Liver Fat Is Increased in Type 2 Diabetic Patients and Underestimated by Serum Alanine Aminotransferase Compared With Equally Obese Nondiabetic Subjects

Kotronen, Anna; Juurinen, Leena; Hakkarainen, Antti; Westerbacka, Jukka; Corner, A. H.; Bergholm, Robert; Yki‐Järvinen, Hannele

doi:10.2337/dc07-1463

Cited by 172 publications

(143 citation statements)

References 28 publications

(28 reference statements)

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“…Moreover, although weaker, these relationships were still seen when no adjustment was made for BMI, a strong confounding factor for liver fat content (44). Additional adjustment for glucose tolerance status in the second replication cohort did not influence this relationship, implying that this association cannot be attributed to the effect of type 2 diabetes on the degree of hepatic steatosis (20). We have used concentrations of gGT and TG as surrogate markers of liver fat content, markers which provide only an estimate of the actual amount of hepatic fat.…”

Section: Discussionmentioning

confidence: 90%

Genetic variation in the ADIPOR2 gene is associated with liver fat content and its surrogate markers in three independent cohorts

Kotronen¹,

Yki‐Järvinen²,

Aminoff³

et al. 2009

European Journal of Endocrinology

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Aims: We investigated whether polymorphisms in candidate genes involved in lipid metabolism and type 2 diabetes are related to liver fat content. Methods: Liver fat content was measured using proton magnetic resonance spectroscopy ( 1 H-MRS) in 302 Finns, in whom single nucleotide polymorphisms (SNPs) in acyl-CoA synthetase long-chain family member 4 (ACSL4), adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2), and the three peroxisome proliferator-activated receptors (PPARA, PPARD, and PPARG) were analyzed. To validate our findings, SNPs significantly associated with liver fat content were studied in two independent cohorts and related to surrogate markers of liver fat content. Results: In the Finnish subjects, polymorphisms in ACSL4 (rs7887981), ADIPOR2 (rs767870), and PPARG (rs3856806) were significantly associated with liver fat content measured with 1 H-MRS after adjusting for age, gender, and BMI. Anthropometric and circulating parameters were comparable between genotypes. In the first validation cohort of w 600 Swedish men, ACSL4 rs7887981 was related to fasting insulin and triglyceride concentrations, and ADIPOR2 rs767870 to serum g glutamyltransferase concentrations after adjusting for BMI. The SNP in PPARG (rs3856806) was not significantly associated with any relevant metabolic parameter in this cohort. In the second validation cohort of w3000 subjects from Western Finland, ADIPOR2 rs767870, but not ACSL4 rs7887981 was related to fasting triglyceride concentrations. Conclusions: Genetic variation, particularly in the ADIPOR2 gene, contributes to variation in hepatic fat accumulation in humans.

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Section: Discussionmentioning

confidence: 90%

Genetic variation in the ADIPOR2 gene is associated with liver fat content and its surrogate markers in three independent cohorts

Kotronen¹,

Yki‐Järvinen²,

Aminoff³

et al. 2009

European Journal of Endocrinology

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“…It has been shown that nonalcoholic fatty liver disease, including hepatic steatosis, is closely related via enhanced inflammation to insulin resistance, metabolic syndrome, and cardiovascular disease [21][22][23][24] . Tabuchi et al 25) reported that ezetimibe inhibits the absorption of oxidized cholesterol and its deposition in the liver.…”

Section: Discussionmentioning

confidence: 99%

Ezetimibe Ameliorates Metabolic Disorders and Microalbuminuria in Patients with Hypercholesterolemia

Yagi

Akiyama

Aihara

et al. 2010

JAT

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Aim:Ezetimibe, an inhibitor of Niemann-Pick C1-like 1 protein, has been shown to reduce the intestinal absorption of cholesterol. We investigated whether it also has beneficial effects on metabolic disorder and/or renal insufficiency in patients with hypercholesterolemia. Methods: Ezetimibe was administered to 38 Japanese patients with hypercholesterolemia to obtain appropriate low-density lipoprotein cholesterol (LDL-chol) levels. Age-and sex-matched patients with hypercholesterolemia (n 38) were the controls. We evaluated the effects of ezetimibe before and 4 to 8 weeks after ezetimibe treatment. Results: Ezetimibe significantly decreased LDL-chol levels and metabolic syndrome-related factors, including body weight, waist circumference, blood pressure; homeostasis model assessment insulin resistance (HOMA-IR), and urinary albumin excretion, were significantly reduced. In addition, it decreased the level of high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor (TNF)-, the urinary excretion of 8-hydroxy-2'-deoxyguanosine, a parameter of oxidative stress, and increased the urinary excretion of nitrate and nitrite (NOx). In the controls we observed no such changes. Excepting the decrease in the serum TNF-level, the effects of ezetimibe were not correlated with decreased LDL-chol levels. Conclusion: Ezetimibe ameliorated the status of metabolic syndrome and microalbuminuria, reduced inflammation and oxidative stress, and increased nitric oxide bioavailability in a LDL-chol reductiondependent and -independent manner.

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“…However, a few clinical series observed that hepatic steatosis is a risk factor for NAFLD progression, mainly in the presence of obesity and type 2 diabetes [12]. Liver fat content is ∼80% higher in type 2 diabetic patients than in age-, sex-and BMImatched non-diabetic patients with NAFLD, and their serum liver enzymes are not as representative of the severity of intra-hepatic fat accumulation [13]. These data explain why type 2 diabetes is a risk factor for NAFLD progression, and are consistent with studies reporting a high standardised mortality ratio for liver disease in type 2 diabetes [14].…”

Section: Epidemiology and Natural History Of Nafldmentioning

confidence: 99%

Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon?

2008

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Non-alcoholic fatty liver disease (NAFLD), comprising a spectrum of conditions ranging from pure steatosis to steatohepatitis and cirrhosis, has reached epidemic proportions and represents the most common cause of chronic liver disease in the community. The prevalence of NAFLD has been estimated to be between 20% and 30% in the general population, but this value is much higher (∼70-80%) in type 2 diabetic patients, who are also at higher risk of developing advanced fibrosis and cirrhosis. Increasing recognition of the importance of NAFLD and its strong relationship with the metabolic syndrome has stimulated an interest in the possible role of NAFLD in the development of cardiovascular disease (CVD). Several epidemiological studies indicate that NAFLD, especially in its more severe forms, is linked to an increased risk of CVD, independently of underlying cardiometabolic risk factors. This suggests that NAFLD is not merely a marker of CVD, but may also be actively involved in its pathogenesis. The possible molecular mediators linking NAFLD and CVD include the release of pro-atherogenic factors from the liver (C-reactive protein, fibrinogen, plasminogen activator inhibitor-1 and other inflammatory cytokines) as well as the contribution of NAFLD per se to whole-body insulin resistance and atherogenic dyslipidemia, in turn favouring CVD progression. The clinical impact of NAFLD on CVD risk deserves particular attention in view of the implications for screening and surveillance strategies in the growing number of patients with NAFLD.

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Liver Fat Is Increased in Type 2 Diabetic Patients and Underestimated by Serum Alanine Aminotransferase Compared With Equally Obese Nondiabetic Subjects

Cited by 172 publications

References 28 publications

Genetic variation in the ADIPOR2 gene is associated with liver fat content and its surrogate markers in three independent cohorts

Genetic variation in the ADIPOR2 gene is associated with liver fat content and its surrogate markers in three independent cohorts

Ezetimibe Ameliorates Metabolic Disorders and Microalbuminuria in Patients with Hypercholesterolemia

Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon?

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