Regulation of the Function of T Follicular Helper Cells and B Cells in Type 1 Diabetes Mellitus by the OX40/OX40L Axis.

OBJECTIVE/MAIN OUTCOME: To study the expression of OX40 on T follicular helper (Tfh) cells and the ligand OX40L on antigen-presenting cells (APCs) in peripheral blood of patients with Type 1 diabetes mellitus (T1DM) and the role of OX40 signaling in promoting Tfh cells to assist B-cell differentiation. DESIGN: Cross-sectional study. SETTING: Endocrinology department of a university hospital. PARTICIPANTS: Twenty-five patients with T1DM and 35 with newly diagnosed T2DM from January 2021-December 2021 (39 males, 21 females; mean age: 31.0 ± 4.5, range: 19-46 years). INTERVENTIONS: None. METHODS: The peripheral blood proportion of CD4+CD25-CD127+CXCR5+PD1+ Tfh cells in patients with T1DM or T2DM and the OX40L expression in CD14+ monocytes and CD19+ B cells were analyzed by flow cytometry. The OX40 signal effect on Tfh-cell function was analyzed by co-incubating B cells with Tfh cells under different conditions. Flow cytometry detected the ratio of CD19-CD138+ plasmacytes. RESULTS: The Tfh cells ratio and intracellular IL-21 expression in peripheral blood was significantly higher in patients with T1DM than with T2DM, and the OX40 expression in peripheral Tfh cells and OX40L expression in APC were significantly higher in T1DM. After adding OX40L protein, the CD19-CD138+-plasmacytes percentage was significantly increased and higher in T1DM. Blocking of anti-OX40L monoclonal antibodies significantly reduced the plasmacytes ratio. CONCLUSIONS: The peripheral Tfh cells proportion increased and the OX40 expression in peripheral Tfh cells was upregulated in patients with T1DM versus patients with T2DM. OX40/OX40L signaling enhanced the Tfh-cell function to assist B-cell differentiation, which may contribute to the pathogenesis of T1DM.

Efficacy and Safety of Mazdutide in Chinese Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial.

OBJECTIVE: We conducted a randomized, double-blind, placebo-controlled phase 2 trial to evaluate the efficacy and safety of mazdutide, a once-weekly glucagon-like peptide 1 and glucagon receptor dual agonist, in Chinese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Adults with type 2 diabetes inadequately controlled with diet and exercise alone or with stable metformin (glycated hemoglobin A1c [HbA1c] 7.0-10.5% [53-91 mmol/mol]) were randomly assigned to receive 3 mg mazdutide (n = 51), 4.5 mg mazdutide (n = 49), 6 mg mazdutide (n = 49), 1.5 mg open-label dulaglutide (n = 50), or placebo (n = 51) subcutaneously for 20 weeks. The primary outcome was change in HbA1c from baseline to week 20. RESULTS: Mean changes in HbA1c from baseline to week 20 ranged from -1.41% to -1.67% with mazdutide (-1.35% with dulaglutide and 0.03% with placebo; all P < 0.0001 vs. placebo). Mean percent changes in body weight from baseline to week 20 were dose dependent and up to -7.1% with mazdutide (-2.7% with dulaglutide and -1.4% with placebo). At week 20, participants receiving mazdutide were more likely to achieve HbA1c targets of <7.0% (53 mmol/mol) and ≤6.5% (48 mmol/mol) and body weight loss from baseline of ≥5% and ≥10% compared with placebo-treated participants. The most common adverse events with mazdutide included diarrhea (36%), decreased appetite (29%), nausea (23%), vomiting (14%), and hypoglycemia (10% [8% with placebo]). CONCLUSIONS: In Chinese patients with type 2 diabetes, mazdutide dosed up to 6 mg was generally safe and demonstrated clinically meaningful HbA1c and body weight reductions.

IFN-γ enhances the therapeutic efficacy of MSCs-derived exosome via miR-126-3p in diabetic wound healing by targeting SPRED1.

BACKGROUND AND AIMS: The traditional treatment of diabetic wounds is unsatisfactory. Exosomes isolated from bone marrow mesenchymal stem cells (BMSCs) promote the healing of diabetic wounds. However, whether the exosomes secreted by interferon (IFN)-γ-pretreated BMSCs have an enhanced therapeutic effect on diabetic wound healing and the relevant mechanisms remain unclear. METHODS: In this study, we isolated exosomes from the corresponding supernatants of BMSCs with (IExos) or without IFN-γ treatment (NExos). Human umbilical vein endothelial cells (HUVECs) were used to investigate the proliferation, migration, and tube formation under different treatments in vitro. Diabetic mice were induced by intraperitoneal administration of streptozotocin, and a circular full-thickness dermal defect was then made on the back of each mouse, followed by a multisite subcutaneous injection of phosphate buffered saline or exosomes. Hematoxylin-eosin (H&E) staining, Masson's trichrome staining, and histological analysis were performed to assess the speed and quality of wound healing. RESULTS: NExos treatment accelerated the healing of diabetic wounds by promoting angiogenesis in vivo and in vitro, and IExos exhibited superior therapeutic efficiency. MicroRNA (miR)-126-3p was significantly increased in IExos, and exosomal miR-126-3p promoted angiogenesis and diabetic wound healing via its transfer to HUVECs. miR-126-3p regulates SPRED1 by directly targeting the 3'-UTR. Mechanistically, IFN-γ-pretreated BMSCs secreted miR-126-3p-enriched exosomes, which enhanced the function of HUVECs and promoted angiogenesis via the SPRED1/Ras/Erk pathway. CONCLUSION: Exosomal miR-126-3p secreted from IFN-γ-pretreated BMSCs exhibited higher therapeutic efficacy than NExos in diabetic wound healing by promoting angiogenesis via the SPRED1/Ras/Erk axis.

Mitochondrial respiratory complex I deficiency inhibits brown adipogenesis by limiting heme regulation of histone demethylation.

Mitochondrial functions play a crucial role in determining the metabolic and thermogenic status of brown adipocytes. Increasing evidence reveals that the mitochondrial oxidative phosphorylation (OXPHOS) system plays an important role in brown adipogenesis, but the mechanistic insights are limited. Herein, we explored the potential metabolic mechanisms leading to OXPHOS regulation of brown adipogenesis in pharmacological and genetic models of mitochondrial respiratory complex I deficiency. OXPHOS deficiency inhibits brown adipogenesis through disruption of the brown adipogenic transcription circuit without affecting ATP levels. Neither blockage of calcium signaling nor antioxidant treatment can rescue the suppressed brown adipogenesis. Metabolomics analysis revealed a decrease in levels of tricarboxylic acid cycle intermediates and heme. Heme supplementation specifically enhances respiratory complex I activity without affecting complex II and partially reverses the inhibited brown adipogenesis by OXPHOS deficiency. Moreover, the regulation of brown adipogenesis by the OXPHOS-heme axis may be due to the suppressed histone methylation status by increasing histone demethylation. In summary, our findings identified a heme-sensing retrograde signaling pathway that connects mitochondrial OXPHOS to the regulation of brown adipocyte differentiation and metabolic functions.

Therapeutic effects on the development of heart failure with preserved ejection fraction by the sodium-glucose cotransporter 2 inhibitor dapagliflozin in type 2 diabetes.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a common disease with high morbidity and lacks effective treatment. We investigated the protective effects of the long-term application of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin on diabetes-associated HFpEF in a rat model. Serum proteomics and metabolomics analysis were also conducted in type 2 diabetic patients with HFpEF treated with dapagliflozin. METHODS: Male Zucker diabetic fatty (ZDF) rats were used as a model of diabetic cardiomyopathy. From weeks 16 to 28, animals were given a vehicle or dapagliflozin (1 mg/kg) once daily. Primary blood biochemistry indices, echocardiography, histopathology, and cardiac hemodynamics were determined during the study period. The key markers of myocardial fibrosis, nitro-oxidative stress, inflammation, apoptosis, autophagy, and AMPK/mTOR signaling were examined. Additionally, healthy controls and individuals with type 2 diabetes were enrolled and 16 serum samples from 4 groups were randomly selected. Serum proteome and metabolome changes after dapagliflozin treatment were analyzed in diabetic individuals with HFpEF. RESULTS: Dapagliflozin effectively prevented the development of HFpEF in rats with diabetes by mitigating nitro-oxidative stress, pro-inflammatory cytokines, myocardial hypertrophy, and fibrosis, reducing apoptosis, and restoring autophagy through AMPK activating and mTOR pathway repressing. Proteomics and metabolomics revealed that cholesterol and high-density lipoprotein particle metabolism, nicotinate and nicotinamide metabolism, arginine biosynthesis, and cAMP and peroxisome proliferator-activated receptor (PPAR) signaling are the major disturbed pathways in HFpEF patients treated with dapagliflozin. CONCLUSION: Long-term treatment with dapagliflozin significantly prevented the development of HFpEF in diabetic rats. Dapagliflozin could be a promising therapeutic strategy in managing HFpEF individuals with type 2 diabetes.

Efficacy and safety of empagliflozin in combination with insulin in Chinese patients with type 2 diabetes and insufficient glycaemic control: A phase III, randomized, double-blind, placebo-controlled, parallel study.

AIM: To evaluate the efficacy and safety of empagliflozin in combination with insulin ± oral antidiabetic drugs (OADs) over 24 weeks, in Chinese patients with type 2 diabetes (T2D) who had insufficient glycaemic control. MATERIALS AND METHODS: This was a randomized, double-blind, placebo-controlled, parallel group, multicentre phase III study. Adult patients with T2D and insufficient glycaemic control who received insulin ± up to two OADs were randomized (1:1:1) to receive empagliflozin 10 or 25 mg, or placebo for 24 weeks. The primary endpoint was change from baseline in HbA1c at week 24. RESULTS: Of 219 randomized patients, 73 patients were in each treatment group; baseline characteristics were comparable among the groups. There was a significantly larger decrease from baseline in HbA1c (adjusted mean treatment difference -0.99 and -0.98 for in the empagliflozin 10 and 25 mg groups, respectively; P < .0001) with both doses of empagliflozin than with placebo. There were also significantly larger decreases from baseline in fasting plasma glucose, 2-hour postprandial glucose and body weight with both empagliflozin doses than with placebo. Among patients in the empagliflozin 10 mg, 25 mg and placebo groups, 17.8%, 9.6% and 11.0% reported confirmed hypoglycaemic events, respectively (nominal P = .2422 and .7661 in the empagliflozin 10 and 25 mg groups, respectively), and no Clinical Events Committee-confirmed diabetic ketoacidosis events were reported. CONCLUSIONS: In Chinese patients with T2D, empagliflozin combined with insulin ± OADs improved glycaemic control and was well tolerated, without an increased risk of hypoglycaemia.

A systematic review and meta-analysis of observational studies of the association between the use of incretin-based therapies and the risk of pancreatic cancer.

BACKGROUND: Some early reports in the medical literature have raised concern about a possible increased risk of pancreatic cancer associated with the use of two broad classes of incretin-based therapies, dipeptidyl peptidase-4 inhibitors, and glucagon-like peptide-1 receptor agonists. This possibility has been somewhat mitigated by the null findings meta-analyses of randomized controlled trials, but the usefulness of their findings was hampered by serious shortcomings of lack of power and representativeness. These shortcomings can typically be addressed by observational studies, but observational studies on the topic have yielded conflicting findings. A systematic review and meta-analysis of observational studies was performed to qualitatively and quantitatively appraise the totality of evidence on the association between the use of incretin-based therapies and the risk of pancreatic cancer in routine clinical practice. METHODS: The PubMed, Web of Science, Embase, and Google Scholar databases were searched. The study quality was appraised using the ROBINS-I tool and based on the presence of pharmacoepidemiology biases. A random-effects model was used to estimate the summary relative risks with corresponding CIs. RESULTS: A total of 14 studies were included. The qualitative assessment revealed that all studies had inadequate follow-up (≤5 years), 12 studies were suspected to suffer from time-lag bias (due to inappropriate choice of comparator group) to varying extent, five studies included prevalent users, five studies did not implement exposure lag period, five studies had a serious risk of bias due to confounding, and one study had a time-window bias. The quantitative assessment showed no indication of an increased risk when all studies were pooled together (RR 1.04, 95% CI 0.87, 1.24) and when the analysis was restricted to the studies with the least bias (RR 0.77, 95% CI 0.51, 1.17). However, the pooled RRs were more frequently higher in the studies with less rigorous design and analysis. Specifically, a tendency toward an increased risk was observed in the studies with (RR 1.34, 95% CI 1.04, 1.72) or possibly with (RR 1.10, 95% CI 0.89, 1.36) time-lag bias, in the studies that did not apply (RR 1.23, 95% CI 0.93, 1.63) or with potentially inadequate exposure lag period of 6 months (RR 1.13, 95% CI 0.66, 1.94), in the studies that inappropriate comparator group of a combination of unspecified (RR 1.49, 95% CI 1.25, 1.78) or non-insulin (RR 1.15, 95% CI 0.93, 1.42) antidiabetic drugs, and in the studies with serious risk of bias due to confounding (RR 1.18, 95% CI 0.56, 2.49). CONCLUSIONS: In summary, the totality of evidence from observational studies does not support the claim that the use of incretin-based therapies is associated with an increased risk of pancreatic cancer in routine clinical practice. The increased risk of pancreatic cancer observed in observational studies reflects bias resulting from suboptimal methodological approaches, which need to be avoided by future studies.

Association between plasma growth arrest-specific protein 6 and carotid atherosclerosis in type 2 diabetes mellitus.

BACKGROUND AND AIMS: Growth arrest-specific 6 protein (Gas6) has been established to play important roles in various biological processes, but little is currently known on the role of Gas6 signaling in humans. This research explored the association between Gas6 expression and carotid atherosclerosis (AS) in type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: As many as 126 T2DM patients were recruited in this study and classified into two groups based on their carotid intima-media thickness (CIMT). Meanwhile, 50 healthy individuals were recruited for the normal control group (NC). The subgroups were compared in terms of clinical data and Gas6 expression levels. Gas6 levels were decreased in T2DM patients with or without AS compared to NC subjects (9.64 ± 1.41 ng/ml, 11.38 ± 2.08 ng/ml, and 13.64 ± 2.61 ng/ml, respectively) (p < 0.001). The interaction between Gas6 and AS in T2DM was analyzed by logistic regression model and receiver operating characteristic (ROC) curve analysis. Decreased Gas6 expression was an independent risk factor relevant to AS in T2DM (p = 0.027). The area under the ROC curve to estimate the diagnostic value of low Gas6 expression for AS in T2DM was 0.750. The correlation between Gas6 and other parameters was evaluated by Pearson correlation analysis and linear regression model. Body mass index (BMI), hemoglobin A1c (HbA1c) and tumor necrosis factor-α(TNF-α) were independently correlated with Gas6. CONCLUSION: Low Gas6 expression is an independent risk factor for AS in T2DM. Gas6 expression is affected by BMI, HbA1c and TNF-α levels.

Serum Tenascin-C and Alarin Levels Are Associated with Cardiovascular Diseases in Type 2 Diabetes Mellitus.

Background: Tenascin-C (TNC), an extracellular matrix glycoprotein, is elevated in inflammatory and cardiovascular pathologies, whereas alarin, a novel orexigenic peptide, participates in insulin resistance and glycometabolism. The roles of these molecules in individuals with cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM), clinical conditions associating with metabolic disorders, and chronic inflammation, remain controversial. Our study aimed at determining the potential role of TNC and alarin in CVD adult patients with T2DM. Methods: This was a cross-sectional study. Basic and clinical information for 250 patients with T2DM were analyzed. Based on their cardiovascular disease status, participants were assigned into the CVD and non-CVD groups. Serum TNC and alarin levels were assessed by enzyme-linked immunosorbent assay (ELISA). Results: Serum TNC and alarin concentrations in the CVD group were significantly higher than those of the non-CVD group. Moreover, serum TNC levels were positively correlated with age, waist circumference, and waist-hip ratio; however, they were negatively correlated with TC, LDL-C, and eGFR levels. Alarin levels were positively correlated with BMI, waist circumference, and hip circumference. In logistic regression models, TNC and alarin were also established to be independent determinants for CVD in T2DM patients and their increases were associated with CVD severity. Receiver operating characteristic (ROC) curve analysis showed that the area under curve (AUC) values for TNC and alarin were 0.68 and 0.67, respectively. TNC and alarin were good predictors of CVD occurrence. When the cutoff value for TNC was 134.05 pg/mL, its sensitivity was 69.47% while its specificity was 61.29%. When the cutoff value for alarin was 142.69 pg/mL, sensitivity and specificity were 38.95% and 90.97%, respectively. Conclusion: Elevated TNC and alarin levels are independently associated with the occurrence and severity of CVD in T2DM individuals. Therefore, these two biomarkers are potential diagnostic and prognostic indicators for CVD in diabetics.

Association of serum C1Q/TNF-related protein 4 levels with carotid atherosclerosis in subjects with type 2 diabetes mellitus: A cross-sectional study.

BACKGROUND: Carotid atherosclerosis (CAS) is a common manifestation of macroangiopathy in type 2 diabetes mellitus (T2DM). C1Q/TNF-related protein 4 (CTRP4) was found to be involved in regulation of food intake behaviors and glucolipid metabolism, which were also key factors in the development of CAS. However, the relationship between serum CTRP4 and CAS in T2DM remains unclear. METHODS: A total of 111 participants with T2DM were enrolled in the study and were divided into 2 groups (T2DM group and T2DM + CAS group) according to the result of carotid ultrasound examinations. Serum CTRP4 levels were measured by enzyme linked immunosorbent assay (ELISA). Trend χ2 test and binary stepwise logistic regression were conducted to assess the association between serum CTRP4 and the risk of CAS in T2DM. RESULTS: Serum CTRP4 concentrations in T2DM + CAS group were significantly lower compared with those in T2DM group [7.98 (5.53) vs. 11.29 (7.36) ng/ml, P < 0.01]. The risk of CAS in T2DM decreased with the increasing of CTRP4 quartiles (P for trend < 0.01). Binary stepwise logistic regression suggested that serum CTRP4 might be an independent influence factor for CAS in patients with T2DM (P < 0.01) and high concentrations of serum CTRP4 were related to low risk of CAS in T2DM. CONCLUSIONS: The concentrations of serum CTRP4 are lower in T2DM patients with CAS compared to those without CAS. Serum CTRP4 levels are negatively related to the risk of CAS in T2DM.

Association of Circulating TXNIP Levels with Fatty Liver in Newly Diagnosed Type 2 Diabetes Mellitus.

BACKGROUND AND AIMS: Thioredoxin-interacting protein (TXNIP), a crucial modulator of the redox system, plays a crucial role in modulating lipid/glucose metabolism. Hence, this study aimed to explore whether circulating TXNIP is associated with non-alcoholic fatty liver disease (NAFLD) among patients with type 2 diabetes mellitus (T2DM). METHODS: We enrolled 110 new patients with T2DM. In this study, we determined hepatic fat fraction (HFF), which represents a hepatic fat level, by Dixon magnetic resonance imaging. TXNIP and the other biochemical profiles of the patients were measured using fasting plasma. RESULTS: Among the 110 patients with T2DM, 41 were classified as without fatty liver, whereas 34 and 35 were with mild and moderate-to-severe fatty liver, respectively. The patients with diabetes and advanced fatty liver had significantly higher TXNIP levels (P <0.001) than other patients. The prevalence of severe NAFLD showed an increasing trend with the increase in TXNIP quartiles (for all trends, P <0.05). HFF showed a positive correlation with TXNIP (r = 0.516, P <0.001). Even main risk factors were adjusted, TXNIP level was associated with NAFLD as analyzed by logistic regression. CONCLUSION: TXNIP level remarkably increases among diabetics, which shows its positive relationship with the severity of NAFLD. TXNIP is a promising NAFLD biomarker that offers an efficient way to evaluate and monitor fatty liver progression among patients with T2DM.

Mutation of Beclin1 acetylation site at K414 alleviates high glucose-induced podocyte impairment in the early stage of diabetic nephropathy by inhibiting hyperactivated autophagy.

BACKGROUND: Our group recently reported that a mutation of the novel Beclin1 K414R acetylation site impacts the stability of Beclin1 protein, which decreases autophagy in adipocytes and further impedes adipocyte differentiation and lipolysis. This study was to explore whether Beclin1 acetylation plays a role in the early renal injury induced by high glucose and to further investigate the K414R mutation site in podocytes. METHODS: Male Sprague-Dawley rats were randomized to con (control) and diabetic nephropathy (DN) groups. The DN group was induced by a single 55 mg/kg intraperitoneal injection of streptozotocin and fed a high-fat and high-sugar diet (the con group received an equal volume of the vehicle and fed a plain diet), after 3 days of induction, blood glucose levels were measured to confirm the onset of diabetes. Then, at weeks 0 and 4, the biochemical index was assayed and renal cortex tissues were harvested. MPC5 podocytes were cultured in vitro. Beclin1 (K414R)-pLVX-ZsGreen1-N1(wild-type or mutant) lentiviral plasmids were transfected into podocytes. Western blot or immunoprecipitation was used to test proteins or the acetylation levels respectively, and immunohistochemistry was used to analyze morphological changes of podocytes. Immunofluorescence was used to detect the aggregation of LC3 puncta. RESULTS: The acetylation level of Beclin1 was upregulated with podocyte injury exacerbated in high glucose at 24 h and that a mutation at K414R could inhibit hyperactivated autophagy, which ameliorated podocyte impairment. CONCLUSION: These findings suggest that the acetylation site at K414 is a critical molecule and drug target and that further research into this area is warranted.

Assessment of peripheral neuropathy in type 2 diabetes by diffusion tensor imaging.

BACKGROUND: To evaluate the diagnostic accuracy of diffusion tensor imaging (DTI) in diabetic peripheral neuropathy (DPN) for patients with type 2 diabetes and detect the correlations with electrophysiology. METHODS: A total of 27 patients with type 2 diabetes with DPN, 24 patients with type 2 diabetes without peripheral neuropathy (NDPN), as well as 32 healthy controls (HC) were enrolled in this study. Clinical examinations and neurophysiologic tests were used to determine the presence of DPN. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of peripheral nerves, including the tibial nerve (TN) and common peroneal nerve (CPN), were calculated. Receiver operating characteristic (ROC) analysis was performed for FA and ADC values. Pearson's correlation coefficient was used to assess the correlation between DTI and electrophysiology parameters in the patient group. RESULTS: The tibial and common peroneal nerve FAs were lowest (P=0.003, 0.001, respectively) and ADC was highest (P=0.004, 0.005, respectively) in the DPN group. The FA value of the axonal injury group was lower than that in the demyelination group (P=0.035, 0.01, respectively), while the ADC value was higher (P=0.02, 0.01, respectively). In the DPN group, FA value was positively correlated with motor conduction velocity (MCV) (tibial nerve: r=0.420, P=0.007; common peroneal nerve: r=0.581, P<0.001) and motor amplitude (MA) (tibial nerve: r=0.623, P<0.001; common peroneal nerve: r=0.513; P=0.001), while ADC values was negatively correlated with MCV (tibial nerve: r=-0.320, P=0.044; common peroneal nerve: r=-0.569; P<0.001), and MA (tibial nerve: r=-0.491, P=0.001; common peroneal nerve: r=-0.524; P=0.001). CONCLUSIONS: With a lower FA value and higher ADC value, DTI accurately discriminated DPN. The DTI multi-parameter quantitative analysis of peripheral nerves differentiated DPN axonal injury from the demyelinating lesion, and hence, could be applied in the diagnosis of DPN.

Association Between Serum Cystatin C and Thyroid Diseases: A Systematic Review and Meta-Analysis.

Background: Cystatin C (CysC) is often used to diagnose and monitor renal diseases. Although some studies have investigated the association between serum CysC levels and thyroid diseases, their reported results were inconsistent. Therefore, the relationship between CysC levels and thyroid diseases remains controversial. Aim: This meta-analysis aimed to statistically evaluate serum CysC levels in patients with thyroid diseases. Methods: A literature search was conducted using the PubMed, Web of Science, Embase, EBSCO, and Wiley Online Library databases. The following search terms were used for the title or abstract: "Cystatin C" or "CysC" in combination with the terms "thyroid disease", "thyroid function", "hypothyroidism", or "hyperthyroidism". The results of the systematic analysis were presented as standardized mean differences (SMDs) with corresponding 95% confidence intervals (CIs). Results: Eleven articles (1,265 cases and 894 controls) were included in the meta-analysis. The results of the meta-analysis showed that the serum CysC levels of patients with hyperthyroidism were significantly higher than those of the controls (SMD: 1.79, 95% CI [1.34, 2.25]), and the serum CysC levels of patients with hypothyroidism were significantly lower than those of the controls (SMD -0.59, 95% CI [-0.82, -0.36]). Moreover, the treatment of thyroid diseases significantly affected serum CysC levels. Conclusions: To the best of our knowledge, this meta-analysis is the first to evaluate serum CysC levels in patients with thyroid diseases. Our findings suggest that thyroid function affects serum CysC levels and that serum CysC may be an effective marker for monitoring thyroid diseases. Systematic Review Registration: PROSPERO [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=258022], identifier CRD42021258022].

Decreased serum C1Q/TNF-related protein 4 concentrations are associated with type 2 diabetes mellitus.

OBJECTIVE: To detect serum C1Q/TNF-related protein 4 (CTRP4) concentrations in patients with newly diagnosed type 2 diabetes mellitus (T2DM) and evaluate the correlation between CTRP4 and other variables in T2DM. METHOD: Sixty-five patients with newly diagnosed T2DM and eighty-nine healthy volunteers were enrolled in this study. Anthropometric and biochemical data of the study participants was collected, and serum CTRP4 concentrations were detected by enzyme-linked immunosorbent assay (ELISA) kit. The correlation between serum CTRP4 and other indexes was analyzed by Spearman correlation analysis. Trend χ2 test and binary multivariate stepwise logistic regression were performed to assess the correlation between CTRP4 and the risk of T2DM. RESULTS: Serum CTRP4 concentrations in the T2DM group were significantly lower than those in the control group (P < .01). Spearman correlation analysis showed that CTRP4 concentrations were negatively correlated with BMI, hs-CRP, HOMA-IR, FBG and TG (r = - 0.430, - 0.453, - 0.371, - 0.361, - 0.506, P < .05), and positively correlated with HDL-c (r = 0.303, P < .05). Trend χ2 test indicated that with the increase of CTRP4 levels in the population, the risk of T2DM presented a general downward trend (P < .01). Binary multivariate stepwise logistic regression suggested that serum CTRP4 was an independent impact factor for T2DM and high serum CTRP4 levels were related to the decreased risk of T2DM (P < .05). CONCLUSIONS: Serum CTRP4 concentrations decrease in patients with newly diagnosed T2DM. Serum CTRP4 levels are negatively associated with the risk of T2DM.

Influencing factors for hepatic fat accumulation in patients with type 2 diabetes mellitus.

BACKGROUND: Non-alcoholic fatty liver disease has become the most common chronic liver disease worldwide, which originates from the accumulation of triglyceride (TG) in the liver. Patients with type 2 diabetes mellitus (T2DM) are considered to have a predisposition to hepatic steatosis. However, the influencing factors for hepatic fat accumulation in T2DM patients remain unclear. AIM: To investigate the influencing factors for hepatic fat accumulation in T2DM patients. METHODS: We enrolled 329 T2DM patients admitted to the Endocrinology Department of the First Affiliated Hospital of Soochow University, who underwent MR mDIXON-Quant examination to quantify the hepatic fat fraction (HFF). According to body mass index (BMI), the patients were divided into normal weight, overweight, and obese groups. The differences in general statistics, biochemical parameters, islet function, and HFF were compared among the three groups. The associations between HFF and other parameters and the influences of various parameters on the severity of hepatic fat accumulation were analyzed. RESULTS: The HFF of T2DM patients gradually increased in the normal weight, overweight, and obese groups (P < 0.05). Spearman correlation analysis showed that in T2DM patients, HFF was negatively correlated with age and high-density lipoprotein cholesterol (P < 0.05), whereas it was positively correlated with BMI, waist-hip ratio, fasting plasma glucose, alanine aminotransferase (ALT), aspartate aminotransferase, bilirubin, glutamyl transpeptidase, lactate dehydrogenase, albumin (ALB), uric acid (UA), total cholesterol, TG, low-density lipoprotein cholesterol (LDL-C), C-reactive protein, free triiodothyronine, fasting insulin, fasting C-peptide, and homeostasis model assessment of insulin resistance (P < 0.05). Multiple linear regression analysis showed significant positive influences of BMI, ALT, LDL-C, UA, and ALB on HFF in T2DM patients (P < 0.05). Binary logistic regression analysis showed that BMI, ALT, ALB, and LDL-C were independent risk factors for moderate to severe fatty liver in T2DM patients, and obesity increased the risk of being complicated with moderate to severe fatty liver by 4.03 times (P < 0.05). CONCLUSION: The HFF of T2DM patients increases with BMI. Higher BMI, ALT, ALB, and LDL-C are independent risk factors for moderate to severe fatty liver in T2DM patients.

Role of Thioredoxin-Interacting Protein in Diabetic Fatty Kidney Induced by Advanced Glycation End-Products.

Advanced glycation end-products (AGEs) have been identified as the etiological factors associated with the fatty kidney. Thioredoxin-interacting protein (TXNIP) might be a mediator involved in AGE-induced fatty kidney. This study focused on investigating how TXNIP affected the AGE-mediated renal lipid deposition. In an in vivo experiment, the db/db mice injected with the lentiviral vector encoding shRNA targeting TXNIP were given the AIN-76 basal or the high-AGE diet. TXNIP-targeting siRNA-transfected human renal proximal tubular epithelial (HK-2) cells were exposed to AGE-BSA in a study in vitro. The results showed that the silencing of TXNIP reduced tubular lipid droplets and intracellular cholesterol content, as well as upregulated Insig-1 and downregulated HMGCoAR, LDLr, nSREBP-2, and SCAP in the kidneys of the db/db mice, the high-AGE-diet-fed db/db mice, and AGE-BSA-treated HK-2 cells. Furthermore, AGE-BSA enhanced SCAP-SREBP-2 complex formation while promoting their transportation to the Golgi apparatus. However, these could be inhibited by TXNIP silencing in the HK-2 cells. The above findings indicated that TXNIP knockdown mitigated the accumulation of renal tubular lipids in diabetes through the regulation of SCAP, thereby inhibiting the SCAP-SREBP-2 signaling pathway, resulting in reduced cholesterol uptake and synthesis. Therefore, TXNIP might be a potential therapeutic target to treat a diabetic fatty kidney.

Effect of a Novel Macrophage-Regulating Drug on Wound Healing in Patients With Diabetic Foot Ulcers: A Randomized Clinical Trial.

Importance: Delayed healing of diabetic foot ulcers (DFUs) is known to be caused by dysregulated M1/M2-type macrophages, and restoring the balance between these macrophage types plays a critical role in healing. However, drugs used to regulate M1/M2 macrophages have not yet been studied in large randomized clinical trials. Objective: To compare the topical application of ON101 cream with use of an absorbent dressing (Hydrofiber; ConvaTec Ltd) when treating DFUs. Design, Setting, and Participants: This multicenter, evaluator-blinded, phase 3 randomized clinical trial was performed in 21 clinical and medical centers across the US, China, and Taiwan from November 23, 2012, to May 11, 2020. Eligible patients with debrided DFUs of 1 to 25 cm2 present for at least 4 weeks and with Wagner grade 1 or 2 were randomized 1:1 to receive ON101 or control absorbent dressings. Interventions: Twice-daily applications of ON101 or a absorbent dressing changed once daily or 2 to 3 times a week for 16 weeks, with a 12-week follow-up. Main Outcomes and Measures: The primary outcome was the incidence of complete healing, defined as complete re-epithelialization at 2 consecutive visits during the treatment period assessed on the full-analysis set (FAS) of all participants with postrandomization data collected. Safety outcomes included assessment of the incidences of adverse events, clinical laboratory values, and vital signs. Results: In the FAS, 236 eligible patients (175 men [74.2%]; mean [SD] age, 57.0 [10.9] years; mean [SD] glycated hemoglobin level, 8.1% [1.6%]) with DFUs classified as Wagner grade 1 or 2 (mean [SD] ulcer area, 4.8 [4.4] cm2) were randomized to receive either the ON101 cream (n = 122) or the absorbent dressing (n = 114) for as long as 16 weeks. The incidence of complete healing in the FAS included 74 patients (60.7%) in the ON101 group and 40 (35.1%) in the comparator group during the 16-week treatment period (difference, 25.6 percentage points; odds ratio, 2.84; 95% CI, 1.66-4.84; P < .001). A total of 7 (5.7%) treatment-emergent adverse events occurred in the ON101 group vs 5 (4.4%) in the comparator group. No treatment-related serious adverse events occurred in the ON101 group vs 1 (0.9%) in the comparator group. Conclusions and Relevance: In this multicenter randomized clinical trial, ON101 exhibited better healing efficacy than absorbent dressing alone in the treatment of DFUs and showed consistent efficacy among all patients, including those with DFU-related risk factors (glycated hemoglobin level, ≥9%; ulcer area, >5 cm2; and DFU duration, ≥6 months). Trial Registration: ClinicalTrials.gov Identifier: NCT01898923.

Effectiveness of companion-intensive multi-aspect weight management in Chinese adults with obesity: a 6-month multicenter randomized clinical trial.

BACKGROUND: Obesity is a globally increasing health epidemic requiring early lifestyle intervention. Our main objective was to examine the effectiveness of companion-intensive multi-aspect weight management (CIMWM) in Chinese adults with obesity. METHODS: In this 6-month, prospective, open-label, multicenter, randomized controlled clinical trial, we recruited 272 obese adults aged 18-50 years with a body mass index (BMI) ≥ 28.0 kg/m2 and capable of using smartphones. CIMWM (n = 136) offered both daily online instructions and monthly face-to-face guidance by physicians, dietitians, and health managers along with the provision of meal replacements in the first 3 months. Traditional multi-aspect weight management (TMWM, n = 136) provided monthly face-to-face guidance by the same panel of professionals and the same meal replacements as CIMWM group, but required subjects to complete daily self-monitoring instead of offering daily online instructions. Body composition and metabolic parameters were assessed at baseline, 1, 2, 3, and 6 months by physicians. The primary outcomes were clinically-significant weight loss and changes in BMI and body composition. RESULTS: Participants in both groups showed significantly reduced BMI, body fat mass (BFM), visceral fat area (VFA), and HOMA-IR (p < 0.05). CIMWM was shown to be superior to TMWM in the improvement of clinically-significant weight loss, BMI, total cholesterol (TC), the body composition parameters BFM and the skeletal muscle mass-to-visceral fat area ratio (S/V) (p < 0.05). The non-alcoholic fatty liver disease score (NFS) was negatively related to S/V at baseline. After weight management, NFS was lowered among individuals with levels in the highest tertile (p < 0.05). Metabolic memory in terms of the continuous reduction of BMI, BFM, and TC was retained up to 6 months in spite of participants transferring to self-monitoring assessment in the final 3 months. CONCLUSIONS: The CIMWM strategy in obese Chinese adults is proved to be more effective than TMWM in weight loss, and motivates greater adherence to intervention and lifestyle reprogramming. Trial registration Chinese Clinical Trial Registry, ChiCTR1800017463, Registered July 31, 2018. http://www.chictr.org.cn/showproj.aspx?proj=29649 .