Myristic Acid Supplementation Aggravates High Fat Diet-Induced Adipose Inflammation and Systemic Insulin Resistance in Mice.

Saturated fatty acids (SFAs) are considered to be detrimental to human health. One of the SFAs, myristic acid (MA), is known to exert a hypercholesterolemic effect in mice as well as humans. However, its effects on altering adipose tissue (AT) inflammation and systemic insulin resistance (IR) in obesity are still unclear. Here, we sought to determine the effects of a high fat (HF) diet supplemented with MA on obesity-associated metabolic disorders in mice. Wild-type C57BL/6 mice were fed a HF diet in the presence or absence of 3% MA for 12 weeks. Plasma lipids, plasma adipokines, AT inflammation, systemic IR, glucose homeostasis, and hepatic steatosis were assessed. The body weight and visceral adipose tissue (VAT) mass were significantly higher in mice receiving the HF+MA diet compared to HF diet-fed controls. Plasma total cholesterol levels were marginally increased in HF+MA-fed mice compared to controls. Fasting blood glucose was comparable between HF and HF+MA-fed mice. Interestingly, the plasma insulin and HOMA-IR index, a measure of insulin resistance, were significantly higher in HF+MA-fed mice compared to HF controls. Macrophage and inflammatory markers were significantly elevated in the AT and AT-derived stromal vascular cells upon MA feeding. Moreover, the level of circulating resistin, an adipokine promoting insulin resistance, was significantly higher in HF+MA-fed mice compared with HF controls. The insulin tolerance test revealed that the IR was higher in mice receiving the MA supplementation compared to HF controls. Moreover, the glucose tolerance test showed impairment in systemic glucose homeostasis in MA-fed mice. Analyses of liver samples showed a trend towards an increase in liver TG upon MA feeding. However, markers of oxidative stress and inflammation were reduced in the liver of mice fed an MA diet compared to controls. Taken together, our data suggest that chronic administration of MA in diet exacerbates obesity-associated insulin resistance and this effect is mediated in part, via increased AT inflammation and increased secretion of resistin.

Implications of the Hemoglobin Glycation Index on the Diagnosis of Prediabetes and Diabetes.

OBJECTIVE: Fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG) from a 75-g oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) can lead to different results when diagnosing prediabetes and diabetes. The Hemoglobin Glycation Index (HGI) quantifies the interindividual variation in glycation resulting in discrepancies between FPG and HbA1c. We used data from the Vitamin D and Type 2 Diabetes (D2d) study to calculate HGI, to identify HGI-associated variables, and to determine how HGI affects prediabetes and diabetes diagnosis. MEASUREMENTS: A linear regression equation [HbA1c (%) = 0.0164 × FPG (mg/dL) + 4.2] was derived using the screening cohort (n = 6829) and applied to calculate predicted HbA1c. This was subtracted from the observed HbA1c to determine HGI in the baseline cohort with 2hPG data (n = 3945). Baseline variables plus prediabetes and diabetes diagnosis by FPG, HbA1c, and 2hPG were compared among low, moderate, and high HGI subgroups. RESULTS: The proportion of women and Black/African American individuals increased from low to high HGI subgroups. Mean FPG decreased and mean HbA1c increased from low to high HGI subgroups, consistent with the HGI calculation; however, mean 2hPG was not significantly different among HGI subgroups. CONCLUSIONS: High HGI was associated with Black race and female sex as reported previously. The observation that 2hPG was not different across HGI subgroups suggests that variation in postprandial glucose is not a significant source of population variation in HGI. Exclusive use of HbA1c for diagnosis will classify more Black individuals and women as having prediabetes compared with using FPG or 2hPG.

A combination of Omega-3 PUFAs and COX inhibitors: A novel strategy to manage obesity-linked dyslipidemia and adipose tissue inflammation.

We previously reported that fish oil in combination with cyclooxygenase (COX) inhibitors exerts enhanced hypolipidemic and anti-inflammatory effects in mice. Here, we sought to determine the effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in combination with naproxen (NX), a COX inhibitor, on dyslipidemia and gene expression in adipose tissue (AT) in humans. Obese dyslipidemic patients were randomly assigned to one of these interventions for 12 wk: 1) Standard nutrition counseling (control), 2) ω-3 PUFAs (2 g twice daily), 3) NX (220 mg twice daily), and 4) ω-3 PUFAs (2 g twice daily) + NX (220 mg twice daily). The serum triglycerides showed a trend towards a reduction and a significant reduction (P<0.05) in ω-3 and ω3 + NX-treated subjects, respectively, compared to control. The mRNA expression of vascular cell adhesion molecule-1 (Vcam1), an inflammatory marker, increased significantly in AT of ω-3 PUFA-treated subjects but not in ω-3 PUFAs+NX-treated group. The plasma level of glycine-conjugated hyodeoxycholic acid, a secondary bile acid with hypolipidemic property, increased significantly in ω-3 PUFAs + NX-treated group. Our data suggest that combining NX with ω-3 PUFAs increases their effectiveness in reducing serum TG and favorably altering AT gene expression and plasma bile acid profile.

Baseline Characteristics of the Vitamin D and Type 2 Diabetes (D2d) Study: A Contemporary Prediabetes Cohort That Will Inform Diabetes Prevention Efforts.

OBJECTIVE: To describe baseline characteristics of the Vitamin D and Type 2 Diabetes (D2d) study, the first large U.S. diabetes prevention clinical trial to apply current American Diabetes Association (ADA) criteria for prediabetes. RESEARCH DESIGN AND METHODS: This is a multicenter (n = 22 sites), randomized, double-blind, placebo-controlled, primary prevention clinical trial testing effects of oral daily 4,000 IU cholecalciferol (D3) compared with placebo on incident diabetes in U.S. adults at risk for diabetes. Eligible participants were at risk for diabetes, defined as not meeting criteria for diabetes but meeting at least two 2010 ADA glycemic criteria for prediabetes: fasting plasma glucose (FPG) 100-125 mg/dL, 2-h postload glucose (2hPG) after a 75-g oral glucose load 140-199 mg/dL, and/or a hemoglobin A1c (HbA1c) 5.7-6.4% (39-46 mmol/mol). RESULTS: A total of 2,423 participants (45% of whom were women and 33% nonwhite) were randomized to cholecalciferol or placebo. Mean (SD) age was 59 (9.9) years and BMI 32 (4.5) kg/m2. Thirty-five percent met all three prediabetes criteria, 49% met the FPG/HbA1c criteria only, 9.5% met the 2hPG/FPG criteria only, and 6.3% met the 2hPG/HbA1c criteria only. Black participants had the highest mean HbA1c and lowest FPG concentration compared with white, Asian, and other races (P < 0.01); 2hPG concentration did not differ among racial groups. When compared with previous prediabetes cohorts, the D2d cohort had lower mean 2hPG concentration but similar HbA1c and FPG concentrations. CONCLUSIONS: D2d will establish whether vitamin D supplementation lowers risk of diabetes and will inform about the natural history of prediabetes per contemporary ADA criteria.

A combination of dietary N-3 fatty acids and a cyclooxygenase-1 inhibitor attenuates nonalcoholic fatty liver disease in mice.

We sought to determine whether a combination of purified n-3 fatty acids (n-3) and SC-560 (SC), a cyclooxygenase-1-specific inhibitor, is effective in ameliorating nonalcoholic fatty liver disease in obesity. Female wild-type mice were fed a high-fat and high-cholesterol diet (HF) supplemented with n-3 in the presence or absence of SC. Mice treated with SC alone exhibited no change in liver lipids, whereas n-3-fed mice tended to have lower hepatic lipids. Mice given n-3+SC had significantly lower liver lipids compared with HF controls indicating enhanced lipid clearance. Total and sulfated bile acids were significantly higher only in n-3+SC-treated mice compared with chow diet (CD) controls. Regarding mechanisms, the level of pregnane X receptor (PXR), a nuclear receptor regulating drug/bile detoxification, was significantly higher in mice given n-3 or n-3+SC. Studies in precision-cut liver slices and in cultured hepatoma cells showed that n-3+SC enhanced not only the expression/activation of PXR and its target genes but also the expression of farnesoid X receptor (FXR), another regulator of bile synthesis/clearance, indicating that n-3+SC can induce both PXR and FXR. The mRNA level of FGFR4 which inhibits bile formation showed a significant reduction in Huh 7 cells upon n-3 and n-3+SC treatment. PXR overexpression in hepatoma cells confirmed that n-3 or SC each induced the expression of PXR target genes and in combination had an enhanced effect. Our findings suggest that combining SC with n-3 potentiates its lipid-lowering effect, in part, by enhanced PXR and/or altered FXR/FGFR4 signaling.