Lipid-induced insulin resistance is prevented in lean and obese myotubes by AICAR treatment.

The molecular mechanisms of obesity-associated insulin resistance are becoming increasingly clear, and the effects of various lipid molecules, such as diacylglycerol and ceramide, on the insulin signal are being actively explored. To better understand the divergent response to lipid exposure between lean and obese, we incubated primary human muscle cells from lean [body mass index (BMI) <25 kg/m(2)] and morbidly obese (BMI >40 kg/m(2)) subjects with the saturated fatty acid palmitate. Additionally, given that AMPK-activating drugs are widely prescribed for their insulin-sensitizing effects, we sought to determine whether 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR)-stimulated AMPK activation could prevent or reverse the deleterious effects of lipid on insulin signaling. We found that a 1-h palmitate incubation in lean myotubes reduced (P < 0.05) insulin-stimulated phosphoprotein kinase B (Akt), Akt substrate 160 (AS160), and inhibitory factor kappaBalpha (IkappaBalpha) mass, all of which were prevented with AICAR inclusion. With a longer incubation, we observed that myotubes from morbidly obese individuals appear to be largely resistant to the detrimental effects of 16 h lipid exposure as was evident, in contrast to the lean, by the absence of a reduction in insulin-stimulated insulin receptor substrate (IRS)-1 Tyr phosphorylation, phospho-Akt, and phospho-AS160 (P < 0.05). Furthermore, 16 h lipid exposure significantly reduced IkappaBalpha levels and increased phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and IRS1-Ser(312) in lean myotubes only (P < 0.05). Despite a divergent response to lipid between lean and obese myotubes, AICAR inclusion improved insulin signaling in all myotubes. These findings suggest an important role for regular exercise in addition to offering a potential mechanism of action for oral AMPK-activating agents, such as thiazolidinediones and metformin.

Instrument-Assisted Soft Tissue Mobilization: A Systematic Review and Effect-Size Analysis.

OBJECTIVE: To determine the overall effectiveness of instrument-assisted soft tissue mobilization (IASTM) in improving range of motion (ROM), pain, strength, and patient-reported function in order to provide recommendations for use. We also sought to examine the influence of IASTM on injured and healthy participants, body part treated, and product used. DATA SOURCES: We searched the Academic Search Premier, Alt Healthwatch, CINAHL Complete, Cochrane Library, MEDLINE with full text, NLM PubMed, Physical Education Index, Physiotherapy Evidence Database (PEDro), SPORTDiscus with full text, and Web of Science databases for articles published from 1997 through 2016. The Boolean string advantEDGE OR astym OR graston OR iastm OR "instrument assist* soft tissue mobil*" OR "augment* soft tissue mobil*" OR "myofascial release" OR "instrument assist* massage" OR "augment* massage" OR "instrument assist* cross fiber massage" was used. STUDY SELECTION: Included articles were randomized controlled trials that measured ROM, pain, strength, or patient-reported function and compared IASTM treatment with at least 1 other group. DATA EXTRACTION: Thirteen articles met the inclusion criteria. Four independent reviewers assessed study quality using the PEDro and Centre for Evidence-Based Medicine scales. Twelve articles were included in the effect-size analysis. DATA SYNTHESIS: The average PEDro score for studies of uninjured participants was 5.83 (range = 5 to 7) and that for studies of injured participants was 5.86 (range = 3 to 7). Large effect sizes were found in outcomes for ROM (uninjured participants), pain (injured participants), and patient-reported function (injured participants). The different IASTM tools used in these studies revealed similar effect sizes in the various outcomes. CONCLUSIONS: The current literature provides support for IASTM in improving ROM in uninjured individuals as well as pain and patient-reported function (or both) in injured patients. More high-quality research involving a larger variety of patients and products is needed to further substantiate and allow for generalization of these findings.

Mechanism for improved insulin sensitivity after gastric bypass surgery.

CONTEXT: Surgical treatments of obesity have been shown to induce rapid and prolonged improvements in insulin sensitivity. OBJECTIVE: The aim of the study was to investigate the effects of gastric bypass surgery and the mechanisms that explain the improvement in insulin sensitivity. DESIGN: We performed a cross-sectional, nonrandomized, controlled study. SETTING: This study was conducted jointly between the Departments of Exercise Science and Physiology at East Carolina University in Greenville, North Carolina. SUBJECTS: Subjects were recruited into four groups: 1) lean [body mass index (BMI) < 25 kg/m(2); n = 93]; 2) weight-matched (BMI = 25 to 35 kg/m(2); n = 310); 3) morbidly obese (BMI > 35 kg/m(2); n = 43); and 4) postsurgery patients (BMI approximately 30 kg/m(2); n = 40). Postsurgery patients were weight stable 1 yr after surgery. MAIN OUTCOME MEASURES: Whole-body insulin sensitivity, muscle glucose transport, and muscle insulin signaling were assessed. RESULTS: Postsurgery subjects had insulin sensitivity index values that were similar to the lean and higher than morbidly obese and weight-matched control subjects. Glucose transport was higher in the postsurgery vs. morbidly obese and weight-matched groups. IRS1-pSer(312) in the postsurgery group was lower than morbidly obese and weight-matched groups. Inhibitor kappaBalpha was higher in the postsurgery vs. the morbidly obese and weight-matched controls, indicating reduced inhibitor of kappaB kinase beta activity. CONCLUSIONS: Insulin sensitivity and glucose transport are greater in the postsurgery patients than predicted from the weight-matched group, suggesting that improved insulin sensitivity after bypass is due to something other than, or in addition to, weight loss. Improved insulin sensitivity is related to reduced inhibitor of kappaB kinase beta activity and enhanced insulin signaling in muscle.

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

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 ß oxidation and is associated with worsening muscle SI.

Insulin sensitivity is related to glycemic control in type 2 diabetes and diabetes remission after Roux-en Y gastric bypass.

BACKGROUND: After initial onset, adequate glycemic control in patients with type 2 diabetes (T2DM) presents a continuing challenge even with aggressive pharmacologic treatment, and longer disease duration is associated with poorer resolution in response to Roux-en Y gastric bypass (RYGB). Skeletal muscle insulin sensitivity is an important determinant of glycemic control. We investigated whether skeletal muscle insulin sensitivity is predictive of T2DM resolution with RYGB and is in general lower in patients with longer-duration T2DM. METHODS: Insulin sensitivity (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: Pre-RYGB SI and duration but not AIRg were predictive of T2DM resolution by RYGB. In addition, HbA1c was greater and SI and AIRg lower in long- (8+ years) compared with short-duration (1- to 7-year) T2DM. Multiple linear regression analysis demonstrated that SI explained 32% and AIRg 21% of the variance in HbA1c, respectively. CONCLUSION: The current results suggest that pre-RYGB SI is predictive of T2DM resolution after RYGB, skeletal muscle insulin sensitivity and ß-cell function worsen after the onset of T2DM, and low skeletal muscle insulin sensitivity as well as low ß cell function contribute to poor glycemic control in T2DM.

Effect of short-term exercise training on intramyocellular lipid content.

The purpose of this study was to investigate the influence of exercise training on intramyocellular lipid (IMCL) content and test the hypothesis that the effect of endurance-oriented exercise training on IMCL is dependent on characteristics of the population studied. Lean (N = 11, body mass index (BMI) = 22.2 ± 0.7 kg·m⁻²), obese (N = 14, BMI = 38.8 ± 1.7 kg·m⁻²), and type 2 diabetic (N = 9, BMI = 35.5 ± 2.5 kg·m⁻²) participants were examined before and after 10 consecutive days of endurance-oriented (60 min·day⁻¹ at ~70% [Formula: see text]O(2peak)) exercise training. IMCL and muscle glycogen were measured by Oil-Red-O and periodic acid - Schiff staining, respectively. The results indicated that IMCL was elevated (p < 0.05) in the obese and diabetic groups compared with the lean subjects prior to training. After training, IMCL content decreased (-35%) in the participants with type 2 diabetes; there were no changes in IMCL in the lean or obese groups. Muscle glycogen content was lower in the diabetic subjects than in the lean subjects both before and after training. These data indicate that changes in IMCL with exercise training do not exhibit a universal response but rather depend on the metabolic status of the population studied.

Roux-en-Y gastric bypass corrects hyperinsulinemia implications for the remission of type 2 diabetes.

CONTEXT: Roux-en-Y gastric bypass (RYGB) has been shown to induce rapid and durable reversal of type 2 diabetes. OBJECTIVE: The aim of the study was to investigate a possible mechanism for the remission of type 2 diabetes after RYGB. DESIGN: A cross-sectional, nonrandomized, controlled study was conducted. Surgery patients were studied before RYGB and 1 wk and 3 months after surgery. SETTING: This study was conducted at East Carolina University. SUBJECTS: Subjects were recruited into three groups: 1) lean controls with no surgery [body mass index (BMI) < 25 kg/m²; n = 9], 2) severely obese type 2 diabetic patients (BMI > 35 kg/m²; n = 9), and 3) severely obese nondiabetic patients (BMI > 35 kg/m²; n = 9). INTERVENTION: Intervention was RYGB. RESULTS: One week after RYGB, diabetes was resolved despite continued insulin resistance (insulin sensitivity index was approximately 50% of lean controls) and reduced insulin secretion during an iv glucose tolerance test (acute insulin response to glucose was approximately 50% of lean controls). Fasting insulin decreased and was no different from lean control despite continued elevated glucose in the type 2 diabetic patients compared with lean. CONCLUSIONS: After RYGB, fasting insulin decreases to levels like those of lean control subjects and diabetes is reversed (fasting blood glucose < 125 mg/dl). This leads us to propose that 1) exclusion of food from the foregut corrects hyperinsulinemia and 2) fasting insulin is dissociated from the influence of fasting glucose, insulin resistance, and BMI. The mechanisms for reversal of diabetes in the face of reduced insulin remain a paradox.

Duodenal-jejunal bypass surgery does not increase skeletal muscle insulin signal transduction or glucose disposal in Goto-Kakizaki type 2 diabetic rats.

BACKGROUND: Duodenal-jejunal bypass (DJB) has been shown to reverse type 2 diabetes (T2DM) in Goto-Kakizaki (GK) rats, a rodent model of non-obese T2DM. Skeletal muscle insulin resistance is a hallmark decrement in T2DM. The aim of the current work was to investigate the effects of DJB on skeletal muscle insulin signal transduction and glucose disposal. It was hypothesized that DJB would increase skeletal muscle insulin signal transduction and glucose disposal in GK rats. METHODS: DJB was performed in GK rats. Sham operations were performed in GK and nondiabetic Wistar-Kyoto (WKY) rats. At 2 weeks post-DJB, oral glucose tolerance (OGTT) was measured. At 3 weeks post-DJB, insulin-induced signal transduction and glucose disposal were measured in skeletal muscle. RESULTS: In GK rats and compared to sham operation, DJB did not (1) improve fasting glucose or insulin, (2) improve OGTT, or (3) increase skeletal muscle insulin signal transduction or glucose disposal. Interestingly, skeletal muscle glucose disposal was similar between WKY-Sham, GK-Sham, and GK-DJB. CONCLUSIONS: Bypassing of the proximal small intestine does not increase skeletal muscle glucose disposal. The lack of skeletal muscle insulin resistance in GK rats questions whether this animal model is adequate to investigate the etiology and treatments for T2DM. Additionally, bypassing of the foregut may lead to different findings in other animal models of T2DM as well as in T2DM patients.

Lipid partitioning, incomplete fatty acid oxidation, and insulin signal transduction in primary human muscle cells: effects of severe obesity, fatty acid incubation, and fatty acid translocase/CD36 overexpression.

CONTEXT: Intracellular lipid partitioning toward storage and the incomplete oxidation of fatty acids (FA) have been linked to insulin resistance. OBJECTIVE: To gain insight into how intracellular lipid metabolism is related to insulin signal transduction, we examined the effects of severe obesity, excess FA, and overexpression of the FA transporter, FA translocase (FAT)/CD36, in primary human skeletal myocytes. DESIGN, SETTING, AND PATIENTS: Insulin signal transduction, FA oxidation, and metabolism were measured in skeletal muscle cells harvested from lean and severely obese women. To emulate the obesity phenotype in our cell culture system, we incubated cells from lean individuals with excess FA or overexpressed FAT/CD36 using recombinant adenoviral technology. RESULTS: Complete oxidation of FA was significantly reduced, whereas total lipid accumulation, FA esterification into lipid intermediates, and incomplete oxidation were up-regulated in the muscle cells of severely obese subjects. Insulin signal transduction was reduced in the muscle cells from severely obese subjects compared to lean controls. Incubation of muscle cells from lean subjects with lipids reduced insulin signal transduction and increased lipid storage and incomplete FA oxidation. CD36 overexpression increased FA transport capacity, but did not impair complete FA oxidation and insulin signal transduction in muscle cells from lean subjects. CONCLUSIONS: Cultured myocytes from severely obese women express perturbations in FA metabolism and insulin signaling reminiscent of those observed in vivo. The obesity phenotype can be recapitulated in muscle cells from lean subjects via exposure to excess lipid, but not by overexpressing the FAT/CD36 FA transporter.