Reduced Lipid Oxidation in Skeletal Muscle From Type 2 Diabetic Subjects May Be of Genetic Origin

Gaster, Michael; Rustan, Arild C.; Aas, Vigdis; Beck‐Nielsen, Henning

doi:10.2337/diabetes.53.3.542

Cited by 167 publications

(176 citation statements)

References 41 publications

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“…A lower capacity for fatty acid uptake in the diabetic leg muscles is also in agreement with similar findings in human cultured vastus lateralis muscle cells [28]. However, subsequent data on human cultured myotubes from the vastus lateralis did not indicate substantial differences between myotubes from diabetic patients and matched controls [29]. The decrease of palmitate uptake with insulin has been reported previously for the leg [7,30] and the arm [31] of healthy subjects.…”

Section: Discussionsupporting

confidence: 90%

“…The decrease of palmitate uptake with insulin has been reported previously for the leg [7,30] and the arm [31] of healthy subjects. Nevertheless, when fatty acid levels were maintained during the insulin infusion, the fatty acid uptake by skeletal muscle was actually increased in rat muscle preparations [32,33] and in cultured cells from the vastus lateralis muscle [28,29]. These observations imply that the reduction in limb fatty acid uptake with insulin is caused more by reduced limb fatty acid availability than by lessened skeletal muscle insulin sensitivity.…”

Section: Discussionmentioning

confidence: 94%

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Heterogeneity in limb fatty acid kinetics in type 2 diabetes

et al. 2005

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Aims/hypothesis: In order to test the hypothesis that disturbances in skeletal muscle fatty acid metabolism with type 2 diabetes are not equally present in the upper and lower limbs, we studied fatty acid kinetics simultaneously across the arm and leg of type 2 diabetic patients (n=6) and matched control subjects (n=7) for 5 h under baseline conditions and during a 4-h hyperinsulinaemiceuglycaemic clamp. Methods: Limb fatty acid kinetics was determined by means of continuous [U-13 C]palmitate infusion and measurement of arteriovenous differences. Results: The systemic palmitate rate of appearance was 3.6±0.4 and 2.7±0.3 μmol·kg lean body mass −1 ·min −1 and decreased during the clamp by 26% (p=0.04) and 43% (p<0.01) in the diabetic patients and in the control subjects respectively. At baseline, palmitate uptake across the arm was similar in the two groups, whereas leg palmitate uptake was lower than in the arm in the diabetic patients. During the clamp, palmitate uptake decreased in the arm (−48%, p=0.02) and the leg (−38%, p=0.04) of the control subjects, whereas it decreased in the arm (−30%, p=0.04) but not in the leg of the diabetic patients. Similarly, during the clamp palmitate release was substantially suppressed in the arm (−47%, p<0.01) and the leg of the control subjects (−45%, p<0.01), but only in the arm of the diabetic patients (−45%, p<0.01). Conclusions/interpretation: The present data indicate that type 2 diabetes is characterised by heterogeneity in the dysregulation of skeletal muscle fatty acid metabolism, with only the leg, but not the arm, showing an impairment of fatty acid kinetics at baseline and during a hyperinsulinaemic-euglycaemic clamp causing a physiological increase in insulin concentration.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 94%

Heterogeneity in limb fatty acid kinetics in type 2 diabetes

et al. 2005

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“…This conclusion was further sustained by the observation that the relationship linking fasting whole-body lipid oxidation and insulin sensitivity was not detectable in the NOR control group, when it was segregated by quartiles of lipid oxidation, suggesting that this alteration may be peculiar to individuals with a genetic risk of developing type 2 diabetes in the future. A disturbed oxidative enzyme activity has also been described in the skeletal muscle of type 2 diabetic and obese individuals using an in vitro studies approach [23,24]. A dysfunction of mitochondria was proposed as a possible cause of the impairment of lipid oxidation in the skeletal muscle of type 2 diabetic patients [25], and a specific age-associated decline in mitochondrial function has been suggested as a possible pathogenic factor in the development of insulin resistance in the elderly [26].…”

Section: Discussionmentioning

confidence: 99%

Reduced whole-body lipid oxidation is associated with insulin resistance, but not with intramyocellular lipid content in offspring of type 2 diabetic patients

Lattuada¹,

Costantino²,

Caumo³

et al. 2005

Diabetologia

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Aims/hypothesis: Intramyocellular lipid accumulation and insulin resistance are thought to be due to reduced lipid oxidation in a human model of high risk of developing type 2 diabetes. Methods: We studied 32 offspring of type 2 diabetic parents and 32 control individuals by means of DXA, indirect calorimetry, insulin clamp and 1 H MRS of the calf muscles, and differences between and within study groups were analysed before and after segregation by quartiles of fasting lipid oxidation. Results: In comparison with control subjects, the offspring showed impaired insulin sensitivity, which was associated with higher fasting intramyocellular lipid content (Spearman's rho −0.35; p=0.04), but fasting lipid oxidation did not differ between groups (1.21±0.46 vs. 1.25±0.37 mg·kg −1 lean body mass per min; p=0.70). Nevertheless, offspring in the lowest quartile of lipid oxidation had the most severe impairment of insulin sensitivity and a strong association was shown between lipid oxidation and insulin sensitivity within quartiles (Spearman's rho 0.47; p=0.01); this was not observed within the control group (Spearman's rho 0.13; p=0.47). Intramyocellular lipid content was not significantly different within quartiles of lipid oxidation in either of the groups. Conclusions/interpretation: Insulin sensitivity improved across increasing quartiles of fasting lipid oxidation in the offspring group, but remained constant in the control group, supporting the hypothesis that impaired fat oxidation is a primary pathogenic factor of insulin resistance in people with a genetic background for type 2 diabetes. Despite their association with impaired insulin sensitivity, soleus and tibialis anterior intramyocellular lipid content remained constant across increasing quartiles of fasting lipid oxidation within both groups.

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“…The study of IMCL accumulation in humans is limited by the small amount of material available. Primary human myotubes isolated from patients suffering from type 2 diabetes have been shown to retain and display the majority of the defects previously observed ex vivo [5][6][7]. This in vitro muscle system provides an attractive model, in which lipid accumulation can be evaluated independently of the systemic influences of the in vivo environment.…”

Section: Introductionmentioning

confidence: 92%

Intramyocellular lipid accumulation is associated with permanent relocation ex vivo and in vitro of fatty acid translocase (FAT)/CD36 in obese patients

et al. 2010

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Aims/hypothesis Intramyocellular lipids (IMCL) accumulation is a classical feature of metabolic diseases. We hypothesised that IMCL accumulate mainly as a consequence of increased adiposity and independently of type 2 diabetes. To test this, we examined IMCL accumulation in two different models and four different populations of participants: muscle biopsies and primary human muscle cells derived from non-obese and obese participants with or without type 2 diabetes. The mechanism regulating IMCL accumulation was also studied. Methods Muscle biopsies were obtained from ten non-obese and seven obese participants without type 2 diabetes, and from eight non-obese and eight obese type 2 diabetic patients. Mitochondrial respiration, citrate synthase activity and both ON, Canada Diabetologia (2010) 53:1151-1163 DOI 10.1007/s00125-010-1708 accumulation is dependent upon obesity or type 2 diabetes and is related to sarcolemmal FAT/CD36 relocation. In cultured myotubes, IMCL content and FAT/CD36 relocation are independent of type 2 diabetes, suggesting that distinct factors in obesity and type 2 diabetes contribute to permanent FAT/CD36 relocation ex vivo.

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Reduced Lipid Oxidation in Skeletal Muscle From Type 2 Diabetic Subjects May Be of Genetic Origin

Cited by 167 publications

References 41 publications

Heterogeneity in limb fatty acid kinetics in type 2 diabetes

Heterogeneity in limb fatty acid kinetics in type 2 diabetes

Reduced whole-body lipid oxidation is associated with insulin resistance, but not with intramyocellular lipid content in offspring of type 2 diabetic patients

Intramyocellular lipid accumulation is associated with permanent relocation ex vivo and in vitro of fatty acid translocase (FAT)/CD36 in obese patients

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