Frontiers in Endocrinology最新文献

Background: Management of type 2 diabetes mellitus (T2DM) during Ramadan fasting presents unique challenges due to prolonged fasting periods, irregular meal schedules, and altered medication timing, potentially impacting glycemic control. Ertugliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, has been shown to improve glycemic control in T2DM effectively. However, the effectiveness of ertugliflozin during Ramadan fasting, a period with unique glycemic challenges, has not been studied extensively.

Methods: This study was a multicenter, real-life experience study involving 1373 adult patients with known T2DM for at least one year, an HbA1c level of less than 10%, and who intended to fast during Ramadan. Participants were divided into two groups: the Ertu group (n=703), consisting of patients who had been on a stable dose of ertugliflozin for at least three months before Ramadan, and the non-Ertu group (n=670), which included patients receiving other oral antihyperglycemic drugs (OADs) except ertugliflozin. Patients attended a baseline visit one month before the first day of Ramadan and a follow-up visit within one month after the last day of Ramadan. Both visits included history taking, physical examinations, and laboratory tests. The primary endpoints were changes in HbA1c levels, body weight, body mass index (BMI), and the incidence of hypoglycemia during Ramadan fasting.

Results: The mean age of the study participants was 50.37 ± 11.14 (SD) years, with 40.6% male and 58.7% female. Patients receiving ertugliflozin showed significant reduction in HbA1C (-0.65 ± 0.67% vs. -0.22 ± 0.64%, p<0.001), body weight (-1.24 ± 2.58 kg vs. -0.36 ± 3.41 kg, p<0.001), and BMI (-0.48 ± 1.03 kg/m² vs. -0.11 ± 1.33 kg/m², p<0.001) compared to the non-Ertu group. Hypoglycemia was reported in 0.3% of the ertugliflozin group and 0.7% of the other group, with comparable adverse events (p=.23; ≥0.05), indicating a favorable safety profile for ertugliflozin during fasting.

Conclusion: This study demonstrates that ertugliflozin is effective and safe for patients with T2DM during Ramadan fasting.

Introduction: We previously demonstrated that progesterone (P4) can promote breast cancer cell proliferation and migration through activating the P4 receptor (PR)/cSrc-mediated signaling pathway. It has been suggested that high level of Src homology region 2 domain-containing phosphatase-2 (SHP2) might be involved in breast oncogenesis. This study aimed to investigate whether SHP2 is involved in the P4-mediated cSrc activation in breast cancer cells.

Methods: T47D, MCF-7 and BT-483 breast cancer cell lines were used in this study. Cell proliferation and migration were examined using MTT technique and wound healing assay, respectively. Immunoprecipitation assay and Western blot analysis were performed to evaluate protein-protein interaction and protein expression, respectively. Small interfering RNA (siRNA) technique was used to knock down protein expression.

Results: Knockdown of SHP2 expression abolished the P4-promoted cell proliferation and migration in T47D, MCF and BT-483 cell lines, suggesting that presence of SHP2 is essential for the P4-increased proliferation and migration of breast cancer cell lines. P4 (50 nM) treatment increased the complex formations of PR-cSrc-SHP2-caveolin-1, SHP2-p140Cap, and SHP2-Csk, and the level of p-cSrcY416 (activated form of cSrc). However, knockdown of SHP2 expression increased the complex formations of PR-cSrc-caveolin-1-Csk-p140Cap and the levels of p-caveolin-1, p-Csk and p-cSrcY527 (inactivated form of cSrc).

Discussion: Our data suggest that SHP2 can bind to cSrc-negative regulatory proteins (p140Cap and Csk), hence preventing the interaction between cSrc and cSrc-negative regulatory proteins, leading to decreased phosphorylation of cSrc Y527 and prolonged cSrc activation. These findings highlight the role of SHP2 in the P4-promoted breast cancer cell proliferation and migration.

Lysosome, a highly dynamic organelle, is an important nutrient sensing center. They utilize different ion channels and transporters to complete the mission in degradation, trafficking, nutrient sensing and integration of various metabolic pathways to maintain cellular homeostasis. Glucose homeostasis relies on tightly regulated insulin secretion by pancreatic β cells, and their dysfunction is a hallmark of type 2 diabetes. Glucagon also plays an important role in hyperglycemia in diabetic patients. Currently, lysosome has been recognized as a nutrient hub to regulate the homeostasis of insulin and other hormones. In this review, we will discuss recent advances in understanding lysosome-mediated autophagy and lysosomal proteins involved in maintaining insulin and glucagon homeostasis, as well as their contributions to the etiology of diabetes.

Background: The treatment of obesity and type 2 diabetes (T2D) in Prader-Willi syndrome (PWS) is still a challenge. Glucagon-like peptide 1 receptor agonists (GLP-1 RA) are attractive options, since they effectively reduce weight and improve blood glucose, without increasing the risk of hypoglycemia. However, data on their use in PWS are scarce.

Case description: In 2019, a 27-year-old male came to our Clinic because of first appearance of severe hyperglycemia (fasting plasma glucose 22.5 mmol/L). Based on clinical presentation, PWS was suspected, and diagnosis was confirmed by genetic tests. The patient was discharged on a basal-bolus insulin therapy managed by his parents due to his cognitive impairment. In spite of COVID-19 pandemic, the patient achieved tight glycemic control (HbA1c 41 mmol/mol) with non-severe hypoglycemic events in the face of significant body weight (BW) increase (+ 13 kg vs baseline). Insulin therapy was then discontinued, and once-weekly semaglutide (up to 0,5 mg weekly) was started. At 12-month follow-up, BW dropped from 79 to 73 kg while maintaining excellent glycemic control (HbA1c 40 mmol/mol). At 24-month follow-up, glycemic control remained optimal (HbA1c 38 mmol/mol) with further BW reduction (71 kg). Neither hypoglycemia nor gastro-intestinal or psychiatric adverse events were reported.

Conclusion: This case supports the potential use of semaglutide for the treatment of subjects with PWS, obesity and T2D. Ad hoc trials are needed to evaluate the long-term efficacy and tolerability in these subjects.

Background: Recently, weight-adjusted-waist index (WWI), a new index for evaluating obesity, has been developed. This study aimed to examine the association between WWI and T2DM in Chinese urban adults.

Method: A total of 5,0978 eligible participants drawn from the prospective REACTION study (Cancer Risk Assessment in Chinese People with Diabetes) were included in this study. Participants were divided into 3 groups based on baseline WWI levels. Pearson correlation analysis and binary logistic regression analysis were conducted to explore the association of WWI with T2DM risk factors and with T2DM risk.

Results: The prevalence of obesity, central obesity and T2DM was 14.2%, 46.8% and 11.0% respectively, with a median age of 57 years. Logistic analysis showed that the WWI was significantly associated with the risk of T2DM. Compared to the lowest tertile of WWI (T1) serving as the reference group, the second tertile (T2) and the third tertile (T3) were associated with a 0.218-fold [1.218 (1.152, 1.288), P <0.001] and 0.286-fold [1.286 (1.212, 1.364), P <0.001] increase in the odds of developing T2DM respectively. After adjusting for all factors with the exception of the stratified variable, this association held true in age, sex, BMI, hypertension, and hyperlipidemia subgroup and was especially pronounced in those aged <60 years, BMI ≥24 kg/m², and males, with interactions between WWI and age, sex, and BMI (P for interaction <0.05).

Conclusion: WWI was positively associated with T2DM in Chinese urban adults, especially in young and middle-aged males with BMI ≥24 kg/m².

Background: The aim of this study was to explore the genetic level association between obesity, lipids, adipokines, and cognitive ability using bidirectional Mendelian randomization (MR) strategies.

Methods: Summary data for three obesity indicators [body mass index (BMI), body fat percentage (BFP) and waist-hip ratio (WHR)], three lipid indicators [HDL cholesterol (HDL), LDL cholesterol (LDL) and triglycerides (TG)], three adipokines [circulating leptin (LEP), Agouti-related protein (AgRP) and Adiponectin (APDN)], and four cognitive ability indicators [cognitive function (CF), cognitive performance (CP), simple reaction time (SRT) and fluid intelligence score (FIS)] were collected. Bidirectional inverse-variance weighted Mendelian randomization (MR) was employed to evaluate the relationship between adiposity and cognitive function. We employed genetic instruments for adiposity indicators as exposures in one direction, and repeated the analysis in the opposite direction using instruments for cognitive function. Sensitivity analyses were conducted to explore heterogeneity and potential horizontal pleiotropy.

Results: Genetically predicted adiposity showed robust associations with markers of cognitive ability. Higher genetically predicted obesity indicators (such as BMI, BFP and WHR), and lipid and adipokineslevels (such as HDL and AgRP) with reduced cognitive ability indicators (such as CF and CP). In the opposite direction, FIS and SRT may influence BMI and HDL respectively. MR estimates for the effects of cognition ability on all obesity, lipids and adipokines measures indicated worse FIS and SRT were associated with higher BMI and lower HDL.

Conclusions: Our MR reveals that high BMI, BFP, WHR and AgRP have negative causal direct effects with cognitive ability, while high HDL and ADPN have positive causal direct effects with cognitive ability. For the reverse causal direction, our consistent findings that worse cognitive function such as SRT and FIS may influence serum HDL level and BMI.

The prevalence of diabetes continues to rise in the United States along with a shortage of endocrinologists. One proposed solution to this challenge is to deliver more specialty health care services through remote patient monitoring (RPM). Here, we describe our initial experience with an RPM program for diabetes care at the University of Colorado. We enrolled 211 patients with primarily uncontrolled type 2 diabetes into the Diabetes Home and Remote Care Program (DHRCP). Remote care replaced traditional brick-and-mortar care while patients were enrolled. A certified diabetes care and education specialists (CDCES) contacted patients every 1-2 weeks to provide lifestyle coaching and assess medication compliance. With oversight from an endocrinologist, frequent medication adjustments were made by the CDCES. Analysis performed on 106 (50.2%) patients who met graduation criteria and had a hemoglobin A1c (HbA1c) completed upon program graduation showed an average decrease in HbA1c from 10.4% to 7.0% (p<0.001). Overall, our results demonstrate that RPM is an effective care model for improving glycemic control in patients with diabetes.

Background: Many components in follicular fluid (FF), such as peptide hormones, cytokines, and steroids, undergo dynamic changes during folliculogenesis and have important roles in follicular development. Because systemic inflammation has also been found to contribute to diminished ovarian reserve (DOR) in previous studies, do certain serum/FF inflammatory biomarkers affect both follicular development and ovarian function?

Methods: Serum samples from the menstruation phase (n=26), serum samples from the ovulation phase (n=26), FF samples of mature oocytes (n=26), and FF samples of immature oocytes (n=10) were collected. Olink proteomic proximity extension assay (PEA) technology was used to compare the differentially expressed proteins (DEPs), and patients were divided into two subgroups-the normal ovarian reserve (NOR) group and the DOR group-for further bioinformatics analysis and verification by enzyme-linked immunosorbent assay (ELISA).

Results: In total, 16 DEPs were detected between the mature group and the immature group (FF), and 11 DEPs were detected between the ovulation group and the menstruation group (serum). Further subdivision of the ovarian reserve subgroups revealed 22 DEPs in FF and 3 DEPs in serum. Among all four comparisons, only the expression of oncostatin M (OSM) significantly differed. The OSM signaling pathway, the IL-10 anti-inflammatory signaling pathway, and the PI3K-Akt signaling pathway are three notable pathways involved in affecting ovarian reserve capacity according to bioinformatics analysis. In addition, the concentration of estradiol on the hCG day was slightly but positively correlated with OSM (r=0.457, P=0.029). A significantly greater level of OSM (5.41 ± 2.65 vs. 3.94 ± 1.23 pg/mL, P=0.007) was detected in the serum of NOR patients via ELISA verification, and the sensitivity and specificity of ovarian reserve division were 50.00% and 83.33%, respectively.

Conclusion: This study proposed that immunological changes assessed by PEA technology affect ovarian function in humans and that OSM may serve as a potential inflammatory biomarker for ovarian function in serum, thus revealing alterations in FF.

Background: Metabolic syndrome (MetS) and sarcopenia (SP) are increasingly significant public health issues in aging societies, sharing common pathophysiological mechanisms and being associated with severe health consequences. This study investigates the impact of MetS and SP on all-cause and cause-specific mortality using a longitudinal, nationally representative population-based cohort.

Methods: The study analyzed data from the National Health and Nutrition Examination Survey (NHANES) conducted between 1999 and 2018. Mortality data were obtained from the National Death Index up to December 2019.

Results: Among the 21,962 participants, 13,517 (61.5%) had neither MetS nor SP(MetS-/SP-), 5,407 (24.6%) had MetS only(MetS+/SP-), 2,698 (12.2%) had SP only(MetS-/SP+), and 340 (1.5%) had both MetS and SP(MetS+/SP+). Compared to the group without MetS and SP, the groups with MetS only, SP only, and both MetS and SP showed increased all-cause mortality, with adjusted hazard ratios (HR) of 1.23 (95% CI: 1.11-1.37), 1.63 (95% CI: 1.41-1.89), and 1.61 (95% CI: 1.33-1.95), respectively. The MetS+/SP+ group had the highest overall mortality risk (trend test p<0.0001). For cause-specific mortality, the MetS+/SP+ group exhibited increased cardiovascular mortality (HR: 1.89, 95% CI: 1.27-2.81), cardiac mortality (HR: 1.89, 95% CI: 1.25-2.86), respiratory mortality (HR: 2.63, 95% CI: 1.29-5.35), and diabetes mortality (HR: 8.79, 95% CI: 2.62-29.45) compared to the group without MetS and SP.

Conclusion: The coexistence of MetS and SP significantly increases the risk of all-cause and cause-specific mortality. Individuals with either condition may require more vigilant management to prevent the onset of the other condition, thereby reducing mortality rates. These findings highlight the importance of integrated healthcare strategies targeting both MetS and SP to improve patient outcomes and longevity.

Introduction: Metastasis is the major cause of thyroid cancer morbidity and mortality. However, the mechanisms are still poorly understood.

Methods: We performed genome-wide transcriptome analysis comparing gene expression profile of metastatic thyroid cancer cells (Met) with primary tumor cells established from transgenic mouse models of papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), poorly differentiated thyroid cancer (PDTC), and anaplastic thyroid cancer (ATC).

Results: Genes involved in tumor microenvironment (TME), inflammation, and immune escape were significantly overexpressed in Met cells. Notably, IL-6-mediated inflammatory and PD-L1 pathways were highly active in Met cells with increased secretion of pro-inflammatory and pro-metastatic cytokines such as CCL2, CCL11, IL5, IL6, and CXCL5. Furthermore, Met cells showed robust overexpression of Tbxas1, a thromboxane A synthase 1 gene that catalyzes the conversion of prostaglandin H2 to thromboxane A2 (TXA2), a potent inducer of platelet aggregation. Application of aspirin, a TXA2 inhibitor, significantly reduced lung metastases. Mertk, a member of the TAM (Tyro, Axl, Mertk) family of RTKs, was also overexpressed in Met cells, which led to increased MAPK activation, epithelial-mesenchymal transition (EMT), and enrichment of cancer stem cells. Braf-mutant Met cells developed resistance to BRAFV600E inhibitor PLX4720, but remained sensitive to β-catenin inhibitor PKF118-310.

Conclusion: We have identified several overexpressed genes/pathways in thyroid cancer metastasis, making them attractive therapeutic targets. Given the complexity of metastasis involving multiple pathways (PD-L1, Mertk, IL6, COX-1/Tbxas1-TXA2), simultaneously targeting more than one of these pathways may be warranted to achieve better therapeutic effect for metastatic thyroid cancer.