Role of Mitochondrial Dysfunction in Muscle Insulin Resistance

Impaired muscle insulin action at an early stage in life could be the result from an intrinsic/genetic inability of muscle to increase its oxidative capacity upon demand, as reported in lean FH+ subjects and/or an acquired defect from excessive exogenous substrate (i.e., FFA) as in obesity and T2DM. Diminished lipid oxidative capacity has been reported by many laboratories in insulin-resistant lean FH+ and obese individuals, as well as in patients with T2DM (133, 134, 184, 206, 215-218). In Mexican-American FH+ subjects from San Antonio, Texas (219) , and in Caucasian populations (220), it has been reported that there is a coordinate reduction of genes involved in oxidative metabolism in insulin-resistant diabetic and nondiabetic FH+ Mexican-Americans. Several studies have manipulated FFA availability to muscle and shown that a reduction of FFA availability prevents FFA-induced insulin resistance. Knockout mice with deletions in the fatty acid transport protein 1 (FATP1) or alterations in the activation of inflammatory pathways such as JNK, inhibitor of NF kB kinase P subunit (IKKP), or PKC0 have all shown resistance to FFA-induced insulin resistance (134). Within our group, Richardson et al. (221) have reported that a 48-h increase in plasma FFA by means of a lipid infusion in healthy subjects in significantly reduced proliferator activated receptor-y cofactor-1 (PGC-1) mRNA, along with messenger ribonucleic acids (mRNAs) for a number of nuclear encoded mitochondrial genes. Moreover, using microarray analysis, lipid infusion caused a significant overexpression of extracellular matrix genes and connective tissue growth factor. Quantitative reverse transcription PCR showed that the mRNA/protein expression of collagens and multiple extracellular matrix genes were also elevated after lipid infusion, in striking similarity to what has been observed in insulin-resistant subjects with a fatty liver in nonalcoholic steaothepatitis (as discussed below in the liver section of this chapter) (222, 223), linking functional and structural abnormalities in different tissues by FFA oversupply. On the contrary, if plasma FFA levels are reduced by acipimox, an inhibitor of adipose tissue lipolysis, there is an enhancement of insulin action in FH+ subjects (224), as well as in obese (225) and T2DM (225, 226) patients.

Recent studies have suggested that in insulin-resistant states, such as in FH+ and in T2DM subjects, there is an intrinsic mitochondrial substrate oxidation defect responsible for the accumulation of IMCL. In T2DM there are numerous functional and structural mitochondrial abnormalities when tissue from vastus lateralis muscle biopsies are examined (216, 227, 228). Lean, insulin-resistant FH+ subjects have a reduced mitochondrial substrate oxidation capacity as measured by the incorporation of 13C label into C; glutamate following [2- ( 3C] acetate infusion by MRS (210) . Consistent with these findings, Brehm et al. (229) have reported that when plasma FFA levels are maintained in the upper limit of the physiological range at 1,000 ^mol/L during an hyperinsulinemic clamp (plasma insulin increased approximately tenfold), FFA-induced insulin resistance in skeletal muscle was associated with a 70% reduction in insulin-stimulated glucose transport/phosphorylation and a 24% reduction adenosine triphosphate (ATP) synthase flux compared to identical control (saline) studies. Recently, a lower mitochondrial content in muscle of diabetic subjects (rather than decreased function) has been proposed to play a role for the reduced mitochondrial oxidative capacity (230). Taken together, these studies suggest that in genetically predisposed individuals the ability of the mitochondria to increase substrate oxidation may be limited by either a reduction in function and/or an overall mitochondrial content, making skeletal muscle particularly vulnerable to lipotoxicity, as observed in obesity and T2DM.

Psychology Of Weight Loss And Management

Psychology Of Weight Loss And Management

Get All The Support And Guidance You Need To Be A Success At The Psychology Of Weight Loss And Management. This Book Is One Of The Most Valuable Resources In The World When It Comes To Exploring How Your Brain Plays A Role In Weight Loss And Management.

Get My Free Ebook


Post a comment