High Incomplete Skeletal Muscle Fatty Acid Oxidation Explains Low Muscle Insulin Sensitivity in Poorly Controlled T2D

Abstract Context Almost 50% of type 2 diabetic (T2D) patients are poorly controlled [glycated hemoglobin (HbA1c) ≥ 7%]; however, the mechanisms responsible for progressively worsening glycemic control are poorly understood. Lower skeletal muscle mitochondrial respiratory capacity is associated with low insulin sensitivity and the development of T2D. Objective We investigated if skeletal muscle insulin sensitivity (SI) was different between well-controlled T2D (WCD) and poorly controlled T2D (PCD) and if the difference was associated with differences resulting from mitochondrial respiratory function. Design Vastus lateralis muscle mitochondrial respiration, mitochondrial content, mitochondrial enzyme activity, and fatty acid oxidation (FAO) were measured. SI and the acute response to glucose (AIRg) were calculated by MINMOD analysis from glucose and insulin obtained during a modified, frequently sampled, intravenous glucose tolerance test. Results SI and AIRg were lower in PCD than WCD. Muscle incomplete FAO was greater in PCD than WCD and greater incomplete FAO was associated with lower SI and higher HbA1c. Hydroxyacyl-coenzyme A dehydrogenase expression and activity were greater in PCD than WCD. There was no difference in maximal mitochondrial respiration or content between WCD and PCD. Conclusion The current results suggest that greater skeletal muscle incomplete FAO in poorly controlled T2D is due to elevated β oxidation and is associated with worsening muscle SI.

Download Full-text

Human skeletal muscle malonyl-CoA at rest and during prolonged submaximal exercise

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.270.3.e541 ◽

1996 ◽

Vol 270 (3) ◽

pp. E541-E544 ◽

Cited By ~ 33

Author(s):

L. M. Odland ◽

G. J. Heigenhauser ◽

G. D. Lopaschuk ◽

L. L. Spriet

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

High Performance ◽

Human Skeletal Muscle ◽

Vastus Lateralis ◽

Submaximal Exercise ◽

Acid Oxidation ◽

Vastus Lateralis Muscle ◽

Malonyl Coa

Previous literature has indicated that contraction-induced decreases in malonyl-CoA are instrumental in the regulation of fatty acid oxidation during prolonged submaximal exercise. This study was designed to measure malonyl-CoA in human vastus lateralis muscle at rest and during submaximal exercise. Eight males and one female cycled for 70 min (10 min at 40% and 60 min at 65% maximal O2 uptake). Needle biopsies were obtained at rest and at 10 min, 20 min, and 70 min of exercise. Malonyl-CoA content in preexercise biopsy samples determined by high-performance liquid chromatography (HPLC) was 1.53 +/- 0.18 micromol/kg dry mass (dm). Malonyl-CoA content did not change significantly during exercise (1.39 +/- 0.21 at 10 min, 1.46 +/- 0.14 at 20 min, and 1.22 +/- 0.15 micromol/kg dm at 70 min). In contrast, malonyl-CoA content determined by HPLC in perfused rat red gastrocnemius muscle decreased significantly during 20 min of stimulation at 0.7 Hz [3.44 +/- 0.54 to 1.64 +/- 0.23 nmol/g dm, (n=9)]. We conclude that human skeletal muscle malonyl-CoA content 1) is less than reported in rat skeletal muscle at rest, 2) does not decrease with prolonged submaximal exercise, and 3) is not predictive of increased fatty acid oxidation during exercise.

Download Full-text

Skeletal muscle phosphatidylcholine and phosphatidylethanolamine are related to insulin sensitivity and respond to acute exercise in humans

Journal of Applied Physiology ◽

10.1152/japplphysiol.00664.2015 ◽

2016 ◽

Vol 120 (11) ◽

pp. 1355-1363 ◽

Cited By ~ 26

Author(s):

Sean A. Newsom ◽

Joseph T. Brozinick ◽

Katja Kiseljak-Vassiliades ◽

Allison N. Strauss ◽

Samantha D. Bacon ◽

...

Keyword(s):

Mass Spectrometry ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Acute Exercise ◽

Contractile Function ◽

Vastus Lateralis ◽

Mass Spectrometry Analysis ◽

Vastus Lateralis Muscle ◽

Intravenous Glucose ◽

Exercise In Humans

Several recent reports indicate that the balance of skeletal muscle phosphatidylcholine (PC) and phosphatidylethanolamine (PE) is a key determinant of muscle contractile function and metabolism. The purpose of this study was to determine relationships between skeletal muscle PC, PE and insulin sensitivity, and whether PC and PE are dynamically regulated in response to acute exercise in humans. Insulin sensitivity was measured via intravenous glucose tolerance in sedentary obese adults (OB; n = 14), individuals with type 2 diabetes (T2D; n = 15), and endurance-trained athletes (ATH; n = 15). Vastus lateralis muscle biopsies were obtained at rest, immediately after 90 min of cycle ergometry at 50% maximal oxygen consumption (V̇o2 max), and 2-h postexercise (recovery). Skeletal muscle PC and PE were measured via infusion-based mass spectrometry/mass spectrometry analysis. ATH had greater levels of muscle PC and PE compared with OB and T2D ( P < 0.05), with total PC and PE positively relating to insulin sensitivity (both P < 0.05). Skeletal muscle PC:PE ratio was elevated in T2D compared with OB and ATH ( P < 0.05), tended to be elevated in OB vs. ATH ( P = 0.07), and was inversely related to insulin sensitivity among the entire cohort ( r = −0.43, P = 0.01). Muscle PC and PE were altered by exercise, particularly after 2 h of recovery, in a highly group-specific manner. However, muscle PC:PE ratio remained unchanged in all groups. In summary, total muscle PC and PE are positively related to insulin sensitivity while PC:PE ratio is inversely related to insulin sensitivity in humans. A single session of exercise significantly alters skeletal muscle PC and PE levels, but not PC:PE ratio.

Download Full-text

The PPARδ agonist, GW501516, promotes fatty acid oxidation but has no direct effect on glucose utilisation or insulin sensitivity in rat L6 skeletal muscle cells

FEBS Letters ◽

10.1016/j.febslet.2007.08.072 ◽

2007 ◽

Vol 581 (24) ◽

pp. 4743-4748 ◽

Cited By ~ 27

Author(s):

Nikolaos Dimopoulos ◽

Maria Watson ◽

Charlotte Green ◽

Harinder S. Hundal

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Insulin Sensitivity ◽

Fatty Acid Oxidation ◽

Direct Effect ◽

Muscle Cells ◽

Skeletal Muscle Cells ◽

Acid Oxidation ◽

Glucose Utilisation ◽

L6 Skeletal Muscle Cells

Download Full-text

PGC-1α-induced improvements in skeletal muscle metabolism and insulin sensitivityThis paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

Applied Physiology Nutrition and Metabolism ◽

10.1139/h09-008 ◽

2009 ◽

Vol 34 (3) ◽

pp. 307-314 ◽

Cited By ~ 46

Author(s):

Arend Bonen

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Insulin Sensitivity ◽

Fatty Acid Oxidation ◽

Insulin Signalling ◽

Metabolic Effects ◽

Zucker Rats ◽

Acid Oxidation ◽

Mitochondrial Fatty Acid ◽

Exercise Induced

The peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α), a nuclear encoded transcriptional coactivator, increases the expression of many genes in skeletal muscle, including those involved with fatty acid oxidation and oxidative phosphorylation. Exercise increases the expression of PGC-1α, and the exercise-induced upregulation of many genes is attributable, in part, to the preceding activation and upregulation of PGC-1α. Indeed, PGC-1α overexpression, like exercise training, increases exercise performance. PGC-1α reductions in humans have been observed in type 2 diabetes, while, in cell lines, PGC-1α mimics the exercise-induced improvement in insulin sensitivity. However, unexpectedly, in mammalian muscle, PGC-1α overexpression contributed to the development of diet-induced insulin resistance. This may have been related to the massive overexpression of PGC-1α, which induced the upregulation of the fatty acid transporter FAT/CD36 and led to an increase in intramuscular lipids, which interfere with insulin signalling. In contrast, when PGC-1α was overexpressed modestly, within physiological limits, mitochondrial fatty acid oxidation was increased, GLUT4 expression was upregulated, and insulin-stimulated glucose transport was increased. More recently, similar PGC-1α-induced improvements in the insulin-resistant skeletal muscle of obese Zucker rats have been observed. These studies suggest that massive PGC-1α overexpression, but not physiologic PGC-1α overexpression, induces deleterious metabolic effects, and that exercise-induced improvements in insulin sensitivity are induced, in part, by the exercise-induced upregulation of PGC-1α.

Download Full-text

Carnitine-Palmitoyltransferase-1 Deficiency Impairs Skeletal Muscle Fatty Acid Oxidation, But Preserves Insulin Sensitivity

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2012.10.184 ◽

2012 ◽

Vol 53 ◽

pp. S99

Author(s):

Shawna E. Wicks ◽

Bolormaa Vandanmagsar ◽

Kimberly R. Haynie ◽

Jingying Zhang ◽

Robert Noland ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Insulin Sensitivity ◽

Fatty Acid Oxidation ◽

Carnitine Palmitoyltransferase ◽

Acid Oxidation ◽

Carnitine Palmitoyltransferase 1

Download Full-text

Similar qualitative and quantitative changes of mitochondrial respiration following strength and endurance training in normoxia and hypoxia in sedentary humans

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00285.2011 ◽

2011 ◽

Vol 301 (4) ◽

pp. R1078-R1087 ◽

Cited By ~ 96

Author(s):

Dominik Pesta ◽

Florian Hoppel ◽

Christian Macek ◽

Hubert Messner ◽

Martin Faulhaber ◽

...

Keyword(s):

Fatty Acid ◽

Oxidative Phosphorylation ◽

Strength Training ◽

Endurance Training ◽

Fatty Acid Oxidation ◽

Muscle Mass ◽

Mitochondrial Respiration ◽

Vastus Lateralis ◽

Acid Oxidation ◽

Hypoxia Group

Endurance and strength training are established as distinct exercise modalities, increasing either mitochondrial density or myofibrillar units. Recent research, however, suggests that mitochondrial biogenesis is stimulated by both training modalities. To test the training “specificity” hypothesis, mitochondrial respiration was studied in permeabilized muscle fibers from 25 sedentary adults after endurance (ET) or strength training (ST) in normoxia or hypoxia [fraction of inspired oxygen (FiO2) = 21% or 13.5%]. Biopsies were taken from the musculus vastus lateralis, and cycle-ergometric incremental maximum oxygen uptake (V̇o2max) exercise tests were performed under normoxia, before and after the 10-wk training program. The main finding was a significant increase ( P < 0.05) of fatty acid oxidation capacity per muscle mass, after endurance and strength training under normoxia [2.6- and 2.4-fold for endurance training normoxia group (ETN) and strength training normoxia group (STN); n = 8 and 3] and hypoxia [2.0-fold for the endurance training hypoxia group (ETH) and strength training hypoxia group (STH); n = 7 and 7], and higher coupling control of oxidative phosphorylation. The enhanced lipid oxidative phosphorylation (OXPHOS) capacity was mainly (87%) due to qualitative mitochondrial changes increasing the relative capacity for fatty acid oxidation ( P < 0.01). Mitochondrial tissue-density contributed to a smaller extent (13%), reflected by the gain in muscle mass-specific respiratory capacity with a physiological substrate cocktail (glutamate, malate, succinate, and octanoylcarnitine). No significant increase was observed in mitochondrial DNA (mtDNA) content. Physiological OXPHOS capacity increased significantly in ETN ( P < 0.01), with the same trend in ETH and STH ( P < 0.1). The limitation of flux by the phosphorylation system was diminished after training. Importantly, key mitochondrial adaptations were similar after endurance and strength training, regardless of normoxic or hypoxic exercise. The transition from a sedentary to an active lifestyle induced muscular changes of mitochondrial quality representative of mitochondrial health.

Download Full-text

Genistein stimulates insulin sensitivity through gut microbiota reshaping and skeletal muscle AMPK activation in obese subjects

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-000948 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000948 ◽

Cited By ~ 3

Author(s):

Martha Guevara-Cruz ◽

Einar T Godinez-Salas ◽

Monica Sanchez-Tapia ◽

Gonzalo Torres-Villalobos ◽

Edgar Pichardo-Ontiveros ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Fatty Acid ◽

Insulin Sensitivity ◽

Gut Microbiota ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Oral Glucose ◽

Model Assessment ◽

Metabolic Endotoxemia

ObjectiveObesity is associated with metabolic abnormalities, including insulin resistance and dyslipidemias. Previous studies demonstrated that genistein intake modifies the gut microbiota in mice by selectively increasing Akkermansia muciniphila, leading to reduction of metabolic endotoxemia and insulin sensitivity. However, it is not known whether the consumption of genistein in humans with obesity could modify the gut microbiota reducing the metabolic endotoxemia and insulin sensitivity.Research design and methods45 participants with a Homeostatic Model Assessment (HOMA) index greater than 2.5 and body mass indices of ≥30 and≤40 kg/m2 were studied. Patients were randomly distributed to consume (1) placebo treatment or (2) genistein capsules (50 mg/day) for 2 months. Blood samples were taken to evaluate glucose concentration, lipid profile and serum insulin. Insulin resistance was determined by means of the HOMA for insulin resistance (HOMA-IR) index and by an oral glucose tolerance test. After 2 months, the same variables were assessed including a serum metabolomic analysis, gut microbiota, and a skeletal muscle biopsy was obtained to study the gene expression of fatty acid oxidation.ResultsIn the present study, we show that the consumption of genistein for 2 months reduced insulin resistance in subjects with obesity, accompanied by a modification of the gut microbiota taxonomy, particularly by an increase in the Verrucomicrobia phylum. In addition, subjects showed a reduction in metabolic endotoxemia and an increase in 5′-adenosine monophosphate-activated protein kinase phosphorylation and expression of genes involved in fatty acid oxidation in skeletal muscle. As a result, there was an increase in circulating metabolites of β-oxidation and ω-oxidation, acyl-carnitines and ketone bodies.ConclusionsChange in the gut microbiota was accompanied by an improvement in insulin resistance and an increase in skeletal muscle fatty acid oxidation. Therefore, genistein could be used as a part of dietary strategies to control the abnormalities associated with obesity, particularly insulin resistance; however, long-term studies are needed.

Download Full-text