***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background —LDL modification by endogenous advanced glycation end products ( AGEs ) is thought to contribute to cardiovascular disease of diabetes . It remains unclear , however , whether exogenous ( diet-derived ) AGEs influence glycoxidation and endothelial cell toxicity of diabetic LDL . Methods and Results —Twenty-four diabetic subjects were r and omized to either a st and ard diet ( here called high-AGE , HAGE ) or a diet 5-fold lower in AGE ( LAGE diet ) for 6 weeks . LDL pooled from patients on HAGE diet ( Db-HAGE-LDL ) was more glycated than LDL from the LAGE diet group ( Db-LAGE-LDL ) ( 192 versus 92 AGE U/mg apolipoprotein B ) and more oxidized ( 5.7 versus 1.5 nmol malondialdehyde/mg lipoprotein ) . When added to human endothelial cells ( ECV 304 or human umbilical vein endothelial cells ) , Db-HAGE-LDL promoted marked ERK1/2 phosphorylation ( pERK1/2 ) ( 5.5- to 10-fold of control ) in a time- and dose-dependent manner compared with Db-LAGE-LDL or native LDL . In addition , Db-HAGE-LDL stimulated NF-κB activity significantly in ECV 304 and human umbilical vein endothelial cells ( 2.3-fold above baseline ) in a manner inhibitable by a MEK inhibitor PD98059 ( 10 μmol/L ) , the antioxidant N-acetyl-l-cysteine , NAC ( 30 mmol/L ) , and the NADPH oxidase inhibitor DPI ( 20 μmol/L ) . In contrast to Db-LAGE-LD and native LDL , Db-HAGE-LDL induced significant soluble vascular cell adhesion molecule-1 production ( 2.3-fold ) , which was blocked by PD98059 , NAC , and DPI . Conclusions —Exposure to daily dietary glycoxidants enhances LDL-induced vascular toxicity via redox-sensitive mitogen-activated protein kinase activation . This can be prevented by dietary AGE restriction Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more BACKGROUND Reactive advanced glycation end products ( AGEs ) , known to promote diabetic tissue damage , occur endogenously as well as in heated foods and are orally absorbed . The relative contribution of diet-derived AGEs to diabetic nephropathy ( DN ) remains unclear . METHODS We tested a st and ard mouse food ( AIN-93 G ) found to be rich in AGEs ( H-AGE diet ) in parallel with a similar diet that contained six-fold lower AGE content ( L-AGE ) , but equal calories , macronutrients , and micronutrients . Non-obese diabetic mice ( NOD ) with type 1 diabetes ( T1D ) and db/db mice with type 2 diabetes ( T2D ) were r and omly assigned to each formula for either 4 or 11 months , during which time renal parameters and AGE levels were assessed . RESULTS Compared to the progressive DN and short survival seen in NOD mice exposed to long-term H-AGE feeding , L-AGE-fed NOD mice developed minimal glomerular pathology and a modest increase in urinary albumin : creatinine ratio ( p<0.005 ) , and a significantly extended survival ( p<0.0001 ) , consistent with lower serum ( p<0.025 ) and kidney AGEs ( p<0.01 ) . Also , in the 4-month study , and in contrast to the H-AGE-fed mice , L-AGE-fed NOD and db/db mice exhibited low levels of renal cortex TGF beta-1 ( p<0.05 ) , laminin B1 mRNA ( p<0.01 ) and alpha 1 IV collagen mRNA ( p<0.05 ) and protein , in concert with reduced serum and kidney AGEs ( p<0.05 , respectively ) . CONCLUSION Intake of high-level , food-derived AGEs is a major contributor to DN in T1D and T2D mice . Avoidance of dietary AGEs provides sustained protection against DN in mice ; providing the rationale for similar studies in human diabetic patients Dietary advanced glycosylation end products ( AGEs ) have been linked to insulin resistance in db/db(++ ) mice . To test whether dietary AGEs play a role in the progression of insulin resistance in normal mice fed high-fat diets , normal C57/BL6 mice were r and omly assigned to high-fat diets ( 35 % g fat ) , either high ( HAGE-HF group ; 995.4 units/mg AGE ) or low ( by 2.4-fold LAGE-HF group ; 329.6 units/mg AGE ) in AGE content for 6 months .  Age-matched C57/BL6 and db/db(++ ) mice fed regular diet ( 5 % g fat , 117.4 units/mg AGE ) served as controls . After 6 months , 75 % of HAGE-HF mice were diabetic and exhibited higher body weight ( P < 0.001 ) , fasting glucose ( P < 0.001 ) , insulin ( P < 0.001 ) , and serum AGEs ( P < 0.01 ) than control mice , while none of the LAGE-HF mice were diabetic despite a similar rise in body weight and plasma lipids . The HAGE-HF group displayed markedly impaired glucose and insulin responses during glucose tolerance tests and euglycemic and hyperglycemic clamps and altered pancreatic islet structure and function compared with those of LAGE-HF mice , in which findings resembled those of control mice . The HAGE-HF group had more visceral fat ( by two- and fourfold ) and more AGE-modified fat ( by two- and fivefold ) than LAGE-HF and control mice , respectively . In the HAGE-HF group , plasma 8-isoprostane was higher ( P < 0.01 ) and adiponectin lower ( P < 0.001 ) than control mice , while in the LAGE-HF group , these were more modestly affected ( P < 0.05 ) . These results demonstrate that the development of insulin resistance and type 2 diabetes during prolonged high-fat feeding are linked to the excess AGEs/advanced lipoxidation end products inherent in fatty diets The augmented consumption of dietary advanced glycation end products ( dAGEs ) has been associated with increased oxidative stress and inflammation , however , there is insufficient information over the effect on insulin resistance . The objective of the present study is to investigate the effect of dAGEs restriction on tumor necrosis factor-α ( TNF-α ) , malondialdehyde , C-reactive protein ( CRP ) , and insulin resistance in DM2 patients . We carried out a r and omized 6 weeks prospect i ve study in two groups of patients : subjects with a st and ard diet ( n = 13 ) , vs low dAGEs ( n = 13 ) . At the beginning and the end of study , we collected anthropometric measurements , and values of circulating glucose , HbA1c , lipids , insulin , serum AGEs , CRP , TNF-α and malondialdehyde . Anthropometric measurements , glucose , and lipids were similar in both groups at base line and at the end of the study . Estimation of basal dAGEs was similar in both groups ; after 6 weeks it was unchanged in the st and ard group but in the low dAGEs group decreased by 44 % ( p<0.0002 ) . Changes in TNF-α levels were different under st and ard diet ( 12.5 ± 14.7 ) as compared with low dAGEs ( −18.36 ± 17.1 , p<0.00001 ) ; changes in malondialdehyde were different in the respective groups ( 2.0 ± 2.61 and −0.83 ± 2.0 , p<0.005 ) no changes were found for insulin levels or HOMA-IR . In conclusion , The dAGEs restriction decreased significantly TNF-α and malondialdehyde levels OBJECTIVE Increased oxidative stress ( OS ) and impaired anti-OS defenses are important in the development and persistence of insulin resistance ( IR ) . Several anti-inflammatory and cell-protective mechanisms , including advanced glycation end product ( AGE ) receptor-1 ( AGER1 ) and sirtuin ( silent mating-type information regulation 2 homolog ) 1 ( SIRT1 ) are suppressed in diabetes . Because basal OS in type 2 diabetic patients is influenced by the consumption of AGEs , we examined whether AGE consumption also affects IR and whether AGER1 and SIRT1 are involved . RESEARCH DESIGN AND METHODS The study r and omly assigned 36 subjects , 18 type 2 diabetic patients ( age 61 ± 4 years ) and 18 healthy subjects ( age 67 ± 1.4 years ) , to a st and ard diet ( > 20 AGE equivalents [Eq]/day ) or an isocaloric AGE-restricted diet ( < 10 AGE Eq/day ) for 4 months . Circulating metabolic and inflammatory markers were assessed . Expression and activities of AGER1 and SIRT1 were examined in patients ’ peripheral blood mononuclear cells ( PMNC ) and in AGE-stimulated , AGER1-transduced ( AGER1 + ) , or AGER1-silenced human monocyte-like THP-1 cells . RESULTS Insulin and homeostasis model assessment , leptin , tumor necrosis factor-α and nuclear factor-κB p65 acetylation , serum AGEs , and 8-isoprostanes decreased in AGE-restricted type 2 diabetic patients , whereas PMNC AGER1 and SIRT1 mRNA , and protein levels normalized and adiponectin markedly increased . AGEs suppressed AGER1 , SIRT-1 , and NAD+ levels in THP-1 cells . These effects were inhibited in AGER1 + but were enhanced in AGER1-silenced cells . CONCLUSIONS Food-derived pro-oxidant AGEs may contribute to IR in clinical type 2 diabetes and suppress protective mechanisms , AGER1 and SIRT1 . AGE restriction may preserve native defenses and insulin sensitivity by maintaining lower basal OS SIRT1 and PPARγ , host defenses regulating inflammation and metabolic functions , are suppressed under chronic high oxidant stress and inflammation ( OS/Infl ) conditions . In diabetes , dietary advanced glycation end products ( dAGEs ) cause OS/Infl and suppress SIRT1 . Herein , we ask whether dAGEs also suppress host defense in adults without diabetes . The relationships between dAGEs and basal SIRT1 mRNA , PPARγ protein levels in mononuclear cells ( MNC ) and circulating inflammatory/metabolic markers were examined in 67 healthy adults aged > 60 years and in 18 subjects , before and after r and om assignment to either a st and ard diet ( regular > 15 AGE Eq/day ) or an isocaloric AGE-restricted diet ( < 10 AGE Eq/day ) for 4 months . Also , the interactions of AGEs and anti-AGE receptor-1 ( AGER1 ) with SIRT1 and PPARγ were assessed in wild type ( WT ) and AGER1-transduced ( AGER1 + ) MNC-like THP-1 cells . We found that dAGE , but not caloric intake , correlated negatively with MNC SIRT1 mRNA levels and positively with circulating AGEs ( sAGEs ) , OS/infl , MNC TNFα and RAGE . Basal MNC PPARγ protein was also lower in consumers of regular vs. AGE-restricted diet . AGE restriction restored MNC SIRT1 and PPARγ , and significantly decreased sAGEs , 8-isoprostanes , VCAM-1 , MNC TNFα and RAGE . Model AGEs suppressed SIRT1 protein and activity , and PPARγ protein in WT , but not in AGER1 + cells in vitro . In conclusion , chronic consumption of high-AGE diets depletes defenses such as SIRT1 and PPARγ , independent of calories , predisposing to OS/Infl and chronic metabolic disease . Restricted entry of oral AGEs may offer a disease-prevention alternative for healthy adults OBJECTIVE High-heat cooking of food induces the formation of advanced glycation end products ( AGEs ) , which are thought to impair glucose metabolism in type 2 diabetic patients . High intake of fructose might additionally affect endogenous formation of AGEs . This parallel intervention study investigated whether the addition of fructose or cooking methods influencing the AGE content of food affect insulin sensitivity in overweight individuals . RESEARCH DESIGN AND METHODS Seventy-four overweight women were r and omized to follow either a high- or low-AGE diet for 4 weeks , together with consumption of either f 
    Output:
    
A high AGE diet increased circulating tumour necrosis factor-alpha and AGEs in all population s. A high AGE diet increased 8-isoprostanes in healthy adults , and vascular cell adhesion molecule-1 ( VCAM-1 ) in patients with diabetes .