Diacylglycerol/protein kinase C signalling: a mechanism for insulin resistance?

Shmueli, E.; Alberti, K. G. M. M.; Record, C. O.

doi:10.1111/j.1365-2796.1993.tb00761.x

Cited by 54 publications

(34 citation statements)

References 44 publications

(7 reference statements)

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“…We expected to see greater changes in TAG, but it is likely that large TAG-rich VLDL characteristic of dyslipidaemic individuals is rapidly metabolised to TAG-poor VLDL. Furthermore, our VLDL fraction did not differentiate between VLDL and IDL and therefore A role for DAGs has been implicated in the aetiology of insulin resistance in the liver through a mechanism involving activation of protein kinase C-ε [27,28]. However, it remains to be determined if hepatic uptake of DAG-enriched lipoproteins could contribute to this pathway.…”

Section: Discussionmentioning

confidence: 99%

Clinical dyslipidaemia is associated with changes in the lipid composition and inflammatory properties of apolipoprotein-B-containing lipoproteins from women with type 2 diabetes

et al. 2012

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Aims/hypothesis The aim of this study was to use lipidomics to determine if the lipid composition of apolipoprotein-Bcontaining lipoproteins is modified by dyslipidaemia in type 2 diabetes and if any of the identified changes potentially have biological relevance in the pathophysiology of type 2 diabetes. Methods VLDL and LDL from normolipidaemic and dyslipidaemic type 2 diabetic women and controls were isolated and quantified with HPLC and mass spectrometry. A detailed molecular characterisation of VLDL triacylglycerols (TAG) was also performed using the novel ozone-induced dissociation method, which allowed us to distinguish vaccenic acid (C18:1 n-7) from oleic acid (C18:1 n-9) in specific TAG species. Results Lipid class composition was very similar in VLDL and LDL from normolipidaemic type 2 diabetic and control participants. By contrast, dyslipidaemia was associated with significant changes in both lipid classes (e.g. increased diacylglycerols) and lipid species (e.g. increased C16:1 and C20:3 in phosphatidylcholine and cholesteryl ester and increased C16:0 [palmitic acid] and vaccenic acid in TAG). Levels of palmitic acid in VLDL and LDL TAG correlated with insulin resistance, and VLDL TAG enriched in palmitic acid promoted increased secretion of proinflammatory mediators from human smooth muscle cells. Conclusions We showed that dyslipidaemia is associated with major changes in both lipid class and lipid species composition in VLDL and LDL from women with type 2 diabetes. In addition, we identified specific molecular lipid species that both correlate with clinical variables and are proinflammatory. Our study thus shows the potential of advanced lipidomic methods to further understand the pathophysiology of type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

Clinical dyslipidaemia is associated with changes in the lipid composition and inflammatory properties of apolipoprotein-B-containing lipoproteins from women with type 2 diabetes

et al. 2012

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“…The accumulation of IMTG is associated with skeletal muscle insulin resistance (3,13,15,19,23,28,29,31,36,39). Kelly and Goodpaster (20) have proposed that the accumulation of TG within obese skeletal muscle is due to a defect in fatty acid oxidation.…”

Section: Discussionmentioning

confidence: 99%

“…Data have shown that intramyocellular triacylglycerols (IMTG) are increased with obesity and NIDDM (14,19,21). In addition, the accumulation of IMTG is associated with skeletal muscle insulin resistance (3,13,15,19,23,28,29,31,36,39). It is believed, however, that the accumulation of IMTG is not the direct cause of the development of insulin resistance but that IMTG is an inert marker for the presence of other lipid intermediates (diacylglycerol, fatty acyl-CoAs, or ceramide, etc.…”

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confidence: 99%

Skeletal muscle lipid metabolism with obesity

Hulver

Berggren

Cortright

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

288

246

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. Skeletal muscle lipid metabolism with obesity. Am J Physiol Endocrinol Metab 284: E741-E747, 2003. First published December 27, 2002 10.1152/ajpendo.00514.2002The objectives of this study were to 1) examine skeletal muscle fatty acid oxidation in individuals with varying degrees of adiposity and 2) determine the relationship between skeletal muscle fatty acid oxidation and the accumulation of long-chain fatty acyl-CoAs. Muscle was obtained from normal-weight [n ϭ 8; body mass index (BMI) 23.8 Ϯ 0.58 kg/m 2 ], overweight/obese (n ϭ 8; BMI 30.2 Ϯ 0.81 kg/m 2 ), and extremely obese (n ϭ 8; BMI 53.8 Ϯ 3.5 kg/m 2 ) females undergoing abdominal surgery. Skeletal muscle fatty acid oxidation was assessed in intact muscle strips. Long-chain fatty acyl-CoA concentrations were measured in a separate portion of the same muscle tissue in which fatty acid oxidation was determined. Palmitate oxidation was 58 and 83% lower in skeletal muscle from extremely obese (44.9 Ϯ 5.2 nmol ⅐ g Ϫ1 ⅐ h Ϫ1 ) patients compared with normal-weight (71.0 Ϯ 5.0 nmol ⅐ g Ϫ1 ⅐ h Ϫ1 ) and overweight/obese (82.2 Ϯ 8.7 nmol ⅐ g Ϫ1 ⅐ h Ϫ1 ) patients, respectively. Palmitate oxidation was negatively (R ϭ Ϫ0.44, P ϭ 0.003) associated with BMI. Long-chain fatty acyl-CoA content was higher in both the overweight/obese and extremely obese patients compared with normal-weight patients, despite significantly lower fatty acid oxidation only in the extremely obese. No associations were observed between long-chain fatty acyl-CoA content and palmitate oxidation. These data suggest that there is a defect in skeletal muscle fatty acid oxidation with extreme obesity but not overweight/obesity and that the accumulation of intramyocellular long-chain fatty acyl-CoAs is not solely a result of reduced fatty acid oxidation.long-chain fatty acyl-coenzyme A; intramyocellular triacylglycerol; fatty acids THE PREVALENCE OF OVERWEIGHT/OBESITY and insulin resistance is continually increasing and is associated with increased risk for the development of non-insulin-dependent diabetes mellitus (NIDDM), hypertension, and cardiovascular disease (5,11,24). The cellular mechanisms responsible for insulin resistance with overweight and obesity are not yet clear. Data have shown that intramyocellular triacylglycerols (IMTG) are increased with obesity and NIDDM (14,19,21). In addition, the accumulation of IMTG is associated with skeletal muscle insulin resistance (3,13,15,19,23,28,29,31,36,39). It is believed, however, that the accumulation of IMTG is not the direct cause of the development of insulin resistance but that IMTG is an inert marker for the presence of other lipid intermediates (diacylglycerol, fatty acyl-CoAs, or ceramide, etc.), which have been directly linked to defects in insulin signaling (8,17,25,32,37).To date, the mechanism(s) responsible for the accretion of IMTG and intermediates of lipid metabolism in intact skeletal muscle are not evident. Two possibilities include an increase in lipid synthesis and/or a reduction in fatty acid oxidation, both of which may res...

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“…We have recently shown that hepatic concentrations of diacylglycerols, the immediate precursors of triglycerides [47], but not of ceramides are directly related to hepatic fat content in the human liver [44]. Since both ceramides and diacylglycerols are able to cause insulin resistance by interfering with insulin signalling pathway [39] and [48], diacylglycerols rather than ceramides might contribute to hepatic insulin resistance in human NAFLD.…”

Section: Hepatic Lipids and Insulin Resistancementioning

confidence: 99%

From the metabolic syndrome to NAFLD or vice versa?

Vanni

Bugianesi

Kotronen

et al. 2010

Digestive and Liver Disease

433

351

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The metabolic syndrome encompasses metabolic and cardiovascular risk factors which predict diabetes and cardiovascular disease (CVD) better than any of its individual components. Nonalcoholic fatty liver disease (NAFLD) comprises a disease spectrum which includes variable degrees of simple steatosis (nonalcoholic fatty liver, NAFL), nonalcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is the hepatic manifestation of the metabolic syndrome, with insulin resistance as the main pathogenetic mechanism. Recent data indicate that hyperinsulinemia is probably the consequence rather than cause of NAFLD and NAFLD can be considered an independent predictor of cardiovascular disease. Serum free fatty acids derived from lipolysis of visceral adipose tissue are the main source of hepatic triglycerides in NAFLD, although hepatic de novo lipogenesis and dietary fat supply contribute to the pathogenesis of NAFLD. Approximately 10-25% NAFLD patients develop NASH, the evolutive form of hepatic steatosis. Presumably in a genetically predisposed environment, this increased lipid overload overwhelms the oxidative capacity and reactive oxygen species are generated, leading to lipid peroxidation, cytokine induction, chemoattraction of inflammatory cells, hepatic stellate cell activation and finally fibrogenesis with extracellular matrix deposition. No currently available therapies for NAFLD and NASH exist. Recently nuclear receptors have emerged as key regulators of lipid and carbohydrate metabolism for which specific pharmacological ligands are available, making them attractive therapeutic targets for NAFLD and NASH.Abbreviations ALT, alanine aminotransferase; BMI, body mass index; CVD, cardiovascular disease; FFA, free fatty acids; HDL, high density lipoprotein; 1H-MRS, proton magnetic resonance spectroscopy; IDF, International Diabetes Federation; LDL, low density lipoprotein; NAFLD, nonalcoholic fatty liver disease; SNP, single nucleotide polymorphism; VLDL, very low density lipoprotein IntroductionThe metabolic syndrome is a cluster of metabolic and cardiovascular risk factors which predicts diabetes and cardiovascular disease (CVD) better than any of its individual components [1]. The latest definition of the metabolic syndrome by International Diabetes Federation (IDF) includes abdominal obesity defined by increased waist circumference (≥94 cm in men and ≥80 cm in women) and two or more of the following features: elevated blood pressure, fasting glucose or triglyceride concentrations, or low HDL cholesterol [1]. The term nonalcoholic fatty liver disease (NAFLD) comprises a disease spectrum which includes variable degrees of simple steatosis (nonalcoholic fatty liver, NAFL), nonalcoholic steatohepatitis (NASH) and cirrhosis [2] and [3]. NAFLD can be considered the hepatic manifestation of the metabolic syndrome. Simple steatosis is benign, whereas NASH is defined by the presence of hepatocyte injury, inflammation and/or fibrosis which can lead to cirrhosis, liver failure and hepatocellular carcinoma. In contrast to t...

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Diacylglycerol/protein kinase C signalling: a mechanism for insulin resistance?

Cited by 54 publications

References 44 publications

Clinical dyslipidaemia is associated with changes in the lipid composition and inflammatory properties of apolipoprotein-B-containing lipoproteins from women with type 2 diabetes

Clinical dyslipidaemia is associated with changes in the lipid composition and inflammatory properties of apolipoprotein-B-containing lipoproteins from women with type 2 diabetes

Skeletal muscle lipid metabolism with obesity

From the metabolic syndrome to NAFLD or vice versa?

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