Mechanism of free fatty acid-induced insulin resistance in humans.

Roden, Michael; Price, Thomas B.; Perseghin, Gianluca; Petersen, Kitt Falk; Rothman, Douglas L.; Cline, Gary W.; Shulman, Gerald I.

doi:10.1172/jci118742

Cited by 1,347 publications

(1,065 citation statements)

References 30 publications

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“…A combination of 13 C-and 31 P-MRS opens multiple views on the carbohydrate metabolism (131)(132)(133)(134), which is particularly promising in the different forms of insulinand non-insulin-dependent diabetes patients. While glucose-6-phosphate can observed in the 31 P-MR spectrum, 13 C-MRS gives access to glycogen and glucose, especially in connection with an infusion of 13 C-enriched [1-13 C]glucose.…”

Section: Combination Of 1 H-mrs Of Imcl and Other Mrs Techniquesmentioning

confidence: 99%

Role of proton MR for the study of muscle lipid metabolism

et al. 2006

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1 H-MR spectroscopy (MRS) of intramyocellular lipids (IMCL) became particularly important when it was recognized that IMCL levels are related to insulin sensitivity. While this relation is rather complex and depends on the training status of the subjects, various other influences such as exercise and diet also influence IMCL concentrations. This may open insight into many metabolic interactions; however, it also requires careful planning of studies in order to control all these confounding influences. This review summarizes various historical, methodological, and practical aspects of 1 H-MR spectroscopy (MRS) of muscular lipids. That includes a differentiation of bulk magnetic susceptibility effects and residual dipolar coupling that can both be observed in MRS of skeletal muscle, yet affecting different metabolites in a specific way. Fitting of the intra-(IMCL) and extramyocellular (EMCL) signals with complex line shapes and the transformation into absolute concentrations is discussed. Since the determination of IMCL in muscle groups with oblique fiber orientation or in obese subjects is still difficult, potential improvement with high-resolution spectroscopic imaging or at higher field strength is considered. Fat selective imaging is presented as a possible alternative to MRS and the potential of multinuclear MRS is discussed. 1 H-MRS of muscle lipids allows non-invasive and repeated studies of muscle metabolism that lead to highly relevant findings in clinics and patho-physiology.

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Section: Combination Of 1 H-mrs Of Imcl and Other Mrs Techniquesmentioning

confidence: 99%

Role of proton MR for the study of muscle lipid metabolism

et al. 2006

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“…Elevated fatty acid delivery and/or impaired fatty acid oxidation result in net intramyocellular accumulation of triacylglycerol and fatty acid metabolites (such as fatty acyl-CoA, ceramides and diacylglycerol). The latter are likely to induce defects in the insulin signalling cascade, thus causing insulin resistance [4][5][6][7][8][9][10] in skeletal muscle.…”

Section: Introductionmentioning

confidence: 99%

Substrate source utilisation in long-term diagnosed type 2 diabetes patients at rest, and during exercise and subsequent recovery

et al. 2006

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Aims/hypothesis Disturbances in substrate source metabolism and, more particularly, in fatty acid metabolism, play an important role in the aetiology and progression of type 2 diabetes. However, data on substrate source utilisation in type 2 diabetes are inconclusive. Methods [U-13 C]palmitate and [6,6-2 H 2 ]glucose tracers were used to assess plasma NEFA and glucose oxidation rates and to estimate the use of muscle-and/or lipoproteinderived triacylglycerol and muscle glycogen. Subjects were ten male patients who had a long-term (7±1 years) diagnosis of type 2 diabetes and were overweight, and ten matched healthy, male control subjects. Muscle biopsy samples were collected before and after exercise to assess muscle fibre type-specific intramyocellular lipid and glycogen content.

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“…More recent insights from various lipid infusion studies have led to an alternative mechanism [9][10][11][12][13]. The latter suggests that elevated NEFA delivery and/or impaired FA oxidation result in intramyocellular accumulation of triacylglycerol (TG) and FA metabolites (such as fatty acyl-CoA, ceramides and diacylglycerol), which induce defects in the insulin signalling cascade, causing skeletal muscle insulin resistance [9,10,[13][14][15][16][17]. Insulin resistance can subsequently lead to development of the hyperglycaemic and/or hyperinsulinaemic state that is associated with type 2 diabetes.…”

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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Mechanism of free fatty acid-induced insulin resistance in humans.

Cited by 1,347 publications

References 30 publications

Role of proton MR for the study of muscle lipid metabolism

Role of proton MR for the study of muscle lipid metabolism

Substrate source utilisation in long-term diagnosed type 2 diabetes patients at rest, and during exercise and subsequent recovery

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

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