Studies in animals have documented that, compared with glucose, dietary fructose induces dyslipidemia and insulin resistance. To assess the relative effects of these dietary sugars during sustained ...consumption in humans, overweight and obese subjects consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks. Although both groups exhibited similar weight gain during the intervention, visceral adipose volume was significantly increased only in subjects consuming fructose. Fasting plasma triglyceride concentrations increased by approximately 10% during 10 weeks of glucose consumption but not after fructose consumption. In contrast, hepatic de novo lipogenesis (DNL) and the 23-hour postprandial triglyceride AUC were increased specifically during fructose consumption. Similarly, markers of altered lipid metabolism and lipoprotein remodeling, including fasting apoB, LDL, small dense LDL, oxidized LDL, and postprandial concentrations of remnant-like particle-triglyceride and -cholesterol significantly increased during fructose but not glucose consumption. In addition, fasting plasma glucose and insulin levels increased and insulin sensitivity decreased in subjects consuming fructose but not in those consuming glucose. These data suggest that dietary fructose specifically increases DNL, promotes dyslipidemia, decreases insulin sensitivity, and increases visceral adiposity in overweight/obese adults.
Prospective studies in humans examining the effects of fructose consumption on biological markers associated with the development of metabolic syndrome are lacking. Therefore we investigated the ...relative effects of 10 wks of fructose or glucose consumption on plasma uric acid and RBP-4 concentrations, as well as liver enzyme (AST, ALT, and GGT) activities in men and women.
As part of a parallel arm study, older (age 40-72), overweight and obese male and female subjects (BMI 25-35 kg/m2) consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 wks. Fasting and 24-h blood collections were performed at baseline and following 10 wks of intervention and plasma concentrations of uric acid, RBP-4 and liver enzyme activities were measured.
Consumption of fructose, but not glucose, led to significant increases of 24-h uric acid profiles (P < 0.0001) and RBP-4 concentrations (P = 0.012), as well as plasma GGT activity (P = 0.04). Fasting plasma uric acid concentrations increased in both groups; however, the response was significantly greater in subjects consuming fructose (P = 0.002 for effect of sugar). Within the fructose group male subjects exhibited larger increases of RBP-4 levels than women (P = 0.024).
These findings suggest that consumption of fructose at 25% of energy requirements for 10 wks, compared with isocaloric consumption of glucose, may contribute to the development of components of the metabolic syndrome by increasing circulating uric acid, GGT activity, suggesting alteration of hepatic function, and the production of RBP-4.
(1) Background: Clinical results on the effects of excess sugar consumption on insulin sensitivity are conflicting, possibly due to differences in sugar type and the insulin sensitivity index (ISI) ...assessed. Therefore, we compared the effects of consuming four different sugars on insulin sensitivity indices derived from oral glucose tolerance tests (OGTT). (2) Methods: Young adults consumed fructose-, glucose-, high-fructose corn syrup (HFCS)-, sucrose-, or aspartame-sweetened beverages (SB) for 2 weeks. Participants underwent OGTT before and at the end of the intervention. Fasting glucose and insulin, Homeostatic Model Assessment-Insulin Resistance (HOMA-IR), glucose and insulin area under the curve, Surrogate Hepatic Insulin Resistance Index, Matsuda ISI, Predicted M ISI, and Stumvoll Index were assessed. Outcomes were analyzed to determine: (1) effects of the five SB; (2) effects of the proportions of fructose and glucose in all SB. (3) Results: Fructose-SB and the fructose component in mixed sugars negatively affected outcomes that assess hepatic insulin sensitivity, while glucose did not. The effects of glucose-SB and the glucose component in mixed sugar on muscle insulin sensitivity were more negative than those of fructose. (4) Conclusion: the effects of consuming sugar-SB on insulin sensitivity varied depending on type of sugar and ISI index because outcomes assessing hepatic insulin sensitivity were negatively affected by fructose, and outcomes assessing muscle insulin sensitivity were more negatively affected by glucose.
► LNCaP cells with regulated expression of AR splice variants were generated. ► The AR-V7 variant is resistant to treatment with the Hsp90 inhibitor, Geldanamycin. ► AR-V7 is resistant to MJC13, a ...FKBP52-Hsp90-AR specific inhibitor.
Androgen ablation therapy is the most common treatment for advanced prostate cancer (PCa), but most patients will develop castration-resistant prostate cancer (CRPC), which has no cure. CRPC is androgen-depletion resistant but androgen receptor (AR) dependent. AR is a nuclear receptor whose transcriptional activity is regulated by hormone binding to the ligand-binding domain (LBD). Constitutively active AR splice variants that lack LBDs often are expressed in CRPC. The expression of these variants indicates that methods to inhibit AR activity that do not rely on inactivating the LBD are needed. Heat shock protein 90 (Hsp90), a potential therapeutic target in PCa, is an AR chaperone crucial for proper folding, hormone binding and transcriptional activity of AR. We generated LNCaP cell lines with regulated expression of the AR-V7 variant as well as a cell line expressing artificially truncated AR (termed AR-NTD) to characterize splice variant function. Using an Hsp90 inhibitor, Geldanamycin (GA), and an AR-Hsp90-FKBP52 specific inhibitor, MJC13, we sought to determine if the AR variants also require Hsp90 and associated co-chaperone, FKBP52, for their activity. GA inhibits AR transcriptional activity but has little effect on AR-V7 activity. Moreover, GA decreases the stability of AR protein, with no effect on AR-V7 levels. Full-length AR activity is strongly inhibited by MJC13 while AR-V7 is unaffected. Thus, the variants are resistant to inhibitors of the Hsp90-AR heterocomplex. Although Hsp90 inhibitors will continue to inhibit growth promoting kinases and signaling through activated full-length AR in CRPC, AR signaling through variants will be retained.
The structures of the silica polymorphs α-quartz and stishovite have been geometry optimized at highly simulated isotropic pressure within the framework of Density Functional Theory. The atoms of the ...high-pressure polymorph stishovite are virtually incompressible with the bonded radii for Si and O atoms decreasing by only 0.04 and 0.08 Å, respectively, at 100 GPa. In compensating for the increase in the effective interatomic potential associated with the compression of the Si-O bonded interactions, the electron density at the bond critical point between the bonded pair increases from 0.69 to 0.89 e/Å 3. The bonded radii of the Si and O atoms for α-quartz decrease by 0.006 and 0.008 Å, respectively, between 1 bar and 26.4 GPa. The impact of simulated, isotropic pressure on the bonded radii of the atoms for three perovskites YAlO3, LaAlO3, and CaSnO3 was also examined at high pressure. For the YAlO3 perovskite, the bonded radii for Y and Al decrease by 0.06 and 0.05 Å, respectively, at 80 GPa, while the electron density between the bonded atoms increases by 0.12 and 0.15 e/Å3, on average. The calculations also show that the coordination number of the Y atom increases from 9 to 10 while the coordination number of the O1 atom increases concomitantly in the structure from 5 to 6 at 20 GPa. Hence pressure not only promotes an increase in the coordination number of the metal atoms but also a necessary concomitant increase in the coordination number of the O atoms. The bonded radii, determined at a lower pressure between 0.0 and 15 GPa for LaAlO3 and CaSnO3, decrease a smaller amount with the radii for the La and Ca atoms decreasing by 0.03 and 0.04 Å, respectively, while the radii for the smaller Al and Sn atoms decrease by 0.01 and 0.02 Å, respectively. In general, O atoms are more compressible than the metal atoms, but overall the calculations demonstrate that the bonded radii for the atoms in crystals are virtually incompressible when subjected to high pressure. The reason that the bonded radii change little when subjected to high pressure is ascribed to the changes in the effective interatomic potentials that result in increased repulsion when the atoms are squeezed together.
Studies in rodents and humans suggest that high-fructose corn syrup (HFCS)-sweetened diets promote greater metabolic dysfunction than sucrose-sweetened diets.
To compare the effects of consuming ...sucrose-sweetened beverage (SB), HFCS-SB, or a control beverage sweetened with aspartame on metabolic outcomes in humans.
A parallel, double-blinded, NIH-funded study. Experimental procedures were conducted during 3.5 days of inpatient residence with controlled feeding at a research clinic before (baseline) and after a 12-day outpatient intervention period. Seventy-five adults (18-40 years) were assigned to beverage groups matched for sex, body mass index (18-35 kg/m2), and fasting triglyceride, lipoprotein and insulin concentrations. The intervention was 3 servings/day of sucrose- or HFCS-SB providing 25% of energy requirement or aspartame-SB, consumed for 16 days. Main outcome measures were %hepatic lipid, Matsuda insulin sensitivity index (ISI), and Predicted M ISI.
Sucrose-SB increased %hepatic lipid (absolute change: 0.6 ± 0.2%) compared with aspartame-SB (-0.2 ± 0.2%, P < 0.05) and compared with baseline (P < 0.001). HFCS-SB increased %hepatic lipid compared with baseline (0.4 ± 0.2%, P < 0.05). Compared with aspartame-SB, Matsuda ISI decreased after consumption of HFCS- (P < 0.01) and sucrose-SB (P < 0.01), and Predicted M ISI decreased after consumption of HFCS-SB (P < 0.05). Sucrose- and HFCS-SB increased plasma concentrations of lipids, lipoproteins, and uric acid compared with aspartame-SB. No outcomes were differentially affected by sucrose- compared with HFCS-SB. Beverage group effects remained significant when analyses were adjusted for changes in body weight.
Consumption of both sucrose- and HFCS-SB induced detrimental changes in hepatic lipid, insulin sensitivity, and circulating lipids, lipoproteins and uric acid in 2 weeks.
Increased hepatic lipid content and decreased insulin sensitivity have critical roles in the development of cardiometabolic diseases. Therefore, our objective was to investigate the dose-response ...effects of consuming high fructose corn syrup (HFCS)-sweetened beverages for two weeks on hepatic lipid content and insulin sensitivity in young (18-40 years) adults (BMI 18-35 kg/m
). In a parallel, double-blinded study, participants consumed three beverages/day providing 0% (aspartame:
= 23), 10% (
= 18), 17.5% (
= 16), or 25% (
= 28) daily energy requirements from HFCS. Magnetic resonance imaging for hepatic lipid content and oral glucose tolerance tests (OGTT) were conducted during 3.5-day inpatient visits at baseline and again at the end of a 15-day intervention. During the 12 intervening outpatient days participants consumed their usual diets with their assigned beverages. Significant linear dose-response effects were observed for increases of hepatic lipid content (
= 0.015) and glucose and insulin AUCs during OGTT (both
= 0.0004), and for decreases in the Matsuda (
= 0.0087) and Predicted M (
= 0.0027) indices of insulin sensitivity. These dose-response effects strengthen the mechanistic evidence implicating consumption of HFCS-sweetened beverages as a contributor to the metabolic dysregulation that increases risk for nonalcoholic fatty liver disease and type 2 diabetes.
Context:
Results from animal studies suggest that consumption of large amounts of fructose can promote inflammation and impair fibrinolysis. Data describing the effects of fructose consumption on ...circulating levels of proinflammatory and prothrombotic markers in humans are unavailable.
Objective:
Our objective was to determine the effects of 10 wk of dietary fructose or glucose consumption on plasma concentrations of monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), E-selectin, intercellular adhesion molecule-1, C-reactive protein, and IL-6.
Design and Setting:
This was a parallel-arm study with two inpatient phases (2 wk baseline, final 2 wk intervention), conducted in a clinical research facility, and an outpatient phase (8 wk) during which subjects resided at home.
Participants:
Participants were older (40–72 yr), overweight/obese (body mass index = 25–35 kg/m2) men (n = 16) and women (n = 15).
Interventions:
Participants consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 wk. Blood samples were collected at baseline and during the 10th week of intervention.
Main Outcome Measures:
Fasting concentrations of MCP-1 (P = 0.009), PAI-1 (P = 0.002), and E-selectin (P = 0.048) as well as postprandial concentrations of PAI-1 (P < 0.0001) increased in subjects consuming fructose but not in those consuming glucose. Fasting levels of C-reactive protein, IL-6, and intercellular adhesion molecule-1 were not changed in either group.
Conclusions:
Consumption of fructose for 10 wk leads to increases of MCP-1, PAI-1, and E-selectin. These findings suggest the possibility that fructose may contribute to the development of the metabolic syndrome via effects on proinflammatory and prothrombotic mediators.
Wildfires in the Great Basin have resulted in widespread loss of Wyoming big sagebrush (Artemisia tridentata Nutt. ssp. wyomingensis Beetle & Young), an ecologically important shrub that has proven ...difficult to establish from seed. We sought to identify optimal seeding practices for Wyoming big sagebrush in the context of postfire seeding operations involving rangeland drills. In an experiment replicated at three burned sites in the northern Great Basin, we compared Wyoming big sagebrush establishment across treatments differing by seed delivery technique, timing, and rate of seed application. A seed mix containing bunchgrasses was drill-seeded in alternate rows using one of two drill-types (conventional or minimum-till), and a mix containing sagebrush was either delivered by drill to the soil surface in remaining rows or broadcast by hand (simulating aerial seeding) following drilling in fall or winter. Drill-delivery of sagebrush seed was accompanied by drag chains (conventional drill) or imprinter wheels (minimum-till drill) to improve seed-soil contact and was carried out at multiple seeding rates (ca. 50,250, and 500 pure live seed m-2). During 2 yr following seeding, sagebrush establishment was lower at two sites (yr 1: ≤ 1.2 plants m-2; yr 2: ≤ 0.8 plants m-2) compared with a third site (yr 1: ≤ 4.1 plants m-2; yr 2: ≤ 2.0 plants m-2) where treatment differences were more pronounced and significant. Wherever density differed between treatments, it was consistently higher in certain treatment levels (minimum-till > conventional drill, drill-delivery > broadcast-delivery, fall broadcast > winter broadcast, and higher rates > lower rates). Densities declined between years at two sites, but we did not find evidence that declines were due to densitydependent mortality. Results indicate that seeding success can likely be enhanced by using a minimum-till imprinter seeding method and using seeding rates higher than typical postfire seeding recommendations for Wyoming big sagebrush.
Haemoglobin variants, Sickle (HbS) and foetal (HbF) have been associated with malaria protection. This study explores epistatic interactions between HbS and HbF on malaria infection.
The study was ...conducted between March 2004 and December 2013 within the sickle cell disease (SCD) programme at Muhimbili National Hospital, Tanzania. SCD status was categorized into HbAA, HbAS and HbSS using hemoglobin electrophoresis and High Performance Liquid Chromatography (HPLC). HbF levels were determined by HPLC. Malaria was diagnosed using rapid diagnostic test and/or blood film. Logistic regression and generalized estimating equations models were used to evaluate associations between SCD status, HbF and malaria.
2,049 individuals with age range 0-70 years, HbAA 311(15.2%), HbAS 241(11.8%) and HbSS 1,497(73.1%) were analysed. At enrolment, malaria prevalence was significantly higher in HbAA 13.2% compared to HbAS 1.24% and HbSS 1.34% (p<0.001). Mean HbF was lower in those with malaria compared to those without malaria in HbAA (0.43% vs 0.82%) but was the reverse in HbSS (8.10% vs 5.59%). An increase in HbF was associated with a decrease in risk of malaria OR=0.50 (95%CI: 0.28, 0.90; p=0.021) in HbAA, whereas for HbSS the risk of malaria increased OR=2.94 (1.44, 5.98; p=0.003). A similar pattern was seen during multiple visits; HbAA OR=0.52 (0.34, 0.80; p=0.003) vs HbSS OR=2.01 (1.27, 3.23; p=0.003).
Higher prevalence of malaria in HbAA compared to HbAS and HbSS confirmed the protective effect of HbS. Lower prevalence of malaria in HbAA with high HbF supports a protective effect of HbF. However, in HbSS, the higher prevalence of malaria with high levels of HbF suggests loss of malaria protection. This is the first epidemiological study to suggest a negative epistasis between HbF and HbS on malaria.
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