Mediation effect of body mass index on the association between serum magnesium level and insulin resistance in children from Mexico City.

BACKGROUND/OBJECTIVES: Reduced serum magnesium (Mg) levels have been associated with obesity, insulin resistance (IR), type 2 diabetes, and metabolic syndrome in adults. However, in the children population, the evidence is still limited. In this cross-sectional study, we aimed to analyze the association of serum Mg levels with the frequency of overweight and obesity and cardiometabolic traits in 189 schoolchildren (91 girls and 98 boys) between 6 and 12 years old from Mexico City. SUBJECTS/METHODS: Anthropometrical data were collected and biochemical parameters were measured by enzymatic colorimetric assay. Serum Mg level was analyzed by inductively coupled plasma mass spectrometry (ICP-MS). The triglyceride-glucose (TyG) index was used as a surrogate marker to evaluate IR. RESULTS: Serum Mg level was negatively associated with overweight (Odds ratio [OR] = 0.377, 95% confidence interval [CI] 0.231-0.614, p < 0.001) and obesity (OR = 0.345, 95% CI 0.202-0.589, p < 0.001). Serum Mg level resulted negatively associated with body mass index (BMI, ß = -1.16 ± 0.26, p < 0.001), BMI z-score (ß = -0.48 ± 0.10, p < 0.001) and TyG index (ß = -0.04 ± 0.04, p = 0.041). Through a mediation analysis was estimated that BMI z-score accounts for 60.5% of the negative association of serum Mg level with IR (Sobel test: z = 2.761; p = 0.005). CONCLUSION: Our results evidence that BMI z-score mediate part of the negative association of serum Mg level and IR in Mexican schoolchildren.

Serum levels of anti-inflammatory/proinflammatory adipocytokines, and copper levels in overweight and obese women in an adult Mexican population.

BACKGROUND: An imbalance between adipokines and micronutrient concentrations, such as those of copper (Cu), has been linked to dysregulation of energy homeostasis leading to weight gain and the development of other comorbidities; however, information on this issue remains limited. Our aim was to investigate the correlation between Cu status and serum adipokine levels and their relationship in normal-weight, overweight, and obese adult women. METHODS: Sixty patients were evaluated and classified according to their body mass index (BMI) and biochemical parameters; adipokines and Cu were measured at fasting. RESULTS: Leptin (Lep) and resistin (Res) levels were elevated, whereas adiponectin (Adpn) and ghrelin (Ghr) values were decreased in overweight and obese women (p = 0.001). The mean Adpn/Lep ratio was <0.5 in overweight and obese subjects, while the Lep/Ghr ratio increased significantly in relation to weight gain, suggesting an inverse link between the ratios of these hormones in the regulation of obesity. The analysis revealed a positive association between BMI and Cu levels in obese women. Moreover, a negative association between Cu and Res in normal-weight subjects was found. CONCLUSIONS: Circulating fasting Res levels are negatively associated with serum Cu concentration in normal-weight adult women. We also observed a close relationship between Adpn/Lep and Lep/Ghr ratios with obesity. However, more observational studies are required to confirm these results in future research.

Relationship of Serum Zinc Levels with Cardiometabolic Traits in Overweight and Obese Schoolchildren from Mexico City.

Zinc (Zn) participates as a cofactor for many enzymes in the cellular metabolism, and its serum levels have been associated with different metabolic diseases, especially obesity (OB). Nevertheless, its associations are not clear in the children population. The objective of this study is to evaluate the association between serum Zn levels (SZn) with overweight/obesity status (OW/OB), as well as its cardiometabolic traits in a population of children in Mexico City. Anthropometrical data (body mass index z score (BMIz)), demographic variables (age and sex), and cardiometabolic traits (total cholesterol (TC), high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), triglycerides (TG), fasting plasma glucose (FPG), and insulin) were analyzed in this cross-sectional study. SZn were measured by inductively coupled plasma mass spectrometry (ICP-MS). The population included 210 children from Mexico City (girls (n = 105) and boys (n = 105)) between ages 6 and 10 years. Normal-weight (NW) schoolchildren had higher SZn concentrations (66 µg/dL; IQR: 48 to 91) compared to OW or OB schoolchildren (61 µg/dL; IQR: 45 to 76). The data showed a significant negative association between SZn and BMIz without sex exclusion (r = - 0.181 and p = 0.009). The boy's population did not show an association between the SZn and BMIz compared to the girl's population which showed a significant negative association (r = - 0.277 and p = 0.004). In addition, other associations were found between SZn and TC (boys (r = 0.214 and p = 0.025), LDLc (boys (r = 0.213 and p = 0.029), and TG (girls (r = - 0.260 and p = 0.007)). Moreover, 38.6% of the total children in our population study had Zn deficiency (ZnD). NW schoolchildren had higher SZn concentrations compared to OW or OB schoolchildren. A diet low in Zn can be a factor to evaluate in the development of childhood OB in Mexico. However, further studies need to be performed on the children Mexican population to replicate and confirm our findings.

Overweight and Obesity Are Positively Associated with Serum Copper Levels in Mexican Schoolchildren.

Due to its relationship with oxidative stress and inflammation responses, obesity and its cardiometabolic implications have been related with serum copper (Cu). Hence, we analyzed the association of overweight (OW) and obesity (OB) status and cardiometabolic traits with serum Cu level in Mexican schoolchildren. Anthropometrical data and cardiometabolic traits were analyzed in this cross-sectional study. Serum Cu level was measured by inductively coupled plasma mass spectrometry. The study involved 191 schoolchildren (93 girls and 98 boys) with a mean age of 8.054 ± 1.170 years. Children with OW and OB had higher serum Cu levels than children with normal weight (NW) (mean difference: OW vs NW = 51.85 µg dL-1, OB vs NW = 47.22 µg dL-1, p < 0.001). In a multiple linear regression model, OW and OB status were positively associated with serum Cu levels (ßOW = 49.85, 95% confidence interval (95% CI) 35.84-63.87, p < 0.001; ßOB = 44.38, 95% CI 27.70-61.05, p < 0.001). We did not identify any significant association between cardiometabolic traits and serum Cu level. In conclusion, our results show an association of the presence of OW and OB with higher serum Cu levels, for the first time in Mexican schoolchildren. However, further functional studies are needed to better understand the role of Cu in the pathophysiology of obesity.

Serum zinc levels are associated with obesity and low-density lipoprotein cholesterol in Mexican adults.

PURPOSE: Little is known about the association between serum zinc (Zn) levels and obesity in the Mexican population. Therefore, we tested the association between serum Zn levels, obesity status, and serum lipid levels in a sample of Mexican adults. METHODS: Anthropometric data and serum levels of total cholesterol, high- and low-density lipoprotein cholesterol (HDL-C and LDL-C, respectively), and triglycerides were analyzed in 96 Mexican adults. Serum Zn was measured with inductively coupled plasma mass spectrometry. An individual data meta-analysis of the association between serum Zn, overweight, and obesity status was performed in 172 adults from two different provinces in Mexico. RESULTS: Serum Zn was negatively associated with body mass index (BMI, ß = -0.034 ± 0.013, p = 2.0 ×10-6) and obesity (odds ratio [OR]= 0.990, 95% confidence interval [CI]= 0.980-0.999, p = 3.4 ×10-5). The association between Zn level and obesity in Mexican adults was confirmed with an individual data meta-analysis (OR= 0.977, 95% CI= 0.966-0.988, p = 3.4 ×10-5). In addition, a significant interaction effect between serum Zn level and sex was observed on LDL-C level (ß = 7.010 ± 3.295, p = 0.037). Serum Zn was negatively associated with LDL-C levels in women (ß = -0.188 ± 0.074, p = 0.016). CONCLUSION: Our results confirm the negative association of serum Zn level with obesity. For the first time, we show a sex-specific association between serum Zn and LDL-C levels in a Mexican population. However, further studies are needed in larger and more varied Mexican cohorts to replicate and confirm our findings.

Serum lead levels and its association with overweight and obesity.

BACKGROUND: Lead (Pb) exposure has been associated with cardiovascular diseases and metabolic syndrome, nevertheless its association with obesity, type 2 diabetes, and dyslipidemia markers has been little explored in Mexico. Therefore, we evaluated the association of serum Pb levels (Pb-S), with body mass index (BMI), fasting plasma glucose (FPG), total cholesterol (TC), and triglycerides (TG). METHODS: A cross-sectional study was performed on 85 Mexican adults (57 women and 28 men). BMI was calculated, while FPG, TC, and TG were measured by the enzymatic colorimetric method. Total Pb-S levels were measured using inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: The study population was 20.3 ± 1.9 years old, showed an average of Pb-S of 0.0982 ± 0.068 µg dL-1, and presented a frequency of overweight (OW) and obesity (OB) of 50.5% and 18.8%, respectively. Men had higher average FPG than women (Women= 83.930 ± 5.662 vs Men= 84.953 ± 6.495; p = 0.037). When we analyzed anthropometric and clinical variables, Pb-S and frequency of OW and OB were observed to increase within the categories of Pb-S tertiles (<0.001). The averages of Pb-S were 0.051 ± 0.035 µg dL-1, 0.107 ± 0.067 µg dL-1, and 0.151 ± 0.063 µg dL-1 for individuals with normal weight (NW), OW, and OB, respectively. In addition, an analysis adjusted for age and sex shows Pb-S is positively associated with BMI (ß = 2.76 ± 0.498, p = <0.001). CONCLUSION: Our results evidence a significant association between Pb-S and the increase of BMI in Mexican adults and highlight the important health impact that may represent environmental Pb exposure.

Relationship Between Serum Levels of Arsenic, Cadmium, and Mercury and Body Mass Index and Fasting Plasma Glucose in a Mexican Adult Population.

In Mexico, few studies have analyzed the associations between toxic elements and metabolic diseases. In the present study, we analyzed the associations between serum arsenic (As), cadmium (Cd), and mercury (Hg) levels and body mass index (BMI) and fasting plasma glucose (FPG) in a Mexican adult population. Anthropometric data corresponding to 86 Mexican healthy adults (59 females and 27 men) were analyzed. FPG was analyzed by an enzymatic colorimetric method, and serum As, Cd, and Hg levels were analyzed by inductively coupled plasma-mass spectrometry (ICP-MS). The data show that the median serum As, Cd, and Hg levels were relatively higher in females (As = 1.78 ng mL-1, Cd = 1.00 ng mL-1, Hg = 0.96 ng mL-1) than those in males (As = 1.22 ng mL-1, Cd = 0.91 ng mL-1, Hg = 0.95 ng mL-1). However, these differences were not statistically significant (p ≥ 0.097). We also found that the median level of As significantly increased with an increase in the body weight categories (normal weight = 1.08; overweight = 1.50; obesity = 2.75; p < 0.001). In addition, a positive association between serum As levels and FPG before and after adjustment for BMI was demonstrated (RhoUnadjusted = 0.012; (RhoAdjusted = 0.243, p = 0.032). Serum As levels are positively associated with BMI and FPG in the adult population of Mexico. Nevertheless, these results need to be replicated and confirmed with a larger sample size.

Lipid Modulation in the Formation of ß-Sheet Structures. Implications for De Novo Design of Human Islet Amyloid Polypeptide and the Impact on ß-Cell Homeostasis.

Human islet amyloid polypeptide (hIAPP) corresponds to a 37-residue hormone present in insulin granules that maintains a high propensity to form ß-sheet structures during co-secretion with insulin. Previously, employing a biomimetic approach, we proposed a panel of optimized IAPP sequences with only one residue substitution that shows the capability to reduce amyloidogenesis. Taking into account that specific membrane lipids have been considered as a key factor in the induction of cytotoxicity, in this study, following the same design strategy, we characterize the effect of a series of lipids upon several polypeptide domains that show the highest aggregation propensity. The characterization of the C-native segment of hIAPP (residues F23-Y37), together with novel variants F23R and I26A allowed us to demonstrate an effect upon the formation of ß-sheet structures. Our results suggest that zwitterionic phospholipids promote adsorption of the C-native segments at the lipid-interface and ß-sheet formation with the exception of the F23R variant. Moreover, the presence of cholesterol did not modify this behavior, and the ß-sheet structural transitions were not registered when the N-terminal domain of hIAPP (K1-S20) was characterized. Considering that insulin granules are enriched in phosphatidylserine (PS), the property of lipid vesicles containing negatively charged lipids was also evaluated. We found that these types of lipids promote ß-sheet conformational transitions in both the C-native segment and the new variants. Furthermore, these PS/peptides arrangements are internalized in Langerhans islet ß-cells, localized in the endoplasmic reticulum, and trigger critical pathways such as unfolded protein response (UPR), affecting insulin secretion. Since this phenomenon was associated with the presence of cytotoxicity on Langerhans islet ß-cells, it can be concluded that the anionic lipid environment and degree of solvation are critical conditions for the stability of segments with the propensity to form ß-sheet structures, a situation that will eventually affect the structural characteristics and stability of IAPP within insulin granules, thus modifying the insulin secretion.

Ceramide Metabolism Balance, a Multifaceted Factor in Critical Steps of Breast Cancer Development.

Ceramides are key lipids in energetic-metabolic pathways and signaling cascades, modulating critical physiological functions in cells. While synthesis of ceramides is performed in endoplasmic reticulum (ER), which is altered under overnutrition conditions, proteins associated with ceramide metabolism are located on membrane arrangement of mitochondria and ER (MAMs). However, ceramide accumulation in meta-inflammation, condition that associates obesity with a chronic low-grade inflammatory state, favors the deregulation of pathways such as insulin signaling, and induces structural rearrangements on mitochondrial membrane, modifying its permeability and altering the flux of ions and other molecules. Considering the wide biological processes in which sphingolipids are implicated, they have been associated with diseases that present abnormalities in their energetic metabolism, such as breast cancer. In this sense, sphingolipids could modulate various cell features, such as growth, proliferation, survival, senescence, and apoptosis in cancer progression; moreover, ceramide metabolism is associated to chemotherapy resistance, and regulation of metastasis. Cell⁻cell communication mediated by exosomes and lipoproteins has become relevant in the transport of several sphingolipids. Therefore, in this work we performed a comprehensive analysis of the state of the art about the multifaceted roles of ceramides, specifically the deregulation of ceramide metabolism pathways, being a key factor that could modulate neoplastic processes development. Under specific conditions, sphingolipids perform important functions in several cellular processes, and depending on the preponderant species and cellular and/or tissue status can inhibit or promote the development of metabolic and potentially breast cancer disease.

Modulation of Amyloidogenesis Controlled by the C-Terminal Domain of Islet Amyloid Polypeptide Shows New Functions on Hepatocyte Cholesterol Metabolism.

The islet amyloid polypeptide (IAPP) or amylin maintains a key role in metabolism. This 37-residues-peptide could form pancreatic amyloids, which are a characteristic feature of diabetes mellitus type 2. However, some species do not form amyloid fibril structures. By employing a biomimetic approach, we generated an extensive panel of optimized sequences of IAPP, which could drastically reduce aggregation propensity. A structural and cellular characterization analysis was performed on the C-terminal domain with the highest aggregation propensity. This allowed the observation of an aggregative phenomenon dependent of the lipid environment. Evaluation of the new F23R variant demonstrated inhibition of ß-sheet structure and, therefore, amyloid formation on the native C-terminal, phenomenon that was associated with functional optimization in calcium and cholesterol management coupled with the optimization of insulin secretion by beta cells. When F23R variant was evaluated in microglia cells, a model of amyloidosis, cytotoxic conditions were not registered. In addition, it was found that C-terminal sequences of IAPP could modulate cholesterol metabolism in hepatocytes through regulation of SREBP-2, apoA-1, ABCA1, and LDLR, mechanism that may represent a new function of IAPP on the metabolism of cholesterol, increasing the LDL endocytosis in hepatocytes. Optimized sequences with only one residue modification in the C-terminal core aggregation could diminish ß-sheet formation and represent a novel strategy adaptable to other pharmacological targets. Our data suggest a new IAPP function associated with rearrangements on metabolism of cholesterol in hepatocytes.