Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents.

Perseghin, Gianluca; Scifo, Paola; Cobelli, Francesco De; Pagliato, E; Battezzati, Alberto; Arcelloni, Cinzia; Vanzulli, Angelo; Testolin, G.; Pozza, G.; Maschio, Alessandro Del; Luzi, Livio

doi:10.2337/diabetes.48.8.1600

Cited by 785 publications

(669 citation statements)

References 43 publications

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“…IMTG is best correlated with an individual's degree of insulin resistance, regardless of BMI [6][7][8]. No differences in IMTG were observed in LGI or HGI, indicating that hyperglycaemia-hyperinsulinaemia is not sufficient to elicit higher levels of IMTG in myotubes of post-diabetes mellitus participants.…”

Section: Discussionmentioning

confidence: 91%

“…The molecular mechanisms responsible for the progression of insulin resistance are still poorly understood. Ectopic accumulation of lipid in skeletal muscle (intramuscular triacylglycerol [IMTG]) is associated with obesity and highly correlated with the development of insulin resistance [6][7][8]. However, the observation that lean, insulin-sensitive endurance-trained athletes have high levels of IMTG has led to the hypothesis that altered or incomplete lipid metabolism may be an important factor in the progression of insulin resistance (reviewed by van Loon and Goodpaster [9]).…”

Section: Introductionmentioning

confidence: 99%

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Increased susceptibility to oxidative damage in post-diabetic human myotubes

et al. 2009

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Aims/hypothesis Obesity is an important risk factor for the development of type 2 diabetes, but not all obese individuals develop this complication. The clinical signs of type 2 diabetes can often be reversed with weight loss; however, it is unknown whether the skeletal muscle oxidative stress associated with type 2 diabetes remains after weight loss. We hypothesised that chronic exposure to high glucose and insulin would re-elicit impaired metabolism in primary myotubes from patients with a history of type 2 diabetes. Methods Obese participants with or without type 2 diabetes completed a standardised weight loss protocol, following which all participants were euglycaemic and had similar indices of insulin sensitivity. Satellite cells were isolated from muscle biopsies and differentiated under low or high glucose and insulin conditions (HGI).

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Increased susceptibility to oxidative damage in post-diabetic human myotubes

et al. 2009

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“…The IMCL content, which in many [1][2][3][4] but not all studies [45,46] has been shown to be increased in insulin resistance, was also one focus of our experiments. The effects of TGRLs on insulin signalling and glucose homeostasis followed a time-dependent fashion.…”

Section: Discussionmentioning

confidence: 96%

“…high plasma levels of NEFAs, dyslipidaemia and pronounced postprandial lipaemia. A fourth lipid abnormality suggested to be a determinant of insulin resistance is the increase of intramyocellular lipid (IMCL) content in skeletal muscle [1][2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Human triglyceride-rich lipoproteins impair glucose metabolism and insulin signalling in L6 skeletal muscle cells independently of non-esterified fatty acid levels

et al. 2005

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Aims/hypothesis: Elevated fasting and postprandial plasma levels of triglyceride-rich lipoproteins (TGRLs), i.e. VLDL/remnants and chylomicrons/remnants, are a characteristic feature of insulin resistance and are considered a consequence of this state. The aim of this study was to investigate whether intact TGRL particles are capable of inducing insulin resistance. Methods: We studied the effect of highly purified TGRLs on glycogen synthesis, glycogen synthase activity, glucose uptake, insulin signalling and intramyocellular lipid (IMCL) content using fully differentiated L6 skeletal muscle cells. Results: Incubation with TGRLs diminished insulin-stimulated glycogen synthesis, glycogen synthase activity, glucose uptake and insulin-stimulated phosphorylation of Akt and glycogen synthase kinase 3. Insulin-stimulated tyrosine phosphorylation of IRS-1, and IRS-1-and IRS-2-associated phosphatidylinositol 3-kinase (PI3K) activity were not impaired by TGRLs, suggesting that these steps were not involved in the lipoprotein-induced effects on glucose metabolism. The overall observed effects were time-and dose-dependent and paralleled IMCL accumulation. NEFA concentration in the incubation media did not increase in the presence of TGRLs indicating that the effects observed were solely due to intact lipoprotein particles. Moreover, co-incubation of TGRLs with orlistat, a potent active-site inhibitor of various lipases, did not alter TGRL-induced effects, whereas co-incubation with receptor-associated protein (RAP), which inhibits interaction of TGRL particles with members of the LDL receptor family, reversed the TGRL-induced effects on glycogen synthesis and insulin signalling. Conclusions/ interpretation: Our data suggest that the accumulation of TGRLs in the blood stream of insulin-resistant patients may not only be a consequence of insulin resistance but could also be a cause for it.

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“…Numerous studies have reported the association between elevated plasma NEFA concentrations, intramyocellular triacylglycerol (IMTG, often also abbreviated to IMCL) accumulation and the development of insulin resistance and/or type 2 diabetes [1][2][3][4][5][6][7]. The Randle (glucose-fatty acid) cycle has often been used to explain the mechanism behind skeletal muscle insulin resistance induced by fatty acid (FA) [8].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of adipose tissue lipolysis increases intramuscular lipid use in type 2 diabetic patients

et al. 2005

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Aims/hypothesis: In the present study, we investigated the consequences of adipose tissue lipolytic inhibition on skeletal muscle substrate use in type 2 diabetic patients. Materials and methods: We studied ten type 2 diabetic patients under the following conditions:(1) at rest; (2) during 60 min of cycling exercise at 50% of maximal workload capacity and subsequent recovery. Studies were done under normal, fasting conditions (control trial: CON) and following administration of a nicotinic acid analogue (low plasma non-esterified fatty acid trial: LFA). Continuous [U-13 C]palmitate and [6,6 -2 H 2 ]glucose infusions were applied to quantify plasma NEFA and glucose oxidation rates, and to estimate intramuscular triacylglycerol (IMTG) and glycogen use. Muscle biopsies were collected before and after exercise to determine net changes in lipid and glycogen content specific to muscle fibre type. Results: Following administration of the nicotinic acid analogue (Acipimox), the plasma NEFA rate of appearance was effectively reduced, resulting in lower NEFA concentrations in the LFA trial (p<0.001). Plasma NEFA oxidation rates were substantially reduced at rest, during exercise and subsequent recovery in the LFA trial.The lower plasma NEFA oxidation rates were compensated by an increase in IMTG and endogenous carbohydrate use (p<0.05). Plasma glucose disposal rates did not differ between trials. In accordance with the tracer data, a greater net decline in type I muscle fibre lipid content was observed following exercise in the LFA trial (p<0.05). Conclusions/interpretation: This study shows that plasma NEFA availability regulates IMTG use, and that adipose tissue lipolytic inhibition, in combination with exercise, could be an effective means of augmenting intramuscular lipid and glycogen use in type 2 diabetic patients in an overnight fasted state.

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Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents.

Cited by 785 publications

References 43 publications

Increased susceptibility to oxidative damage in post-diabetic human myotubes

Increased susceptibility to oxidative damage in post-diabetic human myotubes

Human triglyceride-rich lipoproteins impair glucose metabolism and insulin signalling in L6 skeletal muscle cells independently of non-esterified fatty acid levels

Inhibition of adipose tissue lipolysis increases intramuscular lipid use in type 2 diabetic patients

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