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Prolonged fasting identifies skeletal muscle mitochondrial dysfunction as consequence rather than cause of human insulin resistance.

Hoeks J, van Herpen NA, Mensink M, Moonen-Kornips E, van Beurden D, Hesselink MK, Schrauwen P - Diabetes (2010)

Bottom Line: Indeed, FFA levels were increased approximately ninefold after 60 h of fasting in healthy male subjects, leading to elevated intramuscular lipid levels and decreased muscular insulin sensitivity.Despite an increase in whole-body fat oxidation, we observed an overall reduction in both coupled state 3 respiration and maximally uncoupled respiration in permeabilized skeletal muscle fibers, which could not be explained by changes in mitochondrial density.These findings confirm that the insulin-resistant state has secondary negative effects on mitochondrial function.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Biology, School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands. j.hoeks@hb.unimaas.nl

ABSTRACT

Objective: Type 2 diabetes and insulin resistance have been associated with mitochondrial dysfunction, but it is debated whether this is a primary factor in the pathogenesis of the disease. To test the concept that mitochondrial dysfunction is secondary to the development of insulin resistance, we employed the unique model of prolonged fasting in humans. Prolonged fasting is a physiologic condition in which muscular insulin resistance develops in the presence of increased free fatty acid (FFA) levels, increased fat oxidation and low glucose and insulin levels. It is therefore anticipated that skeletal muscle mitochondrial function is maintained to accommodate increased fat oxidation unless factors secondary to insulin resistance exert negative effects on mitochondrial function.

Research design and methods: While in a respiration chamber, twelve healthy males were subjected to a 60 h fast and a 60 h normal fed condition in a randomized crossover design. Afterward, insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp, and mitochondrial function was quantified ex vivo in permeabilized muscle fibers using high-resolution respirometry.

Results: Indeed, FFA levels were increased approximately ninefold after 60 h of fasting in healthy male subjects, leading to elevated intramuscular lipid levels and decreased muscular insulin sensitivity. Despite an increase in whole-body fat oxidation, we observed an overall reduction in both coupled state 3 respiration and maximally uncoupled respiration in permeabilized skeletal muscle fibers, which could not be explained by changes in mitochondrial density.

Conclusions: These findings confirm that the insulin-resistant state has secondary negative effects on mitochondrial function. Given the low insulin and glucose levels after prolonged fasting, hyperglycemia and insulin action per se can be excluded as underlying mechanisms, pointing toward elevated plasma FFA and/or intramuscular fat accumulation as possible causes for the observed reduction in mitochondrial capacity.

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Related in: MedlinePlus

Indirect calorimetry results after 60 h of fasting in the basal state and upon the hyperinsulinemic-euglycemic clamp. A shows that metabolic flexibility, defined as the change in respiratory exchange ratio upon insulin stimulation, is blunted upon prolonged fasting. B and C display whole-body lipid and carbohydrate oxidation, respectively. White bars/circles represent the fed condition; black bars/circles represent the fasted condition. Values are mean ± SE. *P < 0.05.
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Figure 3: Indirect calorimetry results after 60 h of fasting in the basal state and upon the hyperinsulinemic-euglycemic clamp. A shows that metabolic flexibility, defined as the change in respiratory exchange ratio upon insulin stimulation, is blunted upon prolonged fasting. B and C display whole-body lipid and carbohydrate oxidation, respectively. White bars/circles represent the fed condition; black bars/circles represent the fasted condition. Values are mean ± SE. *P < 0.05.

Mentions: Metabolic flexibility was blunted in the fasted condition when compared with the fed condition (Fig. 3A, P < 0.001). Basal whole-body fat oxidation was increased by 1.5-fold upon prolonged fasting (Fig. 3B, P < 0.001). During the glucose clamp, fat oxidation significantly decreased in both conditions (P ≤ 0.001), but the suppression was significantly less in the fasted condition (Fig. 3B, P < 0.001). Basal carbohydrate oxidation after fasting was only ∼35% of the value obtained in the fed situation (P < 0.001), but increased in both conditions during the glucose clamp (Fig. 3C). However, this insulin-induced change in carbohydrate oxidation was blunted upon fasting (P < 0.001).


Prolonged fasting identifies skeletal muscle mitochondrial dysfunction as consequence rather than cause of human insulin resistance.

Hoeks J, van Herpen NA, Mensink M, Moonen-Kornips E, van Beurden D, Hesselink MK, Schrauwen P - Diabetes (2010)

Indirect calorimetry results after 60 h of fasting in the basal state and upon the hyperinsulinemic-euglycemic clamp. A shows that metabolic flexibility, defined as the change in respiratory exchange ratio upon insulin stimulation, is blunted upon prolonged fasting. B and C display whole-body lipid and carbohydrate oxidation, respectively. White bars/circles represent the fed condition; black bars/circles represent the fasted condition. Values are mean ± SE. *P < 0.05.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2927932&req=5

Figure 3: Indirect calorimetry results after 60 h of fasting in the basal state and upon the hyperinsulinemic-euglycemic clamp. A shows that metabolic flexibility, defined as the change in respiratory exchange ratio upon insulin stimulation, is blunted upon prolonged fasting. B and C display whole-body lipid and carbohydrate oxidation, respectively. White bars/circles represent the fed condition; black bars/circles represent the fasted condition. Values are mean ± SE. *P < 0.05.
Mentions: Metabolic flexibility was blunted in the fasted condition when compared with the fed condition (Fig. 3A, P < 0.001). Basal whole-body fat oxidation was increased by 1.5-fold upon prolonged fasting (Fig. 3B, P < 0.001). During the glucose clamp, fat oxidation significantly decreased in both conditions (P ≤ 0.001), but the suppression was significantly less in the fasted condition (Fig. 3B, P < 0.001). Basal carbohydrate oxidation after fasting was only ∼35% of the value obtained in the fed situation (P < 0.001), but increased in both conditions during the glucose clamp (Fig. 3C). However, this insulin-induced change in carbohydrate oxidation was blunted upon fasting (P < 0.001).

Bottom Line: Indeed, FFA levels were increased approximately ninefold after 60 h of fasting in healthy male subjects, leading to elevated intramuscular lipid levels and decreased muscular insulin sensitivity.Despite an increase in whole-body fat oxidation, we observed an overall reduction in both coupled state 3 respiration and maximally uncoupled respiration in permeabilized skeletal muscle fibers, which could not be explained by changes in mitochondrial density.These findings confirm that the insulin-resistant state has secondary negative effects on mitochondrial function.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Biology, School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands. j.hoeks@hb.unimaas.nl

ABSTRACT

Objective: Type 2 diabetes and insulin resistance have been associated with mitochondrial dysfunction, but it is debated whether this is a primary factor in the pathogenesis of the disease. To test the concept that mitochondrial dysfunction is secondary to the development of insulin resistance, we employed the unique model of prolonged fasting in humans. Prolonged fasting is a physiologic condition in which muscular insulin resistance develops in the presence of increased free fatty acid (FFA) levels, increased fat oxidation and low glucose and insulin levels. It is therefore anticipated that skeletal muscle mitochondrial function is maintained to accommodate increased fat oxidation unless factors secondary to insulin resistance exert negative effects on mitochondrial function.

Research design and methods: While in a respiration chamber, twelve healthy males were subjected to a 60 h fast and a 60 h normal fed condition in a randomized crossover design. Afterward, insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp, and mitochondrial function was quantified ex vivo in permeabilized muscle fibers using high-resolution respirometry.

Results: Indeed, FFA levels were increased approximately ninefold after 60 h of fasting in healthy male subjects, leading to elevated intramuscular lipid levels and decreased muscular insulin sensitivity. Despite an increase in whole-body fat oxidation, we observed an overall reduction in both coupled state 3 respiration and maximally uncoupled respiration in permeabilized skeletal muscle fibers, which could not be explained by changes in mitochondrial density.

Conclusions: These findings confirm that the insulin-resistant state has secondary negative effects on mitochondrial function. Given the low insulin and glucose levels after prolonged fasting, hyperglycemia and insulin action per se can be excluded as underlying mechanisms, pointing toward elevated plasma FFA and/or intramuscular fat accumulation as possible causes for the observed reduction in mitochondrial capacity.

Show MeSH
Related in: MedlinePlus