Changes in serum tumor markers in type 2 diabetes mellitus with microalbuminuria.

Objectives: The objective of this study was to investigate changes in serum tumor markers in type 2 diabetes mellitus (T2DM) with microalbuminuria and analyze the relationship between tumor markers and microalbuminuria. Methods: A total of 956 T2DM patients aged 40-70 years hospitalized in the Department of Endocrinology, Xinhua Hospital, China, affiliated with Shanghai Jiaotong University School of Medicine, were enrolled from January 2018 to December 2020. The sample comprised 313 T2DM patients with microalbuminuria and 643 T2DM patients with normal urinary microalbumin levels. After assessing the changes in serum tumor markers in T2DM with microalbuminuria, we analyzed the risk of microalbuminuria by the serum tumor marker category using multiple logistic regression analysis. Results: Serum CEA, CA199, CA125, CA153, CA211, SCC, CA242, and CA50 levels were significantly higher in T2DM patients with microalbuminuria than in those without microalbuminuria, while serum AFP levels were lower in the microalbuminuria group (P < 0.05). Following adjustment of confounders, serum CEA, CA211, and SCC were independently associated with microalbuminuria in T2DM. An ROC curve was used to estimate the cutoff point of tumor markers for microalbuminuria. Taking the values under the cutoff points as a reference, values for CEA, CA211, and SCC above the cutoff points indicated a significantly high risk of microalbuminuria. The OR of increased CEA for microalbuminuria was 2.006 (95%CI 1.456-2.765), the OR of increased CA211 for microalbuminuria was 1.505 (95%CI 1.092-2.074), and the OR of increased SCC for microalbuminuria was 1.958 (95%CI 1.407-2.724). Conclusion: Several serum tumor markers were related to microalbuminuria in T2DM. Serum tumor markers such as CEA, SCC, and CA211 may indicate early diabetic nephropathy, particularly when elevated in combination.

In-depth urinary and exosome proteome profiling analysis identifies novel biomarkers for diabetic kidney disease.

Diabetic kidney disease (DKD) is a major microvascular complication of type 2 diabetes mellitus (T2DM). Monitoring the early diagnostic period and disease progression plays a crucial role in treating DKD. In this study, to comprehensively elucidate the molecular characteristics of urinary proteins and urinary exosome proteins in type 2 DKD, we performed large-scale urinary proteomics (n=144) and urinary exosome proteomics (n=44) analyses on T2DM patients with albuminuria in varying degrees. The dynamics analysis of the urinary and exosome proteomes in our study provides a valuable resource for discovering potential urinary biomarkers in patients with DKD. A series of potential biomarkers, such as SERPINA1 and transferrin (TF), were detected and validated to be used for DKD diagnosis or disease monitoring. The results of our study comprehensively elucidated the changes in the urinary proteome and revealed several potential biomarkers reflecting the progression of DKD, which provide a reference for DKD biomarker screening.

Inhibition of Arid1a increases stem/progenitor cell-like properties of liver cancer.

ARID1A, a key subunit of the SWI/SNF chromatin remodeling complex, exhibits recurrent mutations in various types of human cancers, including liver cancer. However, the function of ARID1A in the pathogenesis of liver cancer remains controversial. Here, we demonstrate that Arid1a knockout may result in states of different cell differentiation, as indicated by single-cell RNA sequencing (scRNA-seq) analysis. Bulk RNA-seq also revealed that Arid1a deficiency upregulated these genes related to cell stemness and differentiation, but downregulated genes related to the hepatic functions. Furthermore, we confirmed that deficiency of Arid1a increased the expression of hepatic stem/progenitor cell markers, such as Cd133 and Epcam, and enhanced the self-renewal ability of cells. Mechanistic studies revealed that Arid1a loss remodeled the chromatin accessibility of some genes related to liver functions. Thus, Arid1a deficiency might contribute to cancer development by increasing the number of stem/progenitor-like cells through dysregulating the expression of these genes related to cell stemness, differentiation and liver functions.

The Impact of Village Rules and Formal Environmental Regulations on Farmers' Cleaner Production Behavior: New Evidence from China.

Village rules and formal environmental regulations are of great significance for standardizing farmers' cleaner production behavior, promoting green transformation of agriculture and realizing sustainable development of agriculture. Based on the survey data of 946 farmers in five provinces of China, taking seed coating technology, soil testing and formulated fertilization technology, subsoiling tillage technology, green technology for pest and disease control and straw returning technology as examples, this article empirically analyzes the impact of village rules and formal environmental regulations on farmers' cleaner production behavior by using the multivariate probit model. When formal environmental regulations are relatively lacking or weak, village rules can be used as a useful supplement to formal environmental regulations to promote farmers' participation in cleaner production. Based on this, this article argues that the important reason for formal environmental regulations falling into relative system failure is that village rules have not been paid enough attention in promoting farmers' cleaner production behavior. In the future, we should not only continue to strengthen the role of formal environmental regulations in farmers' cleaner production, but also cultivate the informal institution represented by the village rules, and build the regulatory system of mutual support between informal institution and formal institution.

BoxCar increases the depth and reproducibility of diabetic urinary proteome analysis.

PURPOSE: Mass spectrometry-based proteomics performs well in high throughput detection of urinary proteins. Nonetheless, protein identification depth and reproducibility remain the challenges in diabetic urinary proteome with high complexity and broad dynamic range, especially for low-abundant proteins. As a new data acquisition strategy, the BoxCar method was reported to benefit for low-abundant protein identification. Whether it is propitious to diabetic samples with high dynamic range proteomes has not been discussed yet. We aimed to apply BoxCar method to diabetic urine sample analysis, and to compare it with standard data dependent acquisition (DDA) method on protein identification in detail. EXPERIMENTAL DESIGN: We performed seven technical replicates analysis on two urine samples from healthy individuals and diabetic patients to evaluate protein detection of BoxCar and standard DDA methods on single sample. Further comparison of two methods was made on multiple diabetic urine samples. RESULTS: BoxCar could increase over 20% of identified proteins and performed better quantitative reproducibility than standard DDA method either in single or multiple diabetic urinary samples. BoxCar also improved the detection of low-abundant proteins. Functional enrichment analysis of normal albuminuria or microalbuminuria samples indicated that BoxCar acquired more diabetes-related biological information. CONCLUSIONS AND CLINICAL RELEVANCE: The study demonstrates that BoxCar could enhance the depth and reproducibility in diabetic urinary proteome analysis, which provides reference for mass spectrometry approach selection in clinical urinary proteomic research.

Elevated Serum Triglycerides are Associated with Ketosis-Prone Type 2 Diabetes in Young Individuals.

PURPOSE: Ketosis-prone type 2 diabetes (KPT2D) is increasingly recognized in young adults. However, the role of blood lipids in KPT2D, especially serum triglycerides (TGs), is not yet clearly understood. PATIENTS AND METHODS: We retrospectively evaluated 409 young patients diagnosed with KPT2D or classical type 2 diabetes (T2D) attending an academic tertiary hospital. Clinical characteristics and laboratory findings were compared between KPT2D and T2D patients. ANOVA or a non-parametric test analyses were used to evaluate differences in clinical characteristics and laboratory findings. Multivariate regression analyses and stratified analyses were used to further investigate differences in serum TGs levels between KPT2D and T2D individuals. RESULTS: KPT2D is a subtype of T2D with traits of overweight or obesity. However, hyperglycemia and impaired ß-cell functions were more severe in KPT2D patients. Serum TGs levels were significantly higher (P = 0.0003) in KPT2D individuals. Furthermore, the proportion of very high serum TGs levels was 6-fold higher (P < 0.0001) in KPT2D than in T2D patients. Elevated serum TGs were associated with young KPT2D patients. CONCLUSION: Lifestyle changes as well as lipid-lowering treatments might be effective in lowering the incidence of ketosis as well as stabilizing disease progression.

Prevalence and Gender Differences of Metabolic Syndrome in Young Ketosis-Prone Type 2 Diabetic Individuals: A Retrospective Study.

PURPOSE: This study aimed to identify the prevalence and gender differences of metabolic syndrome in young new-onset ketosis-prone type 2 diabetic (KPT2D) individuals. PATIENTS AND METHODS: A retrospective study was conducted in Shanghai Xin Hua Hospital from 2007 to 2019. A total of 304 patients from 12 to 40 years of age with newly diagnosed diabetes presenting with ketosis were analyzed. The clinical features and laboratory results of KPT2D and type 1 diabetic (T1D) individuals were compared. Prevalence and gender differences of metabolic syndrome in the KPT2D subjects were analyzed. RESULTS: The prevalence of metabolic syndrome (P < 0.0001) was significantly higher in young KPT2D than T1D subjects. The prevalence of high blood pressure (P < 0.0001), central obesity (P < 0.0001), low plasma HDL-C concentration (P = 0.045), and hypertriglyceridemia (P < 0.0001) was elevated in the KPT2D subjects compared with T1D. Male predominance (89%) was presented in the KPT2D subjects. The prevalence of metabolic syndrome (P = 0.0002) was significantly higher in young male than female KPT2D subjects. The presence of central obesity (P < 0.0001) and high blood pressure (P =0.03) was higher in male KPT2D subjects than female. The presence of serum triglyceride concentrations ≥ 2.3mmol/L was significantly higher (P = 0.011) in male KPT2D subjects than female. CONCLUSION: Significantly higher prevalence of metabolic syndrome in young KPT2D patients compared with T1D patients could be an important reference for diabetic differential diagnosis. KPT2D presented a higher predominance in young males, who had higher prevalence of metabolic syndrome than young females.

SENP1-mediated deSUMOylation of USP28 regulated HIF-1α accumulation and activation during hypoxia response.

BACKGROUND: The ubiquitin-specific protease 28 (USP28) is an oncogenic deubiquitinase, which plays a critical role in tumorigenesis via antagonizing the ubiquitination and degradation of tumor suppressor protein FBXW7-mediated oncogenic substrates. USP28 controls hypoxia-dependent angiogenesis and metastasis by preventing FBXW7-dependent hypoxia-inducible transcription factor-1α (HIF-1α) degradation during hypoxia. However, it remains unclear how USP28 activation and HIF-1α signaling are coordinated in response to hypoxia. METHODS: The in vitro deubiquitinating activity assay was used to determine the regulation of USP28 by hypoxia. The co-immunoprecipitation and GST Pull-down assays were used to determine the interaction between USP28 and SENP1. The in vivo deSUMOylation assay was performed to determine the regulation of USP28 by SENP1. The luciferase reporter assay was used to determine the transcriptional activity of HIF-1α. RESULTS: Here, we report that USP28 is a SUMOylated protein in normoxia with moderate deubiquitinating activity towards HIF-1α in vitro, while hypoxia and HIF-1α activate USP28 through SENP1-mediated USP28 deSUMOylation to further accumulate HIF-1α protein in cells. In agreement with this, a SUMOylation mutant USP28 showed enhanced ability to increase HIF-1α level as well as control the transcriptional activity of HIF-1α. CONCLUSION: Collectively, our results reveal a novel SENP1-USP28-HIF-1α positive feedback loop to maximize the concentration of HIF-1a protein and amplify its downstream effects during hypoxia response.

ARID1A represses hepatocellular carcinoma cell proliferation and migration through lncRNA MVIH.

ARID1A, encoding the BAF250a subunit of SWI/SNF complex, has a high mutation frequency in numerous types of cancer. LncRNAs, a type of non-coding RNAs longer than 200 nucleotides, have been reported to interplay with SWI/SNF complex during cancer progression. However, whether the interaction between ARID1A and lncRNA affects hepatocellular carcinoma (HCC) still needs to be investigated. Here, we reveal that ARID1A interacts with lncRNA MVIH through some region(s) or domain(s) including ARID domain and C-terminal ARID1A protein binding domain. ARID1A upregulates its downstream target CDKN1A and suppresses HCC cell proliferation and migration through inhibiting MVIH. Our data suggests that deficiency or loss of functional mutations of ARID1A in HCC cells might contribute to the increased activity of certain cancer-promoting lncRNAs.

Comparison between New-Onset and Old-Diagnosed Type 2 Diabetes with Ketosis in Rural Regions of China.

Objectives. Type 2 diabetes (T2D) with ketosis was common because of late diagnosis and lacking adequate treatment in rural regions of China. This study aimed to provide the data of T2D with ketosis among inpatients in a south-west border city of China. Methods. Data of 371 patients of T2D with ketosis who were hospitalized between January 2011 and July 2015 in Baoshan People's Hospital, Yunnan, China, were analyzed. New-onset and old-diagnosed T2D patients presenting with ketosis were compared according to clinical characteristics, laboratory results, and chronic diabetic complications. Results. Overall, the blood glucose control was poor in our study subjects. Male predominated in both groups (male prevalence was 68% in new-onset and 64% in old-diagnosed groups). Overweight and obesity accounted for 50% in new-onset and 46% in old-diagnosed cases. Inducements of ketosis were 13.8% in new-onset and 38.7% in old-diagnosed patients. Infections were the first inducements in both groups. The prevalence of chronic complications of diabetes was common in both groups. Conclusions. More medical supports were needed for the early detection and adequate treatment of diabetes in rural areas of China.

Characteristics of Type 2 Diabetes with Ketosis in Baoshan, Yunnan of China.

OBJECTIVES: The study provided data to demonstrate the characteristics of type 2 diabetes (T2D) with ketosis in rural parts of south-west border of China in order to help health professionals with optimizing diabetic care. METHODS: All hospitalized adult diabetic patients consecutively between January 2011 and July 2015 in Baoshan People's Hospital, Yunnan province of China, were evaluated. T2D with ketosis, ordinary T2D (without ketosis), and type 1 diabetes (T1D) patients were analyzed according to the clinical and biochemical parameters and chronic complications in these subjects. RESULTS: The prevalence of T2D with ketosis was 12% in the whole study subjects. Overweight and obese patients were predominant (49.1%) in T2D patients with ketosis. The mean HbA1c (13.3 ± 3.1%, P = 0.01), fasting plasma glucose (16.9 ± 6 mmol/L, P < 0.0001), and plasma triglyceride (4.0 ± 4.0 mmol/L, P < 0.0001) in T2D patients with ketosis were significantly higher than ordinary T2D patients without ketosis. Infections were the most common inducements in T2D patients with ketosis. Chronic complications including peripheral neuropathy (34.9%), retinopathy (12.7%), diabetic foot (18.1%), and persistent microalbuminuria (11.7%) were common in T2D patients with ketosis. CONCLUSIONS: . This study indicated the poor glycemic control in diabetic patients in rural areas of south-west part of China. More efforts were urgently required to popularize public health education and improve medical quality in diabetic treatment in these regions.

Does Fish Oil Have an Anti-Obesity Effect in Overweight/Obese Adults? A Meta-Analysis of Randomized Controlled Trials.

CONTEXT: Accumulating evidence has suggested favorable effects of fish oil on weight loss in animal experiments; however, findings remain inconsistent in humans. OBJECTS: The meta-analysis was performed to investigate the influence of fish oil on some parameters of body composition in overweight/obese adults. DESIGN: Human randomized, placebo-controlled trials were identified by a systematic search of Embase, PubMed, the Cochrane Library, web of science and reference lists of related reviews and articles. The random-effects model was used to estimate the calculated results. RESULTS: In total, 21 studies with 30 study arms were included in this analysis. Calculated results of the meta-analysis demonstrated that fish oil had no effect on reducing body weight (overall SMD = -0.07, 95% CI -0.21 to 0.07, P = 0.31) and BMI (overall SMD = -0.09, 95% CI -0.22 to 0.03, P = 0.14) whether alone or combined with life modification intervention in overweight/obese subjects. However, waist circumference was significantly reduced (SMD = -0.23, 95% CI -0.40 to -0.06, P = 0.008) in those with fish oil supplementation combined with life modification intervention. Waist hip ratio (WHR) was significantly reduced (overall SMD = -0.52 95% CI -0.76 to -0.27, P < 0.0005) in fish oil supplemented individuals with or without combination life modification intervention. CONCLUSION: Current evidence cannot support an exact anti-obesity role of n-3 polyunsaturated fatty acids (PUFAs) in overweight/obese subjects. However, these subjects may benefit from reducing abdominal fat with fish oil supplementation especially when combined with life modification intervention. Further large-scale and long-term clinical trials are needed to gain definite conclusions.

Trace glucose fluxes in individuals with prediabetes using stable isotopes.

BACKGROUND: The glucose fluxes of individuals with prediabetes in Chinese population are not clear. This study was to determine whether the endogenous glucose production (EGP), oral glucose rate of appearance (Ra) and glucose rate of disappearance (Rd) were different in Chinese individuals with prediabetes under fasting conditions and following an oral glucose challenge. METHODS: Five subjects with type 2 diabetes, 5 subjects with prediabetes and 5 non-diabetic subjects matched for age, weight, fat free mass and body mass index underwent a 180 minute stable glucose isotope tracing ([6, 6-(2)H2] glucose, [1-(13)C] glucose, and [U-(13)C] glucose) study under fasting and after ingestion of a 75 g oral glucose load. Isotope glucose enrichment was measured by gas chromatography-mass spectrometry. Insulin sensitivity was estimated using the oral glucose tolerance test (OGTT)-derived insulin sensitivity index, ß cell function was determined by the insulinogenic index (δI30/δG30). RESULTS: The insulin sensitivity index (P = 0.043) and insulinogenic index (P = 0.021) were decreased in subjects with prediabetes compared with non-diabetes. Fasting EGP was slightly higher (P = 0.29) and postprandial EGP was comparable in subjects with prediabetes and non-diabetes during 120 minutes after glucose ingestion, but nadir EGP occurred later in prediabetic than non-diabetic subjects. Ra did not differ among the three groups. Rd was substantially lower in subjects with prediabetes than non-diabetes after glucose intake (P = 0.013). CONCLUSION: The mild hyperglycemia observed among individuals with prediabetes may result from decreased Rd during the postprandial state.

Effect of ß2-adrenergic receptor polymorphisms on epinephrine and exercise-stimulated lipolysis in humans.

The ß2-adrenergic system is an important regulator of human adipose tissue lipolysis. Polymorphisms that result in amino acid substitutions in the ß2-adrenergic receptor have been reported to alter lipolysis. We hypothesized that variations in the amino acid at position 16 of the ß2-adrenergic receptor would result in different lipolytic responses to intravenous epinephrine and exercise. 17 volunteers homozygous for glycine at position 16 (Gly/Gly, nine female) and 16 volunteers homozygous for arginine at position 16 (Arg/Arg, eight female) of the ß2-adrenergic receptor participated in this study. On one study day participants received infusions of epinephrine at submaximal (5 ng kg(-1) min(-1)) and maximal (40 ng kg(-1) min(-1)) lipolytic doses. The other study day volunteers bicycled for 90 min at 50-60% of maximum oxygen consumption (VO2max). [9,10-(3)H] Palmitate was infused both days to measure free fatty acid - palmitate kinetics. Oxygen consumption was measured using indirect calorimetry. Palmitate release rates in response to epinephrine and exercise were not different in the Gly/Gly and Arg/Arg participants. The only statistically significant difference we observed was a lesser ΔVO2 in Arg/Arg volunteers in response to the submaximal epinephrine infusion. The polymorphisms resulting in Arg/Arg and Gly/Gly at position 16 of the ß2-adrenergic receptor do not result in clinically meaningful differences in lipolysis responses to epinephrine or submaximal exercise.

Tracing fasting glucose fluxes with unstressed catheter approach in streptozotocin induced diabetic rats.

OBJECTIVE: Blood glucose concentrations of type 1 diabetic rats are vulnerable, especially to stress and trauma. The present study aimed to investigate the fasting endogenous glucose production and skeletal muscle glucose uptake of Streptozotocin induced type 1 diabetic rats using an unstressed vein and artery implantation of catheters at the tails of the rats as a platform. RESEARCH DESIGN AND METHODS: Streptozotocin (65 mg·kg⁻¹) was administered to induce type 1 diabetic state. The unstressed approach of catheters of vein and artery at the tails of the rats was established before the isotope tracer injection. Dynamic measurement of fasting endogenous glucose production was assessed by continuously infusing stable isotope [6, 6-²H2] glucose, while skeletal muscle glucose uptake by bolus injecting radioactively labeled [1-¹4C]-2-deoxy-glucose. RESULTS: Streptozotocin induced type 1 diabetic rats displayed polydipsia, polyphagia, and polyuria along with overt hyperglycemia and hypoinsulinemia. They also had enhanced fasting endogenous glucose production and reduced glucose uptake in skeletal muscle compared to nondiabetic rats. CONCLUSIONS: The dual catheters implantation at the tails of the rats together with isotope tracers injection is a save time, unstressed, and feasible approach to explore the glucose metabolism in animal models in vivo.

Castration-induced testosterone deficiency increases fasting glucose associated with hepatic and extra-hepatic insulin resistance in adult male rats.

BACKGROUND: Testosterone deficiency is associated with insulin resistance. However, how testosterone deficiency affects insulin actions remains unclear. The aim of this study was to investigate the influence of castration-induced testosterone deficiency on the metabolic kinetics of glucose and to evaluate the hepatic and extra-hepatic insulin sensitivity, in advanced-age male Sprague-Dawley (SD) rats. METHODS: Ten-week-old male SD rats were randomly divided into three groups: (1) a control group (n = 10) in which the rats underwent sham castration (2) a castrated group (TD group for testosterone deficiency, n = 10) in which the rats underwent bilateral orchidectomy surgery and (3) a castrated group given testosterone propionate via intraperitoneal injection (25 mg/kg/day) to supplement androgen (TD + TP group, n = 10). At ten weeks after castration in the noted groups, all rats were subjected to an oral glucose tolerance test (OGTT), a pyruvate tolerance test (PTT) and an insulin tolerance test (ITT). Twenty weeks following that treatment, all rats underwent a hyperinsulinemic-euglycemic clamp procedure in conjunction with isotope--labeled glucose and glycerol tracer infusions. The rate of appearance (Ra) of glucose, glycerol and gluconeogenesis (GNG), hepatic glucose production and the rate of glucose disappearance (Rd) were assessed. Glucose uptake was determined by measuring the 2-deoxy-D-14C-glucose in the gastrocnemius muscles. RESULTS: Ten weeks after castration in the TD group, the fasting blood glucose and insulin levels were significantly increased (p < 0.01), the glucose-- induced insulin secretion was impaired and ITT revealed a temporarily increased whole body insulin sensitivity compared with the control group; 30 weeks after castration, the Ra of glucose, Ra of glycerol, as well as the HGP and GNG were also increased (p < 0.01), while the exogenous glucose infusion rate and uptake glucose in the muscle markedly decreased (p < 0.01). CONCLUSIONS: Castration-induced testosterone deficiency primarily increases fasting blood glucose levels. The clamp experiments revealed a clear insulin resistance both at the hepatic and extra-hepatic levels.