Association of neutrophil-lymphocyte ratio with all-cause and cardiovascular mortality in US adults with diabetes and prediabetes: a prospective cohort study.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR) is a novel hematological parameter to assess systemic inflammation. Prior investigations have indicated that an increased NLR may serve as a potential marker for pathological states such as cancer and atherosclerosis. However, there exists a dearth of research investigating the correlation between NLR levels and mortality in individuals with diabetes and prediabetes. Consequently, this study aims to examine the connection between NLR and all-cause as well as cardiovascular mortality in the population of the United States (US) with hyperglycemia status. METHODS: Data were collected from a total of 20,270 eligible individuals enrolled for analysis, spanning ten cycles of the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. The subjects were categorized into three groups based on tertiles of NLR levels. The association of NLR with both all-cause and cardiovascular mortality was evaluated using Kaplan-Meier curves and Cox proportional hazards regression models. Restricted cubic splines were used to visualize the nonlinear relationship between NLR levels and all-cause and cardiovascular mortality in subjects with diabetes after accounting for all relevant factors. RESULTS: Over a median follow-up period of 8.6 years, a total of 1909 subjects with diabetes died, with 671 deaths attributed to cardiovascular disease (CVD). And over a period of 8.46 years, 1974 subjects with prediabetes died, with 616 cases due to CVD. The multivariable-adjusted hazard ratios (HRs) comparing high to low tertile of NLR in diabetes subjects were found to be 1.37 (95% CI, 1.19-1.58) for all-cause mortality and 1.63 (95% CI, 1.29-2.05) for CVD mortality. And the correlation between high to low NLR tertile and heightened susceptibility to mortality from any cause (HR, 1.21; 95% CI, 1.03-1.43) and CVD mortality (HR, 1.49; 95% CI, 1.08-2.04) remained statistically significant (both p-values for trend < 0.05) in prediabetes subjects. The 10-year cumulative survival probability was determined to be 70.34%, 84.65% for all-cause events, and 86.21%, 94.54% for cardiovascular events in top NLR tertile of diabetes and prediabetes individuals, respectively. Furthermore, each incremental unit in the absolute value of NLR was associated with a 16%, 12% increase in all-cause mortality and a 25%, 24% increase in cardiovascular mortality among diabetes and prediabetes individuals, respectively. CONCLUSIONS: The findings of this prospective cohort study conducted in the US indicate a positive association of elevated NLR levels with heightened risks of overall and cardiovascular mortality among adults with diabetes and prediabetes. However, potential confounding factors for NLR and the challenge of monitoring NLR's fluctuations over time should be further focused.

Ghrelin regulates the endoplasmic reticulum stress signalling pathway in gestational diabetes mellitus.

OBJECTIVE: We aimed to investigate the effects and mechanisms of the ghrelin-regulated endoplasmic reticulum stress (ERS) signalling pathway in gestational diabetes mellitus (GDM). METHODS: Pregnant female C57BL/6 mice were randomly divided into a normal group, GDM group (high-fat diet + STZ), GDM + ghrelin group (acyl ghrelin), and GDM + ghrelin + ghrelin inhibitor group ([D-lys3]-GHRP-6). We measured body weight, the intake of water and food, glucose, cholesterol, triglyceride and fasting insulin levels in each group. HE staining was used to observe the morphological changes in the pancreas. The TUNEL method was used to detect the apoptosis rate of islet cells. qPCR and Western boltting were performed to detect the relative expression levels of PERK, ATF6, IREIα, GRP78, CHOP and caspase-12, which are related to the ERS signalling pathway in the pancreas. Then, NIT-1 cells were cultured to verify whether ghrelin regulates ERS under high-glucose or tunicamycin conditions. RESULTS: Compared with the GDM group, the GDM + ghrelin group showed improved physical conditions and significantly decreased the fasting blood glucose, glucose tolerance, cholesterol, triglyceride and fasting insulin levels. Damaged islet areas were inhibited by ghrelin in the GDM group. The GDM + ghrelin group showed reduced ß-cell apoptosis compared to the GDM and GDM + ghrelin + ghrelin inhibitor groups. ERS-associated factors (PERK, ATF6, IREIα, GRP78, CHOP and caspase-12) mRNA and protein levels were obviously lower in the GDM + ghrelin group than in the GDM group, while expression levels were restored in the inhibitor group. Ghrelin treatment improved the high-glucose or tunicamycin-induced apoptosis, increased insulin levels and upregulation of GRP78, CHOP and caspase-12 in NIT-1 cells. CONCLUSION: Ghrelin suppressed ERS signalling and apoptosis in GDM mice and in NIT-1 cells. This study established a link between ghrelin and GDM, and the targeting of ERS with ghrelin represents a promising therapeutic strategy for GDM.

Effectiveness of Global Leadership Initiative on Malnutrition and Subjective Global Assessment for diagnosing malnutrition and predicting wound healing in patients with diabetic foot ulcers.

Malnutrition significantly hampers wound healing processes. This study aimed to compare the effectiveness of the Global Leadership Initiative on Malnutrition (GLIM) and Subjective Global Assessment (SGA) in diagnosing malnutrition and predicting wound healing in patients with diabetic foot ulcers (DFU). GLIM criteria were evaluated for sensitivity (SE), specificity (SP), positive predictive value, negative predictive value and kappa (κ) against SGA as the reference. Modified Poisson regression model and the DeLong test investigated the association between malnutrition and non-healing ulcers over 6 months. This retrospective cohort study included 398 patients with DFU, with a mean age of 66·3 ± 11·9 years. According to SGA and GLIM criteria, malnutrition rates were 50·8 % and 42·7 %, respectively. GLIM criteria showed a SE of 67·3 % (95 % CI 60·4 %, 73·7 %) and SP of 82·7 % (95 % CI 76·6 %, 87·7 %) in identifying malnutrition, with a positive predictive value of 80·0 % and a negative predictive value of 71·1 % (κ = 0·50) compared with SGA. Multivariate analysis demonstrated that malnutrition, as assessed by SGA, was an independent risk factor for non-healing (relative risk (RR) 1·84, 95 % CI 1·45, 2·34), whereas GLIM criteria were associated with poorer ulcer healing in patients with estimated glomerular filtration rate ≥ 60 ml/min/1·73m2 (RR: 1·46, 95 % CI 1·10, 1·94). SGA demonstrated a superior area under the receiver's operating characteristic curve for predicting non-healing compared with GLIM criteria (0·70 (0·65-0·75) v. 0·63 (0·58-0·65), P < 0·01). These findings suggest that both nutritional assessment tools effectively identify patients with DFU at increased risk, with SGA showing superior performance in predicting non-healing ulcers.

Replacing of sedentary behavior with physical activity and the risk of mortality in people with prediabetes and diabetes: a prospective cohort study.

BACKGROUND: Sedentary behavior is prevalent among people with diabetes and is associated with unfavorable cardiometabolic health. However, there is limited evidence regarding the impact of replacing sedentary time (ST) with physical activity on mortality in people with prediabetes and diabetes. We prospectively examined the association between accelerometer-measured ST and mortality among people with prediabetes and diabetes after adjusting for demographic characteristics, lifestyle factors, and moderate- to vigorous-intensity PA (MVPA). We further determined the effect of replacing ST with equal time of different types of physical activities on all-cause mortality. METHODS: We included 1242 adults with prediabetes and 1037 with diabetes from the National Health and Nutrition Examination Survey. Restricted cubic splines were fitted to determine the dose-response association between ST and overall mortality. Isotemporal substitution modeling was used to explore the hazard ratio (HR) effects of ST replacement. RESULTS: During a median follow-up of 14.1 years, 424 adults with prediabetes and 493 with diabetes died. Compared with the lowest tertile of ST, the multivariable-adjusted HRs for all-cause mortality in the highest tertile were 1.76 (95% confidence interval [CI] 1.19, 2.60) for participants with prediabetes and 1.76 (1.17, 2.65) for those with diabetes. Additionally, a linear association between ST and all-cause mortality was observed in adults with prediabetes and diabetes, with HRs for each 60 min/day increment in ST of 1.19 (1.10, 1.30) and 1.25 (1.12, 1.40), respectively. Isotemporal substitution results indicated that individuals with prediabetes whose ST was replaced by 30 min of light-intensity physical activity (LPA) and MVPA had 9% and 40% lower all-cause mortality, respectively. In people with diabetes, replacing sedentary behavior with an equivalent time of LPA and MVPA was also associated with mortality risk reduction (HR 0.89; 95% CI 0.84, 0.95 for LPA; HR 0.73; 95% CI 0.49, 1.11 for MVPA). CONCLUSIONS: Higher ST was associated in a dose-response manner with an increased risk of premature mortality among adults with prediabetes and diabetes. Statistically replacing ST with LPA was potentially beneficial for health in this high-risk population.

Periostin Acts as a Bridge between Gestational Diabetes Mellitus (GDM) and Chronic Inflammation to Modulate Insulin Resistance by Modulating PPARα/NF-κB/TNF-α Signaling Pathway.

INTRODUCTION: Gestational diabetes mellitus (GDM) is considered an imbalance of glucose metabolism and insulin resistance during pregnancy. AIMS/OBJECTIVE: To evaluate the levels of periostin (POSTN) in patients with GDM and investigate the association between POSTN and GDM. MATERIALS AND METHODS: A total of 30 pregnant women (NC group) and 30 pregnant women with GDM (GDM group) were involved. The GDM mouse model was established by intraperitoneally injecting streptozotocin. The oral glucose tolerance test (OGTT), insulin, and insulin resistance indices were tested. An immunohistochemical and Western blot assay was conducted to determine the expression of POSTN, PPARα, TNF-α, and NF-κB. HE staining was performed to evaluate inflammation in the placental tissues of women with GDM and GDM mice. POSTN-siRNA was transfected into glucose-pretreated HTR8 cells, and pAdEasy-m-POSTN shRNA was infected in GDM mice. The RT-PCR assay determined the gene transcription of POSTN, TNF-α, NF-κB, and PPARα. RESULTS: Pregnantwomen in theGDMgroup demonstrated significantly higherOGTT (p < 0.05), insulin levels (p < 0.05) and insulin resistance (p < 0.05) compared to those of the NC group. The serum levels of POSTN in pregnantwomen of theGDMgroup were significantly higher than that of theNC group (p < 0.05). The obvious inflammation was activated in pregnant women in the GDMgroup. POSTN-siRNAsignificantly enhanced the cell viability of glucose-treated HTR8 cells compared to that without glucose treatment (p < 0.05). POSTNsiRNA (pAdEasy-m-POSTN shRNA) markedly reduced the glucose level of glucose-treated HTR8 cells (GDM mice) compared to that without treatment (p < 0.05). POSTN-siRNA (pAdEasy-m-POSTN shRNA) promoted PPARα gene transcription (p < 0.05) and inhibited NF-κB/TNF-α gene transcription (p < 0.05) in glucose-treated HTR8 cells (GDMmice) compared to thosewithout treatment. POSTN-siRNAmodulated NF- κB/TNF-α pathway mediated inflammation by regulating PPARα in HTR8 cells and GDMmice. PPARα participated in POSTN-associated inflammation. pAdEasy-m-POSTN shRNA inhibited T-CHO/TG levels in GDM mice compared to those without treatment (p < 0.05). All the effects of POSTN-siRNA (pAdEasy-m- POSTN shRNA) were obviously blocked by PPARα inhibitor treatment. CONCLUSION: POSTN levels were significantly higher in pregnant women with GDM and were associated with chronic inflammation and PPARα expression. POSTN may act as a bridge between GDM and chronic inflammation to modulate insulin resistance by modulating PPARα/NF-κB/TNF-α signaling pathway.

Relationship of liver fat content with systemic metabolism and chronic complications in patients with type 2 diabetes mellitus.

OBJECTIVE: This study investigated the correlation of liver fat content (LFC) with metabolic characteristics and its association with chronic complications in type 2 diabetes mellitus (T2DM) patients. METHODS: Eighty-one prospectively enrolled T2DM patients were divided into non-alcoholic fatty liver disease (NAFLD) group and the non-NAFLD group according to the presence of NAFL complications. LFC was determined by MRI IDEAL-IQ Sequence, and patients were divided into 4 groups according to LFC by quartile method. Basic information, metabolic indexes, and occurrence of chronic complications in different groups were analyzed and compared. RESULTS: BMI, SBP, DBP, TG, ALT, AST, GGT, UA, HbA1c, FCP, 2 h CP, HOMA-IR, and HOMA-IS in the NAFLD group were significantly higher than the non-NAFLD group (P < 0.05). The incidences of chronic complications in the NAFLD group were higher than in the non-NAFLD group but not statistically significant (P > 0.05). BMI, SBP, DBP, TC, TG, ALT, AST, FCP, 2 h CP, HOMA-IR, and HOMA-IS showed significant differences between the patients with different LFC, and these indexes were significantly higher in patients with higher LFC than those with lower LFC (P < 0.05). Moreover, diabetes duration, TC, HOMA-IR, and LFC were the risk factors for ASCVD complications, while diabetes duration, TG, and LDL-C were risk factors for DN complications. Also, diabetes duration and SBP were risk factors for both DR and DPN complications in T2DM patients (P < 0.05). CONCLUSION: LFC is positively correlated with the severity of the systemic metabolic disorder and chronic complications in T2DM patients.

TSH levels within the normal range and risk of cardiovascular and all-cause mortality among individuals with diabetes.

BACKGROUND: Evidence regarding thyroid-stimulating hormone (TSH) levels within the normal range and mortality in adults with diabetes is scarce. This study aimed to identify the association between TSH levels and cardiovascular disease (CVD) and all-cause mortality among euthyroid patients with diabetes. METHODS: This prospective cohort study included 1830 adults with diabetes from the Third National Health and Nutrition Examination Survey III. Mortality outcomes were ascertained by linkage to National Death Index records through December 31, 2019. Participants were categorized by tertiles of TSH levels (low-normal, 0.39-1.30 mIU/L; medium-normal, 1.30-2.09 mIU/L; high-normal, 2.09-4.60 mIU/L). Multivariable Cox proportional hazards models were used to explore the association between TSH levels within the normal range and overall and CVD mortality. Furthermore, restricted cubic spline analyses were used to determine the nonlinear relationship between TSH levels and mortality. RESULTS: During a median follow-up of 17.1 years, 1324 all-cause deaths occurred, including 525 deaths from CVD. After multivariate adjustment, a U-shaped relationship was observed between TSH levels in euthyroid status and all-cause or CVD mortality among patients with diabetes (both P < 0.05 for nonlinearity). Compared with participants with medium-normal TSH levels, those with high-normal TSH levels had a significantly higher risk of all-cause (hazard ratio, 1.31; 95% confidence interval, 1.07-1.61) and CVD (1.52; 1.08-2.12) mortality. Similarly, low-normal TSH levels also increased all-cause (1.39; 1.12-1.73) and CVD (1.69; 1.17-2.44) mortality risk. In stratum-specific analyses, we found that high-normal TSH levels were associated with higher mortality risk in younger (< 60 years) patients with diabetes but not in older (≥ 60 years) participants. CONCLUSION: Low- and high-normal serum TSH levels were associated with increased all-cause and CVD mortality in euthyroid adults with diabetes. Further studies are needed to confirm the present observation in a wider population.

Elevated LINC00894 relieves the oncogenic properties of thyroid cancer cell by sponging let-7e-5p to promote TIA-1 expression.

LINC00894 plays an important role in cancer cell proliferation and invasion in breast and kidney cancer. However, its role in thyroid cancer proliferation and metastasis remains unclear. In this study, data on LINC00894 expression in thyroid cancer tissues were obtained from GEPIA2. miRNA expression in thyroid cancer tissues was obtained from starBase 3.0 and OncomiR. Cell proliferation was evaluated using CCK-8, and Transwell chambers were used for the migration and invasion assays. LINC00894 and let-7e-5p expressions in thyroid cancer cells were measured using qRT-PCR. Meanwhile, TIA-1 expression in thyroid cancer cells was analyzed via western blotting. We found that LINC00894 expression was markedly reduced in thyroid cancer tissues and cells, and low expression of LINC00894 was associated with poor prognosis in thyroid cancer. LINC00894 overexpression inhibited the proliferation, migration, and invasion of CAL-62 and TPC-1 cells. Additionally, let-7e-5p expression was substantially enhanced in CAL-62 and TPC-1 cells. LINC00894 overexpression promoted TIA-1 expression by acting as a sponge of let-7e-5p. Finally, let-7e-5p weakened the function of LINC00894 in thyroid cancer cells via reduction in TIA-1 levels. In conclusion, our data suggest that increased LINC00894 expression reduces the oncogenic properties of thyroid cancer cells by sponging let-7e-5p to promote TIA-1 expression.

Capecitabine-induced severe diabetes and hypokalemia: a case report.

BACKGROUND: Capecitabine is widely used in chemotherapy for breast, colorectal, and gastric cancers. The frequent adverse reactions of capecitabine mainly include gastrointestinal side effects, anemia, and cardiovascular toxicity. Here, we report a rare case of severe hyperglycemia and hypokalemia during long-term treatment with capecitabine. CASE PRESENTATION: A 48-year-old Chinese female was hospitalized with the complaint of breathlessness and weakness after activity, for 1 month. Her past history is significant for a diagnosis of right-sided breast cancer 7 years ago. She underwent right mastectomy, following which capecitabine was started 1.5 years prior to the current admission as part of her primary treatment at the discovery of systemic osseous metastasis. Her fasting plasma glucose and hemoglobin A1c levels were quite normal 7 months ago but increased to 15.3 mmol/L and 11.2%, respectively, at the present admission. Her serum potassium level was as low as 2.5 mmol/L. Plasma autoantibodies related to islets and insulin were all negative. Capecitabine was discontinued, and an insulin pump and potassium supplement were given after admission. Her blood sugar and potassium levels returned to their normal ranges soon. Self-injection of insulin was withdrawn completely at 2 months after discharge, and no oral hypoglycemic agents were added. Her plasma glucose and electrolyte levels were at normal levels at her 1-year follow-up. CONCLUSION: Glucose intolerance and hypokalemia may be rare but serious adverse effects during long-term chemotherapy with capecitabine.

AGEs-induced MMP-9 activation mediated by Notch1 signaling is involved in impaired wound healing in diabetic rats.

AIMS: To elucidate the relationship between advanced glycation end products (AGEs), Notch1 signaling, nuclear factor-kappa B (NF-κB), and matrix metalloproteinase-9 (MMP-9) in diabetic wound healing in vitro and in vivo. METHODS: We incubated primary keratinocytes with AGEs alone or AGEs along with γ-secretase inhibitor DAPT, and established diabetic rat wound model by intraperitoneal streptozotocin treatment. The Notch1 signaling components and MMP-9 expression were detected by qPCR, western blotting and gelatin zymography. RESULTS: The exposure of primary keratinocytes to AGEs led to a significant increase in Notch intracellular domain (NICD), Delta-like 4 (Dll4), and Hes1; however, Notch1 expression was inhibited by the RAGE siRNA. Furthermore, MMP-9 activation was up-regulated, secondary to AGEs treatment. In contrast, increased MMP-9 expression by AGEs-stimulation was eliminated after treatment with DAPT. NF-κB activation participated in the Notch1-modulated MMP-9 expression. Notably, in the diabetic animal model, inhibition of the Notch signaling pathway with DAPT attenuated NICD and MMP-9 overexpression, improved collagen accumulation, and ultimately accelerated diabetic wound healing. CONCLUSIONS: These findings identified that activation of the Notch1/NF-κB/MMP-9 pathway, in part, mediates the repressive effects of AGEs on diabetic wound healing and that targeting this pathway may be a potential strategy to improve impaired diabetic wound healing.

Bioinformatic Analysis Identifies Biomarkers and Treatment Targets in Primary Sjögren's Syndrome Patients with Fatigue.

We aim to identify the common genes, biological pathways, and treatment targets for primary Sjögren's syndrome patients with varying degrees of fatigue features. We select datasets about transcriptomic analyses of primary Sjögren's syndrome (pSS) patients with different degrees of fatigue features and normal controls in peripheral blood. We identify common differentially expressed genes (DEGs) to find shared pathways and treatment targets for pSS patients with fatigue and design a protein-protein interaction (PPI) network by some practical bioinformatic tools. And hub genes are detected based on the PPI network. We perform biological pathway analysis of common genes by Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Lastly, potential treatment targets for pSS patients with fatigue are found by the Enrichr platform. We discovered that 27 DEGs are identified in pSS patients with fatigue features and the severe fatigued pSS-specific gene is RTP4. DEGs are mainly localized in the mitochondria, endosomes, endoplasmic reticulum, and cytoplasm and are involved in the biological process by which interferon acts on cells and cells defend themselves against viruses. Molecular functions mainly involve the process of RNA synthesis. The DEGs of pSS are involved in the signaling pathways of viruses such as hepatitis C, influenza A, measles, and EBV. Acetohexamide PC3 UP, suloctidil HL60 UP, prenylamine HL60 UP, and chlorophyllin CTD 00000324 are the four most polygenic drug molecules. PSS patients with fatigue features have specific gene regulation, and chlorophyllin may alleviate fatigue symptoms in pSS patients.

Impact of TPOAb-negative maternal subclinical hypothyroidism in early pregnancy on adverse pregnancy outcomes.

PURPOSE: To investigate the effect of subclinical hypothyroidism on pregnancy outcomes of women early in their pregnancy with different thyroid-stimulating hormone levels and thyroid peroxidase antibody-negative status and to explore reasonable thyroid-stimulating hormone levels for subclinical hypothyroidism in early pregnancy. METHODS: A total of 2378 women early in their pregnancy were studied retrospectively. The baseline characteristics were collected from medical records. Pregnancy outcomes were compared between the euthyroidism and subclinical hypothyroidism groups that were diagnosed by 2011 or 2017 American Thyroid Association guidelines. In addition, the effect of different maternal thyroid-stimulating hormone levels on adverse pregnancy outcomes was analyzed using binary logistic regression. RESULTS: According to the 2011 American Thyroid Association diagnostic criteria of subclinical hypothyroidism, the prevalence of pregnancy outcomes was not significantly higher in the subclinical hypothyroidism group than in the euthyroidism group. However, pregnant women with subclinical hypothyroidism identified by the 2017 American Thyroid Association criteria had a higher risk of premature delivery (odds ratio = 3.93; 95% confidence interval = 1.22-12.64), gestational diabetes mellitus (odds ratio = 2.69; 95% confidence interval = 1.36-5.32), and gestational anemia (odds ratio = 3.28; 95% confidence interval = 1.60-6.75). Moreover, no differences in the prevalence of adverse pregnancy outcomes were observed between the mildly elevated thyroid-stimulating hormone group (2.5 < thyroid-stimulating hormone ⩽4.0 mIU/l) and the normal thyroid-stimulating hormone group (0.27 < thyroid-stimulating hormone ⩽2.5 mIU/l). The significantly elevated thyroid-stimulating hormone group (4.0 < thyroid-stimulating hormone < 10.0 mIU/l) had a higher prevalence of premature delivery, gestational diabetes mellitus, and gestational anemia than the normal thyroid-stimulating hormone group, even after controlling for potential confounding factors. CONCLUSION: A mildly elevated thyroid-stimulating hormone level or maternal subclinical hypothyroidism diagnosed by 2011 American Thyroid Association guidelines during early pregnancy in thyroid peroxidase antibody-negative women was not associated with adverse pregnancy outcomes. However, maternal subclinical hypothyroidism identified by the 2017 American Thyroid Association guidelines increased the risks of several adverse pregnancy outcomes in women untreated with levothyroxine. The 2017 American Thyroid Association guidelines could be more reasonable for the diagnosis of subclinical hypothyroidism in southern China.

Protective effect of exosomes derived from bone marrow mesenchymal stem cells on rats with diabetic nephropathy and its possible mechanism.

OBJECTIVE: To investigate the effect of exosomes derived from bone marrow mesenchymal stem cells (BMMSC-Exos) on diabetic nephropathy (DN) rats and its possible mechanism. METHODS: Thirty rats were divided into the following three groups of 10 rats each: the NC group (normal rats), the DN group (rats with DN), and the BM group (DN rats injected with BMMSC-Exo). Blood glucose level, renal function, blood lipid level, and plasma viscosity of the rats were detected. Renal tissue morphology was observed using hematoxylin-eosin staining. Expression levels of JAK2 and STAT3 in rats' kidneys were measured by RT-PCR and western blot. RESULTS: The rats in the DN group had higher levels of blood glucose, blood lipids, and blood viscosity, worse renal function, and lower body weight than those in the NC group (all P<0.05). After treatment with BMMSC-Exos, rats in the BM group had markedly decreased levels of blood glucose, blood lipids, and blood viscosity, improved renal function, and higher body weight compared to those in the DN group (all P<0.05). The renal tissues in the NC group had intact structure, and no hyperplastic or hypertrophic cells were observed. In the DN group, the renal glomerulus and mesangial matrix were abnormal, and the capillary lumen and renal tubule lumen were depressed and blocked, accompanied by interstitial edema. Pathologic changes in the renal glomerulus and tubule in the BM group were less severe than those in the DN group. The DN rats had higher expression levels of JAK2 and STAT3 than normal rats, and the rats treated with BMMSC-Exos had lower levels of JAK2 and STAT3 compared to the DN rats (all P<0.05). CONCLUSION: BMMSC-Exo can achieve a good therapeutic effect in DN, which may be due to its ability to lower the blood glucose level, improve renal function, and inhibit JAK2/STAT3 expression.

Efficacy and safety of PEGylated exenatide injection (PB-119) in treatment-naive type 2 diabetes mellitus patients: a Phase II randomised, double-blind, parallel, placebo-controlled study.

AIMS/HYPOTHESIS: Glucagon-like peptide 1 receptor agonists (GLP-1 RA) such as exenatide are used as monotherapy and add-on therapy for maintaining glycaemic control in patients with type 2 diabetes mellitus. The current study investigated the safety and efficacy of once-weekly PB-119, a PEGylated exenatide injection, in treatment-naive patients with type 2 diabetes. METHODS: In this Phase II, randomised, placebo-controlled, double-blind study, we randomly assigned treatment-naive Chinese patients with type 2 diabetes in a 1:1:1:1 ratio to receive subcutaneous placebo or one of three subcutaneous doses of PB-119 (75, 150, and 200 µg) for 12 weeks. The primary endpoint was the change in HbA1c from baseline to week 12, and other endpoints were fasting plasma glucose, 2 h postprandial glucose (PPG), and proportion of patients with HbA1c < 53 mmol/mol (<7.0%) and ≤48 mmol/mol (≤6.5%) at 2, 4, 8 and 12 weeks of treatment. Safety was assessed in all patients who received at least one dose of study drug. RESULTS: We randomly assigned 251 patients to one of the four treatment groups (n = 62 in placebo and 63 each in PB-119 75 µg, 150 µg and 200 µg groups). At the end of 12 weeks, mean differences in HbA1c in the treatment groups were -7.76 mmol/mol (95% CI -9.23, -4.63, p < 0.001) (-0.72%, 95% CI -1.01, -0.43), -12.89 mmol/mol (95% CI -16.05, -9.72, p < 0.001) (-1.18%, 95% CI -1.47, -0.89) and -11.14 mmol/mol (95% CI -14.19, -7.97, p <0 .001) (-1.02%, 95% CI -1.30, -0.73) in the 75 µg, 150 µg and 200 µg PB-119 groups, respectively, compared with that in the placebo group after adjusting for baseline HbA1c. Similar results were also observed for other efficacy endpoints across different time points. There was no incidence of treatment-emergent serious adverse event, severe hypoglycaemia or death. CONCLUSIONS/INTERPRETATION: All tested PB-119 doses had superior efficacy compared with placebo and were safe and well tolerated over 12 weeks in treatment-naive Chinese patients with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03520972 FUNDING: The study was funded by National Major Scientific and Technological Special Project for Significant New Drugs Development and PegBio.

A Chinese Family with Familial Dysalbuminemic Hyperthyroxinemia (FDH) due to R242H Mutation on Human Albumin Gene: Reevaluating the Role of FDH in Patients with Asymptomatic Hyperthyroxinemia.

OBJECTIVE: Familial dysalbuminemic hyperthyroxinemia (FDH) has now become an established cause for spurious asymptomatic hyperthyroxinemia. Several different codon mutations on albumin gene had been identified. We here provided an established but rarely reported heterozygous mutation based on gene sequencing results from a Chinese family. METHODS: The proband is a 14-year-old girl with light goiter and asymptomatic clinical presentations, whose thyroid function test by a one-step immunoassay showed increased free thyroxine (FT4) and free triiodothyronine (FT3) but nonsuppressed thyrotropin (TSH). All thyroid auto-antibodies were in the normal range. Blood samples were collected from her and most of her immediate family members for target gene sequencing and verification. RESULTS: Hyperthyroxinemia was also confirmed in the proband's mother and one of her uncles and his son. In the proband and these three pedigrees, the high-throughput gene screening sequencing and the following Sanger sequencing disclosed a heterozygous mutation in the albumin gene, which located in its exon 7 (c.725G > A), and correspondingly leads to an arginine replacement with a histidine (R242H) in its protein. This is an established mutation named as R218H if present without signal peptide sequence. CONCLUSIONS: For patients with asymptomatic hyperthyroxinemia, FDH should be clinically excluded before embarking on further investigations for other specific causes.

Sevelamer hydrochloride suppresses proliferation of parathyroid cells during the early phase of chronic renal failure in rats.

AIM: We examined the effects of sevelamer on parathyroid cell proliferation and secondary hyperparathyroidism in rats following induction of early-phase of chronic renal failure (CRF) by unilateral ureteral obstruction (UUO). METHODS: For 5 days, rats in the control group received normal food, rats in the sevelamer group (SH) received control food plus 5% sevelamer, and rats in the low protein group (LP) received low protein food. Five rats of each group were killed at baseline (day 0). All other rats were given UUO, and five rats per group were killed on days 3, 7, 14, and 28 after UUO. Changes in body weight, serum phosphorus, calcium, intact-parathyroid hormone (i-PTH), creatinine (SCr), creatinine clearance rate (CCR), blood urea nitrogen (BUN), and 24-h urinary phosphorus were determined. Parathyroid tissues were removed for histological examination of proliferating cell nuclear antigen-positive (PCNA+) cells. RESULTS: Measurement of body weight, BUN, and SCr in the controls indicated successful establishment of this model of early-phase CRF. The controls also had remarkable proliferation of PCNA+ cells beginning on day 3, but this did not occur in the SH or LP groups. After 28 days, serum phosphorus had decreased more in the SH and LP groups than in the control group, and phosphorus excretion was much greater in the control group than in the SH and LP groups. The three groups had similar increases in serum i-PTH. CONCLUSION: Sevelamer rapidly lowered the serum phosphorus and inhibited the proliferation of PCNA+ cells in this experimental model of early-phase CRF.

The effects of protein intake on albuminuria in different estimated glomerular filtration rate: A population-based study.

BACKGROUND: Chronic kidney disease (CKD) is a serious condition associated with early mortality, decreased quality of life, and increased health-care expenditures. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) collected from 1999 to 2012 were used. Subjects were divided into 4 estimated glomerular filtration rate (eGFR) categories: stage 1: eGFR≥90mL/min/1.73m2, stage 2: eGFR 60-89, stage 3: eGFR 30-59, and stage 4/5: eGFR<30, and 3 age strata (<45y, 45-64, 65+). Associations between protein intake and albuminuria were determined. RESULTS: A total of 45,259 subjects were included. Despite decreasing protein intake, there was a significant increase in the prevalence of albuminuria with decreasing levels of eGFR. Multivariable analysis showed that albuminuria was associated with daily protein intake in patients ≥65years old with stage 1 disease, and that diabetes was associated with albuminuria in patients ≥65years old with stage 2 and 3 diseases. Overall, albuminuria in patients with stage 1 disease was associated with hours of sitting per day and blood glucose level. CONCLUSION: Albuminuria was associated with daily protein intake in patients of 45-64years old with stage 1 CKD disease, and was associated with hours of sitting per day and blood glucose level. These data further support the importance of lifestyle changes in the management of CKD, especially in patients with early-stage disease.

Febuxostat Attenuates Renal Damage besides Exerting Hypouricemic Effect in Streptozotocin-Induced Diabetic Rats.

Aim. In this study, we aimed to investigate the effects of febuxostat, a novel inhibitor of xanthine oxidase (XO), on renal damage in streptozotocin- (STZ-) induced diabetic rats. Methods. Diabetes was induced by the intraperitoneal injection of STZ in male Sprague-Dawley rats. Sham-injected rats served as controls. The control and diabetic rats were treated with and without febuxostat for 8 weeks, respectively. Fasting blood and 24-h urine samples were collected every 4 weeks. Rat livers were extracted for detecting gene expression, content, and bioactivity of XO. Results. Diabetic rats showed significantly increased serum uric acid (SUA), serum creatinine (SCr), and urea nitrogen (BUN) levels. Daily urinary albumin (UAE), uric acid (UUA), and creatinine (UCr) excretion were also significantly increased in these rats. In diabetic rats, at week 8, febuxostat decreased SUA by 18.9%, while UAA was increased by 52.0%. However, UCr and urinary urea nitrogen (UUN) levels remained unchanged, while SCr and BUN levels decreased by >30% in these rats. Although hepatic gene expression, content, and activity of XO increased significantly in diabetic rats, febuxostat only slightly decreased its content. Conclusions. Febuxostat significantly attenuated renal damage in STZ-induced diabetic rats in addition to exerting hypouricemic effect.

Serum uric acid is associated with incident chronic kidney disease in middle-aged populations: a meta-analysis of 15 cohort studies.

BACKGROUND: Mounting evidence indicates that elevated serum uric acid may increase the incidence of chronic kidney disease (CKD). Our goal was to systematically evaluate longitudinal cohort studies for the association of serum uric acid levels and incident CKD. METHODS: We searched electronic databases and the reference lists of relevant articles. The primary outcome was incident CKD, which was defined as an eGFR less than 60 mL/min/1.73 m2 at the follow-up examination. Study-specific risk estimates were combined using random-effects models. The included studies were stratified into subgroups, and meta-regression analyses were performed. RESULTS: Fifteen unique cohorts with a total of 99,205 individuals and 3,492 incident CKD cases were included. The relative risk of CKD was 1.22 (95% CI 1.16-1.28, I2 = 65.9%) per 1 mg/dL serum uric level increment. This positive association was consistently observed in subgroups stratified according to most of the study-level characteristics. The observed positive association was more pronounced among group with a mean age <60 years (RR 1.26, 95% CI 1.21-1.31), and low-level heterogeneity was observed in the findings for this age group (I2 = 46.4%, P = 0.022). However, no association was observed among studies with a mean age≥60 years (RR 1.04, 95% CI 0.96-1.13), and no evidence of heterogeneity was evident among the studies (I2 = 0%, P = 0.409). This mean age-related difference in the association between serum uric acid levels and CKD was significant (P = 0.004). The sensitivity analysis results were consistent when the analyses were restricted to studies that controlled for proteinuria and metabolic syndrome. CONCLUSIONS: Our meta-analysis demonstrated a positive association between serum uric acid levels and risk of CKD in middle-aged patients independent of established metabolic risk factors. Future randomized, high-quality clinical trials are warranted to determine whether lowering uric acid levels is beneficial in CKD.