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

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 = 12) and matched obese controls (n = 12) participated in aerobic cycling training for 10 wk. Endurance-trained athletes (n = 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 approximately 50%, approaching the levels observed in the nondiabetic subjects. A strong inverse association between insulin sensitivity and SS lipid volume was found (r(2)=0.62, P = 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.

[1]  J. Wojtaszewski,et al.  Higher intramuscular triacylglycerol in women does not impair insulin sensitivity and proximal insulin signaling. , 2009, Journal of applied physiology.

[2]  K. Sahlin,et al.  Maximal lipid oxidation in patients with type 2 diabetes is normal and shows an adequate increase in response to aerobic training , 2009, Diabetes, obesity & metabolism.

[3]  N. Ørtenblad,et al.  Distinct effects of subcellular glycogen localization on tetanic relaxation time and endurance in mechanically skinned rat skeletal muscle fibres , 2009, The Journal of physiology.

[4]  J. Helge,et al.  Dual Regulation of Muscle Glycogen Synthase during Exercise by Activation and Compartmentalization* , 2009, The Journal of Biological Chemistry.

[5]  M. Febbraio,et al.  Overexpression of Carnitine Palmitoyltransferase-1 in Skeletal Muscle Is Sufficient to Enhance Fatty Acid Oxidation and Improve High-Fat Diet–Induced Insulin Resistance , 2009, Diabetes.

[6]  M. Fiatarone Singh,et al.  Adaptations to exercise training within skeletal muscle in adults with type 2 diabetes or impaired glucose tolerance: a systematic review , 2009, Diabetes/metabolism research and reviews.

[7]  Mauro Dell'Amico,et al.  2. Theoretical Foundations , 2009 .

[8]  Christopher B. Newgard,et al.  Molecular and metabolic mechanisms of insulin resistance and β-cell failure in type 2 diabetes , 2008, Nature Reviews Molecular Cell Biology.

[9]  A. Bonen,et al.  Modest PGC-1α Overexpression in Muscle in Vivo Is Sufficient to Increase Insulin Sensitivity and Palmitate Oxidation in Subsarcolemmal, Not Intermyofibrillar, Mitochondria* , 2008, Journal of Biological Chemistry.

[10]  H. Galbo,et al.  Denervation and High-Fat Diet Reduce Insulin Signaling in T-Tubules in Skeletal Muscle of Living Mice , 2008, Diabetes.

[11]  L. Goodyear,et al.  Large GLUT4 Vesicles Are Stationary While Locally and Reversibly Depleted During Transient Insulin Stimulation of Skeletal Muscle of Living Mice , 2007, Diabetes.

[12]  M. Tarnopolsky,et al.  Quantitative assessment of human muscle glycogen granules size and number in subcellular locations during recovery from prolonged exercise , 2007, The Journal of physiology.

[13]  J. Helge,et al.  Contraction-mediated glucose uptake is increased in men with impaired glucose tolerance. , 2007, Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme.

[14]  Bente Kiens,et al.  Skeletal muscle lipid metabolism in exercise and insulin resistance. , 2006, Physiological reviews.

[15]  Keir J. Menzies,et al.  Differential susceptibility of subsarcolemmal and intermyofibrillar mitochondria to apoptotic stimuli. , 2005, American journal of physiology. Cell physiology.

[16]  G. Perseghin.  Muscle lipid metabolism in the metabolic syndrome , 2005, Current opinion in lipidology.

[17]  B. Goodpaster,et al.  Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. , 2005, Diabetes.

[18]  Hyo Jeong Kim,et al.  Effect of exercise training on muscle glucose transporter 4 protein and intramuscular lipid content in elderly men with impaired glucose tolerance , 2004, European Journal of Applied Physiology.

[19]  L. V. van Loon,et al.  Intramyocellular lipid content in type 2 diabetes patients compared with overweight sedentary men and highly trained endurance athletes. , 2004, American journal of physiology. Endocrinology and metabolism.

[20]  H. Hoppeler,et al.  Influences of endurance training on the ultrastructural composition of the different muscle fiber types in humans , 1985, Pflügers Archiv.

[21]  P. Morris,et al.  Direct assessment of muscle glycogen storage after mixed meals in normal and type 2 diabetic subjects. , 2003, American journal of physiology. Endocrinology and metabolism.

[22]  G. Cooney,et al.  Disassociation of muscle triglyceride content and insulin sensitivity after exercise training in patients with Type 2 diabetes , 2003, Diabetologia.

[23]  H. Hoppeler,et al.  Plasticity of skeletal muscle mitochondria: structure and function. , 2003, Medicine and science in sports and exercise.

[24]  Simon C Watkins,et al.  Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. , 2001, The Journal of clinical endocrinology and metabolism.

[25]  M. Rennie,et al.  Fat utilization during exercise: adaptation to a fat‐rich diet increases utilization of plasma fatty acids and very low density lipoprotein‐triacylglycerol in humans , 2001, The Journal of physiology.

[26]  H. Beck-Nielsen,et al.  Morphometric documentation of abnormal intramyocellular fat storage and reduced glycogen in obese patients with Type II diabetes , 2001, Diabetologia.

[27]  A. Tremblay,et al.  Elevated intramyocellular lipid concentration in obese subjects is not reduced after diet and exercise training. , 2001, American journal of physiology. Endocrinology and metabolism.

[28]  J. Holst,et al.  Reference intervals for glucose, beta-cell polypeptides, and counterregulatory factors during prolonged fasting. , 2001, American journal of physiology. Endocrinology and metabolism.

[29]  L. Mandarino,et al.  Fuel selection in human skeletal muscle in insulin resistance: a reexamination. , 2000, Diabetes.

[30]  L. DiPietro,et al.  Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study , 1999, Diabetologia.

[31]  Konrad Sandau,et al.  Unbiased Stereology. Three‐Dimensional Measurement in Microscopy. , 1999 .

[32]  S. Lillioja,et al.  Skeletal Muscle Triglyceride Levels Are Inversely Related to Insulin Action , 1997, Diabetes.

[33]  D. Hood,et al.  Protein Import into Subsarcolemmal and Intermyofibrillar Skeletal Muscle Mitochondria , 1996, The Journal of Biological Chemistry.

[34]  B. Fielding,et al.  Intramuscular triglyceride and muscle insulin sensitivity: evidence for a relationship in nondiabetic subjects. , 1996, Metabolism: clinical and experimental.

[35]  G. Heigenhauser,et al.  Progressive effect of endurance training on metabolic adaptations in working skeletal muscle. , 1996, The American journal of physiology.

[36]  E. Meléndez-Hevia,et al.  Optimization of molecular design in the evolution of metabolism: the glycogen molecule. , 1993, The Biochemical journal.

[37]  B. Saltin,et al.  Skeletal muscle substrate utilization during submaximal exercise in man: effect of endurance training. , 1993, The Journal of physiology.

[38]  D. Hood,et al.  Properties of skeletal muscle mitochondria isolated from subsarcolemmal and intermyofibrillar regions. , 1993, The American journal of physiology.

[39]  R G Shulman,et al.  Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. , 1990, The New England journal of medicine.

[40]  H. J. G. GUNDERSEN,et al.  Some new, simple and efficient stereological methods and their use in pathological research and diagnosis , 1988, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[41]  B. Saltin,et al.  Skeletal Muscle Adaptability: Significance for Metabolism and Performance , 1985 .

[42]  George W.C. Hung,et al.  Stereological methods, vol. 2: Theoretical foundations: By Ewald R. Weibel. Academic Press, New York, 1980. xiv + 340 pp., $62.50 , 1984 .

[43]  Jan Fridén,et al.  Morphometric analyses of human muscle fiber types , 1982, Muscle & nerve.

[44]  W. C. Bruijn.  Glycogen, its chemistry and morphologic appearance in the electron microscope , 1973 .

[45]  W. D. de Bruijn,et al.  Glycogen, its chemistry and morphologic appearance in the electron microscope. I. A modified OsO 4 fixative which selectively contrasts glycogen. , 1973, Journal of ultrastructure research.