Ceramide d18:1/24:1 as a potential biomarker to differentiate obesity subtypes with unfavorable health outcomes.

BACKGROUND: The criteria for metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) remain controversial. This research aimed to identify a potential biomarker to differentiate the subtypes of obesity. METHODS: The study conducted a lipidomic evaluation of ceramide in the serum of 77 Chinese adults who had undergone hyperinsulinemic-euglycemic clamps. These adults were divided into three groups according to the clinical data: normal weight control group (N = 21), MHO (N = 20), and MUO (N = 36). RESULTS: The serum Cer d18:1/24:1 level in the MHO group was lower than that in the MUO group. As the Cer d18:1/24:1 level increased, insulin sensitivity decreased, and the unfavorable parameters increased in parallel. Multivariate logistic regression analysis revealed that serum Cer d18:1/24:1 levels were independently correlated with MUO in obesity. Individuals with higher levels of Cer d18:1/24:1 also had an elevated risk of cardiovascular disease. Most ceramide subtype levels increased in obesity compared to normal-weight individuals, but the levels of serum Cer d18:0/18:0 and Cer d18:1/16:0 decreased in obesity. CONCLUSIONS: The relationships between ceramide subtypes and metabolic profiles might be heterogeneous in populations with different body weights. Cer d18:1/24:1 could be a biomarker that can be used to differentiate MUO from MHO, and to better predict who will develop unfavorable health outcomes among obese individuals. TRIAL REGISTRATION: The First Affiliated Hospital of Nanjing Medical University's Institutional Review Board authorized this study protocol, and all participants provided written informed consent (2014-SR-003) prior to study entry.

Rare Diseases in Glycosphingolipid Metabolism.

Sphingolipidoses is a cluster of genetic rare disorders regarding glycosphingolipid metabolism, classified as lysosomal storage disorders (LSD). Here, we focus on eight inheritable diseases, including GM1 gangliosidosis, GM2 gangliosidosis, Fabry disease, Gaucher's disease, metachromatic leukodystrophy, Krabbe disease, Niemann-Pick disease A and B, and Farber disease. Mostly, pathogenic mutations in the key enzyme are loss-function, resulting in accumulation of substrates and deficiency of products. Thus, cellular overload of substrates causes lipotoxicity, which is deleterious to cellular and organ function. In the terms of clinical manifestations in sphingolipidoses, multiple systems and organs, especially central nervous system (CNS) are usually affected. As for diagnosis strategy, enzymatic activity assay and genetic sequencing are helpful. Up till now, limited treatment approaches have approved for treating sphingolipidoses, with some potential strategies for further evaluation. In general, enzyme replacement therapy (ERT), substrate reduction therapy (SRT), and molecular chaperones are feasible choices for enzyme deficiency disorders, but these therapies are limited to relieve CNS lesions and symptoms due to prevention from blood-brain barrier. Other possible treatments such as gene therapy, bone marrow transplantation (BMT), and hematopoietic stem cell transplantation (HSCT) need further evaluation.

Rare Diseases Related with Lipoprotein Metabolism.

Rare diseases are gathering increasing attention in last few years, not only for its effects on innovation scientific research, but also for its propounding influence on common diseases. One of the most famous milestones made by Michael Brown and Joseph Goldstein in metabolism field is the discovery of the defective gene in familial hypercholesterolemia, a rare human genetic disease manifested with extreme high level of serum cholesterol (Goldstein JL, Brown MS, Proc Natl Acad Sci USA 70:2804-2808, 1973; Brown MS, Dana SE, Goldstein JL, J Biol Chem 249:789-796, 1974). Follow-up work including decoding the gene function, mapping-related pathways, and screening therapeutic targets are all based on the primary finding (Goldstein JL, Brown MS Arterioscler Thromb Vasc Biol 29:431-438, 2009). A series of succession win the two brilliant scientists the 1985 Nobel Prize, and bring about statins widely used for lipid management and decreasing cardiovascular disease risks. Translating the clinical extreme phenotypes into laboratory bench work has turned out to be the first important step in the paradigm conducting translational and precise medical research. Here we review the main categories of rare disorders related with lipoprotein metabolism, aiming to strengthen the notion that human rare inheritable genetic diseases would be the window to know ourselves better, to treat someone more efficiently, and to lead a healthy life longer. Few rare diseases related with lipoprotein metabolism were clustered into six sections based on changes in lipid profile, namely, hyper- or hypocholesterolemia, hypo- or hyperalphalipoproteinemia, abetalipoproteinemia, hypobetalipoproteinemia, and sphingolipid metabolism diseases. Each section consists of a brief introduction, followed by a summary of well-known disease-causing genes in one table, and supplemented with one or two diseases as example for detailed description. Here we aimed to raise more attention on rare lipoprotein metabolism diseases, calling for more work from basic research and clinical trials.

Associations between Vitamin D Levels and Insulin Resistance in Non-Diabetic Obesity: Results from NHANES 2001-2018.

OBJECTIVE: Obesity is often accompanied by insulin resistance (IR) and diabetes. We explored the association between vitamin D levels and IR in non-diabetic obesity. METHODS: We conducted a cross-sectional study based on the data of National Health and Nutrition Examination Survey (NHANES) from 2001 to 2018. Non-diabetic individuals (aged ≥20 years) with obesity (BMI ≥ 30kg/m2) were included in the study. And HOMA-IR ≥ 2.5 was defined as IR. The multivariable linear regression models were constructed to evaluate the associations between levels of 25(OH)D and HOMA-IR. We calculated the odds ratio (OR) and 95% confidential intervals (CIs) for associations between 25(OH)D deficiency and IR in obesity using multivariable logistic regression models. RESULTS: Overall, a total of 3887 individuals were included in this study. Serum vitamin D level was significant lower in obesity participants with IR than that of non-IRs. The linear regression models showed that vitamin D level was inversely associated with HOMA-IR in obesity after adjusting for covariables (ß=-0.15, 95%CI (-0.28, -0.02), p = 0.028). And the multivariable logistic regression models indicated an association between vitamin D deficiency and IR in obesity ((OR= 1.38, 95%CI (1.09-1.73), p = 0.007)). The further stratified regression analyses among different BMI demonstrated that vitamin D deficiency (OR = 1.4, 95%CI (1.05,1.86), p = 0.022) only contributed to developing IR in class I obesity. CONCLUSION: This study suggested an association of vitamin D levels with IR in obesity. And vitamin D deficiency contributed to IR in class I obesity.

Diabetes Pharmacotherapy and its effects on the Skeletal Muscle Energy Metabolism.

The disorders of skeletal muscle metabolism in patients with Type 2 diabetes mellitus (T2DM), such as mitochondrial defection and glucose transporters (GLUTs) translocation dysfunctions, are not uncommon. Therefore, when anti-diabetic drugs were used in various chronic diseases associated with hyperglycemia, the impact on skeletal muscle should not be ignored. However, current studies mainly focus on muscle mass rather than metabolism or functions. Anti-diabetic drugs might have a harmful or beneficial impact on skeletal muscle. In this review, we summarize the upto- date studies on the effects of anti-diabetic drugs and some natural compounds on skeletal muscle metabolism, focusing primarily on emerging data from pre-clinical to clinical studies. Given the extensive use of anti-diabetic drugs and the common sarcopenia, a better understanding of energy metabolism in skeletal muscle deserves attention in future studies.

Vitamin A influences the incretin hormone profiles by activating the retinoic acid receptor ß.

BACKGROUND: This study aimed to investigate the impact of Vitamin A (VA) on intestinal glucose metabolic phenotypes. METHODS: Male C57BL/6 mice were randomized assigned to a VA-normal diet (VAN) or a VA-deficient diet (VAD) for 12 weeks. After12 weeks, the VAD mice were given 30 IU/g/d retinol for 10 days and VAN diet (VADN) for 10 weeks. By using glucose tolerance tests, immunofluorescence staining, quantitative polymerase chain reaction, siRNA transduction, and enzyme-linked immunosorbent assay, the glucose metabolic phenotypes as well as secretory function and intracellular hormone changes of STC-1 were assessed. RESULTS: VAD mice showed a decrease of glucose-stimulated insulin secretion and a loss of intestinal glucagon-like peptide-1 (GLP-1) expression. Through reintroducing dietary VA to VAD mice, the intestinal VA levels, GLP-1 expression and normal glucose can be restored. The incubation with retinol increased VA signaling factors expression within STC-1 cells, especially retinoic acid receptor ß (RARß). The activation of RARß restored intracellular incretin hormone synthesis and secretory function. CONCLUSIONS: VA deficiency leads to an imbalance of intestinal glucose metabolic phenotypes through a mechanism involving RARß signaling pathway, suggesting a new method to achieve the treatment for VAD induced glucose metabolism impairment.

Impaired Insulin Clearance as the Initial Regulator of Obesity-Associated Hyperinsulinemia: Novel Insight Into the Underlying Mechanism Based on Serum Bile Acid Profiles.

OBJECTIVE: To investigate the roles of insulin clearance and insulin secretion in the development of hyperinsulinemia in obese subjects and to reveal the association between insulin clearance and bile acids (BAs). RESEARCH DESIGN AND METHODS: In cohort 1, insulin secretion, sensitivity, and endogenous insulin clearance were evaluated with an oral glucose tolerance test in 460 recruited participants. In cohort 2, 81 participants underwent an intravenous glucose tolerance test and a hyperinsulinemic-euglycemic clamp to assess insulin secretion, endogenous and exogenous insulin clearance, and insulin sensitivity. Based on insulin resistance levels ranging from mild to severe, obese participants without diabetes were further divided into 10 quantiles in cohort 1 and into tertiles in cohort 2. Forty serum BAs were measured in cohort 2 to examine the association between BAs and insulin clearance. RESULTS: All obese participants had impaired insulin clearance, and it worsened with additional insulin resistance in obese subjects without diabetes. However, insulin secretion was unchanged from quantile 1 to 3 in cohort 1, and no difference was found in cohort 2. After adjustments for all confounding factors, serum-conjugated BAs, especially glycodeoxycholic acid (GDCA; ß = -0.335, P = 0.004) and taurodeoxycholic acid (TDCA; ß = -0.333, P = 0.003), were negatively correlated with insulin clearance. The ratio of unconjugated to conjugated BAs (ß = 0.335, P = 0.002) was positively correlated with insulin clearance. CONCLUSIONS: Hyperinsulinemia in obese subjects might be primarily induced by decreased insulin clearance rather than increased insulin secretion. Changes in circulating conjugated BAs, especially GDCA and TDCA, might play an important role in regulating insulin clearance.

Prevalence of HIV infection and associated risk factors among men who have sex with men (MSM) in Harbin, P. R. China.

OBJECTIVE: To assess the prevalence of HIV infection and characteristically risk of factors which associated with HIV infection among MSM in Harbin, China. METHODS: A face-to-face questionnaire interview was conducted among 463 Men Who Have Sex with Men (MSM) who were recruited by the snowball sampling in Harbin from April, 2011 to July, 2011. The questionnaire mainly included demographics, AIDS knowledge, homosexual behavior and the status of intervention in MSM. Blood specimens were obtained and tested for the diagnoses of HIV, syphilis and hepatitis C virus (HCV). Associations between above exposed factors and HIV infection were analyzed using a univariate analysis and forward stepwise logistic regression. RESULTS: The prevalence of HIV and syphilis was 9.5 and 14.3%. The awareness rate of AIDS was 86.8%. The rate of unprotected sexual behavior was 57.6% of MSM during the past 6 months. The univariate analysis identified that the age (age ≥ 35 years old), cohabitation, more than 10 years of homosexual behavior and more than 10 homosexual partners were risk factors which associated with the HIV infection, and that protected sex during the past 6 months was a protective factor for the HIV infection. The multivariate analysis identified that the duration of homosexual behavior and commercial sexual behavior were independent risk factors which associated with the HIV infection, and the protected sex during the past 6 months was a protective factor for the HIV infection. CONCLUSION: The prevalence of HIV among MSM in Harbin has been rapidly increasing in the past few years. Targeted, tailored, and comprehensive interventions are urgently needed to prevent the HIV infection from MSM.