Circulating MicroRNA-122 Is Associated With the Risk of New-Onset Metabolic Syndrome and Type 2 Diabetes
Peter WilleitPhilipp SkroblinAlexander R. MoschenXiaoke YinDorothee KaudewitzAnna ZampetakiTemo BarwariMeredith WhiteheadCristina M. RamírezLeigh GoedekeNoemí RotllánEnzo BonoraAlun D. HughesPeter SanterCarlos Fernández‐HernandoHerbert TilgJohann WilleitStefan KiechlManuel Mayr
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MicroRNA-122 (miR-122) is abundant in the liver and involved in lipid homeostasis, but its relevance to the long-term risk of developing metabolic disorders is unknown. We therefore measured circulating miR-122 in the prospective population-based Bruneck Study (n = 810; survey year 1995). Circulating miR-122 was associated with prevalent insulin resistance, obesity, metabolic syndrome, type 2 diabetes, and an adverse lipid profile. Among 92 plasma proteins and 135 lipid subspecies quantified with mass spectrometry, it correlated inversely with zinc-α-2-glycoprotein and positively with afamin, complement factor H, VLDL-associated apolipoproteins, and lipid subspecies containing monounsaturated and saturated fatty acids. Proteomics analysis of livers from antagomiR-122–treated mice revealed novel regulators of hepatic lipid metabolism that are responsive to miR-122 inhibition. In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT, n = 155), 12-month atorvastatin reduced circulating miR-122. A similar response to atorvastatin was observed in mice and cultured murine hepatocytes. Over up to 15 years of follow-up in the Bruneck Study, multivariable adjusted risk ratios per one-SD higher log miR-122 were 1.60 (95% CI 1.30–1.96; P < 0.001) for metabolic syndrome and 1.37 (1.03–1.82; P = 0.021) for type 2 diabetes. In conclusion, circulating miR-122 is strongly associated with the risk of developing metabolic syndrome and type 2 diabetes in the general population.Metabolic syndrome is also known as the insulin resistance syndrome (or syndrome X) in recognition of the pivotal pathogenic role of impaired insulin action. Various definitions of the metabolic syndrome have been proposed. The main features are abdominal adiposity, glucose intolerance, hypertriglyceridemia, low levels of high-density lipoprotein (HDL) cholesterol, hypertension in variable combinations, and in association with insulin resistance and hyperinsulinemia. Insulin resistance is implicated in common age-related diseases, including cognitive dysfunction and frailty syndrome. Non-alcoholic fatty liver disease (NAFLD), a disorder closely associated with hepatic and whole-body insulin resistance, the metabolic syndrome, and type 2 diabetes, has attained epidemic proportions. The clinical associations between hypertension, insulin resistance, and other components of the metabolic syndrome are demonstrated. Trials of bariatric surgery in patients with morbid obesity and the metabolic syndrome showed beneficial results, including decreased insulin resistance and lower levels of inflammatory cytokines.
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Nonalcoholic fatty liver disease (NAFLD), hepatic insulin resistance, and type 2 diabetes are all strongly associated and are all reaching epidemic proportions. Whether there is a causal link between NAFLD and hepatic insulin resistance is controversial. This review will discuss recent studies in both humans and animal models of NAFLD that have implicated increases in hepatic diacylglycerol (DAG) content leading to activation of novel protein kinase Cϵ (PKCϵ) resulting in decreased insulin signaling in the pathogenesis of NAFLD-associated hepatic insulin resistance and type 2 diabetes. The DAG-PKCϵ hypothesis can explain the occurrence of hepatic insulin resistance observed in most cases of NAFLD associated with obesity, lipodystrophy, and type 2 diabetes.
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Background: Metabolic syndrome (MetS) is a constellation of cardiometabolic risk determinants comprising of obesity, insulin resistance, dyslipidaemia and hypertension. In view of the epidemic of metabolic syndrome, this prospective, comparative study done in OPD setting in a tertiary care centre of central India aimed at finding out the changes in lipid profile, a surrogate marker of cardiovascular morbidities on treatment with low dose atorvastatin versus the usual care group.Methods: Patients satisfying NCEP-ATPIII criteria for metabolic syndrome were divided into two groups. Group A received treatment with 20 mg Atorvastatin along with target driven treatment for hypertension and elevated glucose, as required. Group B received the same except for atorvastatin. Serum lipid profiles were recorded and changes were compared before and after study duration of 3 months. Also, cardiac events were kept track of during follow up.Results: At the end of study it was found that treatment mediated changes in the lipid profile were highly significant (p<0.001) and favourable in group A as compared to Group B. Also, lesser cardiovascular outcomes were observed in Group A patients.Conclusions: The study concludes that among patients with metabolic syndrome, those treated with statins benefitted more than those who did not take statin therapy. This benefit in the correction of serum lipid profile also translated in terms of decreased cardiovascular outcomes in Group A patients. Hence, low dose atorvastatin therapy provides a potential approach for treatment of patients with metabolic syndrome.
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Abstract Psoriasis in adults is associated with an increased risk of metabolic disease. Various cardiometabolic comorbidities have been reported in childhood psoriasis, but only a few studies have analyzed the prevalence of metabolic syndrome. We performed a single-center prospective study investigating the prevalence of metabolic syndrome and insulin resistance in children with psoriasis. The prevalence of metabolic syndrome was evaluated in 60 pre-pubertal children with psoriasis (age: 3–10 years), accordingly to recently established criteria for the diagnosis of metabolic syndrome in children. Insulin resistance was considered altered when the homeostatic model assessment (HOMA-IR) for insulin resistance was ≥ 90th sex- and age-specific percentile and HOMA 2-IR was > 1.8. Eighteen (30%) children with psoriasis were found to have metabolic syndrome. Sixteen (27%) children were found to have insulin resistance. Conclusion : Our data underline the importance of assessing metabolic syndrome not only in adults and adolescents but also in young children with psoriasis. What is Known: • Psoriasis in adults is strongly associated with metabolic disease and insulin resistance. • Very limited data are available on the prevalence of metabolic syndrome and insulin resistance in pre-pubertal children with psoriasis . What is New: • This study reports that in pre-pubertal children with psoriasis, there is a high prevalence of metabolic syndrome and insulin resistance. • In children with psoriasis metabolic syndrome risk factors should be assessed .
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Abstract: Homeostasis model assessment of insulin resistance (HOMA-IR) is a method to measure insulin resistance. HOMA-IR cut-offs for identifying metabolic syndrome might vary across populations and body mass index (BMI) levels. We aimed to investigate HOMA-insulin resistance cut-offs that best discriminate individuals with insulin resistance and with metabolic syndrome for each BMI category in a large sample of adults without diabetes in the baseline of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Among the 12,313 participants with mean age of 51.2 (SD 8.9) years, the prevalence of metabolic syndrome was 34.6%, and 60.1% had overweight or obesity. The prevalence of metabolic syndrome among normal weight, overweight and obesity categories were, respectively, 13%, 43.2% and 60.7%. The point of maximum combined sensitivity and specificity of HOMA-IR to discriminate the metabolic syndrome was 2.35 in the whole sample, with increasing values at higher BMI categories. This investigation contributes to better understanding HOMA-IR values associated with insulin resistance and metabolic syndrome in a large Brazilian adult sample, and that use of cut-off points according to ROC curve may be the better strategy. It also suggests that different values might be appropriate across BMI categories.
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To evaluate the effect of a lower dose (20 mg) of atorvastatin on hs-CRP concentrations in patients with ACS.Group A (n = 50) patients received atorvastatin 20 mg day(-1) for 4 weeks in addition to standard anti-anginal treatment. Group B (n = 50) patients received standard anti-anginal treatment without atorvastatin.hs-CRP concentrations decreased in both groups, but the decrease was greater in group A. The decrease in hs-CRP was also significantly greater in the subgroups of smoking, hypertension and past history of cardiovascular disease with atorvastatin.The use of a lower dose (20 mg) of atorvastatin can offer an attractive approach for early treatment of patients with ACS.
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Background: The metabolic syndrome or insulin resistance syndrome is widely prevalent and multifactorial disorder. The majority of persons with metabolic syndrome have insulin resistance. Insulin resistance and / or associated hyperinsulinemia are believed to be the direct cause of other metabolic syndrome risk factors. The present work is being done to assess the insulin status and to assess the correlation between insulin status and other component of metabolic syndrome.Methods: The present work is being carried out in 112 cases of metabolic syndrome, defined as per modified NCEP ATP III (MS-4) criteria. Serum insulin of all cases was measured by chemiluminescent microparticle immunoassay (CMIA) technique.Results: It was observed that 62% of the patients of metabolic syndrome had elevated serum insulin level (Hyperinsulinemia). Hyperinsulinemia was found to be significantly associated with diastolic hypertension and HDL in males. A high association was also noted with BMI. Insulin resistance (HOMA-IR >2.50) was significantly associated with waist circumference in males (p value<0.05).Conclusions: It was observed that metabolic syndrome is associated with elevated serum insulin levels and each component of metabolic syndrome, both biochemical as well as clinical, is associated with hyper-insulinemia and this reflects the presence of insulin resistance in subjects of study.
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Objective To determine that atorvastatin might have anti-inflammatory effects in acute coronary syndromes(ACS) with C-reactive protein(CRP) reduction.Methods Ninety-two patients with ACS were assigned to three groups: high dose atorvastatin group(31 cases),taking atorvastatin 40 mg daily.Standard dose atorvastatin group(31 cases),taking atorvastatin 10 mg daily,and control group(30 cases),only receiving conventional therapy.CRP levels,lipid profiles were measured at first and fifth day and 1 month later.Results The study suggested:(1)CRP levels significantly decreased from baseline to the fifth day and 1 month later in high dose atorvastatin group(P0.05 or 0.001)respectively.Whereas,CRP level markedly reduced from baseline to 1 month late in standard dose atorvastatin group and control group(P0.05).(2) CRP levels were lower in high dose atorvastatin group versus standard dose atorvastatin group at fifth day and 1 month late(P0.05).(3) No correlation was found between changes in CRP and cholesterol levels in high dose atorvastatin group. Conclusions CRP levels in ACS are rapidly reduced with atorvastatin.The study provide evidence that atorvastatin hase faster and earlier anti-inflammatory effects in addition to lipid-lowing effects on ACS.
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We thank Prof. Dogru and colleagues for their interest in our recent article on the importance of adipocyte fatty acid binding protein (AFABP) in nonalcoholic fatty liver disease (NAFLD).1 It is now well accepted that NAFLD is the hepatic manifestation of the metabolic syndrome and as such is intimately associated with insulin resistance, visceral obesity, and dyslipidemia.2 Insulin resistance, which is a key characteristic of both conditions, has also been associated with NAFLD progression from simple steatosis to nonalcoholic steatohepatitis.3 We used the homeostasis model assessment of insulin resistance (HOMA-IR) to reflect the spectrum of insulin sensitivity. This index has been shown to correlate with the results of euglycemic-hyperinsulinemic clamp in patients without diabetes and with type 2 diabetes, including those treated with metformin and other oral hypoglycemic agents.4, 5 We were careful to exclude those taking thiazolidenediones, which have been shown to significantly affect circulating adipokine levels,6, 7 in contrast to sulfonylureas and metformin, which have not.7, 8 Type 2 diabetes eventually ensues in many subjects with increasing insulin resistance and is associated with more progressive fatty liver disease9; therefore, we decided not to exclude subjects with type 2 diabetes in our study. Although we agree it would be interesting to further subclassify subjects by glucose dysregulation status, the use of post hoc subset analysis is far less robust statistically and prone to type 2 error. We agree that metabolic variables and, in particular, measures of insulin resistance are important to consider when interpreting data on adipocytokines, which are intimately related to these factors. Indeed, our data showed the close association between both AFABP and lipocalin-2 to insulin resistance, body mass index, and waist circumference. To ensure our findings were independent of key confounders, we performed multivariate analysis for each histological endpoint in NAFLD using those factors significant on univariate analysis.1 We demonstrated that the association between AFABP and necroinflammatory and fibrotic activity is independent of abdominal obesity (the waist-hip ratio), cholesterol, high-density lipoprotein, and insulin resistance. For further clarity, as suggested by Prof. Dogru, we provide in Table 1 the relationship between AFABP and disease severity in NAFLD, directly controlled for insulin resistance and the key metabolic variables of body mass index, low-density lipoprotein, high-density lipoprotein, triglycerides, and glucose. This conclusively demonstrates that AFABP plays an important role in the pathogenesis of NAFLD independent of metabolic confounders. David van der Poorten*, Kerry-Lee Milner , Donald J. Chisholm , Jacob George*, * Storr Liver Unit, Westmead Millennium Institute, University of Sydney, Sydney, Australia, Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia.
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