Intermuscular adipose tissue (IMAT) is negatively related to insulin sensitivity, but a causal role of IMAT in the development of insulin resistance is unknown. IMAT was sampled in humans to test for ...the ability to induce insulin resistance in vitro and characterize gene expression to uncover how IMAT may promote skeletal muscle insulin resistance. Human primary muscle cells were incubated with conditioned media from IMAT, visceral (VAT), or subcutaneous adipose tissue (SAT) to evaluate changes in insulin sensitivity. RNAseq analysis was performed on IMAT with gene expression compared with skeletal muscle and SAT, and relationships to insulin sensitivity were determined in men and women spanning a wide range of insulin sensitivity measured by hyperinsulinemic-euglycemic clamp. Conditioned media from IMAT and VAT decreased insulin sensitivity similarly compared with SAT. Multidimensional scaling analysis revealed distinct gene expression patterns in IMAT compared with SAT and muscle. Pathway analysis revealed that IMAT expression of genes in insulin signaling, oxidative phosphorylation, and peroxisomal metabolism related positively to donor insulin sensitivity, whereas expression of macrophage markers, inflammatory cytokines, and secreted extracellular matrix proteins were negatively related to insulin sensitivity. Perilipin 5 gene expression suggested greater IMAT lipolysis in insulin-resistant individuals. Combined, these data show that factors secreted from IMAT modulate muscle insulin sensitivity, possibly via secretion of inflammatory cytokines and extracellular matrix proteins, and by increasing local FFA concentration in humans. These data suggest IMAT may be an important regulator of skeletal muscle insulin sensitivity and could be a novel therapeutic target for skeletal muscle insulin resistance.
Evidence from model systems implicates long-chain acyl-coenzyme A synthetase (ACSL) as key regulators of skeletal muscle fat oxidation and fat storage; however, such roles remain underexplored in ...humans.
We sought to determine the protein expression of ACSL isoforms in skeletal muscle at rest and in response to acute exercise and identify relationships between skeletal muscle ACSL and measures of fat metabolism in humans.
Sedentary adults (n = 14 4 males and 10 females, body mass index = 22.2 ± 2.1 kg·m-2, V˙O2max = 32.2 ± 4.5 mL·kg-1⋅min-1) completed two study visits. Trials were identical other than completing 1 h of cycling exercise (65% V˙O2max) or remaining sedentary. Vastus lateralis biopsies were obtained 15-min postexercise (or rest) and 2-h postexercise to determine ACSL protein abundance. Whole-body fat oxidation was assessed at rest and during exercise using indirect calorimetry. Skeletal muscle triacylglycerol (TAG) was measured via lipidomic analysis.
We detected protein expression for four of the five known ACSL isoforms in human skeletal muscle. ACSL protein abundances were largely unaltered in the hours after exercise aside from a transient increase in ACSL5 15-min postexercise (P = 0.01 vs rest). Skeletal muscle ACSL1 protein abundance tended to be positively related with whole-body fat oxidation during exercise (P = 0.07, r = 0.53), when skeletal muscle accounts for the majority of energy expenditure. No such relationship between ACSL1 and fat oxidation was observed at rest. Skeletal muscle ACSL6 protein abundance was positively associated with muscle TAG content at rest (P = 0.05, r = 0.57).
Most ACSL protein isoforms can be detected in human skeletal muscle, with minimal changes in abundance after acute exercise. Our findings agree with those from model systems implicating ACSL1 and ACSL6 as possible determinants of fat oxidation and fat storage within skeletal muscle.
•Insulin and c-peptide release followed a similar time course during cephalic phase period.•C-peptide shows a greater effect size after oral sensory stimulation.•Measure of c-peptide is more ...replicable than insulin across repeated sessions.•Individual differences in CPIR should be considered when drawing conclusions.
Cephalic phase insulin release (CPIR) is a rapid pulse of insulin secreted within minutes of food-related sensory stimulation. Understanding the mechanisms underlying CPIR in humans has been hindered by its small observed effect size and high variability within and between studies. One contributing factor to these limitations may be the use of peripherally measured insulin as an indicator of secreted insulin, since a substantial portion of insulin is metabolized by the liver before delivery to peripheral circulation. Here, we investigated the use of c-peptide, which is co-secreted in equimolar amounts to insulin from pancreatic beta cells, as a proxy for insulin secretion during the cephalic phase period. Changes in insulin and c-peptide were monitored in 18 adults over two repeated sessions following oral stimulation with a sucrose-containing gelatin stimulus. We found that, on average, insulin and c-peptide release followed a similar time course over the cephalic phase period, but that c-peptide showed a greater effect size. Importantly, when insulin and c-peptide concentrations were compared across sessions, we found that changes in c-peptide were significantly correlated at the 2 min (r = 0.50, p = 0.03) and 4 min (r = 0.65, p = 0.003) time points, as well as when participants’ highest c-peptide concentrations were considered (r = 0.64, p = 0.004). In contrast, no significant correlations were observed for changes in insulin measured from the sessions (r = -0.06–0.35, p > 0.05). Herein, we detail the individual variability of insulin and c-peptide concentrations measured during the cephalic phase period, and identify c-peptide as a valuable metric for insulin secretion alongside insulin concentrations when investigating CPIR.
Regular exercise and antihyperglycemic drugs are front‐line treatments for type‐2 diabetes and related metabolic disorders. Leading drugs are metformin, sodium‐glucose cotransporter‐2 inhibitors, and ...glucagon‐like peptide 1 receptor agonists. Each class has strong individual efficacy to treat hyperglycemia, yet the combination with exercise can yield varied results, some of which include blunting of expected metabolic benefits. Skeletal muscle insulin resistance contributes to the development of type‐2 diabetes while improvements in skeletal muscle insulin signaling are among key adaptations to exercise training. The current review identifies recent advances into the mechanisms, with an emphasis on skeletal muscle, of the interaction between exercise and these common antihyperglycemic drugs. The review is written toward researchers and thus highlights specific gaps in knowledge and considerations for future study directions.
The origins of nonalcoholic fatty liver disease (NAFLD) may lie in early intrauterine exposures. Here we examined the maternal response to chronic maternal high-fat (HF) diet and the impact of ...postweaning healthy diet on mechanisms for NAFLD development in juvenile nonhuman primate (NHP) offspring at 1 year of age. Pregnant females on HF diet were segregated as insulin resistant (IR; HF+IR) or insulin sensitive (IS; HF+IS) compared with control (CON)-fed mothers. HF+IR mothers have increased body mass, higher triglycerides, and increased placental cytokines. At weaning, offspring were placed on a CON or HF diet. Only offspring from HF+IR mothers had increased liver triglycerides and upregulated pathways for hepatic de novo lipid synthesis and inflammation that was irreversible upon switching to a healthy diet. These juvenile livers also showed a combination of classical and alternatively activated hepatic macrophages and natural killer T cells, in the absence of obesity or insulin resistance. Our findings suggest that maternal insulin resistance, including elevated triglycerides, insulin, and weight gain, initiates dysregulation of the juvenile hepatic immune system and development of de novo lipogenic pathways that persist in vitro and may be an irreversible "first hit" in the pathogenesis of NAFLD in NHP.
The purpose of this study was to determine the effect of a relatively modest session of exercise on insulin sensitivity and fatty acid uptake the next day in obese adults.
Eleven sedentary obese ...adults (male/female: 3/8; BMI 37 ± 1 kg/m(2); peak oxygen uptake VO2peak 20 ± 1 mL/kg/min) completed three experimental trials. On two of these occasions, subjects exercised to expend 350 kcal in the afternoon. These two exercise trials were identical except for the exercise intensity (50% VO2peak EX50 and 65% VO2peak EX65) and the duration of exercise necessary to expend 350 kcal (EX50 = ≈ 70 min; EX65 = ≈ 55 min). Subjects also completed a control trial (CON), without exercise. The next morning, we measured insulin sensitivity (hyperinsulinemic-euglycemic clamp) and whole-body fatty acid uptake (palmitate rate of disappearance from plasma Rd).
Exercise increased insulin sensitivity the next day, but whereas the 35% improvement after EX50 compared with CON was statistically significant (P = 0.01), the 20% improvement after EX65 was not (P = 0.17). Despite nearly identical values between CON and EX65 (P = 0.88), systemic fatty acid uptake was lower after EX50 compared with EX65 (P = 0.02), but not quite significant compared with CON (P = 0.07). Importantly, the change in fatty acid uptake after exercise compared with CON was negatively correlated with the change in insulin sensitivity for all trials (r = -0.60, P = 0.003).
A relatively modest single session of exercise in obese adults improved insulin sensitivity the next day, and a reduction in systemic fatty acid uptake in the several hours after exercise may be important for this effect.
Context:
Insulin resistance and systemic oxidative stress are prominent features of pregnancies complicated by maternal obesity or gestational diabetes mellitus (GDM). The role of skeletal muscle ...oxidative stress or mitochondrial capacity in obese pregnant women or obese women with GDM is unknown.
Objective:
We investigated whether obese pregnant women, compared with normal weight (NW) pregnant women, demonstrate decreased skeletal muscle mitochondrial enzyme activity and elevated markers of oxidative stress, and if these differences are more severe in obese women diagnosed with GDM.
Design:
We measured mitochondrial enzyme activity and markers of oxidative stress in skeletal muscle tissue from NW pregnant women (n = 10), obese pregnant women with normal glucose tolerance (NGT; n = 10), and obese pregnant women with GDM (n = 8), undergoing cesarean delivery (∼37 wk gestation).
Results:
Electron transport complex-II and manganese superoxide dismutase (MnSOD) enzyme activities were decreased in obese-NGT and obese-GDM, compared with NW women. The glutathione redox ratio (GSH:GSSG) was decreased in obese-NGT and obese-GDM, indicative of increased oxidative stress. Mitochondrial sirtuin (SIRT)3 mRNA content and enzyme activity were lower in skeletal muscle of obese-NGT and obese-GDM women. Importantly, acetylation of MnSOD, a SIRT3 target, was increased in obese-NGT and obese-GDM vs NW women and was inversely correlated with SIRT3 activity (r = −0.603), suggesting a mechanism for reduced MnSOD activity.
Conclusions:
These data show that obese pregnant women demonstrate decreased skeletal muscle mitochondrial respiratory chain enzyme activity and decreased mitochondrial antioxidant defense. Furthermore, reduced skeletal muscle SIRT3 activity may play a role in the increased oxidative stress associated with pregnancies complicated by obesity.
The aim of this study was to employ validated biological markers to quantify the physiologic consequences of exposure to whole-body vibration (WBV) and evaluate the relative impact of mining vehicle ...operator vibration exposure on physiological responses as compared to vertical-axial dominant WBV. In a laboratory-based study with a repeated-measures design, we played actual field-measured floor vibration profiles into a 6-degree-of-freedom motion platform to create different realistic WBV exposures: 1) vertical-dominant vibration collected from long-haul trucks, 2) multi-axial vibration collected from mining heavy equipment vehicles, and 3) no vibration (control condition). Circulating biomarkers of interest were cortisol and catecholamines (epinephrine and norepinephrine) to assess physiological stress, interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) to test for inflammation, thiobarbituric acid reactive substances (TBARS) to measure oxidative stress, and myoglobin and plasma creatine kinase to assess muscle damage. We collected blood samples at pre-exposure (0 h), during-exposure (2 and 4 h), and 2 h into recovery after the WBV exposure (6 h) in all four exposure conditions. The results showed that a single, 4-h acute exposure to WBV may not be sufficient to induce skeletal muscle damage, inflammation or physiologic stress measurable in the blood. No significant differences were observed between conditions for any of the biomarkers that could be attributed to the exposure contrast between vertical-dominant and multi-axial WBV exposures. These findings further indicate known complications of WBV exposure likely arise secondary to chronic, repeated exposures that give rise to subclinical stresses that were not captured here.
•The effect of whole-body vibration (WBV) on physiologic stress was quantified by validated blood-borne biomarkers.•A 4-h acute exposure to WBV did not induce skeletal muscle damage, inflammation or physiologic stress measurable in the blood.•These findings indicate known complications of WBV exposure likely arise secondary to chronic, repeated exposures.
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.
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