cell models, the downregulation of miR-214 was also been detected. According to the measurement of glucose and insulin tolerance and glucose uptake abilities, we found that the overexpression of miR-214 could be used to alleviate IR in the IR models, especially when collaboratively used with DPP4 inhibitor vildagliptin. CONCLUSION: All data revealed that miR-214, as a regulator of DPP4, is decreased in obese patients with IR and may serve as a diagnostic biomarker. The upregulation of miR-214 could improve IR in obese rats and adipocytes, indicating that miR-214 has the therapeutic potential for obesity and IR.

Dysregulation of DPP4 Is Associated with the AMPK/JAK2/STAT3 Pathway in Adipocytes Under Insulin Resistance Status and Liraglutide Intervention.

PURPOSE: Dipeptidyl peptidase 4 (DPP4) is one of the newly identified adipokines, which acts as paracrine in adipose tissue and as endocrine hormones in the liver, muscles and central nervous system. Expression of DPP4 was significantly upregulated in obese patients upon insulin resistance (IR) conditions, but the mechanism underlying the dysregulation of DPP4 remains unclear. This study aimed to investigate the DPP4 expression in adipose tissue and adipocytes under IR conditions or with liraglutide intervention, and explore the potential molecular mechanisms. METHODS: Obesity-associated IR animal and cell models were, respectively, constructed by using high-fat diet and palmitic acid (PA) stimulation. Expression of DPP4 in adipose tissues and adipocytes was estimated by quantitative real-time RT-PCR and Western-blot. Effects of the AMPK/JAK2/STAT3 pathway on DPP4 were examined by regulating the activity of AMPK and the JAK2/STAT signaling. The therapeutic efficacy of liraglutide in the IR models was evaluated, and its regulatory effects on DPP4 expression and the underlying molecular mechanisms were explored. RESULTS: The expression of DPP4 was markedly upregulated in both the animal and cell IR models. In the adipocyte, DPP4 expression was found to be suppressed by the activation of AMPK, and this inhibition effect was mediated by the JAK2/STAT3 signaling. Moreover, liraglutide could alleviate the obesity-induced IR, and led to the downregulation of DPP4 in IR animal and cell models. Liraglutide intervention resulted in the activation of AMPK and deactivation of the JAK2/STAT3 signaling in the adipocytes. CONCLUSION: Taken together, the expression of DPP4 is upregulated in adipose tissues and adipocytes upon IR conditions, but is reduced after liraglutide intervention. The dysregulation of DPP4 in the adipocytes may be performed by the AMPK/JAK2/STAT3 pathway.

Glycine increases glyoxalase-1 function by promoting nuclear factor erythroid 2-related factor 2 translocation into the nucleus of kidney cells of streptozotocin-induced diabetic rats.

AIMS/INTRODUCTION: We have previously reported that glycine suppresses the advanced glycation end-products signaling pathway and mitigates subsequent oxidative stress in the kidneys of diabetic rats. In the present study, we investigated whether this beneficial effect was associated with upregulation of glyoxalase-1 (Glo1) and activation of the nuclear factor erythroid 2-related factor 2 (Nrf2). MATERIALS AND METHODS: Both healthy rats and streptozotocin-induced diabetic rats were administrated with glycine (1% added to the drinking water) for 12 weeks. The function of Glo1, messenger ribonucleic acid (mRNA) and protein expressions of Nrf2, and markers of oxidative status were measured in the kidneys. The mRNA expressions of other downstream signaling molecules of the Nrf2 pathway were also determined. RESULTS: The mRNA and protein expressions, as well as the activity of Glo1, were decreased in the kidneys of diabetic rats, accompanied by diminished glutathione levels. After glycine treatment, these parameters of Glo1 function were markedly increased. Compared with the control group, the levels of Nrf2 mRNA and protein in the total kidney lysis were both markedly elevated in the diabetic group and glycine-treated group. However, the nuclear translocation of Nrf2 was significantly increased in the glycine-treated group than in the diabetic group. In addition, the anti-oxidant capacity and the expressions of other downstream molecules of the Nrf2 signaling pathway were significantly increased after glycine treatment. CONCLUSIONS: The present study shows that glycine might enhance the function of Glo1 and restore anti-oxidant defense by promoting the nuclear translocation of Nrf2, thus inhibiting advanced glycation end-products formation and protecting against renal oxidative stress.

Microbiological profile and clinical characteristics of diabetic foot infection in northern China: a retrospective multicentre survey in the Beijing area.

PURPOSE: We aimed to define the microbiological characteristics of diabetic foot infection in patients in the Beijing area and to explore the demographic and clinical factors correlated with pathogen distribution. METHODOLOGY: As part of a retrospective multicentre surveillance program conducted in eight hospitals in Beijing 2010-2014, we recruited all inpatients for whom bacterial culture had been performed. Demographic, clinical, laboratory and surgery data were obtained from medical records. Statistical analysis was performed to analyse data on microbiological and clinical characteristics.Results/Key findings. A total of 456 cases were included. The culture positivity was 95.4 %. Among all patients with positive cultures, 88 cases (20.2 %) had polymicrobial infections. Five hundred and fifty-one species were isolated from all specimens, including 39.6 % Gram-positive bacteria and 57.5 % Gram-negative bacteria. Enterobacteriaceae accounted for 41.0 % of all isolates. Staphylococcus aureus (17.1 %), Pseudomonas aeruginosa (13.1 %), Proteus spp. (9.8 %), Escherichia coli (9.3 %) and coagulase-negative Staphylococcus (8.3 %) were the most frequently isolated species. The rate of resistance to methicillin was 24.5 % for S. aureus. The susceptibility of P. aeruginosa to all antibiotics was over 60 %. The rate of extended-spectrum ß-lactamase production among E. coli was 52.6 %. P. aeruginosa and Enterobacteriaceae show high sensitivity to piperacillin/tazobactam, carbapenems and amikacin. Multivariate analysis showed that patient age >60 years was independently associated with Gram-negative rods. CONCLUSIONS: Enterobacteriaceae were the most frequently isolated organisms in our area. Older patients were more likely to suffer from Gram-negative rod infections. Gram-negative rods show high sensitivity to piperacillin/tazobactam, carbapenems and amikacin.

Mast Cell and M1 Macrophage Infiltration and Local Pro-Inflammatory Factors Were Attenuated with Incretin-Based Therapies in Obesity-Related Glomerulopathy.

BACKGROUND: The global increase of obesity parallels the obesity-related glomerulopathy (ORG) epidemic. Dipeptidyl peptidase 4 inhibitors and glucagon-like peptide-1 receptor agonists were well recognized to attenuate renal injury independent of glucose control in diabetic nephropathy. There are limited studies focusing on their effects on ORG. We explored the effects of incretin-based therapies on early ORG and the inflammatory responses involved mainly concentrated on mast cell (MC) and macrophage (M) infiltration and local pro-inflammatory factors. METHODS: ORG rat models were induced by high-fat diet and then divided into ORG vehicle, vildagliptin (3 mg/kg/day, qd) and liraglutide (200 µg/kg, bid) treated groups. After 8 weeks of treatments, albuminuria, glomerular histology, renal inflammatory cell infiltration, and pro-inflammatory factors were analyzed. RESULTS: Early ORG model was demonstrated by albuminuria, glomerulomegaly, foot process fusion, and mesangial and endothelial mild proliferation. Incretin-based therapies limited body weight gain and improved insulin sensitivity. ORG was alleviated, manifested by decreased average glomerular area, attenuated mesangial and endothelial cell proliferation, and revived cell-to-cell propagation of podocytes, which contributed to reduced albuminuria. Compared with ORG vehicle, MC and M1 macrophage (pro-inflammatory) infiltration and M1/M2 ratio were significantly decreased; M2 macrophage (anti-inflammatory) was not significantly increased after incretin-based treatments. Tumor necrosis factor-α (TNF-α) and IL-6 in renal cortex were significantly downregulated, while transforming growth factor-ß1 (TGF-ß1) remained unchanged. CONCLUSIONS: Incretin-based treatments could alleviate high-fat diet-induced ORG partly through the systemic insulin sensitivity improvement and the attenuated local inflammation, mainly by the decrease of MC and M1 macrophage infiltration and reduction of TNF-α and IL-6.

Evaluation of Diagnostic Efficiency of Ultrasound Features on Malignant Thyroid Nodules in Chinese Patients.

BACKGROUND: The aim of this study was to evaluate the efficacy of ultrasonic features in predicting the malignancy of thyroid nodules in a group of Chinese patients. METHODS: In all, 762 patients with thyroid nodules (424 malignant and 338 benign) underwent ultrasound (US) check and surgery between March 2011 and July 2014 at Peking University First Hospital were identified. Univariate and receiver operating characteristic (ROC) analyses were performed to calculate the sensitivity, specificity, negative and positive predictive values of each US feature, and the accuracy of their combinations for prediction of malignancy. RESULTS: Patients with malignant nodules were younger and without obvious risk history than those in the benign group (P < 0.001, P = 0.93). No individual US sign was fully predictive of a malignant lesion. The Youden indexes of irregular margins and hypoechogenicity were the first and second highest in all US features, which were 51.9% and 45.2%, respectively. The sensitivity of solid components (89.7%) and hypoechogenicity (89.2%) and the specificity of taller-than-wide shape (98.5%) and microcalcifications (90.6%) were the first and second highest in all US features. Intranodular flow on a color Doppler examination was a weak predictor of malignancy. Under ROC analysis excepting intranodular flow, the 95% confidence interval (CI) of areas under the curves of hypoechogenicity and irregular margins with any one of the US features were overlapped that of five-feature combinations (95% CI: 0.850-0.901). CONCLUSIONS: We should be alert with taller-than-wide shape and microcalcifications. Intranodular flow was a weak predictor of malignancy. According to Youden indexes and ROC analysis, irregular margins and hypoechogenicity combined with solid component or taller-than-wide shapes or microcalcifications have a high predicative value for malignant thyroid nodules in Chinese patients.

Liraglutide reduces lipogenetic signals in visceral adipose of db/db mice with AMPK activation and Akt suppression.

Liraglutide, a glucagon-like peptide-1 analog, has been proved to reduce body weight and visceral adipose tissue (VAT) in human studies. In this study, we aimed at examining lipogenetic signal changes in VAT after weight-loss with liraglutide in db/db mice. The mice were divided into two groups: liraglutide-treated group (n=14, 8-week-old, fasting glucose. >10 mmol/L, liraglutide 300 µg/kg twice a day for 4 weeks) and control group (n=14, saline). We found body weight gain and food intake were reduced after liraglutide treatment (P<0.05). Compared to the control group, the VAT weights were significantly lower in the treated group (2.32±0.37 g versus 3.20±0.30 g, P<0.01) than that in control group. In VAT, compared with control group, the lipogenetic transcription factors PPARγ and C/EBPα expressions were both reduced with pAMPK and pACC increased 3.5-fold and 2.31-fold respectively, while pAkt and pP38MAPK were reduced 0.38-fold and 0.62-fold respectively (P<0.01). In conclusion, VAT was reduced after weight loss with AMPK activation and Akt suppression with liraglutide treatment, which was associated with reduction of lipogenetic process in VAT.