phenanthrenes and Metabolic-Syndrome

Insulin resistance causes type 2 diabetes; therefore, increasing insulin sensitivity is a therapeutic approach against type 2 diabetes. Activating AMP-activated protein kinase (AMPK) is an effective approach for treating diabetes, and reduced insulin receptor substrate-1 (IRS-1) protein levels have been suggested as a molecular mechanism causing insulin resistance. Thus, dual targeting of AMPK and IRS-1 might provide an ideal way to treat diabetes. We found that 15,16-dihydrotanshinone I (DHTS), as a C1-Ten protein tyrosine phosphatase inhibitor, increased IRS-1 stability, improved glucose tolerance and reduced muscle atrophy. Identification of DHTS as a C1-Ten inhibitor revealed a new function of C1-Ten in AMPK inhibition, possibly through regulation of IRS-1. These findings suggest that C1-Ten inhibition by DHTS could provide a novel therapeutic strategy for insulin resistance-associated metabolic syndrome through dual targeting of IRS-1 and AMPK.

Topics: AMP-Activated Protein Kinases; Animals; Cell Line; Enzyme Activation; Furans; Glucose; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Muscular Atrophy; Phenanthrenes; Protein Tyrosine Phosphatases; Quinones; Signal Transduction

Polycyclic aromatic hydrocarbons (PAH) are both man-made and naturally occurring environmental pollutants that may be related to cardiometabolic health risk.. To determine whether PAH is associated with obesity in the adult population and to examine whether urinary concentrations of PAH metabolites are associated with differences in how obesity relates to 3 or more risk factors for the metabolic syndrome (3RFMetS), type 2 diabetes (T2D), hypertension, and dyslipidemia.. A total of 4765 adult participants from the 2001-2008 National Health and Nutrition Examination Survey were examined. The association between 8 urinary hydroxylated PAH metabolites, obesity, and health were examined using weighted logistic regressions adjusting for age, sex, ethnicity, PIR, smoking status, and urinary creatinine.. There was a positive dose-dependent association between obesity and 2-phenanthrene quintiles (P trend <0.0001). Contrarily, higher quintiles of 1-naphthalene were associated with lower risk of obesity (P trend = 0.0004). For a given BMI, those in the highest quintile of 2-naphthalene, 2-fluorene, 3-fluorene and 2-phenanthrene had a 66-80% greater likelihood of 3RFMetS (P≤0.05) compared to low levels. Higher quintiles of 1-naphthalene, 2-naphthalene, 2-phenanthrene and 1-pyrene were associated with a 78-124% greater likelihood of T2D (P≤0.05) compared to low levels while high 1-naphthalene, 2-naphthalene, 2-fluorene, 3-fluorene and 2-phenanthrene were associated with a 38-68% greater likelihood of dyslipidemia (P≤0.05) compared to lower levels. Finally, 2-naphthalene and 2-phenanthrene were positively associated with hypertension (P trend = 0.008 and P trend = 0.02 respectively).. PAH is related to obesity and the expression of a number of obesity-related cardiometabolic health risk factors. Future research is needed to bring to light the mechanistic pathways related to these findings.

Topics: Adult; Biomarkers; Canada; Creatinine; Diabetes Mellitus, Type 2; Dyslipidemias; Environmental Pollutants; Female; Fluorenes; Humans; Hypertension; Logistic Models; Male; Metabolic Syndrome; Middle Aged; Naphthalenes; Nutrition Surveys; Obesity; Phenanthrenes; Pyrenes; Risk

The putative selective estrogen receptor modulator (+)-Z-bisdehydrodoisynolic acid (Z-BDDA) has been found to improve cardiovascular risk in rodents. The objective of this study was to investigate the effectiveness of (+)-Z-BDDA compared with the antidiabetic drug, rosiglitazone, in treating obesity and risk factors associated with the metabolic syndrome.. Female Zucker Diabetic Fatty rats were randomly assigned to three treatment groups for 29 weeks: control (C), 1.8 mg (+)-Z-BDDA/kg diet [control diet + (+)-Z-BDDA (CB)], or 100 mg rosiglitazone/kg diet [control diet + rosiglitazone (CR)]. At sacrifice, physiological, biochemical, and molecular parameters were examined.. CB animals gained less weight and exhibited a decrease in total body lipids (p < 0.05) as compared with C or CR rats. Body weight and total body lipids were the highest in CR rats (p < 0.05). Liver weights in CB and CR rats were lower (p < 0.05) than in C rats, whereas kidney weights were lower in CB (p < 0.05) than in C and CR animals. Fasting plasma glucose was lower (p < 0.05) in the CB and CR animals when compared with C animals. C rats exhibited the highest concentration of total plasma cholesterol, and CR-treated rats exhibited the lowest concentration. Plasma triglycerides followed the same pattern as plasma cholesterol. Histomorphometry of heart vasculature revealed that CB and CR treatments produced a significant shift from small to large venules and arterioles compared with C (p < 0.05). Liver expression profiles of peroxisome proliferator-activated receptor (PPAR) alpha, PPARgamma, and PPAR-regulated genes revealed encouraging CB-induced effects.. These results suggest that (+)-Z-BDDA may have applications in treating obesity and complications associated with the metabolic syndrome.

Topics: Animals; Blood Glucose; Body Weight; Cholesterol; Coronary Vessels; Diabetes Mellitus, Experimental; Disease Models, Animal; Female; Gene Expression; Hypoglycemic Agents; Kidney; Liver; Metabolic Syndrome; Obesity; Organ Size; Phenanthrenes; PPAR alpha; PPAR gamma; Random Allocation; Rats; Rats, Zucker; Risk Factors; Rosiglitazone; Selective Estrogen Receptor Modulators; Thiazolidinediones; Triglycerides