High Urine Albumin-to-Creatinine Ratio is Associated with Increased Arterial Stiffness in Diabetes: A Chinese Cross-Sectional Study.

Purpose: Elevated urine albumin-to-creatinine ratio (UACR) is an established risk factor for microvascular disease in the general population. However, it is unclear whether UACR is associated with arterial stiffness in diabetes. We aimed to assess the relationship between UACR levels and the risk of arterial stiffness in patients with diabetes. Methods: From July 2021 to February 2023, a total of 1039 participants were assessed for the risk of arterial stiffness, which was evaluated by brachial-ankle pulse wave velocity (baPWV). The value of UACR≥30 mg/g was defined as high UACR. The UACR level had an abnormal distribution and was log2-transformed for analyses to reduce skewness and volatility. High baPWV was evaluated as categorical variables divided by the highest quartile of the values by sex. The relationship between UACR and arterial stiffness was analyzed by linear curve fitting analyses. Multiple logistic regression models were used to analyze the crude and adjusted odds ratio (OR) of UACR for high baPWV with 95% confidence interval (CI). In addition to applying non-adjusted and multivariate-adjusted models, interaction and stratified analyses were also carried out. Results: The baPWV level was significantly higher in the high UACR group compared with that in the normal UACR group (1861.84 ± 439.12 cm/s vs 1723.13 ± 399.63 cm/s, p<0.001). Adjusted smoothed plots suggested that there are linear relationships between log2-transformed UACR and high baPWV, and Spearman correlation coefficient was 0.226 (0.176-0.276, p<0.001). The OR (95% CI) between log2-transformed UACR and high baPWV were 1.26 (1.19-1.33, p<0.001), and 1.16 (1.08-1.25, p<0.001) respectively in diabetic patients before and after adjusting for potential confounders. Conclusion: The elevated UACR was associated with arterial stiffness in Chinese patients with diabetes.

1. The mean baPWV level was significantly higher in the high UACR group compared with that in the normal UACR group.2. The sex-specific hierarchical analysis revealed that baPWV levels and the incidence of high baPWV were significantly elevated with increased UACR.3. Curvilinear relationships between log2-transformed UACR and the risk of high baPWV.4. Positive association between UACR and high baPWV in patients with diabetes.

GLP-1 receptor agonist liraglutide inhibits the proliferation and migration of thyroid cancer cells.

This research was done to find out how liraglutide affected the growth and movement of two human thyroid cancer cell lines overexpressing GLP-1 receptor (migration of medullary thyroid cancer TT/GLP-1R and papillary thyroid carcinoma TCP-1/GLP-1R). Flow cytometer and cAMP assays were used to identify the expression and activation of GLP-1R in two stable cell lines. Counting Kit-8 for Cells was applied to examine the proliferative ability of cells in two stable cell lines after treatment with different concentrations of liraglutide at indicated time points. To track the capacity for cell migration, the Transwell test was utilized. We found that liralutide-activated GLP-1R could significantly reduce the growth and metastasis of two kinds of thyroid tumor cells, and the inhibitory effect was dose- and time- dependent. The phosphorylatios of Akt, S6K1, and 70SK declined after receiving liraglutide therapy In our previous studies, we found that the GLP-1 receptor agonist Liraglutide inhibited the proliferation and migration of thyroid cancer cells through the PI3K/Akt/mTOR pathway. This finding provides a theoretical basis for the treatment of diabetes mellitus complicated with medullary thyroid cancer, and is relatively safe.

Dorzagliatin add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial.

Metformin, the first-line therapy for type 2 diabetes (T2D), decreases hepatic glucose production and reduces fasting plasma glucose levels. Dorzagliatin, a dual-acting orally bioavailable glucokinase activator targeting both the pancreas and liver glucokinase, decreases postprandial glucose in patients with T2D. In this randomized, double-blind, placebo-controlled phase 3 trial, the efficacy and safety of dorzagliatin as an add-on therapy to metformin were assessed in patients with T2D who had inadequate glycemic control using metformin alone. Eligible patients with T2D (n = 767) were randomly assigned to receive dorzagliatin or placebo (1:1 ratio) as an add-on to metformin (1,500 mg per day) for 24 weeks of double-blind treatment, followed by 28 weeks of open-label treatment with dorzagliatin for all patients. The primary efficacy endpoint was the change in glycated hemoglobin (HbA1c) levels from baseline to week 24, and safety was assessed throughout the trial. At week 24, the least-squares mean change from baseline in HbA1c (95% confidence interval (CI)) was -1.02% (-1.11, -0.93) in the dorzagliatin group and -0.36% (-0.45, -0.26) in the placebo group (estimated treatment difference, -0.66%; 95% CI: -0.79, -0.53; P < 0.0001). The incidence of adverse events was similar between groups. There were no severe hypoglycemia events or drug-related serious adverse events in the dorzagliatin and metformin combined therapy group. In patients with T2D who experienced inadequate glycemic control with metformin alone, dorzagliatin resulted in effective glycemic control with good tolerability and safety profile ( NCT03141073 ).

FOXO3a regulates lipid accumulation and adipocyte inflammation in adipocytes through autophagy : Role of FOXO3a in obesity.

BACKGROUND: FOXO3a is a widely studied transcription factor and plays an important role in a variety of biology. The purpose of this study was to explore the role and potential mechanism of FOXO3a on lipid accumulation and adipocyte inflammation in adipocytes through regulation of autophagy. METHODS: The obese mouse model was successfully induced by high-fat diet. SiRNA targeting FOXO3a was transfected into differentiation of 3T3-L1 adipocytes to reduce the expression of FOXO3a. The culture medium of RAW264.7 cells was added to the differentiated 3T3-L1 adipocytes to form a co-culture system. Subsequently, ELISA or AdipoRed assay was performed to measure the expression of triglyceride (TG) and cholesterol (TC) in mouse adipose tissue or differentiation of 3T3-L1 adipocytes. Adipocyte differentiation was detected by Oil Red O-staining. Ad-mCherry-GFP-LC3II was used to detect the level of autophagy in differentiation of 3T3-L1 adipocytes. Western blotting or qRT-PCR was used to detect the expression of FOXO3a, autophagy-related proteins (beclin 1, CEBPß, PPARγ, ACC1 and KLF4), inflammatory cytokines (TNF-α, IL-1ß, IL-6 and MCP1), NF-κB signal pathway-related proteins or adipokines (Adiponectin, AdipoR1 and resistin) in differentiated 3T3-L1 or RAW264.7 cells. RESULTS: The expression of FOXO3a and autophagy levels were significantly increased in visceral adipose tissue of obese mice and differentiation of 3T3-L1 adipocytes. Downregulation of FOXO3a significantly inhibited the autophagy and lipid accumulation in differentiation of 3T3-L1 adipocytes. In addition, FOXO3a knockdown significantly reduced Lipopolysaccharide (LPS)-induced inflammation and adipokines release in RAW264.7 cells treated with the culture medium of 3T3-L1 adipocytes. These above activity changes could be reversed by autophagy inducer rapamycin. CONCLUSION: FOXO3a could promote lipid accumulation and inflammation in differentiated 3T3-L1 adipocytes by targeting autophagy. Our results provide a new theoretical basis for FOXO3a to regulate obesity.

Efficacy and safety of chiglitazar, a novel peroxisome proliferator-activated receptor pan-agonist, in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, phase 3 trial (CMAP).

Chiglitazar (Carfloglitazar) is a novel non-thiazolidinedione (TZD) structured peroxisome proliferator-activated receptor (PPAR) pan-agonist that has shown promising effects on glycemic control and lipid regulation in patients with type 2 diabetes in previous clinical studies. This randomized phase 3 trial aimed to compare the efficacy and safety of chiglitazar with placebo in patients with type 2 diabetes with insufficient glycemic control by strict diet and exercise alone. Eligible patients were randomly assigned to receive chiglitazar 32 mg (n = 167), chiglitazar 48 mg (n = 166), or placebo (n = 202) once daily. The primary endpoint was the change in glycosylated hemoglobin A1c (HbA1c) at week 24 with superiority of chiglitazar over placebo. The results showed that both chiglitazar 32 and 48 mg resulted in significant and clinically meaningful reductions in HbA1c, and placebo-adjusted estimated treatment differences at week 24 for chiglitazar 32 and 48 mg were -0.87% (95% confidential interval (CI): -1.10 to -0.65; P < 0.0001) and -1.05% (95% CI: -1.29 to -0.81; P < 0.0001), respectively. Secondary efficacy parameters including glycemic control, insulin sensitivity and triglyceride reduction were also significantly improved in the chiglitazar groups. The overall frequency of adverse events and study discontinuation attributable to adverse events were similar among the groups. Low incidences of mild edema and body weight gain were reported in the chiglitazar dose groups. The results from this phase 3 trial demonstrated that the PPAR pan-agonist chiglitazar possesses an overall good efficacy and safety profile in patients with type 2 diabetes inadequately controlled with lifestyle interventions, thereby providing adequate supporting evidence for using this PPAR pan-agonist as a treatment option for type 2 diabetes.

Roles of SHARP1 in thyroid cancer.

SHARP1 is a basic helix­loop­helix transcription factor involved in various cellular processes, including proliferation and differentiation. The present study assessed the role of SHARP1 in the progression and invasion of thyroid cancer. PCR and western blot analysis demonstrated that in thyroid cancer tissues, SHARP1 was significantly downregulated at the mRNA and protein level compared with that in normal tissues. Furthermore, SHARP1 was downregulated in the TT and TPC­1 thyroid cancer cell lines compared with a normal thyroid cell line, while it was upregulated in other thyroid cancer cell lines. Overexpression of SHARP1 in TT and TPC­1 cells significantly inhibited the cell viability, migration and invasion in vitro. Furthermore, the protein and mRNA levels of HIF­1α were found to be decreased in TT and TPC­1 cells following forced overexpression of SHARP1. In addition, silencing of HIF­1α reduced the viability, migration and invasion of TT and TPC-1 cells. In conclusion, the present study indicated that SHARP1 acts as a tumor suppressor in thyroid cancer and that its downregulation may contribute to the proliferation, migration and invasion of thyroid cancer cells through mechanisms possibly involving HIF­1α, suggesting that SHARP1 may be an important therapeutic target for the treatment of thyroid cancer.