Exosomes derived from HUVECs alleviate ischemia-reperfusion induced inflammation in neural cells by upregulating KLF14 expression.

Neuroinflammation plays a key role in the progression of secondary brain injury after ischemic stroke, and exosomes have been increasingly recognized to eliminate inflammatory responses through various mechanisms. This study aimed to explore the effect and possible mechanism of human umbilical vein endothelial cells derived exosomes (H-EXOs) on neuroinflammation. We established a transient middle cerebral artery occlusion/reperfusion (tMCAO/R) in male rats and oxygen-glucose-deprivation/reoxygenation (OGD/R) model in cultured neurons to mimic secondary brain injury after ischemic stroke in vivo. H-EXOs were administered at the same time of reperfusion. Results showed that the production of pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6, and the transcription factor Krüppel-like factor 14 (KLF14) were significantly increased both in rat brain tissue and cultured neural cells after ischemic-reperfusion (I/R) injury. H-EXOs treatment significantly improved the cultured cell viability, reduced infarct sizes, mitigated neurobehavioral defects, and alleviated the expression of pro-inflammatory cytokines compared with the control group, indicating that H-EXOs exerted anti-inflammatory effect against I/R injury. Further studies revealed that the anti-inflammatory effect of H-EXOs could be weakened by small-interfering RNA (siKLF4) transfection. KLF14 was a protective factor produced during cerebral ischemia-reperfusion injury. In conclusion, H-EXOs protect neurons from inflammation after I/R injury by enhancing KLF14 expression.

Carbon budget and evaluation of marine industry in Jiangsu Province, China.

The measurement and evaluation of carbon budget of marine industry is the basis for promoting green and efficient development of marine economy under the goal of carbon neutrality. We constructed a carbon accounting system for the marine industry in Jiangsu Province, and assessed carbon efficiency and neutrality. The results showed that from 2016 to 2020, the total amount of marine carbon sinks in Jiangsu Province were 894.8 to 2773.2 thousand tons, while carbon emissions of major marine industries were 3538.4 to 4350.6 thousand tons. The net emissions of marine industries ranged from 1478.7 to 2906.1 thousand tons. Both of carbon sinks and emissions were significantly increased in this period. In terms of carbon sinks, the offshore wind power accounted for the largest contribution, followed by ecosystem carbon sequestration, and mariculture carbon sequestration was the smallest. In terms of carbon emissions, the marine transportation industry played a dominant role, followed by coastal tourism and marine fisheries, while the marine engineering and construction industry and marine shipping industry accounted for a small proportion. In general, the carbon neutral status showed that marine industry in Jiangsu Province was in carbon deficit from 2016-2020, but the net emissions were decreasing year by year. The net carbon sink efficiency of mariculture in Jiangsu Province was lower than the national level, and carbon efficiency of offshore wind power was stable.

The mechanisms of exosomes in diabetic foot ulcers healing: a detailed review.

As time goes by, the morbidity of diabetes mellitus continues to rise, and the economic burden of diabetic foot ulcers as a common and serious complication of diabetes is increasing. However, currently there is no unified clinical treatment strategy for this complication, and the therapeutic efficacy is unsatisfactory. Recent studies have revealed that biological effects of exosomes involved in multiple stages of the process of wound closure are similar to source cells. Compared with source cells, exosomes possess lowly immunogenicity, highly stability and easily stored, etc. Accumulating evidence confirmed that exosomes promote diabetic wound healing through various pathways such as promoting angiogenesis, collagen fiber deposition, and inhibiting inflammation. The superior therapeutic efficacy of exosomes in accelerating diabetic cutaneous wound healing has attracted an increasing attention. Notably, the molecular mechanisms of exosomes vary among different sources in the chronic wound closure of diabetes. This review focuses on the specific roles and mechanisms of different cell- or tissue-derived exosomes relevant to wound healing. Additionally, the paper provides an overview of the current pre-clinical and clinical applications of exosomes, illustrates their special advantages in wound repair. Furthermore, we discuss the potential obstacles and various solutions for future research on exosomes in the management of diabetic foot ulcer. The aim is to offer novel insights and approaches for the treatment of diabetic foot ulcer.

Targeted gene panel provides advantages over whole-exome sequencing for diagnosing obesity and diabetes mellitus.

A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic cause. Here, we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesity or diabetes. We performed this panel in 481 patients to detect causative variants and compared these results with whole-exome sequencing (WES) data available for 146 of these patients. The coverage of targeted gene panel sequencing was significantly higher than that of WES. The diagnostic yield in patients sequenced by the panel was 32.9% with subsequent WES leading to three additional diagnoses with two novel genes. In total, 178 variants in 83 genes were detected in 146 patients by targeted sequencing. Three of the 178 variants were missed by WES, although the WES-only approach had a similar diagnostic yield. For the 335 samples only receiving targeted sequencing, the diagnostic yield was 32.2%. In conclusion, taking into account the lower costs, shorter turnaround time, and higher quality of data, targeted sequencing is a more effective screening method for monogenic obesity and diabetes compared to WES. Therefore, this approach could be routinely established and used as a first-tier test in clinical practice for specific patients.

Exosomes from Inflamed Macrophages Promote the Progression of Parkinson's Disease by Inducing Neuroinflammation.

Inflammation is a common feature both for Parkinson's disease (PD) and obesity-associated metabolic syndromes. Inflammation mediated by inflamed macrophages in white adipose tissue plays a pivotal role for the pathogenesis of metabolic syndromes. Exosomes are important carriers connecting peripheral tissues and the central nervous system (CNS). Therefore, we speculate that exosomes derived from inflamed macrophages may be involved in the pathological progression of PD. Here, we prepared exosomes from lipopolysaccharide (LPS) or interferon gamma (IFNγ) treated macrophages (inflamed macrophages) and examined their potential roles in PD. Our data showed that exosomes from inflamed macrophages stimulate proinflammatory cytokine expression in primary microglia and astrocytes. In vivo, inflamed macrophage exosomes induce behavioral defects in mice as evidenced by shortened duration in the rotarod test and prolonged latency in the pole test. The treatment of exosomes also reduces tyrosine hydroxylase (TH) positive cells in the substantia nigra pars compacta (SNpc) and striatum. All these PD-like phenotypes are likely due to the activation of microglia and astrocytes induced by exosomes from inflamed macrophages. Exosome sequencing, together with bioinformatics analysis and functional studies, revealed that exosomal miRNAs such as miR-155-5p are likely a key factor for inducing an inflammatory response in glial cells. These results indicate that exosomes derived from inflamed macrophages are likely a causative factor for developing PD. In this regard, inflamed macrophage exosomes might be a linker transducing the peripheral tissue inflammation into the CNS.

A glycogen storage disease type 1a patient with type 2 diabetes.

BACKGROUND: Glycogen storage disease type 1a (GSD1a) is an inborn genetic disease caused by glucose-6-phosphatase-α (G6Pase-α) deficiency and is often observed to lead to endogenous glucose production disorders manifesting as hypoglycemia, hyperuricemia, hyperlipidemia, lactic acidemia, hepatomegaly, and nephromegaly. The development of GSD1a with diabetes is relatively rare, and the underlying pathogenesis remains unclear. CASE PRESENTATION: Here we describe a case of a 25-year-old Chinese female patient with GSD1a, who developed uncontrolled type 2 diabetes mellitus (T2DM) as a young adult. The patient was diagnosed with GSD1a disease at the age of 10 and was subsequently treated with an uncooked cornstarch diet. Recently, the patient was treated in our hospital for vomiting and electrolyte imbalance and was subsequently diagnosed with T2DM. Owing to the impaired secretory function of the patient's pancreatic islets, liver dysfunction, hypothyroidism, severe hyperlipidemia, and huge hepatic adenoma, we adopted diet control, insulin therapy, and hepatic adenoma resection to alleviate this situation. The WES discovered compound heterozygous mutations at the exon 5 of G6PC gene at 17th chromosome in the patient, c.648G>T (p.L216 L, NM_000151.4, rs80356484) in her father and c.674T>C (p.L225 P, NM_000151.4, rs1555560128) in her mother. c.648G>T is a well-known splice-site mutation, which causes CTG changing to CTT at protein 216 and creates a new splicing site 91 bp downstream of the authentic splice site, though both codons encode leucine. c.674T>C is a known missense mutation that causes TGC to become CGC at protein 225, thereby changing from coding for leucine to coding for proline. CONCLUSION: We report a rare case of GSD1a with T2DM. On the basis of the pathogenesis of GSD1a, we recommend attentiveness to possible development of fasting hypoglycemia caused by GSD and postprandial hyperglycemia from diabetes. As the disease is better identified and treated, and as patients with GSD live longer, this challenge may appear more frequently. Therefore, it is necessary to have a deeper and more comprehensive understanding of the pathophysiology of the disease and explore suitable treatment options.

Effects of Variability in Glycemic Indices on Longevity in Chinese Centenarians.

Background: Large fluctuations in blood glucose levels greatly impact the health and life span of elderly individuals. This study describes the characteristics of variability in glycemic indices in centenarians with the aim of emphasizing the importance of glycemic variability in elderly people. Methods: We recruited individuals from Rugao City, Jiangsu Province, China from April 2020 to May 2021. The study cohort included 60 centenarians and 60 first-generation offspring, as well as 20 randomly selected non-cohabitant control individuals aged 60-80 years. A FreeStyle Libre H (hospital version) continuous glucose monitoring (CGM) device (Abbott Ireland UK) was used to measure glycemic variability. The indices measured included the time in target glucose range (TIR), time below target glucose range (TBR), time above target glucose range (TAR), mean amplitude of glycemic excursions (MAGE), mean of daily differences (MODD), coefficient of variation (CV), standard deviation of blood glucose (SDBG), continuous overlapping net glycemic action (CONGA), glucose management indicator (GMI) and estimated glycated hemoglobin (eHbA1c). Logistic regression was used to analyze the association between glycemic variability and longevity. Results: Mean blood glucose (MBG), eHbA1c, GMI, mean fasting plasma glucose (M-FPG) and CONGA were lower in the centenarian group (p all < 0.05). PPGE-2 was higher in the control group than that measured in the centenarian and first-generation offspring groups (p < 0.05). There were no differences between the groups in MAGE, MODD, MAG, or TIR (p > 0.05). The risk of not achieving longevity increased with each one unit increase in MBG by 126% [2.26 (1.05-4.91)], eHbA1c by 67% [1.67 (1.03-2.72)], GMI by 568% [6.68 (1.11-40.30)], M-FPG by 365% [4.65 (1.57-13.75)], M-PPG1h by 98% [1.98 (1.18-3.31)], CONGA1 by 102% [2.02 (1.01-4.06)], Li by 200% [3.00 (1.04-8.61)], and PPGE-2 by 150% [2.50 (1.39-4.50)]. However, the risk of achieving longevity decreased with each unit increase of LBGI by 53% [0.47 (0.28-0.80)], ADRR by 60% [0.40 (0.18-0.86)], and TBR by 11% [0.89 (0.80-0.98)]. Conclusion: Fluctuation in blood glucose levels in centenarians is relatively small. Maintaining an average blood glucose level and keeping blood glucose fluctuations in the normal range is conducive to longevity.

12(S)-hydroxyeicosatetraenoic acid is significantly increased in diabetic kidney disease and associated with renal function decline.

AIMS: 12(S)-hydroxyeicosatetraenoic (12(S)-HETE), an alternate arachidonic acid metabolite, has been recently examined in metabolic disease. However, the role of 12(S)-HETE in diabetic kidney disease (DKD) remains unclear. We studied for the first time the relationship of serum 12(S)-HETE and DKD and renal function parameters in a Chinese population. MATERIALS AND METHODS: We recruited 275 subjects who were diagnosed with type 2 diabetes (T2DM) for more than 10 years, including 149 DKD patients and 126 T2DM patients without DKD. Serum 12(S)-HETE was measured using the enzyme-linked immunosorbent assay. RESULTS: Serum 12(S)-HETE was significantly higher in DKD patients than controls [384.69 (77.54, 1003.05) pg/ml and 17.77 (8.11, 75.13) pg/ml, respectively, p < 0.0001]. Compared to controls, 12(S)-HETE was significantly increased in both macroalbuminuria and microalbuminuria groups (p < 0.0001). Further, the macroalbuminuria group also had a higher serum 12(S)-HETE level compared to the microalbuminuria group (p = 0.0063). Moreover, serum 12(S)-HETE was positively correlated with the albuminuria level (r = 0.5833, p < 0.0001), serum creatinine (r = 0.2725, p < 0.0001), and was negatively associated with the estimated glomerular filtration rate (r = -0.2085, p = 0.0005). Further, receiver operating characteristic analysis (ROC) revealed that 12(S)-HETE had a good performance of distinguishing DKD from controls (AUC 0.828) with a sensitivity of 0.913 and a specificity of 0.711. CONCLUSION: Our findings revealed that serum 12(S)-HETE significantly associated with DKD and disease severity, suggesting that serum 12(S)-HETE may be used as a potential biomarker for the early diagnosis of DKD.

Erratum: Influence of GLP-1 receptor agonist on insulin dosage and blood glucose control of patients with type 2 diabetes mellitus.

[This corrects the article on p. 11814 in vol. 13, PMID: 34786110.].

Fatty Acid-Binding Protein 4 in Patients with and without Diabetic Retinopathy.

BACKGROUND: Fatty acid-binding protein 4 (FABP4) has been demonstrated to be a predictor of early diabetic nephropathy. However, little is known about the relationship between FABP4 and diabetic retinopathy (DR). This study explored the value of FABP4 as a biomarker of DR in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 238 subjects were enrolled, including 20 healthy controls and 218 T2DM patients. Serum FABP4 levels were measured using a sandwich enzyme-linked immunosorbent assay. The grade of DR was determined using fundus fluorescence angiography. Based on the international classification of DR, all T2DM patients were classified into the following three subgroups: non-DR group, non-proliferative diabetic retinopathy (NPDR) group, and proliferative diabetic retinopathy (PDR) group. Multivariate logistic regression analyses were employed to assess the correlation between FABP4 levels and DR severity. RESULTS: FABP4 correlated positively with DR severity (r=0.225, P=0.001). Receiver operating characteristic curve analysis was used to assess the diagnostic potential of FABP4 in identifying DR, with an area under the curve of 0.624 (37% sensitivity, 83.6% specificity) and an optimum cut-off value of 76.4 µg/L. Multivariate logistic regression model including FABP4 as a categorized binary variable using the cut-off value of 76.4 µg/L showed that the concentration of FABP4 above the cut-off value increased the risk of NPDR (odds ratio [OR], 3.231; 95% confidence interval [CI], 1.574 to 6.632; P=0.001) and PDR (OR, 3.689; 95% CI, 1.306 to 10.424; P=0.014). CONCLUSION: FABP4 may be used as a serum biomarker for the diagnosis of DR.

Common variants in genes involved in islet amyloid polypeptide (IAPP) processing and the degradation pathway are associated with T2DM risk: A Chinese population study.

AIM: To explore the genetic effects of SLC30A8, IAPP, PCSK1, PCSK2, CPE, PAM and IDE, key genes involved in IAPP processing and degradation pathway on T2DM risk and metabolic traits in Chinese population. METHODS: Common variants were genotyped in 10936 Chinese subjects by Asian Screening Array and Multi-Ethnic Global Array. Associations of SNPs with occurrences of T2DM and related traits were evaluated through logistic and multiple linear regression. Genetic risk score (GRS) model was constructed based on 6 T2DM-variants, and its relationship with T2DM and related traits was assessed. RESULTS: SLC30A8-rs13266634, PCSK1-rs155980, PCSK2-rs6136035, CPE-rs532192464, PAM-rs7716941, and IDE-rs117929184 were the top SNPs significantly associated with T2DM after adjusting for age, sex, and BMI, associated with blood glucose level, insulin secretion, and insulin sensitivity (all FDR p < 0.05). GRS calculated based on the above SNPs was remarkably correlated with T2DM, blood glucose, and insulin secretion. Furthermore, there was a significant interaction between SLC30A8 and IAPP in patients with T2DM (P = 0.0083). CONCLUSION: Our study showed that common variants in genes involved in IAPP processing and the degradation pathway were associated with T2DM in Chinese population. Subjects with high GRS exhibited poorer glucose metabolism and insulin secretion.

Influence of GLP-1 receptor agonist on insulin dosage and blood glucose control of patients with type 2 diabetes mellitus.

OBJECTIVE: To determine the effect of glucagon-like peptide-1 receptor agonist (GLP-1RA) on cases with type 2 diabetes mellitus (T2DM) in terms of insulin dosage and blood glucose (BG) control. METHODS: A total of 180 patients with T2DM admitted to our hospital between March 2016 and March 2019 were selected and assigned to a GLP-1RA group (GLP-1 group, n=100) and a control group (control group, n=80). Patients in the GLP-1 group were treated with GLP-1RA combined with insulin, while those in the other group were treated with insulin alone. The following items of each patient were determined: Body weight, body mass index (BMI), waist circumference, blood pressure (BP), BG-related indexes, insulin dosage, insulin resistance index, cardiovascular function, serum lipid-related indexes, adverse reactions, total effective rate, and treatment satisfaction. RESULTS: Compared with the control group, the GLP-1 group showed a decrease in weight, BMI, waist circumference, BP, BG-related indexes, and insulin resistance index, consumed less insulin dosage, and also showed a decline in cardiovascular function, serum lipid-related indexes (total cholesterol (TC), triacylglycerol (TG), and low density lipoprotein cholesterol (LDL-C)), an increase in high density lipoprotein cholesterol (HDL-C), less adverse reactions, and higher total effective rate and treatment satisfaction. CONCLUSION: GLP-1RA contributes to better BG control of patients with T2DM, and it reduces the insulin dosage required during operation for its stimulation to the production of insulin.

Shift of Glucose Peak Time During Oral Glucose Tolerance Test is Associated with Changes in Insulin Secretion and Insulin Sensitivity After Therapy with Antidiabetic Drugs in Patients with Type 2 Diabetes.

INTRODUCTION: Delay in peak blood glucose during an oral glucose tolerance test (OGTT) predicts declining ß-cell function and poor ability to regulate glucose metabolism. Glucose peak time has not been used as a comparative indicator of the improvement in islet function after treatment with exenatide, insulin, or oral antidiabetic drugs (OADs). We evaluated the efficacy of three types of antidiabetic drugs on the basis of blood glucose peak time in patients with non-newly diagnosed type 2 diabetes. METHODS: The data from 100 patients with diabetes who completed two OGTTs within 6 months were collected. Thirty-seven of them with type 2 diabetes were treated with Humalog Mix25, 28 patients with OADs (metformin, acarbose, and gliclazide), and 35 patients with exenatide. RESULTS: Glycated hemoglobin improved in all three groups after treatment (P < 0.05). Subcutaneous adipose tissue (P < 0.01) and visceral adipose tissue (P < 0.0001) significantly decreased in the exenatide group. The insulinogenic index (IGI) (P = 0.01) and IGI × oral glucose insulin sensitivity (OGIS) (P = 0.01) improved in the exenatide group only. Homeostatic assessment of ß-cell function (HOMA-ß) and OGIS were greater in the exenatide and OAD groups than in the Humalog Mix25 group (all P < 0.05). A shift to an earlier peak was observed in 57.1%, 35.7%, and 27.0% of patients in the exenatide, OAD, and Humalog Mix25 groups, respectively (P = 0.029). OGIS (odds ratio [OR] 0.54, 95% confidence interval [CI] 0.33-0.89, P = 0.026) and IGI × OGIS (OR 1.72, 95% CI 0.44-6.68, P = 0.012) were independently related to shifts in glucose peak time. CONCLUSION: Exenatide, Humalog Mix25, and OADs improved glycemic metabolism. However, exenatide exhibited superior efficacy in shifting blood glucose peak time to an earlier point, while it improved insulin secretion and insulin sensitivity. Hence, the shift of glucose peak time may be considered an indicator for the evaluation of the effect of hypoglycemic drugs.

Association of serum 25-hydroxyvitamin D with metabolic syndrome and type 2 diabetes: a one sample Mendelian randomization study.

BACKGROUND: Vitamin D deficiency has been associated with type 2 diabetes (T2D) and metabolic syndrome (MS) and its components. However, it is unclear whether a low concentration of vitamin D is the cause or consequence of these health conditions. Thus, this study aimed to evaluate the association of vitamin D concentrations and its genetic risk scores (GRSs) with MS and its component diseases, such as T2D, in middle-aged and elderly participants from rural eastern China. METHODS: A subset of 2393 middle-aged and elderly individuals were selected from 70,458 participants of the Nantong Chronic Diseases Study of 2017-2018 in China. We used two 25-hydroxyvitamin D (25[OH]D) synthesis single-nucleotide polymorphisms (SNPs) (DHCR7-rs12785878 and CYP2R1-rs10741657) and two 25(OH) D metabolism SNPs (GC-rs2282679 and CYP24A1-rs6013897) for creating GRSs, which were used as instrumental variables to assess the effect of genetically lowered 25(OH) D concentrations on MS and T2D based on the Wald ratio. F statistics were used to validate that the four SNPs genetically determined 25(OH) D concentrations. RESULTS: Compared to vitamin D sufficient individuals, individuals with vitamin D insufficiency had an odds ratio (OR [95% confidence interval {CI}]) of MS of 1.30 (1.06-1.61) and of T2D of 1.32 (1.08-1.64), individuals with vitamin D deficiency had an ORs (95% CI) of MS of 1.50 (1.24-1.79) and of T2D of 1.47 (1.12-1.80), and those with vitamin D severe deficiency had an ORs (95% CI) of MS of 1.52 (1.29-1.85) and of T2D of 1.54 (1.27-1.85). Mendelian randomization analysis showed a 25-nmol/L decrease in genetically instrumented serum 25(OH) D concentrations using the two synthesis SNPs (DHCR7 and CYP2R1 genes) associated with the risk of T2D and abnormal diastolic blood pressure (DBP) with ORs of 1.10 (95%CI: 1.02-1.45) for T2D and 1.14 (95%CI: 1.03-1.43) for DBP. CONCLUSIONS: This one sample Mendelian randomization analysis shows genetic evidence for a causal role of lower 25(OH) D concentrations in promoting of T2D and abnormal DBP in middle-aged and elderly participants from rural China.

Relationships between Islet-Specific Autoantibody Titers and the Clinical Characteristics of Patients with Diabetes Mellitus.

Background: Dysimmunity plays a key role in diabetes, especially type 1 diabetes mellitus. Islet-specific autoantibodies (ISAs) have been used as diagnostic markers for different phenotypic classifications of diabetes. This study was aimed to explore the relationships between ISA titers and the clinical characteristics of diabetic patients. Methods: A total of 509 diabetic patients admitted to Department of Endocrinology and Metabolism at the Affiliated Hospital of Nantong University were recruited. Anthropometric parameters, serum biochemical index, glycosylated hemoglobin, urinary microalbumin/creatinine ratio, ISAs, fat mass, and islet ß-cell function were measured. Multiple linear regression analysis was performed to identify relationships between ISA titers and clinical characteristics. Results: Compared with autoantibody negative group, blood pressure, weight, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), visceral fat mass, fasting C-peptide (FCP), 120 minutes C-peptide (120minCP) and area under C-peptide curve (AUCCP) of patients in either autoantibody positive or glutamate decarboxylase antibody (GADA) positive group were lower. Body mass index (BMI), waist circumference, triglycerides (TGs), body fat mass of patients in either autoantibody positive group were lower than autoantibody negative group. GADA titer negatively correlated with TC, LDL-C, FCP, 120minCP, and AUCCP. The islet cell antibody and insulin autoantibody titers both negatively correlated with body weight, BMI, TC, TG, and LDL-C. After adjusting confounders, multiple linear regression analysis showed that LDL-C and FCP negatively correlated with GADA titer. Conclusion: Diabetic patients with a high ISA titer, especially GADA titer, have worse islet ß-cell function, but less abdominal obesity and fewer features of the metabolic syndrome.

Correlation Between Serum Uric Acid Level and Central Body Fat Distribution in Patients with Type 2 Diabetes.

BACKGROUND: The aim of this study was to investigate the correlation between serum uric acid level and central body fat distribution in patients with type 2 diabetes (T2DM). METHODS: A total of 867 patients with T2DM were enrolled. Measurements of central fat distribution were obtained by dual energy X-ray absorptiometry. Patients were stratified into three groups according to their levels of serum uric acid (SUA). Multiple linear regression analysis was used to determine the association between SUA and central body fat distribution. Logistic regression analysis was used to estimate the risk factors for hyperuricemia (HUA). Mediation analysis was applied to assess the overall, direct, and indirect mediators of SUA levels. RESULTS: Multiple linear regression analysis showed that SUA levels were significantly positively correlated with waist circumference (WC), body mass index (BMI), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), Android fat mass, Gynoid fat mass, fasting c-peptide (F-CP), and area under the curve of C-peptide (P < 0.05 for all). VAT [odds ratio (OR), 2.367; 95% confidence interval (CI), 1.078-5.197; P < 0.001)], WC (OR, 1.041; 95% CI, 1.011-1.072; P < 0.001), high-density lipoprotein (OR, 0.274; 95% CI, 0.104-0.727; P < 0.001), and estimated glomerular filtration rate (OR, 0.966; 95% CI, 0.959-0.973; P < 0.001) were found to be independent risk factors for T2DM patients with HUA. After mediation analysis, BMI and central obesity were found to have different partial effects on the association between SUA and F-CP (P < 0.001). CONCLUSION: In patients with T2DM, HUA was positively correlated with F-CP and central body fat distribution, especially VAT. These results suggest that central obesity may play a role in the positive correlation between HUA and insulin resistance (IR).

Effects of Exenatide and Humalog Mix25 on Fat Distribution, Insulin Sensitivity, and ß-Cell Function in Normal BMI Patients with Type 2 Diabetes and Visceral Adiposity.

In China, most normal BMI (body mass index of ≥18.5 to <25 kg/m2) adults with type 2 diabetes (T2DM) exhibit visceral adiposity. This study compared the effects of exenatide and humalog Mix25 on normal BMI patients with T2DM and visceral adiposity. A total of 95 patients were randomized to receive either exenatide or humalog Mix25 treatment for 24 weeks. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were quantified by magnetic resonance imaging (MRI) and liver fat content (LFC) by liver proton magnetic resonance spectroscopy (1H MRS). Each patient's weight, waist circumference, BMI, blood glucose, insulin sensitivity, pancreatic ß-cell function, and fibroblast growth factor 21 (FGF-21) levels were measured. Data from 81 patients who completed the study (40 and 41 in the exenatide and humalog Mix25 groups, respectively) were analysed. The change in 2 h plasma blood glucose was greater in the exenatide group (P = 0.039). HOMA-IR and MBCI improved significantly after exenatide therapy (P < 0.01, P = 0.045). VAT and LFC decreased in both groups (P < 0.01 for all) but to a greater extent in the exenatide group, while SAT only decreased with exenatide therapy (P < 0.01). FGF-21 levels declined more in the exenatide group (P < 0.01), but were positively correlated with VAT in the entire cohort before (r = 0.244, P = 0.043) and after (r = 0.290, P = 0.016) the intervention. The effects of exenatide on glycaemic metabolism, insulin resistance, pancreatic ß-cell function, and fat deposition support its administration to normal BMI patients with T2DM and visceral adiposity.

The effects of oxytocin to rectify metabolic dysfunction in obese mice are associated with increased thermogenesis.

Oxytocin, a protein hormone mainly produced by hypothalamus, has been shown to repress body weight gain in obese animals, in part, by reducing food intake and increasing energy expenditure. Till now, activation of brown fat tissue (BAT) thermogenesis and white adipose tissue (WAT) browning are considered as two main factors for oxytocin-induced energy expenditure. However, the underlying molecular mechanisms are still not understood well. Here, we observed that oxytocin expression in the hypothalamus and its receptor in adipose tissues were induced by cold exposure in mice. In differentiated adipocytes, oxytocin stimulated brown adipocyte specific gene expression by inducing PRDM16. In high fat diet induced obese mice, oxytocin delivery by osmotic minipumps increased body core temperature and decreased body weight gain. Glucose and insulin tolerance were improved by oxytocin. Hyperinsulinemia and fatty liver were ameliorated in oxytocin-treated animals. Moreover, oxytocin treatment induced thermogenic gene expressions in BAT, inguinal WAT (iWAT), and skeletal muscle. Taken together, our findings revealed a new aspect of oxytocin, i.e. oxytocin induces iWAT browning and stimulates thermogenesis in BAT, iWAT and skeletal muscle, through which oxytocin promotes thermogenesis and thus combats obesity and metabolic dysfunctions.

Serum Fibroblast Growth Factor 19 and Total Bile Acid Concentrations Are Potential Biomarkers of Hepatocellular Carcinoma in Patients with Type 2 Diabetes Mellitus.

PURPOSE: Type 2 diabetes mellitus (T2DM) carries a high risk of hepatocellular carcinoma (HCC). Both serum fibroblast growth factor 19 (FGF19) and bile acid concentrations are associated with T2DM and HCC. We aimed at evaluating the relationships between FGF19 and bile acid concentrations and HCC in patients with T2DM. METHODS: Twenty-seven healthy volunteers (control group), 27 patients with T2DM (T2DM group), 16 patients with newly diagnosed HCC (HCC group), and 10 T2DM patients with newly diagnosed HCC (T2DM-HCC group) were studied at the Affiliated Hospital of Nantong University between June 2016 and June 2017. The serum concentrations of serum FGF19 and total bile acids (TBA) were measured in all the participants. Correlation analysis and multiple stepwise regression analysis of the FGF19 and TBA concentrations were performed in all the participants and in the four groups. RESULTS: The concentrations of FGF19 were 220.5 pg/ml, 185.1 pg/ml, 115.8 pg/ml, and 70.4 pg/ml in the HCC, T2DM-HCC, control, and T2DM groups, respectively (p < 0.001), and the TBA concentrations were 21.75 µmol/l, 14.25 µmol/l, 14.25 µmol/l, 14.25 µmol/l, 14.25 p < 0.001), and the TBA concentrations were 21.75 r = 0.777; p < 0.001), and the TBA concentrations were 21.75 r = 0.777; p < 0.001), and the TBA concentrations were 21.75 r = 0.777; p < 0.001), and the TBA concentrations were 21.75 r = 0.777; p < 0.001), and the TBA concentrations were 21.75 r = 0.777; p < 0.001), and the TBA concentrations were 21.75 . CONCLUSIONS: Simultaneous increase of serum FGF19 and TBA levels may be used as indicators of HCC screening at early stage in patients with T2DM.

BMP7 improves insulin signal transduction in the liver via inhibition of mitogen-activated protein kinases.

Bone morphogenetic protein 7 (BMP7), a member of the transforming growth factor-ß (TGF-ß) family, plays pivotal roles in energy expenditure. However, whether and how BMP7 regulates hepatic insulin sensitivity is still poorly understood. Here, we show that hepatic BMP7 expression is reduced in high-fat diet (HFD)-induced diabetic mice and palmitate (PA)-induced insulin-resistant HepG2 and AML12 cells. BMP7 improves insulin signaling pathway in insulin resistant hepatocytes. On the contrary, knockdown of BMP7 further impairs insulin signal transduction in PA-treated cells. Increased expression of BMP7 by adenovirus expressing BMP7 improves hyperglycemia, insulin sensitivity and insulin signal transduction. Furthermore, BMP7 inhibits mitogen-activated protein kinases (MAPKs) in both the liver of obese mice and PA-treated cells. In addition, inhibition of MAPKs recapitulates the effects of BMP7 on insulin signal transduction in cultured hepatocytes treated with PA. Activation of p38 MAPK abolishes the BMP7-mediated upregulation of insulin signal transduction both in vitro and in vivo. Together, our results show that hepatic BMP7 has a novel function in regulating insulin sensitivity through inhibition of MAPKs, thus providing new insights into treating insulin resistance-related disorders such as type 2 diabetes.