Metabolic flexibility and insulin resistance
ABSTRACT Metabolic flexibility is the capacity for the organism to adapt fuel oxidation to fuel availability. The inability to modify fuel oxidation in response to changes in nutrient availability has been implicated in the accumulation of intramyocellular lipid and insulin resistance. The metabolic flexibility assessed by the ability to switch from fat to carbohydrate oxidation is usually impaired during a hyperinsulinemic clamp in insulin-resistant subjects; however, this "metabolic inflexibility" is mostly the consequence of impaired cellular glucose uptake. Indeed, after controlling for insulin-stimulated glucose disposal rate ( amount of glucose available for oxidation), metabolic flexibility is not altered in obesity regardless of the presence of type 2 diabetes. To understand how intramyocellular lipids accumulate and cause insulin resistance, the assessment of metabolic flexibility to high-fat diets is more relevant than metabolic flexibility during a hyperinsulinemic clamp. An impaired capacity to upregulate muscle lipid oxidation in the face of high lipid supply may lead to increased muscle fat accumulation and insulin resistance. Surprisingly, very few studies have investigated the response to high-fat diets. In this review, we discuss the role of glucose disposal rate, adipose tissue lipid storage, and mitochondrial function on metabolic flexibility. Additionally, we emphasize the bias of using the change in respiratory quotient to calculate metabolic flexibility and propose novel approaches to assess metabolic flexibility. On the basis of current evidence, one cannot conclude that impaired metabolic flexibility is responsible for the accumulation of intramyocellular lipid and insulin resistance. We propose to study metabolic flexibility in response to high- fat diets in individuals having contrasting degree of insulin sensitivity and/or mitochondrial characteristics. National Institutes of Health U01-AG-020478 RO1-DK-60412
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ABSTRACT: A hallmark of ageing is dysfunction in nutrient signalling pathways that regulate glucose homeostasis, negatively affecting whole-body energy metabolism and ultimately increasing the organism's susceptibility to disease. Maintenance of insulin sensitivity depends on functional mitochondrial networks, but is compromised by alterations in mitochondrial energy metabolism during ageing. Here we discuss metabolic paradigms that influence mammalian longevity, and highlight recent advances in identifying fundamental signalling pathways that influence metabolic health and ageing through mitochondrial perturbations.Nature cell biology. 02/2015; 17(3):196-203.
- Metabolomics 11/2014; · 3.97 Impact Factor
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ABSTRACT: Insulin causes the exocytic translocation of GLUT4 glucose transporters to stimulate glucose uptake in fat and muscle. Previous results support a model in which TUG traps GLUT4 in intracellular, insulin-responsive vesicles termed GLUT4 storage vesicles (GSVs). Insulin triggers TUG cleavage to release the GSVs; GLUT4 then recycles through endosomes during ongoing insulin exposure. The TUG C-terminus binds a GSV anchoring site comprising Golgin-160 and possibly other proteins. Here, we report that the TUG C-terminus is acetylated. The TUG C-terminal peptide bound the Golgin-160-associated protein, ACBD3 (acyl-CoA binding domain containing 3), and acetylation reduced binding of TUG to ACBD3, but not to Golgin-160. Mutation of the acetylated residues impaired insulin-responsive GLUT4 trafficking in 3T3-L1 adipocytes. ACBD3 overexpression enhanced the translocation of GSV cargos, GLUT4 and IRAP, and ACBD3 was required for intracellular retention of these cargos in unstimulated cells. SIRT2, a NAD+-dependent deacetylase, bound TUG and deacetylated the TUG peptide. SIRT2 overexpression reduced TUG acetylation and redistributed GLUT4 and IRAP to the plasma membrane in 3T3-L1 adipocytes. Mutation of the acetylated residues in TUG abrogated these effects. In mice, SIRT2 deletion increased TUG acetylation and proteolytic processing. During glucose tolerance tests, glucose disposal was enhanced in SIRT2 knockout mice, compared to wildtype controls, without any effect on insulin concentrations. Together, these data support a model in which TUG acetylation modulates its interaction with Golgi matrix proteins and is regulated by SIRT2. Moreover, acetylation of TUG enhances its function to trap GSVs within unstimulated cells, and enhances insulin-stimulated glucose uptake. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.The Journal of biological chemistry. 01/2015;