Trends in Diabetes Mortality in Urban and Rural China, 1987–2019: A Joinpoint Regression Analysis

PurposeDiabetes mellitus is emerging as an epidemic worldwide, and the incidence and prevalence of diabetes have drastically changed in China over the past 30 years, but data on its mortality rate are scarce. This study aimed to analyze the time trends of mortality rates among patients with diabetes in the rural and urban population in China between 1987 and 2019.MethodsThe research data come from China’s annual report on national health statistics and the Chinese Health Statistics Yearbook. Age-standardized mortality rates were calculated by using the direct method based on the World Standard Population from the WHO. Joinpoint regression analysis was employed to estimate the annual percent change and average annual percentage changes of mortality rates of diabetes mellitus.ResultsAn overall trend for increment in diabetes mortality was observed. The crude mortality rates and age-standardized mortality rates of diabetes for urban and rural residents in China showed a significant increasing trend between 1987 and 2019. Mortality due to diabetes in urban areas has been higher than in rural areas for 30 years. However, due to the rapid increase of rural diabetes mortality in the past decade, the gap between the two gradually narrowed. The age-standardized mortality rates of diabetes increased by about 38.5% in urban areas and 254.9% in rural areas over the whole study period. In addition, the age-standardized mortality rate of females with diabetes was higher than that of males, but this pattern began to change in urban areas in 2012. Finally, the age-standardized mortality rates in the elderly population in China are higher with a faster growth rate, especially in rural areas.ConclusionThe mortality rate of diabetes is on the rise in China. The rapid growth of the mortality rate of diabetes in rural areas leads to the reduction of the urban–rural gap. Male mortality rates in urban areas have surpassed those of women. At the same time, the mortality rate of diabetes showed obvious elder-group orientation. As China’s population ages, the burden of death and disability caused by diabetes and its complications will continue to increase. These results indicate that diabetes has become a significant public health problem in China. Such an effect increases the demand for strategies aimed at the prevention and treatment of diabetes mellitus. In addition to the prevention and intervention of diabetes in high-risk groups, it is also necessary to establish diabetes screening networks to identify patients with mild symptoms. Early detection and timely intervention can effectively reduce the incidence and mortality of diabetes.

Independent Variables for Determining the Cumulative Live Birth Rates of Aged Patients with Polycystic Ovary Syndrome or Tubal Factor Infertility: A Retrospective Cohort Study

ObjectiveTo assess whether women of advanced age (≥35 years) with polycystic ovary syndrome (PCOS) have the same cumulative live birth rate (CLBR) as their age-matched controls with tubal factor infertility and to determine the influencing factors on the CLBRs of aged women.DesignA retrospective cohort study.Setting and PopulationA total of 160 women of advanced age (≥35 years) with PCOS and 1073 women with tubal factor infertility were included in our study. All patients underwent their first fresh cycles and subsequent frozen cycles within in one year in our centre from 2015 to 2020.MethodsTo determine independent influencing factors on the CLBRs of these aged patients, a multivariable Cox regression model of CLBR according to the transfer cycle type was constructed. Main outcome measure(s): CLBRs.ResultThe Cox regression model of the CLBRs indicated that there was no significant difference between the PCOS group and the tubal infertility group in terms of advanced age (HR, 0.95; 95% CI, 0.71-1.27, P=0.732). The CLBR significantly decreased for women of advanced reproductive age up to 37 years of age (HR, 0.46; 95% CI, 0.39-0.56, P<0.001). The CLBR increased by 63% when more than ten oocytes were retrieved (HR, 1.63; 95% CI, 1.34-1.98, P<0.001). Patients with an AMH level above 32.13pmol/l were likely to have a 72%(HR, 1.72; 95% CI, 1.08-2.73, = 0.023) and 34% (HR, 1.34; 95% CI, 1.07-1.68, P=0.010)improvement in CLBR compared to those with an AMH below 7.85pmol/l and 7.85-32.12pmol/l, respectively.ConclusionDespite the higher number of oocytes retrieved in PCOS patients, the reproductive window is not extended for PCOS patients compared with tubal factor infertility patients. Age, AMH and the number of oocytes retrieved play crucial roles in the CLBRs of patients of advanced age (≥35 years).

Maternal High-Fat Diet During Pre-Conception and Gestation Predisposes Adult Female Offspring to Metabolic Dysfunction in Mice

The risk of obesity in adulthood is subject to programming in the womb. Maternal obesity contributes to programming of obesity and metabolic disease risk in the adult offspring. With the increasing prevalence of obesity in women of reproductive age there is a need to understand the ramifications of maternal high-fat diet (HFD) during pregnancy on offspring’s metabolic heath trajectory. In the present study, we determined the long-term metabolic outcomes on adult male and female offspring of dams fed with HFD during pregnancy. C57BL/6J dams were fed either Ctrl or 60% Kcal HFD for 4 weeks before and throughout pregnancy, and we tested glucose homeostasis in the adult offspring. Both Ctrl and HFD-dams displayed increased weight during pregnancy, but HFD-dams gained more weight than Ctrl-dams. Litter size and offspring birthweight were not different between HFD-dams or Ctrl-dams. A significant reduction in random blood glucose was evident in newborns from HFD-dams compared to Ctrl-dams. Islet morphology and alpha-cell fraction were normal but a reduction in beta-cell fraction was observed in newborns from HFD-dams compared to Ctrl-dams. During adulthood, male offspring of HFD-dams displayed comparable glucose tolerance under normal chow. Male offspring re-challenged with HFD displayed glucose intolerance transiently. Adult female offspring of HFD-dams demonstrated normal glucose tolerance but displayed increased insulin resistance relative to controls under normal chow diet. Moreover, adult female offspring of HFD-dams displayed increased insulin secretion in response to high-glucose treatment, but beta-cell mass were comparable between groups. Together, these data show that maternal HFD at pre-conception and during gestation predisposes the female offspring to insulin resistance in adulthood.

Intra-Articular Injection of Umbilical Cord Mesenchymal Stem Cells Loaded With Graphene Oxide Granular Lubrication Ameliorates Inflammatory Responses and Osteoporosis of the Subchondral Bone in Rabbits of Modified Papain-Induced Osteoarthritis

AimThis study is to investigate the effects of umbilical cord mesenchymal stem cells (UCMSCs) loaded with the graphene oxide (GO) granular lubrication on ameliorating inflammatory responses and osteoporosis of the subchondral bone in knee osteoarthritis (KOA) animal models.MethodsThe KOA animal models were established using modified papain joint injection. 24 male New Zealand rabbits were classified into the blank control group, GO group, UCMSCs group, and GO + UCMSCs group, respectively. The concentration in serum and articular fluid nitric oxide (NO), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), type II collagen (COL-II), and glycosaminoglycan (GAG) was detected using ELISA, followed by the dissection of femoral condyles and staining of HE and Micro-CT for observation via the microscope.ResultsGO granular lubrication and UCMSCs repaired the KOA animal models. NO, IL-6, TNF-α, GAG, and COL-II showed optimal improvement performance in the GO + UCMSCs group, with statistical significance in contrast to the blank group (P <0.01). Whereas, there was a great difference in levels of inflammatory factors in serum and joint fluid. Micro-CT scan results revealed the greatest efficacy of the GO + UCMSCs group in improving joint surface damage and subchondral bone osteoporosis. HE staining pathology for femoral condyles revealed that the cartilage repair effect in GO + UCMSCs, UCMSCs, GO, and blank groups were graded down.ConclusionUCMSCs loaded with graphene oxide granular lubrication can promote the secretion of chondrocytes, reduce the level of joint inflammation, ameliorate osteoporosis of the subchondral bone, and facilitate cartilage repair.

Co-Administration of Clomiphene Citrate and Letrozole in Mild Ovarian Stimulation Versus Conventional Controlled Ovarian Stimulation Among POSEIDON Group 4 Patients

This retrospective study assessed the effect of the co-administration of clomiphene citrate (CC) and letrozole in mild ovarian stimulation, compared to conventional regimens, among Patient-Oriented Strategies Encompassing Individualized Oocyte Number (POSEIDON) Group 4 patients. There were 114 POSEIDON Group 4 patients undergoing in vitro fertilization treatments with 216 stimulation cycles recruited from a Taiwan’s reproductive center during 2016-2020. Main outcomes were the numbers, quality of retrieved oocytes and embryo development. Pregnancy outcomes were assessed after embryo transfers. Per stimulation cycle, patients receiving mild stimulation with a combination of CC and letrozole (study group) versus those with COS (control group) had lower numbers of pre-ovulatory follicles (2.00 ± 1.23 vs. 2.37 ± 1.23, p=0.0066) and oocytes retrieved (1.83 ± 1.17 vs. 2.37 ± 1.23, p=0.0017), and lower follicular output rate (58.6% vs. 68.38%, p=0.0093) and mature oocyte output rate (44.29% vs. 52.88%, p=0.0386) but a higher top-quality metaphase II oocyte ratio (66.7% vs. 54.59%, p=0.0444) and a similar fertilization rate (91.67% vs. 89.04%, p=0.4660). With adjustment for significant between-group baseline differences using multivariable logistic generalized estimating equation model analyses, there was no statistical difference in oocytes retrieved and embryo development between the study and control groups, and insignificant increases in successful pregnancies in the study group were found compared to the control group (i.e., odds ratios [95% CIs]: 1.13 [0.55, 232] and 1.50 [0.65, 3.49] for ongoing pregnancy and live birth, respectively). For POSEIDON Group 4 patients, cotreatment of CC and letrozole in mild stimulation may increase the high-quality oocyte ratio and yield comparable fertilization rate and pregnancy outcomes.

Potential Role of the Renal Arterial Resistance Index in the Differential Diagnosis of Diabetic Kidney Disease

AimsTo investigate the potential role of renal arterial resistance index (RI) in the differential diagnosis between diabetic kidney disease (DKD) and non-diabetic kidney disease (NDKD) and establish a better-quantified differential diagnostic model.Materials and MethodsWe consecutively reviewed 469 type 2 diabetes patients who underwent renal biopsy in our center. According to the renal biopsy results, eligible patients were classified into the DKD group and the NDKD group. The diagnostic significance of RI was evaluated by receiver operating characteristic (ROC) curve analysis. Logistic regression analysis was used to search for independent risk factors associated with DKD. Then a novel diagnostic model was established using multivariate logistic regression analysis.ResultsA total of 332 DKD and 137 NDKD patients were enrolled for analysis. RI was significantly higher in the DKD group compared with those in the NDKD group (0.70 vs. 0.63, p< 0.001). The optimum cutoff value of RI for predicting DKD was 0.66 with sensitivity (69.2%) and specificity (80.9%). Diabetic retinopathy, diabetes duration ≥ 60 months, HbA1c ≥ 7.0(%), RI ≥ 0.66, and body mass index showed statistical significance in the multivariate logistic regression analysis. Then, we constructed a new diagnostic model based on these results. And the validation tests indicated that the new model had good sensitivity (81.5%) and specificity (78.6%).ConclusionsRI has a potential role in discriminating DKD from NDKD. The RI-based predicting model can be helpful for differential diagnosis of DKD and NDKD.

PFKP Activation Ameliorates Foot Process Fusion in Podocytes in Diabetic Kidney Disease

BackgroundGlycolysis dysfunction is an important pathogenesis of podocyte injury in diabetic kidney disease (DKD). Foot process fusion of podocytes and increased albuminuria are markers of early DKD. Moreover, cytoskeletal remodeling has been found to be involved in the foot process fusion of podocytes. However, the connections between cytoskeletal remodeling and alterations of glycolysis in podocytes in DKD have not been clarified.MethodsmRNA sequencing of glomeruli obtained from db/db and db/m mice with albuminuria was performed to analyze the expression profiling of genes in glucose metabolism. Expressions of phosphofructokinase platelet type (PFKP) in the glomeruli of DKD patients were detected. Clotrimazole (CTZ) was used to explore the renal effects of PFKP inhibition in diabetic mice. Using Pfkp siRNA or recombinant plasmid to manipulate PFKP expression, the effects of PFKP on high glucose (HG) induced podocyte damage were assessed in vitro. The levels of fructose-1,6-bisphosphate (FBP) were measured. Targeted metabolomics was performed to observe the alterations of the metabolites in glucose metabolism after HG stimulation. Furthermore, aldolase type b (Aldob) siRNA or recombinant plasmid were applied to evaluate the influence of FBP level alteration on podocytes. FBP was directly added to podocyte culture media. Db/db mice were treated with FBP to investigate its effects on their kidney.ResultsmRNA sequencing showed that glycolysis enzyme genes were altered, characterized by upregulation of upstream genes (Hk1, and Pfkp) and down-regulation of downstream genes of glycolysis (Pkm, and Ldha). Moreover, the expression of PFKP was increased in glomeruli of DKD patients. The CTZ group presented more severe renal damage. In vitro, the Pfkp siRNA group and ALDOB overexpression group showed much more induced cytoskeletal remodeling in podocytes, while overexpression of PFKP and suppression of ALDOB in vitro rescued podocytes from cytoskeletal remodeling through regulation of FBP levels and inhibition of the RhoA/ROCK1 pathway. Furthermore, targeted metabolomics showed FBP level was significantly increased in HG group compared with the control group. Exogenous FBP addition reduced podocyte cytoskeletal remodeling and renal damage of db/db mice.ConclusionsThese findings provide evidence that PFKP may be a potential target for podocyte injury in DN and provide a rationale for applying podocyte glycolysis enhancing agents in patients with DKD.

Radiofrequency Ablation of Parathyroid Glands to Treat a Patient With Hypercalcemia Caused by a Novel Inactivating Mutation in CaSR

ObjectiveWe identified a novel inactivating mutation in the calcium-sensing receptor (CaSR) gene in a patient with refractory hypocalciuric hypercalcemia and analyzed its function. The effectiveness of radiofrequency ablation of the parathyroid glands to treat hypercalcemia caused by this mutation was explored.MethodsClinical data of patients before and after radiofrequency ablation were retrospectively analyzed. The CaSR mutation (D99N) found in the patient was studied in cell lines. HEK-293 cells were transfected with plasmids containing wild-type (WT) or mutant CaSR genes (D99N and W718X). Expression levels of the respective CaSR proteins were measured, and their functions were assessed by examining the effect of NPS R-568 (a CaSR agonist) on intracellular Ca2+ oscillations and that of exogenous parathyroid hormone (PTH) on intracellular cyclic adenosine monophosphate (cAMP) levels.ResultsThe effectiveness of pharmacological treatment was poor, whereas radiofrequency ablation of the parathyroid glands resulted in controlled blood calcium and PTH levels in the patient. In cell lines, upon NPS R-568 administration, the amplitude of intracellular Ca2+ oscillations in the D99N group was lower than that in the WT group and higher than that in the W718X group. Upon administration of PTH, intracellular cAMP levels in the D99N group were higher than those in the WT group and lower than those in the W718X group.ConclusionThe homozygous mutation D99N reduced CaSR activity and caused more severe hypocalciuric hypercalcemia. For patients with this type of hypercalcemia and poor response to pharmacological treatments, radiofrequency ablation of the parathyroid glands may be a suitable treatment option.

Virus Elimination by Direct-Acting Antiviral Agents Impacts Glucose Homeostasis in Chronic Hepatitis C Patients

Background and AimsChronic hepatitis C virus (HCV) infection is associated with dysregulation of glucose homeostasis, including insulin resistance (IR) and type 2 diabetes. However, independent risk factors associated with IR in chronic HCV-infected patients have not been detailly elucidated. Previous data regarding the impact of HCV elimination by direct-acting antiviral agents (DAAs) on glucose homeostasis is insufficient and controversial. This study aimed to analyze the independent factors associated with IR and to evaluate the changes in glucose homeostasis in chronic HCV-infected patients treated with DAAs therapies.MethodsWe screened 704 patients with chronic HCV infection who underwent treatment with interferon-free DAAs. Patients’ baseline characteristics, biochemical and virological data were collected. The outcome measurements were their IR and β-cell function assessed by the homeostasis model assessment (HOMA) method at baseline and 12-weeks post-treatment.ResultsHigh IR (HOMA-IR ≥ 2.5) was observed in 35.1% of the patients. Multivariable logistic regression analysis revealed that body mass index (BMI) >25 kg/m2, treatment experience, elevated baseline levels of alanine aminotransferase (ALT) and triglyceride, as well as Fibrosis-4 score >3.25 were independently associated with high IR. In patients who achieved sustained virological response (SVR), no significant change in mean HOMA-IR was observed from baseline to 12-weeks post-treatment (2.74 ± 2.78 to 2.54 ± 2.20, p = 0.128). We observed a significant improvement in β-cell secretion stress from 121.0 ± 110.1 to 107.6 ± 93.0 (p = 0.015). Subgroup analysis revealed that SVR was associated with a significant reduction in mean HOMA-IR in patients with baseline HOMA-IR ≥ 2.5 (5.31 ± 3.39 to 3.68 ± 2.57, p < 0.001), HCV genotype 1 (3.05 ± 3.11 to 2.62 ± 2.05, p = 0.027), and treatment experience (4.00 ± 3.37 to 3.01 ± 2.49, p = 0.039).ConclusionsThere were several independent factors associated with IR in patients with chronic HCV infection, including obesity, treatment experience, high serum ALT and triglyceride levels, as well as advanced hepatic fibrosis. After viral elimination by DAAs, we observed a significant reduction in mean HOMA-IR in patients with baseline high IR, HCV genotype 1, and treatment experience.

The Independent Association of TSH and Free Triiodothyronine Levels With Lymphocyte Counts Among COVID-19 Patients

BackgroundBoth lymphopenia and thyroid dysfunction are commonly observed among COVID-19 patients. Whether thyroid function independently correlates with lymphocyte counts (LYM) remains to be elucidated.MethodsWe included consecutive adults without known thyroid disorder admitted to Queen Mary Hospital for COVID-19 from July 2020 to April 2021 who had thyroid-stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3) and LYM measured on admission.ResultsA total of 541 patients were included. Median LYM was 1.22 x 109/L, with 36.0% of the cohort lymphopenic. 83 patients (15.4%) had abnormal thyroid function tests (TFTs), mostly non-thyroidal illness syndrome (NTIS). Patients with lymphopenia had lower TSH, fT4 and fT3 levels than those without. Multivariable stepwise linear regression analysis revealed that both TSH (standardized beta 0.160, p<0.001) and fT3 (standardized beta 0.094, p=0.023), but not fT4, remained independently correlated with LYM, in addition to age, SARS-CoV-2 viral load, C-reactive protein levels, coagulation profile, sodium levels and more severe clinical presentations. Among the 40 patients who had reassessment of TFTs and LYM after discharge, at a median of 9 days from admission, there were significant increases in TSH (p=0.031), fT3 (p<0.001) and LYM (p<0.001). Furthermore, patients who had both lymphopenia and NTIS were more likely to deteriorate compared to those who only had either one alone, and those without lymphopenia or NTIS (p for trend <0.001).ConclusionTSH and fT3 levels showed independent positive correlations with LYM among COVID-19 patients, supporting the interaction between the hypothalamic-pituitary-thyroid axis and immune system in COVID-19.