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.

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.

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.

Association of serum Cyr61 levels with peripheral arterial disease in subjects with type 2 diabetes.

BACKGROUND: The prevalence of peripheral artery disease (PAD) is obviously increased in patients with diabetes. Existing evidence shows that cysteine-rich angiogenic inducer 61 (Cyr61), a 40-kD secreted protein, plays important roles in regulating cellular physiological processes. Recent studies have demonstrated a significant correlation between serum Cyr61 and atherosclerosis. However, the relationship between Cyr61 levels and PAD in patients with type 2 diabetes (T2DM) remains obscure. METHODS: Data from a total of 306 subjects with T2DM were cross-sectionally analysed. The extent of PAD was determined by using the Fontaine classification, which defines four stages. We measured serum Cyr61 concentrations by ELISA in subjects with and without PAD at Fontaine's stage II, III, or IV. Logistic regression models were used to examine the independent association of Cyr61 with PAD. RESULTS: Out of the 306 subjects enrolled, 150 were free from PAD, while 156 had clinically significant PAD. In subjects with PAD, the prevalences of Fontaine classification stages II, III and IV were 48.7%, 32.1%, and 19.2%, respectively. Patients with more advanced PAD had significantly higher Cyr61 (P for trend < 0.001). The prevalence of PAD on the basis of severity increased with increasing Cyr61 quartiles (all P values for trends < 0.001), and the severity of PAD was positively correlated with Cyr61 quartiles (r = 0.227, P = 0.006). The association of Cyr61 levels with PAD remained after adjusting for major risk factors in a logistic regression analysis. CONCLUSIONS: Our results demonstrated that Cyr61 was significantly increased in PAD patients with T2DM and that Cyr61 levels were positively associated with disease severity. Cyr61 could be a promising biomarker and further studies are needed to assess its clinical utility.

Milk in the prevention and management of type 2 diabetes: The potential role of milk proteins.

Globally, diabetes mellitus is not only considered a leading cause of mortality and morbidities but has also created a substantial economic burden. There is growing evidence that foods and their components can be implemented in the prevention and management of type 2 diabetes mellitus (T2DM). Increased dairy consumption has been linked to a lower risk of T2DM. The protective role of dairy foods in the development of T2DM is thought to be largely attributable to dairy nutrients, one of them being dairy protein. There is considerable evidence that milk proteins increase the postprandial insulin response and lower the postprandial blood glucose response in both healthy subjects and patients with T2DM. The exact mechanisms by which milk proteins lower postprandial glucose levels are yet to established; however, the amino acids and bioactive peptides derived from milk proteins are thought to modify a physiological milieu, which includes delayed gastric emptying and the enhancement of incretin and insulin responses, consequently leading to lower postprandial glucose levels. The present review will focus on providing a clear presentation of the potential implementation of milk proteins as a dietary supplement in the prevention and management of T2DM by summarizing the relevant supporting evidence for this particular topic.

Comparative effect of saxagliptin and glimepiride with a composite endpoint of adequate glycaemic control without hypoglycaemia and without weight gain in patients uncontrolled with metformin therapy: Results from the SPECIFY study, a 48-week, multi-centre, randomized, controlled trial.

AIMS: To compare the efficacy and safety of saxagliptin and glimepiride in type 2 diabetes (T2D) patients who are inadequately controlled with metformin monotherapy. MATERIALS AND METHODS: In this 48-week, multi-centre, open-label, randomized, parallel trial (NCT02280486, clinicaltrials.gov), a total of 388 T2D patients were randomized 1:1 to saxagliptin or glimepiride groups. The primary endpoint was achievement of HbA1c <7.0%, without hypoglycaemia, defined as blood glucose <3.9 mmol/L and weight gain <3.0% after 48 weeks of treatment. RESULTS: Over 48 weeks, a greater proportion of patients achieved the primary endpoint with saxagliptin compared with glimepiride (43.3% vs 31.3%; odds ratio, 1.38, 95% CI, 1.05-1.82; P = 0.019), especially among patients with baseline HbA1c <8.0%, duration <5 years or baseline BMI ≥25 kg/m2 . Mean reduction in HbA1c was similar in the two treatment groups at Week 48 (-0.94% with saxagliptin vs -0.98% with glimepiride; P = 0.439). Bodyweight decreased with saxagliptin, but increased with glimepiride over the treatment period, and the treatment difference was -1.6 kg (P < 0.001) at Week 48. The proportion of patients experiencing hypoglycaemia was much lower with saxagliptin vs glimepiride (3.1% vs 12.8%; P < 0.001). CONCLUSIONS: This study provides evidence that, compared to glimepiride, saxagliptin more effectively achieves a composite endpoint of adequate glycaemic control without hypoglycaemia and without weight gain in T2D patients who are inadequately controlled with metformin monotherapy, especially in overweight patients with moderate hyperglycaemia and a relatively short duration of diabetes.

Hypothalamic POMC expression is required for peripheral insulin action on hepatic gluconeogenesis through regulating STAT3 in sepsis rats.

Liver injury and dysregulated glucose homoeostasis are common manifestations during sepsis. Although plenty of studies reported insulin could protect against multiple organ injuries caused by critical infections among patients, little was known about the precise mechanism. We investigated whether liver inflammatory pathway and central neuropeptides were involved in the process. In sepsis rats, hepatic IKK/NF-κB pathway and STAT3 were strongly activated, along with reduced body weight, blood glucose and suppressed hepatic gluconeogenesis (GNG). Peripheral insulin administration efficiently attenuated liver dysfunction and glucose metabolic disorders by suppressing hypothalamic anorexigenic neuropeptide proopiomelanocortin (POMC) expression, hepatic NF-κB pathway and STAT3 phosphorylation. Furthermore, knockdown of hypothalamic POMC significantly diminished protective effect of insulin on hepatic GNG and insulin-induced STAT3 inactivation, but not inflammation or IKK/NF-κB pathway. These results suggest that hepatic IKK/NF-κB pathway mediates the anti-inflammatory effect of insulin in septic rats, and peripheral insulin treatment may improve hepatic GNG by inhibiting STAT3 phosphorylation dependent on hypothalamic POMC expression.

Effects of FGF-23-mediated ERK/MAPK signaling pathway on parathyroid hormone secretion of parathyroid cells in rats with secondary hyperparathyroidism.

This study is supposed to investigate the effect of FGF-23 on parathyroid hormone (PTH) secretion through ERK/MAPK signaling pathway in secondary hyperparathyroidism (SHPT) rat model. Thirty rats were equally served as the normal and SHPT groups. After transfection, parathyroid cells was assigned into blank, NC, pcDNA3.1-FGF-23, siRNA-FGF-23, U0126, and siRNA-FGF-23 + U0126 groups. The serum levels of Calcium (Ca), Phosphorus (P), alkaline phosphatase (ALP), and PTH were detected. HE and immunohistochemical (IHC) staining were used for the histopathological changes and the FGF-23, EKR1/2, and pEKR1/2 expressions. qRT-PCR and Western blotting were performed to determine the mRNA and protein expression of FGF-23, PTH, MAPK, EKR1/2, and Klotho. The proliferation, apoptosis, and cell cycle were all measured for parathyroid cells by CCK-8 assay, TUNEL staining and Flow cytometry. Compared with the normal group, the SHPT group showed increased serum levels PTH, P, ALP, and FGF-23 and mRNA and protein expressions of FGF-23 and PTH, whereas declined Ca and p-ERK1/2 expression, mRNA and protein expression of Klotho, cell apoptosis rate was reduced. Furthermore, compared to the blank and NC groups, the pcDNA3.1-FGF-23 and U0126 groups had a decreased mRNA expression of Klotho, protein expression of EKR1/2 and Klotho, and cell apoptosis rate was down-regulated, whereas the RNA and protein expressions of FGF-23 and PTH were up-regulated, and cell proliferation was elevated. The opposite results were observed in the siRNA-FGF-23 group. Our study demonstrated that FGF-23 could inhibit signaling transduction of ERK/MAPK pathway and accelerate the secretion of PTH in rats with SHPT.

Body fatness at an early age and risk of colorectal cancer.

While there is convincing evidence that excess body fatness in adulthood is positively associated with colorectal cancer risk, the association between body fatness at an early age (≤30 years) and the risk of colorectal cancer has been equivocal. The present meta-analysis was performed to clarify this association. PubMed and Web of Science databases were searched for relevant studies that investigated this association. The risk estimates from each study were transformed into a continuous variable for each 5 kg/m2 increase in body mass index (BMI). A random effects model was used to calculate the summary relative risks (RRs) with 95% confidence intervals (CIs). A total of 15 observational studies (13 cohort studies and two case-control studies) were included in this meta-analysis. Each 5 kg/m2 increase in BMI was significantly associated with a 13% (RR 1.13, 95% CI 1.08, 1.19), 17% (RR 1.17, 95% CI 1.09, 1.25) and 8% (RR 1.08, 95% CI 1.04, 1.11) higher risk of colorectal cancer overall, in men, and in women, respectively. Substantial heterogeneity was observed across studies. Based on the anatomic subsite, each 5 kg/m2 increase in BMI was significantly associated with a 14% (RR 1.14, 95% CI 1.07, 1.22) higher risk of colon cancer, whereas no association (RR 1.03, 95% CI 0.95, 1.13) was observed with rectal cancer. In summary, body fatness at an early age may affect colon cancer risk later in life. Prevention of overweight and obesity in young individuals should be emphasized to prevent early-onset colon cancer attributed to excess body fatness.

Comparison of Ultrasound-Guided Percutaneous Polidocanol Injection Versus Percutaneous Ethanol Injection for Treatment of Benign Cystic Thyroid Nodules.

OBJECTIVES: We compared the efficacy, safety, and cost-effectiveness of ultrasound-guided percutaneous polidocanol injection and percutaneous ethanol injection for the treatment of benign cystic and predominantly cystic thyroid nodules. METHODS: A total of 135 cystic thyroid nodules treated by percutaneous ethanol injection and 136 cystic thyroid nodules treated by percutaneous polidocanol injection were enrolled retrospectively in this study from May 2010 to March 2016. The nodules were followed after 1, 3, 6, and 12 months. Nodule volumes, symptoms scores, and cosmetic scores were assessed before treatment and at follow-up. The therapeutic success rate, safety, and cost-effectiveness between the groups were also compared. RESULTS: No significant differences in the reduction of the nodule volume, volume reduction rate, and therapeutic success were observed between the groups with cystic and predominantly cystic thyroid nodules during follow-up (P > .05). Neither the cosmetic scores (P = .59; P = .42) nor the symptom scores (P = .32; P = .73) in the cystic and predominantly cystic nodules were significantly different between the groups at the last follow-up. The complication rates for ethanol were higher than those for polidocanol (P < .05). However, the cost of polidocanol injection was higher than that of ethanol injection for cystic thyroid nodules (mean ± SD, US$97.18 ± US$22.17 versus US$43.36 ± US$5.51; P < .01). CONCLUSIONS: Ultrasound-guided percutaneous polidocanol injection can be an alternative for sclerotherapy of cystic or predominantly cystic thyroid nodules. However, its cost was higher than that of percutaneous ethanol injection.

US-guided percutaneous microwave ablation for the treatment of benign thyroid nodules.

The aim of this study was to define the effectiveness and safety of ultrasound(US)-guided percutaneous microwave ablation(MWA) for benign thyroid nodules with one session treatment. A total 121 benign thyroid nodules in 100 euthyroid patients underwent MWA in one medical center between August 2014 and December 2015. MWA was performed with an internally cooled antenna under local anesthesia. The volume of the nodule, cosmetic score and symptom score were compared before and after the procedure. The volume reduction rate(VRR) was also evaluated. The side effects and complications were observed. As a result, microwave ablation was associated with a significant decrease in nodule volume{1.05±1.05mL (0.08~4.33mL)vs 8.56±4.21mL(4.05~22.66mL), p <0.001} at 12-month follow-up. The largest diameter was also decreased {1.36±0.53cm(0.60~3.73cm) vs 2.94±0.55cm(2.00~4.40cm) , p<0.001}. The symptom score and cosmetic score were decreased significantly after the procedure(1.71±0.68 vs 3.31±1.13, p<0.001; 1.16±0.37 vs 2.37±0.94, p<0.001). The VRR was 57.66±22.95%, .70.23±20.07%, 85.97±14.04% at 3-, 6- and 12-month follow-up after ablation , respectively. Two patients(2.0%) experienced hoarseness and recovered within 2 months. Two patients(2.0%) developed slight burn on cervical skin. One case(1%) developed Horner Syndrome, recovered within 2 months. Ultrasound-guided percutaneous microwave ablation developed significant volume reduction on benign thyroid nodules, with achieving improvement in symptom score and cosmetic grading. The treatment was well tolerated.

Calcium intake and breast cancer risk: meta-analysis of prospective cohort studies.

Findings from observational studies have suggested a possible relation between Ca and breast cancer risk. However, the results of these studies are inconclusive, and the dose-response relationship between Ca intake and risk of breast cancer remains to be determined. A meta-analysis of prospective studies was conducted to address these issues. PubMed and Embase databases were searched for relevant studies concerning the association between Ca intake and breast cancer up to March 2016. The summary relative risks (RR) with 95 % CI were calculated with a random-effects model. The final analysis included eleven prospective cohort studies involving 26 606 cases and 872 895 participants. The overall RR of breast cancer for high v. low intake of Ca was 0·92 (95 % CI 0·85, 0·99), with moderate heterogeneity (P=0·026, I 2=44·2 %). In the subgroup analysis, the inverse association appeared stronger for premenopausal breast cancer (RR 0·75; 95 % CI 0·59, 0·96) than for postmenopausal breast cancer (RR 0·94; 95 % CI 0·87, 1·01). Dose-response analysis revealed that each 300 mg/d increase in Ca intake was associated with 2 % (RR 0·98; 95 % CI 0·96, 0·99), 8 % (RR 0·92; 95 % CI 0·87, 0·98) and 2 % (RR 0·98; 95 % CI 0·97, 0·99) reduction in the risk of total, premenopausal and postmenopausal breast cancer, respectively. Our findings suggest an inverse dose-response association between Ca intake and risk of breast cancer.

PRDX1 is involved in palmitate induced insulin resistance via regulating the activity of p38MAPK in HepG2 cells.

Studies have identified that type 2 diabetes mellitus (T2DM) patients displayed higher levels of plasma peroxiredoxin1(PRDX1) than non-diabetics. However, the impact of PRDX1 on insulin resistance and the underlying mechanism remains totally unknown. Here, we investigated the influence of PRDX1 on hepatic insulin resistance. We showed that the protein and mRNA levels of PRDX1 were significantly elevated under insulin-resistant conditions. In addition, we showed that interference of PRDX1 ameliorated palmitate-induced insulin resistance in HepG2 cells, which was indicated by elevated phosphorylation of protein kinase B (AKT) and of glycogen synthase kinase-3 (GSK3ß). Furthermore, the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), two key gluconeogenic enzymes, were down-regulated following PRDX1 depletion. Accordingly, glucose uptake was suppressed in PRDX1-interferred HepG2 cells. In addition, Over-expression of PRDX1 enhanced PA-induced insulin resistance in HepG2 cells. Moreover, we found that knocking down PRDX1 improves insulin sensitivity and decreased the activation of p38 mitogen-activated protein kinase (p38MAPK). Our results demonstrate that PRDX1 can induce hepatic insulin resistance by activating p38MAPK signaling and identifies potential targets for new treatments.

Correlation between circulating advanced glycation end products and thioredoxin-interacting protein levels and renal fat content in type 2 diabetes mellitus patients.

BACKGROUND: This study sought to explore the clinical relevance of the associations of serum levels of advanced glycation end products (AGEs), soluble receptor for AGEs (sRAGE), and thioredoxin-interacting protein (TXNIP) with the renal fat fraction (RFF) in individuals with type 2 diabetes mellitus (T2DM). METHODS: A total of 133 patients with T2DM were enrolled in the study. RFF, which represents the renal fat level, was determined utilizing Dixon magnetic resonance imaging (MRI). Serum levels of AGEs, sRAGE, TXNIP, and other biochemical parameters were measured in patients who fasted. RESULTS: RFF in T2DM patients was positively correlated with the fasting levels of C-peptide (CP), triglycerides (TG), AGEs, TXNIP, and sRAGE (P < 0.05) and negatively correlated with the high-density lipoprotein cholesterol (HDL-c) level (P < 0.05). Pearson's correlation analysis indicated that the serum levels of AGEs, sRAGE, and TXNIP were interrelated and positively correlated (P < 0.05). Then, all patients were assigned to four groups according to the RFF quartile. The HC, CP, TG, AGEs, sRAGE, TXNIP, and DKD percentages tended to increase as the RFF quartiles increased, while the HDL-c level tended to decrease (p for trend < 0.05). Next, multiple linear regression analysis was performed using RFF as the dependent variable. After controlling for covariates related to RFF, the results showed that the serum levels of AGEs and TXNIP were still significantly correlated with RFF. CONCLUSION: These results suggest that circulating AGEs and TXNIP levels may be associated with ectopic fat accumulation in the kidneys of T2DM patients and may serve as indicators of the severity of renal fat deposition.

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.

Tribbles pseudokinase 3 promoted renal fibrosis by regulating the expression of DNA damage-inducible transcript 3 in diabetic nephropathy.

Diabetic nephropathy (DN) is a severe complication of prolonged diabetes, impacting millions worldwide with an increasing incidence. This study investigates the role of tribbles pseudokinase 3 (TRIB3), a protein implicated in the progression of DN, focusing on its mechanisms underlying glomerular damage. Through analysis of the Gene Expression Omnibus (GEO) database, we identified TRIB3 among differentially expressed genes in streptozotocin (STZ)-treated C57BL/6J mice. Both in vitro and in vivo experiments were conducted to examine the effects of TRIB3 inhibition on high glucose (HG)-induced damage in podocytes and DN mouse models. The results demonstrated that TRIB3 inhibition reduced inflammatory responses and extracellular matrix (ECM) production in MPC5 cells, mediated by the downregulation of DNA damage-inducible transcript 3 (DDIT3) - a critical regulator of proinflammatory cytokine secretion and ECM synthesis. Inhibiting TRIB3 decreased inflammatory factors and ECM deposition in diabetic mice in vivo, confirming its pivotal role in DN pathogenesis. These findings indicate that TRIB3 and its interaction with DDIT3 contribute significantly to DN by promoting inflammatory cascades and ECM accumulation, presenting potential therapeutic targets for managing the disease.

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.

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.

Effects of ON101 for Hard-to-Heal Diabetic Foot Ulcers in A Randomized Phase III Trial: A Post hoc Analysis.

OBJECTIVE: Hard-to-heal diabetic foot ulcers (DFUs) are associated with higher mortality rates and an increased medical burden for patients. ON101, a new topical cream, exhibited better healing efficacy than the control dressing in a Phase III trial. In this post-hoc analysis, we further identify whether ON101 can improve the healing of ulcers with hard-to-heal risk factors in this cohort of DFU patients. APPROACH: To compare the efficacy of ON101 with absorbent dressing among various hard-to-heal wounds in patients with DFU, a post hoc analysis of a randomized phase III trial included 276 DFU patients was performed by subgrouping those patients based on ulcer depth, location, size, duration, and patients' glycated hemoglobin (HbA1c) levels and body mass index (BMI). RESULTS: In the full analysis set, the proportion of patients achieving healing was 61.7% in the ON101 group and 37.0% in the comparator (P =0.0001). In sub-group analysis according to risk factors, ON101 demonstrated superior healing capacity on Wagner grade 2 ulcers (P < 0.0001); plantar ulcers (P = 0.0016), ulcers size ≥5 cm² (P = 0.0122), ulcers duration ≥3 months (P = 0.0043); for patients with HbA1c ≥9% (P = 0.0285); and patients with BMI ≥25 (P = 0.0005). INNOVATION: ON101, a novel therapeutic drug, can modulate the functions of macrophages and demonstrate superior healing rates to conventional absorbent dressing in patients with hard-to-heal DFUs. CONCLUSIONS: The results of this post hoc study suggest that ON101 is a better therapeutic option than conventional dressing used in treatment for DFU patients with higher HbA1c, BMI, or ulcers with complex conditions such as longer duration, deeper wounds, larger size, and plantar location.