scholarly journals 0295 Skeletal Muscle Diacylglycerol Accumulation and Impaired Insulin Sensitivity During Insufficient Sleep

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A111-A112
Author(s):  
S J Morton ◽  
B C Bergman ◽  
K A Zemski-Berry ◽  
K A Harrison ◽  
I E Schauer ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Lipid Accumulation ◽  
Vastus Lateralis ◽  
Plasma Free Fatty Acid ◽  
Insufficient Sleep ◽  
Impaired Insulin ◽  
Skeletal Muscle Lipid ◽  
Specific Species ◽  
Laboratory Protocol

Abstract Introduction Insufficient sleep impairs insulin sensitivity; however, the mechanism(s) by which this occurs are unknown. We previously reported an elevation in plasma free fatty acid concentration during insufficient sleep, suggesting dysregulated lipid metabolism. Lipid accumulation in muscle—specifically certain species of diacylglycerol (DAG)—is associated with impaired insulin sensitivity. We therefore tested the hypothesis that insufficient sleep leads to skeletal muscle DAG accumulation. Methods As part of an ongoing study, thirteen sedentary, healthy, lean adults (25.8±3.2y; 22.7±1.9kg/m2; 3F; mean±SD) participated in a controlled 6-day in-laboratory protocol with 9h in bed (habitual sleep) followed by 4 nights of 5h in bed (insufficient sleep), achieved by delaying bedtime by 4 hours. For one week prior to the study, participants maintained a 9h sleep schedule. Participants consumed energy balanced diets 3 days prior to and throughout the laboratory protocol. Insulin sensitivity was assessed using a hyperinsulinemic euglycemic clamp before and after insufficient sleep. Skeletal muscle biopsies of the vastus lateralis were taken immediately before each clamp. In a subset of subjects (n=10), quantitative lipidomic analyses using LC/MS/MS were performed on biopsied muscle tissue. Results Insulin sensitivity was impaired following insufficient sleep (10.7±1.5 vs 9.6±1.2 mg/kg/min, p<0.05, mean±SEM). There were no changes in skeletal muscle concentration of total triglycerides (TAGs), nor specific TAG species. However, insufficient sleep tended to increase skeletal muscle accumulation of total 1,2-DAGs (p=0.13) and significantly increased specific saturated species of 1,2-DAG, including Di-C18:0 DAG (p<0.05), previously implicated in insulin resistance. In contrast, 1,3-DAGs are not thought to impair insulin sensitivity and specific species were decreased or unchanged during insufficient sleep. Conclusion Preliminary findings suggest that skeletal muscle lipid accumulation of diacylglycerol species during insufficient sleep may be a contributing mechanism by which insufficient sleep dysregulates metabolic physiology. Support NIH K01DK110138, R03 DK118309, UL1 TR002535, and GCRC RR-00036

124 Skeletal muscle RNA and insulin sensitivity during insufficient sleep

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A50-A51
Author(s):  
Sarah Morton ◽  
Julia Sharp ◽  
Kenneth Wright ◽  
Josiane Broussard
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Vastus Lateralis ◽  
Statistical Significance ◽  
Whole Body ◽  
P Value ◽  
Insufficient Sleep ◽  
Before And After ◽  
Study Participants ◽  
Laboratory Protocol

Abstract Introduction Insufficient sleep is associated with a down-regulation of genes involved in glycolysis, in conjunction with an upregulation of genes involved in lipid metabolism in skeletal muscle. However, whether changes in RNA are associated with impairments in insulin sensitivity is unclear. We therefore tested the hypothesis that insufficient sleep will induce alterations in skeletal muscle RNA that correlate with changes in insulin sensitivity. Methods As part of an ongoing study, sixteen sedentary, healthy, lean adults (24.9±3.4y; 22.6±1.7kg/m2; 6F; mean±SD) participated in a controlled 6-day in-laboratory protocol with 9h in bed (habitual sleep) followed by 4 nights of 5h in bed (insufficient sleep), achieved by delaying bedtime by 4 hours. For one week prior to the study, participants maintained a 9h sleep schedule based on their habitual bed and wake times. Participants consumed energy-balanced diets 3 days prior to and throughout the laboratory protocol. Whole body insulin sensitivity was assessed using glucose infusion rate from a hyperinsulinemic euglycemic clamp before and after 4 nights of insufficient sleep. Skeletal muscle biopsies of the vastus lateralis were taken immediately before each clamp. In a subset of subjects (n=12), RNA sequencing was performed (Novogene Co., Ltd). Generalized linear model likelihood ratio tests were completed using the DESeq2/EdgeR R packages with a false discovery rate (FDR) cut-off of 5%. P-values were adjusted for multiple comparisons using the Benjamini-Hochberg method and a corrected p-value of 0.05 and log2 fold-change of 0 were set as the threshold for statistical significance. Results Insulin sensitivity was impaired by 6% following insufficient sleep (10.1±1.4 vs 9.1±1.1mg/kg/min, p<0.05, mean±SEM). Preliminary results from skeletal muscle RNAseq analyses suggest approximately 25 genes were down-regulated and 60 genes were up-regulated. Down-regulated genes were involved in insulin-like growth factor binding and signal transduction (p=8.4e-11), while up-regulated genes were involved in glycolysis and ATP binding (p=1.1e-9). While there were trends for associations between changes in gene expression and insulin sensitivity, these relationships did not reach statistical significance. Conclusion Preliminary findings suggest insufficient sleep alters skeletal muscle RNA. Changes in these aforementioned pathways may contribute to metabolic dysregulation during insufficient sleep. Support (if any) NIH K01DK110138, R03 DK118309, UL1 TR002535, and GCRC RR-00036

Impaired Insulin Resistance in IF1-Deficient Mice Subjected to a High-Fat Diet with Reduced-Fat Mass and Skeletal Muscle Lipid Accumulation

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 1748-P ◽  
Author(s):  
FENGYUAN HUANG ◽  
KEVIN YANG ◽  
KAMALAMMA SAJA ◽  
YICHENG HUANG ◽  
QINGQIANG LONG ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Lipid Accumulation ◽  
High Fat Diet ◽  
High Fat ◽  
Muscle Lipid ◽  
Reduced Fat ◽  
Impaired Insulin ◽  
Skeletal Muscle Lipid ◽  
Deficient Mice

Twin Conception in Sheep Leads to Impaired Insulin Sensitivity and Sexually Dimorphic Adipose Tissue and Skeletal Muscle Phenotypes in Adulthood

2016 ◽  
Vol 24 (6) ◽  
pp. 865-881 ◽  
Author(s):  
Elise L. Donovan ◽  
Emma J. Buckels ◽  
Serina Hancock ◽  
Danielle Smeitink ◽  
Mark H. Oliver ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Sexually Dimorphic ◽  
Impaired Insulin

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

2016 ◽  
Vol 120 (11) ◽  
pp. 1355-1363 ◽  
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.

scholarly journals Rapid development of systemic insulin resistance with overeating is not accompanied by robust changes in skeletal muscle glucose and lipid metabolism

2013 ◽  
Vol 38 (5) ◽  
pp. 512-519 ◽  
Author(s):  
Andrea S. Cornford ◽  
Alexander Hinko ◽  
Rachael K. Nelson ◽  
Ariel L. Barkan ◽  
Jeffrey F. Horowitz
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Lipid Accumulation ◽  
Rapid Development ◽  
Insulin Response ◽  
Whole Body ◽  
Muscle Lipid ◽  
Wet Weight

Prolonged overeating and the resultant weight gain are clearly linked with the development of insulin resistance and other cardiometabolic abnormalities, but adaptations that occur after relatively short periods of overeating are not completely understood. The purpose of this study was to characterize metabolic adaptations that may accompany the development of insulin resistance after 2 weeks of overeating. Healthy, nonobese subjects (n = 9) were admitted to the hospital for 2 weeks, during which time they ate ∼4000 kcals·day−1 (70 kcal·kg−1 fat free mass·day−1). Insulin sensitivity was estimated during a meal tolerance test, and a muscle biopsy was obtained to assess muscle lipid accumulation and protein markers associated with insulin resistance, inflammation, and the regulation of lipid metabolism. Whole-body insulin sensitivity declined markedly after 2 weeks of overeating (Matsuda composite index: 8.3 ± 1.3 vs. 4.6 ± 0.7, p < 0.05). However, muscle markers of insulin resistance and inflammation (i.e., phosphorylation of IRS-1-Ser312, Akt-Ser473, and c-Jun N-terminal kinase) were not altered by overeating. Intramyocellular lipids tended to increase after 2 weeks of overeating (triacylglyceride: 7.6 ± 1.6 vs. 10.0 ± 1.8 nmol·mg−1 wet weight; diacylglyceride: 104 ± 10 vs. 142 ± 23 pmol·mg−1 wet weight) but these changes did not reach statistical significance. Overeating induced a 2-fold increase in 24-h insulin response (area under the curve (AUC); p < 0.05), with a resultant ∼35% reduction in 24-h plasma fatty acid AUC (p < 0.05). This chronic reduction in circulating fatty acids may help explain the lack of a robust increase in muscle lipid accumulation. In summary, our findings suggest alterations in skeletal muscle metabolism may not contribute meaningfully to the marked whole-body insulin resistance observed after 2 weeks of overeating.

scholarly journals Changes Induced by Physical Activity and Weight Loss in the Morphology of Intermyofibrillar Mitochondria in Obese Men and Women

2006 ◽  
Vol 91 (8) ◽  
pp. 3224-3227 ◽  
Author(s):  
Frederico G. S. Toledo ◽  
Simon Watkins ◽  
David E. Kelley
Keyword(s):  
Physical Activity ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Weight Loss ◽  
Insulin Sensitivity ◽  
Lifestyle Modification ◽  
Vastus Lateralis ◽  
Vastus Lateralis Muscle ◽  
Mitochondrial Content ◽  
The Mean

Abstract Context: In obesity, skeletal muscle insulin resistance may be associated with smaller mitochondria. Objective: Our objective was to examine the effect of a lifestyle-modification intervention on the content and morphology of skeletal muscle mitochondria and its relationship to insulin sensitivity in obese, insulin-resistant subjects. Design: In this prospective interventional study, intermyofibrillar mitochondrial content and size were quantified by transmission electron microscopy with quantitative morphometric analysis of biopsy samples from vastus lateralis muscle. Systemic insulin sensitivity was measured with euglycemic hyperinsulinemic clamps. Setting: The study took place at a university-based clinical research center. Participants: Eleven sedentary, overweight/obese volunteers without diabetes participated in the study. Intervention: Intervention included 16 wk of aerobic training with dietary restriction of 500-1000 kcal/d. Main Outcome Measures: We assessed changes in mitochondrial content and size and changes in insulin sensitivity. Results: The percentage of myofiber volume occupied by mitochondria significantly increased from 3.70 ± 0.31 to 4.87 ± 0.33% after intervention (P = 0.01). The mean individual increase was 42.5 ± 18.1%. There was also a change in the mean cross-sectional mitochondrial area, increasing from a baseline of 0.078 ± 0.007 to 0.091 ± 0.007 μm2 (P &lt; 0.01), a mean increase of 19.2 ± 6.1% per subject. These changes in mitochondrial size and content highly correlated with improvements in insulin resistance (r = 0.68 and 0.72, respectively; P = 0.01). Conclusions: A combined intervention of weight loss and physical activity in previously sedentary obese adults is associated with enlargement of mitochondria and an increase in the mitochondrial content in skeletal muscle. These findings indicate that in obesity with insulin resistance, ultrastructural mitochondrial plasticity is substantially retained and, importantly, that changes in the morphology of mitochondria are associated with improvements in insulin resistance.

scholarly journals Dietary Sphingomyelin Attenuates Adipose Inflammation and Skeletal Muscle Lipid Accumulation in C57BL/6J Mice Fed an Obesogenic Diet

2017 ◽  
Vol 31 ◽  
pp. 966.17-966.17
Author(s):  
Gregory H Norris ◽  
Christina Jiang ◽  
Caitlin M Porter ◽  
Courtney L. Millar ◽  
Christopher N Blesso
Keyword(s):  
Skeletal Muscle ◽  
Lipid Accumulation ◽  
Muscle Lipid ◽  
Skeletal Muscle Lipid ◽  
Obesogenic Diet ◽  
Adipose Inflammation

scholarly journals Maternal Obesity-Impaired Insulin Signaling in Sheep and Induced Lipid Accumulation and Fibrosis in Skeletal Muscle of Offspring1

2011 ◽  
Vol 85 (1) ◽  
pp. 172-178 ◽  
Author(s):  
Xu Yan ◽  
Yan Huang ◽  
Jun-Xing Zhao ◽  
Nathan M. Long ◽  
Adam B. Uthlaut ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Signaling ◽  
Lipid Accumulation ◽  
Maternal Obesity ◽  
Impaired Insulin

Effect of short-term exercise training on insulin-stimulated PI 3-kinase activity in human skeletal muscle

1999 ◽  
Vol 277 (6) ◽  
pp. E1055-E1060 ◽  
Author(s):  
Joseph A. Houmard ◽  
Christopher D. Shaw ◽  
Matthew S. Hickey ◽  
Charles J. Tanner
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Exercise Training ◽  
Kinase Activity ◽  
Vastus Lateralis ◽  
Maximal Oxygen Consumption ◽  
Exercise Bout ◽  
Phosphatidylinositol 3 Kinase ◽  
Insulin Signal Transduction ◽  
Before And After

The purpose of this study was to determine if the improvement in insulin sensitivity with exercise training is associated with enhanced phosphatidylinositol 3-kinase (PI 3-kinase) activity. Nine sedentary men were studied before and after 7 days of exercise training (1 h/day, ≈75% maximal oxygen consumption). Insulin sensitivity was determined with a euglycemic-hyperinsulinemic glucose clamp in the sedentary state and 15–17 h after the final exercise bout. PI 3-kinase activity was determined from samples (vastus lateralis) obtained in the fasted condition and after 60 min of submaximal insulin stimulation during the clamp. After exercise, glucose infusion rate increased ( P < 0.05) significantly (means ± SE, 7.8 ± 0.5 vs. 9.8 ± 0.8 mg ⋅ kg−1 ⋅ min−1), indicating improved insulin sensitivity. Insulin-stimulated (insulin stimulated/fasting) phosphotyrosine immunoprecipitable PI 3-kinase activity also increased significantly ( P < 0.05) with exercise (3.1 ± 0.8-fold) compared with the sedentary condition (1.3 ± 0.1-fold). There was no change in fasting PI 3-kinase activity. These data suggest that an enhancement of insulin signal transduction in skeletal muscle may contribute to the improvement in insulin action with exercise.

scholarly journals β-Hydroxybutyrate is reduced in humans with obesity-related NAFLD and displays a dose-dependent effect on skeletal muscle mitochondrial respiration in vitro

2020 ◽  
Vol 319 (1) ◽  
pp. E187-E195 ◽  
Author(s):  
Jacob T. Mey ◽  
Melissa L. Erickson ◽  
Christopher L. Axelrod ◽  
William T. King ◽  
Chris A. Flask ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Oxygen Consumption ◽  
Insulin Sensitivity ◽  
Mitochondrial Respiration ◽  
Liver Fat ◽  
Whole Body ◽  
Fat Accumulation ◽  
Impaired Insulin ◽  
Hepatic Fat

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation and impaired insulin sensitivity. Reduced hepatic ketogenesis may promote these pathologies, but data are inconclusive in humans and the link between NAFLD and reduced insulin sensitivity remains obscure. We investigated individuals with obesity-related NAFLD and hypothesized that β-hydroxybutyrate (βOHB; the predominant ketone species) would be reduced and related to hepatic fat accumulation and insulin sensitivity. Furthermore, we hypothesized that ketones would impact skeletal muscle mitochondrial respiration in vitro. Hepatic fat was assessed by 1H-MRS in 22 participants in a parallel design, case control study [Control: n = 7, age 50 ± 6 yr, body mass index (BMI) 30 ± 1 kg/m2; NAFLD: n = 15, age 57 ± 3 yr, BMI 35 ± 1 kg/m2]. Plasma assessments were conducted in the fasted state. Whole body insulin sensitivity was determined by the gold-standard hyperinsulinemic-euglycemic clamp. The effect of ketone dose (0.5–5.0 mM) on mitochondrial respiration was conducted in human skeletal muscle cell culture. Fasting βOHB, a surrogate measure of hepatic ketogenesis, was reduced in NAFLD (−15.6%, P < 0.01) and correlated negatively with liver fat ( r2 = 0.21, P = 0.03) and positively with insulin sensitivity ( r2 = 0.30, P = 0.01). Skeletal muscle mitochondrial oxygen consumption increased with low-dose ketones, attributable to increases in basal respiration (135%, P < 0.05) and ATP-linked oxygen consumption (136%, P < 0.05). NAFLD pathophysiology includes impaired hepatic ketogenesis, which is associated with hepatic fat accumulation and impaired insulin sensitivity. This reduced capacity to produce ketones may be a potential link between NAFLD and NAFLD-associated reductions in whole body insulin sensitivity, whereby ketone concentrations impact skeletal muscle mitochondrial respiration.

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