A Newly Developed Indicator of Overeating Saturated Fat Based on Serum Fatty Acids and Amino Acids and Its Association With Incidence of Type 2 Diabetes: Evidence From Two Randomized Controlled Feeding Trials and a Prospective Study.

Objective: Hyper-caloric intake of saturated fatty acids (SFAs) is common in modern societies, probably contributing to the epidemic of type 2 diabetes mellitus (T2DM). This study conducted two randomized controlled trials (RCTs) for developing a new indicator that can assess the nutritional status and examined its association with incidence of T2DM. Methods: In RCT 1, healthy participants were randomly assigned into three groups, namely, control group (n = 40), overfeeding group 1 (100 g butter per day, n = 37), and overfeeding group 2 (120 g butter per day, n = 37). In RCT 2, healthy subjects were randomly assigned into two groups, namely, control group (n = 52) and high-fat group (300-extra kcal/day from diet that was designed by high-fat diet, n = 58). In the prospective cohort, 4,057 participants aged 20-74 years were enrolled and followed up over 5.3 years. Serum profiles of fatty acids and amino acids were measured. Results: In RCT 1, serum fatty acids, including C14:0 and C18:0, increased, whereas C18:2, C20:4, C22:5, and C22:6 decreased; serum amino acids, including tyrosine, alanine, and aminobutyric acid, increased, whereas histidine and glycine decreased (p < 0.05). Among these serum fatty acids and amino acids, changes in C14:0, C20:4, tyrosine, histidine, and glycine were also observed in RCT 2. An indicator was developed based on the five fatty acids and amino acids, namely, C14:0 × tyrosine × 1,000/[C20:4 × (glycine + histidine)], and it significantly identified participants in the intervention group with area under the curve (AUC) (95% CI) being 0.85 (0.77-0.92). The indicator was significantly associated with incidence of T2DM in the prospective cohort with HRs (95% CIs) from bottom quartile to top quartile being 1,1.21 (0.82-1.77), 1.60 (1.12-2.30), 2.04 (1.42-2.94). Conclusion: The newly developed indicator in RCTs can be used in assessing the nutritional status of hypercaloric intake of SFA and predicting the development of T2DM.

Integrated multi-omics uncovers reliable potential biomarkers and adverse effects of zinc deficiency.

BACKGROUND: Zinc deficiency is a worldwide public health problem. Currently, there are no established biomarkers available for the accurate diagnosis of zinc-deficiency in individuals. Additionally, a comprehensive view of the adverse effects of zinc deficiency is lacking. Our aim was to identify superior biomarkers of zinc deficiency and uncover the adverse effects of zinc deficiency. METHODS: We performed multi-omics analysis using serum proteomics-metabolomics and liver proteomics on zinc-deficient rats to identify candidate biomarkers and reveal the associated adverse effects of zinc deficiency. Secondly, the candidate biomarkers were validated in two zinc-deficient populations and an RCT zinc supplementation trial on a zinc-deficient population. RESULTS: Our integrated multi-omics approach revealed numerous biomarkers (>2000) and glutathione metabolism as the most important changed pathway in zinc deficiency. Three candidate biomarkers from glutathione metabolism were validated in repeated zinc-deficient rats by quantitative analysis. Only glutathione sulfotransferase omega-1 (GSTO1) (among 3 candidate biomarkers) was validated in the two zinc-deficient populations and zinc-supplemented population. Compared with serum zinc, serum GSTO1 yielded a better response to zinc supplementation and a higher correlation coefficient with zinc intake and the AUC value and has the potential for diagnosing zinc deficiency. By integrated multi-omics, we identified both established and novel adverse effects of zinc deficiency. CONCLUSIONS: Our integrated multi-omics analysis revealed more complete information about zinc deficiency; GSTO1 was found to be a reliable potential biomarker for diagnosis of zinc deficiency. This trial is registered at http://www.chictr.org.cn/registry.aspx as ChiCTR1900028162.

Extent reflecting overall dietary amino acids composition adherence to the human requirement amino acids pattern is associated with the development of type 2 diabetes.

This study aimed to elucidate whether dietary amino acids (AAs) composition is associated with type 2 diabetes mellitus (T2DM) and to investigate how serum AAs profiles mediated this association. Two prospective cohorts of 1750 and 4024 adults were enrolled. Dietary AAs compositions index (AACI) was developed to reflect the overall quality of dietary AAs composition. Multivariate linear regression and logistic regression models were used to examine associations of AACI and T2DM. The AACI was associated with the incidence of T2DM with the relative risk and 95%CI from the bottom to the top tertiles being 1.00, 1.49 (0.88-2.51) and 2.27 (1.20-4.28), and 1.00, 1.58 (1.13-2.19) and 2.33 (1.56-3.47) in the two cohorts, respectively. The AACI was positively associated with serum valine, isoleucine, glutamic acid and phenylalanine, and it was negatively associated with serum glycine and histidine in both cohorts (P<0.01). Valine, glutamic acid and histidine consistently and partially mediated the association between the AACI and T2DM in the two cohorts, with total mediation effects of 33.4% and 54.6%, respectively. Dietary AAs composition was associated with the incidence of T2DM, meanwhile, the relationship was mediated by some degree of serum AAs. Future dietary strategies should focus on the improvement of the overall quality of dietary AAs compositions.

An isocaloric moderately high-fat diet extends lifespan in male rats and Drosophila.

The health effect of dietary fat has been one of the most vexing issues in the field of nutrition. Few animal studies have examined the impact of high-fat diets on lifespan by controlling energy intake. In this study, we found that compared to a normal diet, an isocaloric moderately high-fat diet (IHF) significantly prolonged lifespan by decreasing the profiles of free fatty acids (FFAs) in serum and multiple tissues via downregulating FFA anabolism and upregulating catabolism pathways in rats and flies. Proteomics analysis in rats identified PPRC1 as a key protein that was significantly upregulated by nearly 2-fold by IHF, and among the FFAs, only palmitic acid (PA) was robustly and negatively associated with the expression of PPRC1. Using PPRC1 transgenic RNAi/overexpression flies and in vitro experiments, we demonstrated that IHF significantly reduced PA, which could upregulate PPRC1 through PPARG, resulting in improvements in oxidative stress and inflammation and prolonging the lifespan.

Temporal relationship between hyperuricemia and obesity, and its association with future risk of type 2 diabetes.

BACKGROUND/OBJECTIVES: Although hyperuricemia and obesity are significantly correlated, their temporal relationship and whether this relationship is associated with future risk of diabetes are largely unknown. This study examined temporal relationship between hyperuricemia and obesity, and its association with future risk of type 2 diabetes. SUBJECTS/METHODS: This study examined two longitudinal cohorts totally including 17,044 subjects from China with an average of 6.0 years follow-up. Measurements of body mass index (BMI), waist circumference (WC), percentage of body fat and fasting serum uric acid were obtained at two time points. Cross-lagged panel and mediation analysis were used to examine the temporal relationship between hyperuricemia and obesity, and the association of this temporal relationship with follow-up diabetes. RESULTS: In combined data of the two cohorts, the cross-lagged path coefficient (ß1 = 0.121; 95% confidence interval (CI): 0.108-0.135) from baseline uric acid to the follow-up BMI was significantly greater than the path coefficient (ß2 = 0.055, 95% CI: 0.038-0.072) from baseline BMI to the follow-up uric acid (P = 8.14e-10 for the difference between ß1 and ß2) with adjustment for covariates. The separate cross-lagged path models of uric acid with WC and percentage of body fat showed temporal patterns similar to that noted for uric acid with BMI. Further, the path coefficient (ß1) from baseline uric acid to follow-up BMI in the group with diabetes was significantly greater than without diabetes (P = 0.003 for the difference of ß1s in the two groups). BMI partially mediated the association of uric acid with risk of diabetes, and the percentage of mediated-association was estimated at 20.3% (95% CI: 15.7-24.8%). Results of these analyses in the combined data were consistent with those in the two cohorts, respectively. CONCLUSIONS: These findings indicated that increased uric acid levels probably associated with obesity and type 2 diabetes, and more definite research is needed to define any role for uric acid in relation to these diseases.

Free fatty acids profile among lean, overweight and obese non-alcoholic fatty liver disease patients: a case - control study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) given its association with obesity and diabetes may perhaps exert distinct free fatty acids (FFA) pattern, but the understanding of this phenomenon is limited. To this effect, we evaluated FFA profiles among healthy subjects and NAFLD patients stratified by body weight, to identify FFA valuable for early diagnosis of NAFLD. METHODS: Serum FFA profiles of healthy and NAFLD (lean, overweight and obese) subjects was determined using gas chromatography-mass spectrometry (GC-MS) and distinctions in FFA patterns were evaluated using one-way ANOVA while Receiver operating characteristics (ROC) and logistic regression models were used to explore FFA significant for diagnosing NAFLD. RESULTS: NAFLD patients presented significantly higher (P < 0.05) serum FFA profiles compared to healthy controls (HC). While total FFA profiles were insignificantly different between lean (2093.33 ± 558.11 µg/ml) and overweight (2420.81 ± 555.18 µg/ml) NAFLD patients, obese NAFLD (2739.01 ± 810.35 µg/ml) presented most significantly elevated (P < 0.05) total FFA profiles compared with HC. Of the four FFA; myristic acid (14:0), palmitoleic acid (16:1), γ-linolenic acid (γ-18:3) and cis-7,10,13,16,19-docosapentaenoic acid (22:5), selected in ROC analysis given their high Youden's index and AUC, only 14:0; 5.58(1.37, 22.76) and 16:1; 4.36(1.34, 14.13) had statistical significant odd ratios. CONCLUSION: Our findings suggest 14:0 and 16:1 are promising for early diagnosis of NAFLD.

Potential Mediating Biomarkers underlying the Association of Body Mass Index or Waist Circumference with Blood Pressure: Results from Three Population-based Studies.

We conducted a comprehensive and in-depth assessment of body mass index (BMI) or waist circumference (WC) related to blood pressure (BP) and determined whether the association is mediated by the possible potential mediators in the cross-sectional survey of the Harbin Cohort Study on Diet, Nutrition and Chronic Non-communicable Diseases of 7094 participants aged 20-74 years, and validated the significant findings in the US National Health and Nutrition Examination Survey four cross-sectional cohorts (2005-2006, 2007-2008, 2009-2010, and 2011-2012) and the cohort data of the Harbin People's Health Study (a median of 4.2 follow-up years). We observed that BMI or WC was positively associated with BP (all P-values < 0.0001). Mediation analyses consistently indicated that these associations were mediated mainly by insulin resistance (IR) as measured by the homeostasis model (HOMA-IR), followed by triglyceride (TG) and total cholesterol (TC), and fasting glucose (FG) in the three studies. The proportions via the mediation of insulin/HOMA-IR were 25~40%, TG and TC were 15~20%, and FG was 2~8%, respectively. These findings suggest that the mediators, insulin/insulin resistance, TG, TC, and FG, could be targeted for preventing hypertension among populations who were overweight or obesity.

A 1H-NMR based metabolomics study of the intervention effect of mangiferin on hyperlipidemia hamsters induced by a high-fat diet.

It has been demonstrated that mangiferin can ameliorate hypertriglyceridemia by modulating the expression levels of genes involved in lipid metabolism in animal experiments, but its effects on the serum metabolic fingerprinting of hyperlipidemia animal models have not been reported. Thus, a NMR-based metabolomics approach was conducted to explore the effects of mangiferin on hyperlipidemia hamsters and to gain a better understanding of the involved metabolic pathways. Hamsters fed with a high-fat diet were orally administered with mangiferin 150 mg per kg BW once a day for 8 weeks. Serum samples were analysed by 1H NMR, and multivariate statistical analysis was applied to the data to identify potential biomarkers. In total, 20 discriminating metabolites were identified. It turned out that mangiferin administration can partly reverse the metabolism disorders induced by a high-fat diet and exerted a good anti-hypertriglyceridemia effect. Mangiferin ameliorated hyperlipidemia by intervening in some major metabolic pathways, involving glycolysis, the TCA cycle, synthesis of ketone bodies, and BCAAs as well as choline and lipid metabolism. These findings provided new essential information on the effects of mangiferin and demonstrated the great potential of this nutrimetabolomics approach.

Elevated circulating stearic acid leads to a major lipotoxic effect on mouse pancreatic beta cells in hyperlipidaemia via a miR-34a-5p-mediated PERK/p53-dependent pathway.

AIMS/HYPOTHESIS: Serum stearic acid (C18:0) is elevated in individuals with hyperlipidaemia and type 2 diabetes. However, the lipotoxicity induced by increased stearic acid in beta cells has not been well described. This study aimed to examine the adverse effects of stearic acid on beta cells and the potential mechanisms through which these are mediated. METHODS: Three groups of C57BL/6 mice were fed a normal diet or a high-stearic-acid/high-palmitic-acid diet for 24 weeks, respectively. The microRNA (miR) profiles of islets were determined by microarray screening. Islet injury was detected with co-staining using the TUNEL assay and insulin labelling. A lentiviral vector expressing anti-miRNA-34a-5p oligonucleotide (AMO-34a-5p) was injected into mice via an intraductal pancreatic route. RESULTS: In both mouse islets and cultured rat insulinoma INS-1 cells, stearic acid exhibited a stronger lipotoxic role than other fatty acids, owing to repression of B cell CLL/lymphoma 2 (BCL-2) and BCL-2-like 2 (BCL-W) by stearic acid stimulation of miR-34a-5p. The stearic-acid-induced lipotoxicity and reduction in insulin secretion were alleviated by AMO-34a-5p. Further investigations in INS-1 cells revealed that p53 was involved in stearic-acid-induced elevation of miR-34a-5p, owing in part to activation of protein kinase-like endoplasmic reticulum kinase (PERK). Conversely, silencing PERK alleviated stearic-acid-induced p53, miR-34a-5p and lipotoxicity. CONCLUSIONS/INTERPRETATION: These findings provide new insight for understanding the molecular mechanisms underlying not only the deleterious impact of stearic-acid-induced lipotoxicity but also apoptosis in beta cells and progression to type 2 diabetes.

The Ratio of Dietary Branched-Chain Amino Acids is Associated with a Lower Prevalence of Obesity in Young Northern Chinese Adults: An Internet-Based Cross-Sectional Study.

This study aims to examine the association between the ratio of dietary branched chain amino acids (BCAA) and risk of obesity among young northern Chinese adults. A total of 948 randomly recruited participants were asked to finish our internet-based dietary questionnaire for the Chinese (IDQC). Associations between dietary BCAA ratio and prevalence of overweight/obesity and abdominal obesity were analyzed. Furthermore, 90 subjects were randomly selected to explore the possible mechanism. Dietary BCAA ratio in obese participants was significantly lower than non-obese participants. We found negative correlations between the ratio of dietary BCAA and body mass index (BMI) (r = -0.197, p < 0.001) or waist circumference (r = -0.187, p < 0.001). Compared with those in the first quartile, the multivariable-adjusted OR (95% CI) of the 3rd and 4th quartiles of dietary BCAA ratio for overweight/obesity were 0.508 (0.265-0.972) and 0.389 (0.193-0.783), respectively (all p < 0.05). After stratification by gender, the significance still existed in the 3rd and 4th quartile in males and the 4th quartile in females. For abdominal obesity, the multivariable-adjusted OR (95% CI) of the 3rd and 4th quartile of dietary BCAA ratio were 0.351 (0.145-0.845) and 0.376 (0.161-0.876), respectively (all p < 0.05). This significance was stronger in males. Further studies indicated that dietary BCAA ratio was inversely associated with 2-h postprandial glucose (2 h-PG) and status of inflammation. In conclusion, a higher ratio of dietary BCAA is inversely associated with prevalence of obesity, postprandial glucose and status of inflammation in young northern Chinese adults.