Chinese Expert Consensus on the Clinical Diagnosis and Management of Statin Intolerance.

The clinical benefits of statins have well-established and recognized worldwide. Although statins are well-tolerated generally, however, the report of statin-related adverse event and statin intolerance are common in China, which results in insufficient use of statins and poor adherence. The main reason may be attributed to confusions or misconceptions in the clinical diagnosis and management in China, including the lack of unified definitions and diagnostic standards, broad grasp of diagnosis, and unscientific management strategies. Based on that, this consensus carefully summarized the statin-related gene polymorphism and statin usage issue among Chinese population, and comprehensively reviewed global research data on statin intolerance, referenced guidelines, and consensus literature on statin intolerance in foreign and different regions, proposes an appropriate and easy to implement statin intolerance definition as well as corresponding diagnostic criteria and management strategies for Chinese clinicians, in order to improve the clinical application of statin drugs and enhance the prevention and treatment level of atherosclerotic cardiovascular disease in China.

Role of omega-3 fatty acids in the prevention and treatment of cardiovascular Diseases: A consensus statement from the Experts' Committee Of National Society Of Cardiometabolic Medicine.

Low-density lipoprotein cholesterol (LDL-C) has been considered as the primary target for the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD). However, there are still residual cardiovascular risks in some patients even if LDL-C achieves the target level. Emerging evidence suggestes that elevated triglyceride (TG) level or triglyceride-rich lipoprotein (TRL) cholesterol (TRL-C) is one of the important components of the residual cardiovascular risks. Omega-3 fatty acids have been shown to be one of the effective drugs for reducing TG. However, its efficacy in reducing the risk of ASCVD is inconsistent in large randomized clinical trials. There is lack of consensus among Experts regarding the application of omega-3 fatty acids in cardiovascular diseases including heart failure, arrhythmia, cardiomyopathy, hypertension, and sudden death. Hence, the current consensus will comprehensively and scientifically present the detailed knowledge about the omega-3 fatty acids from a variety of aspects to provide a reference for its management of omega-3 fatty acids application in the Chinese population.

The chemokine CCL1 triggers an AMFR-SPRY1 pathway that promotes differentiation of lung fibroblasts into myofibroblasts and drives pulmonary fibrosis.

Recruitment of immune cells to the site of inflammation by the chemokine CCL1 is important in the pathology of inflammatory diseases. Here, we examined the role of CCL1 in pulmonary fibrosis (PF). Bronchoalveolar lavage fluid from PF mouse models contained high amounts of CCL1, as did lung biopsies from PF patients. Immunofluorescence analyses revealed that alveolar macrophages and CD4+ T cells were major producers of CCL1 and targeted deletion of Ccl1 in these cells blunted pathology. Deletion of the CCL1 receptor Ccr8 in fibroblasts limited migration, but not activation, in response to CCL1. Mass spectrometry analyses of CCL1 complexes identified AMFR as a CCL1 receptor, and deletion of Amfr impaired fibroblast activation. Mechanistically, CCL1 binding triggered ubiquitination of the ERK inhibitor Spry1 by AMFR, thus activating Ras-mediated profibrotic protein synthesis. Antibody blockade of CCL1 ameliorated PF pathology, supporting the therapeutic potential of targeting this pathway for treating fibroproliferative lung diseases.

Accurate diagnosis and heterogeneity analysis of a 17q12 deletion syndrome family with adulthood diabetes onset and complex clinical phenotypes.

PURPOSE: 17q12 Deletion Syndrome is heterogeneous and the reasons remain unclear. We clarified the clinical characteristics of adulthood diabetes onset 17q12 deletion syndrome and investigated the unclear phenotype-genotype correlation. METHODS: We collected the clinical history and laboratory results of a family with autosomal dominant inheritance diabetes and renopathy. Sanger sequencing of HNF1B and a panel of monogenic diabetic genes were performed to identify the monogenetic diabetes. Semiquantitative PCR and Chromosome 100 K sequence analysis were performed to analyze the copy numbers variation of diabetes related genes. Allelic specific quantitative PCR were used for TBC1D3 and paralogues diagnosis. The reported cases were reviewed and assessed to compare with patients in this study. RESULTS: Differential variants in genomic DNA and clinical presentations among family members were explored to determine the probable phenotype-genotypes correlation. The four patients were diagnosed with 17q12 deletion syndrome with 1.47-1.76 Mb heterogeneous deletion, which led to the haploinsufficiency of HNF1B, ACACA, LHX1, PIGW, miRNA2909 and other genes. The patients had different amount of genes deletion in TBC1D3 and paralogues, which might associate with the heterogeneous clinical phenotypes. CONCLUSIONS: We first reported an adulthood diabetes onset 17q12 deletion syndrome family with the largest number of patients. The heterogeneous clinical phenotypes might be related to the haploinsufficiency of TBC1D3 and its paralogues.

Atypical juvenile hereditary hemochromatosis onset with positive pancreatic islet autoantibodies diabetes caused by novel mutations in HAMP and overall clinical management.

BACKGROUND: Atypical clinical symptoms of juvenile hereditary hemochromatosis (JHH) often leads to misdiagnosis and underdiagnosis bringing ominous outcomes, even death. METHODS: The whole exome was sequenced and interpreted. A literature review assisted to analyze and verify the phenotype-genotype relationships. We revealed the entire process of diagnosis, treatments, and outcome of two diabetic onset of JHH families to provide new insights for genotype-phenotype relation with novel compound heterozygous mutations in the hepcidin antimicrobial peptide (HAMP, OMIM: 606464). RESULTS: Two probands were diagnosed and treated as type 1 diabetes initially because of specific symptoms and positive islet autoantibodies. Poor control of hyperglycemia and progressive symptoms occurred. Sequencing informed that the compound heterozygous and homozygous mutations c.166C>G and c.223C>T in HAMP caused type 1 diabetic-onset JHH. The two patients accessed irregular phlebotomy treatments, and then, experienced poor prognosis. We summarized the process of overall clinical management of reported 26 cases comparing to our novel atypical diabetic onsets Juvenile Hereditary Hemochromatosis cases. CONCLUSION: It was first reported that positive pancreatic islet autoantibodies diabetes onset of JHH resulted from loss-of-function mutations of HAMP, of which the atypical JHH should be differentially diagnosed with type 1 diabetes at the onset. Early administration of phlebotomy and vital organs protection and surveillance might be important for the treatment of atypical JHH.

Different Effects of Structured Education on Glycemic Control and Psychological Outcomes in Adolescent and Adult Patients with Type 1 Diabetes: A Systematic Review and Meta-Analysis.

AIM: This systematic review aimed at investigating the effectiveness of structured education (SE) in improving glycemic control and psychological outcomes in adolescent and adult patients with type 1 diabetes. METHODS: Electronic databases (EMBASE, Medline, PubMed, and the Cochrane Library) and the reference lists of included studies were searched from the beginning of the database through April 2019. Randomized controlled trials comparing SE with a control condition and reporting a change in glycosylated hemoglobin (HbA1c) level were included. The primary outcome was glycemic control measured by HbA1c. Secondary outcomes were diabetes-related distress, well-being, depression, and quality of life. RESULTS: Eighteen studies representing 2759 patients were included. Twelve studies targeted adolescents and six targeted adults. Adolescent patients who were randomized to the intervention group did not show significant improvement of HbA1c in the short (SMD = -0.04; 95% CI: -0.14 to 0.06; P=0.41), medium (SMD = -0.03; 95% CI: -0.13 to 0.07; P=0.41), medium (SMD = -0.03; 95% CI: -0.13 to 0.07; P=0.41), medium (SMD = -0.03; 95% CI: -0.13 to 0.07; P=0.41), medium (SMD = -0.03; 95% CI: -0.13 to 0.07; P=0.41), medium (SMD = -0.03; 95% CI: -0.13 to 0.07. CONCLUSIONS: Development of more efficient SE programs according to the patients' personal characteristics is needed.

Body mass index and C-peptide are important for the promptly differential diagnosis of maturity-onset diabetes from familial type 2 diabetes in outpatient clinic.

Type 2 diabetic patients are becoming younger and having a tendency to family aggregation, they are easily suspected as maturity-onset diabetes of young (MODY) in the outpatient clinic and send to genetic testing. 9 diabetic families were compared in our outpatient clinic who met the primary diagnosis criteria of MODY. Detailed clinical features and laboratory data including gene sequence were collected and analyzed. The patients met the primary clinical diagnostic criteria of MODY for genetic testing at the first look. However, members of families A1 to A3 had normal Body mass index (BMI) and a lower C-peptide level which indicated impaired pancreatic islet function. In contrast, the members with diabetes of families B1 to B6 had normal or increased C-peptide level which indicated insulin resistance and were overweight with BMI. Genetic testing showed that the mutations in HNF1A, INS, KCNJ11 and so on in families A were consistent with the diagnosis of MODY. No pathogenic mutation was found in the members of families B which were diagnosed with familial T2D. Before the clinical laboratory testing and the further gene test, BMI and the concentration of C-peptide are important for the promptly differential diagnosis of MODY from familial type 2 diabetes and medication instruction in the outpatient clinic which could help to alleviate the burden of genetic testing for them.

Intermittent High Glucose Exacerbates A-FABP Activation and Inflammatory Response through TLR4-JNK Signaling in THP-1 Cells.

BACKGROUND: Glucose fluctuation confers additional risks on diabetes-related vascular diseases, but the underlying mechanisms are unknown. Macrophage activation mediated by TLR4-JNK signaling plays an important role during the progress of diabetes. In the present study, we hypothesize that glucose fluctuation results in macrophage inflammation through TLR4-JNK signaling pathways. METHODS: THP-1 cells were treated with normal glucose (5 mM), constant high glucose (25 mM), and intermittent high glucose (rotation per 6 h in 5 mM or 25 mM) for 24 h. The mRNA and protein expression levels of TLR4, p-JNK, and adipocyte fatty acid-binding protein (A-FABP) were determined, and the proinflammatory cytokines TNF-α and IL-1ß were quantified. RESULTS: In constant high glucose, TLR4 expression and JNK phosphorylation levels increased, and this effect was more pronounced in intermittent high glucose. Accordingly, the expression of A-FABP and the release of the proinflammatory cytokines TNF-α and IL-1ß also increased in response to constant high glucose, an effect that also was more evident in intermittent high glucose. The inhibition of p-JNK by SP600125 did not attenuate TLR4 expression, but totally inhibited both A-FABP expression and the production of the proinflammatory cytokines TNF-α and IL-1ß in both constant and intermittent high glucose. CONCLUSIONS: Intermittent high glucose potentiates A-FABP activation and inflammatory responses via TLR4/p-JNK signaling in THP-1 cells. These findings suggest a more detrimental impact of glucose fluctuation on macrophage inflammation in diabetes-related vascular diseases than thus far generally assumed.

Adipocyte Fatty Acid-Binding Protein Promotes Palmitate-Induced Mitochondrial Dysfunction and Apoptosis in Macrophages.

A high level of circulating free fatty acids (FFAs) is known to be an important trigger for macrophage apoptosis during the development of atherosclerosis. However, the underlying mechanism by which FFAs result in macrophage apoptosis is not well understood. In cultured human macrophage Thp-1 cells, we showed that palmitate (PA), the most abundant FFA in circulation, induced excessive reactive oxidative substance production, increased malondialdehyde concentration, and decreased adenosine triphosphate levels. Furthermore, PA treatment also led to mitochondrial dysfunction, including the decrease of mitochondrial number, the impairment of respiratory complex IV and succinate dehydrogenase activity, and the reduction of mitochondrial membrane potential. Mitochondrial apoptosis was also detected after PA treatment, indicated by a decrease in cytochrome c release, downregulation of Bcl-2, upregulation of Bax, and increased caspase-3 activity. PA treatment upregulated the expression of adipocyte fatty acid-binding protein (A-FABP), a critical regulator of fatty acid trafficking and lipid metabolism. Inhibition of A-FABP with BMS309403, a small-molecule A-FABP inhibitor, almost reversed all of these indexes. Thus, this study suggested that PA-mediated macrophage apoptosis through A-FABP upregulation, which subsequently resulted in mitochondrial dysfunction and reactive oxidative stress. Inhibition of A-FABP may be a potential therapeutic target for macrophage apoptosis and to delay the progress of atherosclerosis.

An excessive increase in glutamate contributes to glucose-toxicity in ß-cells via activation of pancreatic NMDA receptors in rodent diabetes.

In the nervous system, excessive activation of NMDA receptors causes neuronal injury. Although activation of NMDARs has been proposed to contribute to the progress of diabetes, little is known about the effect of excessive long-term activation of NMDARs on ß-cells, especially under the challenge of hyperglycemia. Here we thoroughly investigated whether endogenous glutamate aggravated ß-cell dysfunction under chronic exposure to high-glucose via activation of NMDARs. The glutamate level was increased in plasma of diabetic mice or patients and in the supernatant of ß-cell lines after treatment with high-glucose for 72 h. Decomposing the released glutamate improved GSIS of ß-cells under chronic high-glucose exposure. Long-term treatment of ß-cells with NMDA inhibited cell viability and decreased GSIS. These effects were eliminated by GluN1 knockout. The NMDAR antagonist MK-801 or GluN1 knockout prevented high-glucose-induced dysfunction in ß-cells. MK-801 also decreased the expression of pro-inflammatory cytokines, and inhibited I-κB degradation, ROS generation and NLRP3 inflammasome expression in ß-cells exposed to high-glucose. Furthermore, another NMDAR antagonist, Memantine, improved ß-cells function in diabetic mice. Taken together, these findings indicate that an increase of glutamate may contribute to the development of diabetes through excessive activation of NMDARs in ß-cells, accelerating ß-cells dysfunction and apoptosis induced by hyperglycemia.

Genetic diagnosis and treatment of a Chinese ketosis-prone MODY 3 family with depression.

BACKGROUND: To analyze the gene mutation and mental disorder of a Chinese ketosis-prone diabetes (KPD) family, and to make a precise diagnosis and give a treatment for them. METHODS: We studied a Chinese family with a clinical diagnosis of maturity-onset diabetes of the young (MODY). The clinical data and the blood samples were collected. The promotor and coding regions inclusive intron exon boundaries of the HNF1A, HNF4A were detected by polymerase chain reaction (PCR) and direct sequencing. The missense mutation was also analyzed by bioinformatics. Genetic counseling was performed twice a month to relieve the mental disorder of the persons. RESULTS: The missense mutation c.779 C>T (p.T260M) in exon4 of HNF1A gene was detected, and the symptom heterogenicity among persons in this family were found. All the members were retreated with Gliclazide and stopped to use other medicine, the blood glucose of them were well controlled. We also performed an active genetic counseling to them and the mental disorder of the proband's sister was relieved. CONCLUSIONS: A missense mutation of HNF1A gene was first found in Chinese ketosis-prone MODY family with manifestations heterogenicity among the persons. Sulphonylureas medicine and genetic counseling are efficiency ways to treat MODY 3 and its' mental disorder respectively.

Changes of Regulatory T Cells in the Early Stage of Obesity Mice and Their Modulation on Macrophage Subtypes in Visceral Adipose Tissue.

Objective To investigate the changes of regulatory T cells (Tregs) and whether Tregs can modulate the distribution of macrophage subtypes in visceral adipose tissue in the early stage of obesity.Methods After C57BL/6 mice obesity models were successfully established,metabolic parameters and numbers of Tregs and M1/M2 macrophage were measured at 4,10,and 20 weeks.The changes of metabolic parameters and adipose tissue inflammation in obesity mice after rapamycin intervention were evaluated. Results The early-stage obesity models were successfully established.Compared with normal diet mice,high fat diet mice had significantly higher epididymal adipose tissue mass and serum leptin levels(P<0.05).However,there was no statistical difference in blood glucose and insulin levels between these two groups(All P>0.05). Macrophages infiltration in adipose tissue in high fat diet mice gradually increased with time,coincident with decrease in Treg numbers. Increased numbers of Treg,improved metabolic parameters,and decreased ratio of M1/M2 can be seen after rapamycin intervention in mice.Conclusion The decrease of Tregs in the early stage of obesity may contribute to abnormal distribution of macrophage subtypes in visceral adipose.

[Changes in fasting serum cortisol levels in adolescents with type 1 diabetes and elevated depressive symptoms].

OBJECTIVE: To study the changes in serum cortisol levels in adolescents with type 1 diabetes (T1DM) and elevated depressive symptoms. METHODS: Twenty-eight adolescents with T1DM and 31 healthy peers were assessed for depressive symptoms using a depression self-rating scale developed by the Epidemiological Survey Center. Selected subjects were classified into four groups: T1DM with elevated depressive symptoms group (n=15), T1DM without elevated depressive symptoms group (n=13), elevated depressive symptoms without T1DM group (n=15), and normal control group (n=16). Fasting blood samples were collected in the morning, and the levels of serum cortisol were compared among the four groups. The correlations of serum levels of cortisol and glycosylated hemoglobin A1c (HbA1c) with the score of depression self-rating scale were evaluated by Pearson correlation analysis. RESULTS: The fasting serum cortisol levels in the 28 T1DM patients were significantly higher than in the 31 healthy peers (P<0.01). The fasting cortisol levels in the T1DM with elevated depressive symptoms group were significantly higher compared with those in the elevated depressive symptoms without T1DM group and normal control group (P<0.01). In adolescents with T1DM, serum HbA1c level was positively correlated with the score of depression self-rating scale (r=0.481, P=0.010). CONCLUSIONS: The fasting serum cortisol levels in adolescents with T1DM and elevated depressive symptoms are significantly increased, suggesting that the patients with comorbidity of T1DM and depression develop dysfunction of the corticotropin-releasing hormone-adrenocorticotropic hormone-cortisol axis. The elevated depressive symptoms may be associated with a poor control of glucose metabolism.

The clinical application of linagliptin in Asians.

Asia has a growing diabetic population. Linagliptin, a member of dipeptidyl peptidase-4 inhibitor class, is unique in its nonlinear pharmacokinetics with the characteristics of rapid attainment of steady state, little accumulation, predominantly nonrenal route of elimination, prolonged terminal half-life, and sustained inhibition of dipeptidyl peptidase-4 enzyme. No clinically relevant difference in pharmacokinetics was observed between Asians and non-Asians. The management of type 2 diabetes is increasingly challenging with the progression of disease, especially with the requirements of minimal hypoglycemia, weight gain, fluid retention, and other adverse effects. Linagliptin was efficacious and well-tolerated in Asian type 2 diabetes patients with or without renal or hepatic dysfunctions, comparable to that in Caucasians. This review will focus on the usage of linagliptin in clinical studies in Asians.

Current and Future Clinical Applications of Zinc Transporter-8 in Type 1 Diabetes Mellitus.

OBJECTIVE: To evaluate the utility of zinc transporter-8 (ZnT8) in the improvement of type 1 diabetes mellitus (T1DM) diagnosis and prediction, and to explore whether ZnT8 is a potential therapeutic target in T1DM. DATA SOURCES: A search was conducted within the medical database PubMed for relevant articles published from 2001 to 2015. The search terms are as follows: "ZnT8," "type 1 diabetes," "latent autoimmune diabetes in adults," "type 2 diabetes," "islet autoantibodies," "zinc supplement," "T cells," "ß cell," "immune therapy." We also searched the reference lists of selected articles. STUDY SELECTION: English-language original articles and critical reviews concerning ZnT8 and the clinical applications of islet autoantibodies in diabetes were reviewed. RESULTS: The basic function of ZnT8 is maintaining intracellular zinc homeostasis, which modulates the process of insulin biosynthesis, storage, and secretion. Autoantibodies against ZnT8 (ZnT8A) and ZnT8-specific T cells are the reliable biomarkers for the identification, stratification, and characterization of T1DM. Additionally, the results from the animal models and clinical trials have shown that ZnT8 is a diabetogenic antigen, suggesting the possibility of ZnT8-specific immunotherapy as an alternative for T1DM therapy. CONCLUSIONS: ZnT8 is a novel islet autoantigen with a widely potential for clinical applications in T1DM. However, before the large-scale clinical applications, there are still many problems to be solved.

Diabetes self-management, depressive symptoms, metabolic control and satisfaction with quality of life over time in Chinese youth with type 1 diabetes.

AIMS AND OBJECTIVES: To describe the patterns of diabetes self-management, depressive symptoms, metabolic control and satisfaction with quality of life over time in a cohort of Chinese youth with type 1 diabetes and to determine the relationships between these variables over time. BACKGROUND: Nurses have an important role in facilitating optimal self-management and health outcomes in youth with type 1 diabetes. Only a few studies have focused on patterns of diabetes adaptation over time in youth with type 1 diabetes, especially in China. Understanding changes in diabetes self-management, depressive symptoms, metabolic control and satisfaction with quality of life can facilitate assessment and intervention. DESIGN: This is a multi-site longitudinal descriptive study. Data for this report were collected at baseline with 136 eligible Chinese youth and 86 of them were followed up for the second time, 6-12 months after baseline data collection. METHODS: Instruments to measure diabetes self-management, depressive symptoms, metabolic control and satisfaction with quality of life were collected at two time points. The data were collected from July 2009-October 2010. Linear mixed model analysis was used to analyse the longitudinal data. RESULTS: Self-management decreased over time; however, depressive symptoms, metabolic control and satisfaction with quality of life did not change from baseline to 6-12 months in this sample of Chinese youth with type 1 diabetes. A decrease in diabetes self-management over time was associated with worse metabolic control, while an increase in depressive symptoms over time was associated with poorer quality of life satisfaction in this sample. CONCLUSIONS: Chinese youth faced difficulties with diabetes adaptation, especially with the deterioration of diabetes self-management. Improving self-management and decreasing depressive symptoms may enhance diabetes adaptation with respect to metabolic control and quality of life. RELEVANCE TO CLINICAL PRACTICE: The deterioration of diabetes self-management over time in youth with type 1 diabetes in China deserves nurses' careful surveillance. Clinical interventions appropriate to the Chinese culture and health care system are needed to improve self-management and depressive symptoms in Chinese youth with type 1 diabetes.