Increased Liver Fat, Impaired Insulin Clearance, and Hepatic and Adipose Tissue Insulin Resistance in Type 2 Diabetes

Kotronen, Anna; Juurinen, Leena; Tiikkainen, Mirja; Vehkavaara, Satu; Yki‐Järvinen, Hannele

doi:10.1053/j.gastro.2008.03.021

Cited by 302 publications

(270 citation statements)

References 55 publications

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“…An increase in circulating NEFA may contribute to obese NAFLD [38]. In keeping with this, we found a significant correlation between fasting NEFA and liver fat in the obese NAFLD and the PNPLA3-148II but not the PNPLA3-148MM, i.e.…”

Section: Discussionsupporting

confidence: 88%

Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3

et al. 2013

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Aims/hypothesis The rs738409 C>G single-nucleotide polymorphism in PNPLA3 leads to a missense mutation (I148M) which increases liver fat but does not cause insulin resistance. We hypothesised that patients with non-alcoholic fatty liver disease (NAFLD) due to the PNPLA3 variant ('PNPLA3 NAFLD'=PNPLA3-148MM) do not have adipose tissue (AT) inflammation in contrast with those with NAFLD due to obesity ('obese NAFLD'). Methods Biopsy specimens of AT were taken, and PNPLA3 genotype and liver fat ( 1 H-magnetic resonance spectroscopy) were determined in 82 volunteers, who were divided into groups based on either median BMI (obese 36.2± 0.7 kg/m 2 ; non-obese 26.0±0.4 kg/m 2 ) or PNPLA3 genotype. All groups were similar with respect to age and sex.The PNPLA3 subgroups were equally obese (PNPLA3-148MM, 31.1 ± 1.3 kg/m 2 ; PNPLA3-148II, 31.2 ± 0.8 kg/m 2 ), while the obese and non-obese subgroups had similar PNPLA3 genotype distribution. Gene expression of proinflammatory (MCP-1, CD68) and anti-inflammatory (Twist1, ADIPOQ) markers was measured using quantitative real-time RT-PCR. Results Liver fat was similarly increased in obese NAFLD (9.5±1.3% vs 5.1±0.9%, obese vs non-obese, p=0.007) and PNPLA3 NAFLD (11.4± 1.7% vs 5.3± 0.8%, PNPLA3-148MM vs PNPLA3-148II, p<0.001). Fasting serum insulin was higher in the obese than the non-obese group (76±6 vs 47±6 pmol/l, p<0.001), but similar in PNPLA3-148MM and PNPLA3-148II (60±8 vs 62±5 pmol/l, NS). In obese vs non-obese, MCP-1 and CD68 mRNAs were upregulated, whereas those of Twist1 and ADIPOQ were significantly downregulated. AT gene expression of MCP-1, CD68, Twist1 and ADIPOQ was similar in PNPLA3-148MM and PNPLA3-148II groups. Conclusions/interpretation PNPLA3 NAFLD is characterised by an increase in liver fat but no insulin resistance or AT inflammation, while obese NAFLD has all three of these features. Keywords

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Section: Discussionsupporting

confidence: 88%

Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3

et al. 2013

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“…These well-known derangements are major risk factors for development of hepatosteatitis and type-2 diabetes mellitus. [30][31][32] The increased hepatic fat depositionFbeing a hallmark of the metabolic syndromeFappeared to be abolished when mice were fed a diet with a fat content similar as the aforementioned HF diet, but in which 10% of the SFA were replaced by PUFA derived from FO (HF/FO diet). We observed, however, that lipid deposition inside adipose tissue as well as plasma leptin levels were greatly augmented in HF/FO-fed mice as compared with that in those fed the HF diet.…”

Section: Discussionmentioning

confidence: 99%

Metabolic responses to long-term pharmacological inhibition of CB1-receptor activity in mice in relation to dietary fat composition

et al. 2009

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Background and objectives:The antiobesity effects of suppressed endocannabinoid signaling may rely, at least in part, on changes in lipid fluxes. As fatty acids exert specific effects depending on their level of saturation, we hypothesized that the dietary fatty acid composition would influence the outcome of treatment with a CB 1 -receptor antagonist (rimonabant). Methods: Mice were treated with rimonabant (10 mg kg À1 body weight per day) or vehicle while equicalorically fed either a low-fat diet (LF), a high-fat (HF) diet or an HF diet in which 10% of the saturated fatty acids (SFAs) were replaced by polyunsaturated fatty acids (PUFA) from fish oil (FO). Food intake and body weight were registered daily. Indirect calorimetry was performed and feces were collected. After 3 weeks, mice were killed for blood and tissue collection. Results: Relative to the LF diet, the HF diet caused anticipated metabolic derangements, which were partly reversed by the HF/FO diet. The HF/FO diet, however, was most obesity-promoting despite inhibiting lipogenesis as indicated by low gene expression levels of lipogenic enzymes. On all three diets, rimonabant treatment improved metabolic derangements and led to significantly lower body weight gain than their respective controls. This latter effect appeared largest in the HF/FO group, but occurred without major changes in nutrient absorption and energy expenditure. Conclusion: The effects of chronic rimonabant treatment on body weight gain occurred irrespective of diet-induced changes in lipogenic activity, food intake and daily energy expenditure, and were, in fact, most pronounced in HF/FO mice. The effects of dietary PUFA replacement in an HF diet on expansion of adipose tissue might allow the favorable effects of dietary PUFA on dyslipidemia and hepatic steatosis. In light of other disadvantageous effects of weight gain, this might be a risky trade-off.

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“…Patients with Diabetes Mellitus (DM) are at four to five fold increased risk to CAD. Type 2 Diabetes Mellitus (T2DM) are commonly found in association with Non Alcoholic Fatty Liver Disease (NAFLD) [1], the mechanisms of liver injury in T2DM involve insulin resistance (IR), oxidative stress, apoptosis and adipokines [2]. IR results in peripheral lipolysis and upregulates hepatic de novo lipogenesis.…”

Section: Introductionmentioning

confidence: 99%

Association between Hepato-Biliary Status and HbA1C in Type 2 Diabetes Mellitus with Coronary Artery Disease (CAD)

Ramesh¹,

AdhishwarKumaran²,

KuzhandaiVelu³

et al. 2015

JDM

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Bilirubin has both antioxidant activity and cardio-protective potential. Decreased levels are associated with predicting CAD. Recent studies showed that bilirubin has inverse correlation with glycemic status. So in this we evaluated the role of Hepato-biliary function as a marker of predictor CAD in patient with T2DM. Total 100 subjects included 50 T2DM patients with CAD and 50 T2DM without CAD. All the subject venous blood was collected after overnight fasting for biochemical analysis. After the statistical analysis, the results showed significant difference between two groups as follows total bilirubin (0.32 ± 0.15; 0.90 ± 032; p = 0.000), direct bilirubin, indirect bilirubibn, Total Protein, Albumin, ALT, AST, HbA1c. Our finding implies that decreased serum bilirubin increases the risk of CAD in patients with T2DM and it shows inverse correlation between HbA1c and bilirubin.

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Increased Liver Fat, Impaired Insulin Clearance, and Hepatic and Adipose Tissue Insulin Resistance in Type 2 Diabetes

Cited by 302 publications

References 55 publications

Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3

Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3

Metabolic responses to long-term pharmacological inhibition of CB1-receptor activity in mice in relation to dietary fat composition

Association between Hepato-Biliary Status and HbA1C in Type 2 Diabetes Mellitus with Coronary Artery Disease (CAD)

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