***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: CONTEXT Inflammation is hypothesized to play a role in development of type 2 diabetes mellitus ( DM ) ; however , clinical data addressing this issue are limited . OBJECTIVE To determine whether elevated levels of the inflammatory markers interleukin 6 ( IL-6 ) and  C-reactive protein ( CRP ) are associated with development of  type 2 DM in healthy middle-aged women . DESIGN Prospect i ve , nested case-control study . SETTING The Women 's Health Study , an ongoing US primary prevention , r and omized clinical trial initiated in 1992 . PARTICIPANTS From a nationwide cohort of 27 628 women free of diagnosed DM , cardiovascular disease , and cancer at baseline , 188 women who developed diagnosed DM over a 4-year follow-up period were defined as cases and matched by age and fasting status with 362 disease-free controls . MAIN OUTCOME MEASURES Incidence of confirmed clinical ly diagnosed type 2 DM by baseline levels of IL-6 and CRP . RESULTS Baseline levels of IL-6 ( P<.001 ) and CRP ( P<.001 ) were significantly higher among cases than among controls . The relative risks of future DM for women in the highest vs lowest quartile of these inflammatory markers were 7.5 for IL-6 ( 95 % confidence interval [ CI ] , 3.7 - 15.4 ) and 15.7 for CRP ( 95 % CI , 6.5 - 37.9 ) . Positive associations persisted after adjustment for body mass index , family history of diabetes , smoking , exercise , use of alcohol , and hormone replacement therapy ; multivariate relative risks for the highest vs lowest quartiles were 2.3 for IL-6 ( 95 % CI , 0.9 - 5.6 ; P for trend = .07 ) and 4.2 for CRP ( 95 % CI , 1.5 - 12.0 ; P for trend = .001 ) . Similar results were observed in analyses limited to women with a baseline hemoglobin A(1c ) of 6.0 % or less and after adjustment for fasting insulin level . CONCLUSIONS Elevated levels of CRP and IL-6 predict the development of type 2 DM . These data support a possible role for inflammation in diabetogenesis A sub clinical inflammatory reaction has been shown to precede the onset of type 2 ( non-insulin-dependent ) diabetes . We therefore examined prospect ively the effects of the central inflammatory cytokines interleukin (IL)-1beta , IL-6 , and tumor necrosis factor-alpha ( TNF-alpha ) on the development of type 2 diabetes . We design ed a nested case-control study within the prospect i ve population -based European Prospect i ve Investigation into Cancer and Nutrition (EPIC)-Potsdam study including 27,548 individuals . Case subjects were defined to be those who were free of type 2 diabetes at baseline and subsequently developed type 2 diabetes during a 2.3-year follow-up period . A total of 192 cases of incident type 2 diabetes were identified and matched with 384 non-disease-developing control subjects .  IL-6 and TNF-alpha levels were found to be elevated in participants with incident type 2 diabetes , whereas IL-1beta plasma levels did not differ between the groups . Analysis of single cytokines revealed IL-6 as an independent predictor of type 2 diabetes after adjustment for age , sex , BMI , waist-to-hip ratio ( WHR ) , sports , smoking status , educational attainment , alcohol consumption , and HbA(1c ) ( 4th vs. the 1st quartile : odds ratio [ OR ] 2.6 , 95 % CI 1.2 - 5.5 ) . The association between TNF-alpha and future type 2 diabetes was no longer significant after adjustment for BMI or WHR . Interestingly , combined analysis of the cytokines revealed a significant interaction between IL-1beta and IL-6 . In the fully adjusted model , participants with detectable levels of IL-1beta and elevated levels of IL-6 had an independently increased risk to develop type 2 diabetes ( 3.3 , 1.7 - 6.8 ) , whereas individuals with increased concentrations of IL-6 but undetectable levels of IL-1beta had no significantly increased risk , both compared with the low-level reference group . These results were confirmed in an analysis including only individuals with HbA(1c ) < 5.8 % at baseline . Our data suggest that the pattern of circulating inflammatory cytokines modifies the risk for type 2 diabetes . In particular , a combined elevation of IL-1beta and IL-6 , rather than the isolated elevation of IL-6 alone , independently increases the risk of type 2 diabetes . These data strongly support the hypothesis that a sub clinical inflammatory reaction has a role in the pathogenesis of type 2 diabetes Obesity and type 2 diabetes are characterized by insulin resistance , and the common basis of these events is a chronic and systemic inflammatory process marked by the activation of the c-Jun N-terminal kinase ( JNK ) and inhibitor-κB kinase (IKKβ)/nuclear factor-κB ( NFκB ) pathways , up-regulated cytokine synthesis , and endoplasmic reticulum dysfunction . The aim of this study was to evaluate the effects of diacerhein administration , an antiinflammatory drug that reduces the levels of inflammatory cytokines , on insulin sensitivity and signaling in diet-induced obese ( DIO ) mice . Swiss mice were fed with conventional chow ( control group ) or a high-fat diet ( DIO group ) . Later , DIO mice were r and omly subdivided into a new subgroup ( DAR ) that received 20 mg/kg diacerhein for 10 d. Western blotting was used to quantify the expression and phosphorylation of insulin receptor , insulin receptor substrate 1 , and Akt and of inflammatory mediators that modulate insulin signaling in a negative manner ( IKKβ , JNK , and inducible nitric oxide synthase ) . We show here , for the first time , that the administration of diacerhein in DIO mice improved endoplasmic reticulum stress , reduced JNK and IKKβ phosphorylation , and result ed in a marked improvement in fasting glucose , a decrease in macrophage infiltration in adipose tissue , and a reduced expression and activity of proinflammatory mediators accompanied by an improvement in the insulin signaling mainly in the liver and adipose tissue . Taken together , these results indicate that diacerhein treatment improves insulin sensitivity in obesity , mediated by the reversal of sub clinical inflammation , and that this drug may be an alternative therapy for insulin resistance Objective To evaluate the effect of diacerein as an add-on to metformin in patients with type 2 diabetes mellitus ( T2DM ) and inadequate glycemic control . Material s and methods A r and omized , double-blind , placebo-controlled clinical trial was carried out on 12 patients with T2DM and inadequate glycemic control [ glycated hemoglobin A1c ( A1C ) ≥ 7 % ] with metformin as monotherapy ( ≥ 1500 mg per day ) for at least the previous 90 days . Fasting and postpr and ial glucose were measured before and after the pharmacological intervention . A1C , lipid profile , creatinine and uric acid were also evaluated . After r and omization , all patients continued with their dose of metformin . Six subjects received placebo and the other six volunteers took diacerein . Data were tested using the Wilcoxon signed-rank , Mann-Whitney U and chi-square tests . The Institutional Ethics Committee approved the study protocol . Results After 90 days of diacerein as an add-on to metformin , there was a significant decrease in fasting glucose ( 196 ± 79 vs. 149 ± 70 mg/dL , p < 0.05 ) , postpr and ial glucose ( 262 ± 99 vs. 187 ± 70 mg/dlL , p < 0.05 ) and A1C ( 8.4 ± 2.0 vs. 6.7 ± 1.7 % , p < 0.05 ) . Conclusions Diacerein as an add-on to metformin in patients with T2DM  improved their glycemic control BACKGROUND Inflammation may be important in the pathogenesis of atherothrombosis . We studied whether inflammation increases the risk of a first thrombotic event and whether treatment with aspirin decreases the risk . METHODS We measured plasma C-reactive protein , a marker for systemic inflammation , in 543 apparently healthy men participating in the Physicians ' Health Study in whom myocardial infa rct ion , stroke , or venous thrombosis subsequently developed , and in 543 study participants who did not report vascular disease during a follow-up period exceeding eight years . Subjects were r and omly assigned to receive aspirin or placebo at the beginning of the trial . RESULTS Base-line plasma C-reactive protein concentrations were higher among men who went on to have myocardial infa rct ion ( 1.51 vs. 1.13 mg per liter , P<0.001 ) or ischemic stroke ( 1.38 vs. 1.13 mg per liter , P=0.02 ) , but not venous thrombosis ( 1.26 vs. 1.13 mg per liter , P=0.34 ) , than among men without vascular events . The men in the quartile with the highest levels of C-reactive protein values had three times the risk of myocardial infa rct ion ( relative risk , 2.9 ; P<0.001 ) and two times the risk of ischemic stroke ( relative risk , 1.9 ; P=0.02 ) of the men in the lowest quartile . Risks were stable over long periods , were not modified by smoking , and were independent of other lipid-related and non-lipid-related risk factors . The use of aspirin was associated with significant reductions in the risk of myocardial infa rct ion ( 55.7 percent reduction , P=0.02 ) among men in the highest quartile but with only small , nonsignificant reductions among those in the lowest quartile ( 13.9 percent , P=0.77 ) . CONCLUSIONS The base-line plasma concentration of C-reactive protein predicts the risk of future myocardial infa rct ion and stroke . Moreover , the reduction associated with the use of aspirin in the risk of a first myocardial infa rct ion appears to be directly related to the level of C-reactive protein , raising the possibility that antiinflammatory agents may have clinical benefits in preventing cardiovascular disease OBJECTIVE To assess , in a r and omized , double-blind , and placebo-controlled trial , the efficacy and safety of diacerein , an immune modulator anti-inflammatory drug , in improving glycemic control of patients with type 2 diabetes . RESEARCH DESIGN AND METHODS Eighty-four patients with HbA1c between 7.5 and 9.5 % ( 58–80 mmol/mol ) were r and omized to 48-week treatment with placebo ( n = 41 ) or diacerein 100 mg/day ( n = 43 ) . The primary outcome was the difference in mean HbA1c changes during treatment . Secondary outcomes were other efficacy and safety measurements . A general linear regression with repeated measures , adjusted for age , sex , diabetes duration , and each baseline value , was used to estimate differences in mean changes . Both intention-to-treat ( ITT ) analysis and per- protocol analysis ( excluding 10 patients who interrupted treatment ) were performed . RESULTS Diacerein  reduced HbA1c compared with placebo by 0.35 % ( 3.8 mmol/mol ; P = 0.038 ) in the ITT analysis and by 0.41 % ( 4.5 mmol/mol ; P = 0.023 ) in the per- protocol analysis . The peak of effect occurred at the 24th week of treatment ( −0.61 % [ 6.7 mmol/mol ; P = 0.014 ] and −0.78 % [ 8.5 mmol/mol ; P = 0.005 ] , respectively ) , but it attenuated toward nonsignificant differences at the 48th week . No significant effect of diacerein was observed in other efficacy and safety measures . Diarrhea occurred in 65 % of patients receiving diacerein and caused treatment interruption in 16 % . Seven patients in the diacerein group reduced insulin dosage , whereas 10 in the placebo group increased it ; however , mild hypoglycemic events were equally observed . CONCLUSIONS Diacerein  reduced mean HbA1c levels , with peak of effect at the 24th week of treatment . The drug was well tolerated and may be indicated as adjunct treatment in patients with type 2 diabetes , particularly in those with osteoarthritis 
    Output:
    
Although further studies are needed , our findings clearly provide support to the use of diacerein in the clinical management of subjects with type 2 diabetes