An Abnormality of Nonesterified Fatty Acid Metabolism in Diabetes Mellitus

Bierman, Edwin L.; Dole, Vincent P.; Roberts, Thomas N

doi:10.2337/diab.6.6.475

Cited by 299 publications

(38 citation statements)

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“…The serum concentrations of fatty acids are normally below 0.5 mM; but they can rise up to 2 mM during starvation [24] or diabetes [25]. In our experiments, the increase in oxygen consumption was half-maximal with concentrations around 0.1 mM octanoate or oleate (see Fig.…”

Section: Physiological Significance Of the Uncoupling-like Effect Of mentioning

confidence: 77%

Influence of fatty acids on energy metabolism

Soboll

Grundel

Schwabe

et al. 1984

European Journal of Biochemistry

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The uncoupling-like effect of fatty acids [Scholz, R., Schwabe, U., and Soboll, S. (1984) Euv. J. Biochem. 141, 223 -2301 was further substantiated in experiments with perfused rat livers by two ways : firstly the kinetics of changes in metabolic rates (oxygen consumption, ketogenesis, fatty acid oxidation) were analysed; secondly subcellular contents of adenine nucleotides and pH gradients across the mitochondrial membrane were determined following fractionation of freeze-fixed and dried tissues in non-aqueous solvents. The following results were obtained.1. The relaxation kinetics of the increase in oxygen consumption following fatty acid infusion revealed two components, a rapid one with a half-time around 10 s and a slow one with a half-time of more than 100s.2. The rapid component was similar to the kinetics of fatty acid oxidation (ketogenesis and 14C0, production from labelled fatty acids) whereas the half-time of the slow component was in the range of half-times observed with the increase in oxygen consumption following addition of carbonylcyanide p-trifluoromethoxyphenylhydrazone.3. In the presence of fatty acids, the cytosolic ATP concentrations and ATP/ADP ratios decreased, whereas the corresponding parameters for the mitochondrial space were either increased (oleate) or decreased (octanoate). The effects of oleate were dependent on the albumin concentrations in the perfusate. The normally large difference between cytosolic and mitochondrial ATP/ADP ratios became smaller. Similar observations were obtained with uncoupling agents.4. The pH gradient across the mitochondrial membrane as calculated from the subcellular distribution of 5,5 dimethyl[2-14C]~~a~olidine-2,4-dione was inversed following the addition of both carbonylcyanide p-trifluoromethoxyphenylhydrazone and fatty acids, i.e. the mitochondrial matrix became more acidic than the cytosol. The pH gradient was not affected when oleate was added in the presence of high albumin concentrations. The data support the hypothesis that the increase in hepatic oxygen consumption due to octanoate or oleate is, in part, caused by a mechanism similar to uncoupling of oxidative phosphorylation. This mechanism seems not to be an artifact of isolated systems; it may be of physiological importance for processes in which reducing equivalents are removed independently of the ATP demand of the hepatocyte.In the preceding paper [I], it was demonstrated that addition of medium-chain and long-chain fatty acids to perfused livers from fed and starved rats causes a considerable increase in the rate of oxygen consumption. This phenomenon is due to a mitochondrial process; but it can only partially be explained by the ATP balance of hepatic metabolism. Therefore, an 'uncoupling-like' effect of fatty acids on the respiratory chain in the intact cell was suggested.The protonmotive force, i.e. the potential of the mitochondrial membrane ( A $ ) plus the proton potential (LIP,"+$, is assumed to be the primary energy store in oxidative phosphorylation [2]. Experimentally avai...

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Section: Physiological Significance Of the Uncoupling-like Effect Of mentioning

confidence: 77%

Influence of fatty acids on energy metabolism

Soboll

Grundel

Schwabe

et al. 1984

European Journal of Biochemistry

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“…Under certain physiological and pathophysiological conditions that are associated with impaired insulin action (insulin resistance; Table 1), plasma FFA concentrations may be markedly increased. Bierman et al (1) first reported that plasma FFA are elevated in uncontrolled diabetes mellitus. Subsequent studies extended these findings also to nondiabetic but insulin-resistant humans, such as obese patients and first-degree relatives of type 2 diabetic patients (14).…”

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confidence: 98%

How Free Fatty Acids Inhibit Glucose Utilization in Human Skeletal Muscle

2004

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Rat muscle studies suggest competition between free fatty acids (FFA) and glucose for oxidation, resulting in glucose-6-phosphate accumulation. However, FFA decrease glucose-6-phosphate in human skeletal muscle, indicating direct inhibition of glucose transport/phosphorylation. This mechanism could redirect glucose from muscle to brain during fasting and explain the insulin resistance associated with high-lipid diets and obesity.

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“…It is well established in the literature that pathophysiological conditions that are associated with impaired insulin resistance, such as type 2 diabetes and obesity, correlate with elevations in circulating FFAs (15,147). Considerable evidence obtained in both animal and human studies have linked accumulation of intra-myocellular lipids with insulin resistance in obesity and type 2 diabetes (49,75,109,133).…”

Section: Skeletal Muscle Dysfunction In Metabolic Diseasementioning

confidence: 99%

Orphan nuclear receptors: therapeutic opportunities in skeletal muscle

Smith

Muscat²

2006

American Journal of Physiology-Cell Physiology

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Nuclear hormone receptors (NRs) are ligand-dependent transcription factors that bind DNA and translate physiological signals into gene regulation. The therapeutic utility of NRs is underscored by the diversity of drugs created to manage dysfunctional hormone signaling in the context of reproductive biology, inflammation, dermatology, cancer, and metabolic disease. For example, drugs that target nuclear receptors generate over $10 billion in annual sales. Almost two decades ago, gene products were identified that belonged to the NR superfamily on the basis of DNA and protein sequence identity. However, the endogenous and synthetic small molecules that modulate their action were not known, and they were denoted orphan NRs. Many of the remaining orphan NRs are highly enriched in energy-demanding major mass tissues, including skeletal muscle, brown and white adipose, brain, liver, and kidney. This review focuses on recently adopted and orphan NR function in skeletal muscle, a tissue that accounts for approximately 35% of the total body mass and energy expenditure, and is a major site of fatty acid and glucose utilization. Moreover, this lean tissue is involved in cholesterol efflux and secretes that control energy expenditure and adiposity. Consequently, muscle has a significant role in insulin sensitivity, the blood lipid profile, and energy balance. Accordingly, skeletal muscle plays a considerable role in the progression of dyslipidemia, diabetes, and obesity. These are risk factors for cardiovascular disease, which is the the foremost cause of global mortality (>16.7 million deaths in 2003). Therefore, it is not surprising that orphan NRs and skeletal muscle are emerging as therapeutic candidates in the battle against dyslipidemia, diabetes, obesity, and cardiovascular disease.

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An Abnormality of Nonesterified Fatty Acid Metabolism in Diabetes Mellitus

Cited by 299 publications

References 0 publications

Influence of fatty acids on energy metabolism

Influence of fatty acids on energy metabolism

How Free Fatty Acids Inhibit Glucose Utilization in Human Skeletal Muscle

Orphan nuclear receptors: therapeutic opportunities in skeletal muscle

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