Increased subsarcolemmal lipids in type 2 diabetes: effect of training on localization of lipids, mitochondria, and glycogen in sedentary human skeletal muscle

Abstract

Ørtenblad N. Increased subsarcolemmal lipids in type 2 diabetes: effect of training on localization of lipids, mitochondria, and glycogen in sedentary human skeletal muscle. Am J Physiol Endocrinol Metab 298: E706 -E713, 2010. First published December 22, 2009; doi:10.1152/ajpendo.00692.2009.-The purpose of the study was to investigate the effect of aerobic training and type 2 diabetes on intramyocellular localization of lipids, mitochondria, and glycogen. Obese type 2 diabetic patients (n ϭ 12) and matched obese controls (n ϭ 12) participated in aerobic cycling training for 10 wk. Endurance-trained athletes (n ϭ 15) were included for comparison. Insulin action was determined by euglycemic-hyperinsulinemic clamp. Intramyocellular contents of lipids, mitochondria, and glycogen at different subcellular compartments were assessed by transmission electron microscopy in biopsies obtained from vastus lateralis muscle. Type 2 diabetic patients were more insulin resistant than obese controls and had threefold higher volume of subsarcolemmal (SS) lipids compared with obese controls and endurance-trained subjects. No difference was found in intermyofibrillar lipids. Importantly, following aerobic training, this excess SS lipid volume was lowered by ϳ50%, approaching the levels observed in the nondiabetic subjects. A strong inverse association between insulin sensitivity and SS lipid volume was found (r 2 ϭ0.62, P ϭ 0.002). The volume density and localization of mitochondria and glycogen were the same in type 2 diabetic patients and control subjects, and showed in parallel with improved insulin sensitivity a similar increase in response to training, however, with a more pronounced increase in SS mitochondria and SS glycogen than in other localizations. In conclusion, this study, estimating intramyocellular localization of lipids, mitochondria, and glycogen, indicates that type 2 diabetic patients may be exposed to increased levels of SS lipids. Thus consideration of cell compartmentation may advance the understanding of the role of lipids in muscle function and type 2 diabetes. cell compartmentation; transmission electron microscopy; insulin sensitivity INTRAMYOCELLULAR LIPID (IMCL) accumulation in skeletal muscle of humans has been related to impaired insulin sensitivity (20,30). The causality has been challenged by reports of increased IMCL levels in endurance-trained athletes compared with untrained (8) and higher IMCL levels in women than in men without concomitant differences in insulin sensitivity (11,17). Thus many have suggested that high IMCL levels per se do not influence insulin sensitivity but represent a marker of increased fatty acid metabolites such as diacylglycerol (DAG), ceramide, and long-chain acyl-CoAs, which in turn could be detrimental for insulin sensitivity (17,28,31).However, evaluation of the role of IMCL in subcellular fractions has not been considered in previous studies (8,11,20,30). The muscle cell consists mainly of contractile filaments arranged in myofibrils with mitochondria, lipids, gly...

Inorganic Nitrate Mimics Exercise-Stimulated Muscular Fiber-Type Switching and Myokine and γ-Aminobutyric Acid Release

“…T2DM is accompanied by perturbations to muscle physiology, resulting in decreased mitochondrial content and abnormal lipid deposition, impairing the insulin-mediated switch between fat and carbohydrate metabolism (37). Dietary nitrate supplementation exhibits anti-obesity and anti-diabetic properties in rodents; improving homeostatic model assessment for insulin resistance and quantitative insulin sensitivity check index assessments in high-fructose diet-induced insulin resistant rats (5), and improving glucose tolerance in NOS-deficient mice (4); while reducing adiposity in both models.…”

Can resveratrol help to maintain metabolic health?

“…It is well known and well described that physical exercise training is perhaps the single best option for the prevention and treatment of T2DM. Nielsen et al (23) showed that a 10-week aerobic cycling training in obese, male T2DM patients and age-and BMI-matched controls indeed improved mitochondrial content (by ∼40 %) and that this was accompanied by an increase in insulin sensitivity in both groups. In 2010, we performed an exercise-training intervention in T2DM patients and BMI-and age-matched obese controls, and examined mitochondrial function in further detail.…”

Subcellular lipid droplet distribution in red and white muscles in the obese Zucker rat

“…We analysed lipid droplet density in two ways, counting (1) the number of lipid droplets in subsarcolemmal and intermyofibrillar regions normalised to muscle area and (2) the relative percentage of subsarcolemmal lipids. The latter was calculated by determining subsarcolemmal lipids normalised to muscle fibre surface area and intermyofibrillar lipids normalised to the volume beneath the surface area, assuming an average radius of 40 μm and cylindrical shape of the fibres as reported by others [5]. The cross-sectional area of individual lipid droplets was determined using a software package (iTEM; Olympus/SIS).…”

“…These compartments also harbour subsarcolemmal and intermyofibrillar mitochondria, and therefore intramuscular lipid depots are found in close proximity to mitochondria [4]. Recently it has been suggested that the subcellular distribution of intramuscular lipid droplets in the subsarcolemmal region, rather than the total content of various lipid species, contributes to attenuation of insulin signalling in muscle [5]. There are several potential mechanisms that could result in subcellular variations in intramuscular lipid accretion, including regionally selective impairments of mitochondrial fatty acid oxidation and/or increased abundance of the enzymes involved in triacylglycerol esterification.…”

“…Triacylglycerol esterification can be regulated by a number of enzymes, which in most cell types reside on the endoplasmic reticulum, with the exception of glycerol-3-phosphate acyltransferase 1 (GPAT1), which is located on mitochondria [17]. This raises the possibility that partitioning of fatty acyl-CoA to storage or oxidation can occur in close proximity to the mitochondria, a possibility also implied by the intimate spatial relationship between mitochondria and lipid droplets [5,14,18,19]. However, it is currently unknown whether: (1) the enzymes involved in triacylglycerol synthesis are present and differentially associated in subsarcolemmal and/or intermyofibrillar mitochondrial compartments in skeletal muscle; and (2) whether the subcellular presence of these enzymes is altered in muscles from insulin-resistant animals.…”