Ciaran E Fealy

Lerner Research Institute, Cleveland, Ohio, United States

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Publications (7)21.03 Total impact

  • Ciaran E Fealy, Anny Mulya, Nicola Lai, John P Kirwan
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    ABSTRACT: Defects in mitochondrial dynamics - the processes of fission, fusion and mitochondrial autophagy - may contribute to metabolic disease including type 2 diabetes. Dynamin-related protein-1 (Drp1) is a GTPase protein that plays a central role in mitochondrial fission. We hypothesized that aerobic exercise training would decrease Drp1 Ser(616) phosphorylation, and increase fat oxidation and insulin sensitivity in obese (BMI: 34.6±0.8 kg/m(2)) insulin resistant adults. Seventeen subjects performed supervised exercise for 60 min/d, 5 days/week at 80-85% of maximal heart rate for 12 weeks. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp and fat oxidation was determined by indirect calorimetry. Skeletal muscle biopsies were obtained from the vastus lateralis muscle before and after the 12-week program. The exercise intervention increased insulin sensitivity 2.1±0.2 fold (P<0.01) and fat oxidation 1.3±0.3 fold (P<0.01). Phosphorylation of Drp1 at Ser(616) was decreased (Pre vs. Post: 0.81±0.15 vs. 0.58±0.14, AU P<0.05) following the intervention. Furthermore, reductions in Drp1 Ser(616) phosphorylation were negatively correlated with increases in fat oxidation (r=-0.58, P<0.05) and insulin sensitivity (rho=-0.52, P<0.05). We also examined expression of genes related to mitochondrial dynamics. DNM1L (P<0.01), the gene that codes for Drp1, and OPA1 (P=0.05) were significantly upregulated following the intervention, while there was a trend towards an increase in expression of both MFN1 (P=0.08) and MFN2 (P=0.07). These are the first data to suggest that lifestyle-mediated improvements in substrate metabolism and insulin sensitivity in obese insulin resistant adults may be regulated through decreased activation of the mitochondrial fission protein Drp1.
    Journal of applied physiology (Bethesda, Md. : 1985). 06/2014;
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    ABSTRACT: Abstract Background: Metabolic syndrome is prevalent in adults characterized by increased visceral adiposity and insulin resistance (IR). However, the link between pancreatic β-cell function and metabolic syndrome severity in adults across the glucose spectrum is unknown. We hypothesized that poor β-cell function would independently predict a higher metabolic syndrome Z-score (i.e., severity). Methods: Seventy (12 normal glucose tolerant, 37 prediabetic, 21 type 2 diabetic) obese adults [62.4±1.1 year; 34.6±0.6 kg/m(2); data are mean±standard error of the mean (SEM)] participated in this cross-sectional study. A 2-hr 75-gram oral glucose tolerance test (OGTT) was administered, and insulin and glucose area under the curve was determined for calculations of insulin action. Fasting and glucose-stimulated insulin secretion was calculated using homeostasis model assessment of insulin secretion (HOMA-B) and the insulinogenic index (i.e., I0-30/Glc0-30 or I60-120/Glc60-120), respectively. Fasting and postprandial insulin sensitivity was assessed by HOMA-IR and the Matsuda Index, respectively. β-cell function was estimated using the disposition index via HOMA-B/HOMA-IR, I0-30/Glc0-30 or I60-120/Glc60-120×Matsuda Index, which represents basal, first-, and second-phase insulin release, respectively. Body composition (via computerized tomography and dual X-ray absorptiometry) and sex-specific metabolic syndrome Z-scores were calculated from waist circumference, blood pressure, fasting glucose, triglycerides, and high-density lipoproteins. Results: Compared to those with normal glucose tolerance, visceral fat and IR were higher and β-cell function was lower in adults with glucose intolerance and type 2 diabetes mellitus. Elevated visceral fat and IR (HOMA-IR and Matsuda Index) correlated with elevated Z-scores (r=0.51, r=0.54, r=-0.49; all P<0.002, respectively). Basal, first-, and second-phase β-cell function correlated with low Z-scores (r=-0.59, r=-0.51, and r=-0.43, all P<0.001). Insulin secretion significantly predicted the Z-score independent of sex, body fat, blood lipids, blood pressure, IR, and glucose metabolism (P<0.005). Conclusion: β-cell dysfunction is highly correlated with the severity of metabolic syndrome in adults. Future work is warranted to elucidate the mechanism by which cardiometabolic disturbances influence insulin secretion.
    Metabolic syndrome and related disorders 11/2013;
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    ABSTRACT: Fetuin-A is synthesized in the liver and may be associated with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. Lifestyle induced weight loss reduces fetuin-A, but the effect of exercise alone is unknown. We determined the effect of short-term exercise training on plasma fetuin-A in 13 (50.5±3.4yr) obese adults (BMI-33.3±0.9kg/m(2)) with clinically diagnosed NAFLD. Subjects participated in 7-days of supervised exercise training (60min/d at ~85% HRmax) and were instructed to maintain their normal caloric and macronutrient intake. Insulin resistance was assessed by oral glucose tolerance test. Hepatic triglyceride content (HTGC) was determined by proton magnetic resonance imaging. We used C2C12 skeletal muscle cells to examine the direct effect of fetuin-A on 2-deoxyglucose uptake, insulin signaling (phosphorylation (p) of Akt and AS160), and glucose transport (GLUT-4 translocation). Insulin resistance was reduced by 29% (P<0.05) and glucose AUC was decreased by 13% (P<0.01) after the 7 days of exercise. Further, circulating fetuin-A was decreased by 11% (4.2±03 vs. 3.6±0.2nM; P<0.02), and this change correlated with reduced insulin resistance (r=0.62, P<0.04) and glucose AUC (r=0.58; P<0.04). Importantly, the exercise program did not change body weight (P=0.12), HTGC (P=0.73), or aerobic capacity (P=0.14). In vitro experiments revealed that fetuin-A decreased skeletal muscle glucose uptake by down-regulating pAkt and pAS160, and subsequent GLUT-4 translocation to the plasma membrane. Together, our findings highlight a role for fetuin-A in skeletal muscle insulin resistance and suggest that part of the exercise-induced improvement in glucose tolerance in patients with NAFLD may be due to lowering fetuin-A.
    Journal of Applied Physiology 08/2013; · 3.48 Impact Factor
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    ABSTRACT: Context:Hepatic steatosis, insulin resistance, inflammation, low levels of polyunsaturated lipids, and adiponectin are implicated in the development and progression of non-alcoholic fatty liver disease (NAFLD).Objective:We examined the effects of short-term aerobic exercise on these metabolic risk factors.Design and Participants:Obese individuals (N=17, 34.3±1.0 kg/m(2)) with clinically confirmed NAFLD were enrolled in a short-term aerobic exercise program that consisted of 7 consecutive days of treadmill walking at ∼85% of HRmax for 60 min/d. Pre- and post-intervention measures included hepatic triglyceride content, and a lipid saturation index (SI) and polyunsaturated lipid index (PUI) of the liver, obtained by (1)H magnetic resonance (MR) spectroscopy (N=14). Insulin sensitivity was estimated from an oral glucose tolerance test (OGTT), and mononuclear cells were isolated to assess reactive oxygen species (ROS) production during the OGTT. Circulating glucose, insulin, and high molecular weight (HMW) adiponectin were determined from plasma.Main Outcome:Short-term aerobic exercise training improved hepatic lipid composition in patients with NAFLD.Results:Exercise training resulted in an increase in liver PUI (P<0.05), increased insulin sensitivity (Matsuda Index: P<0.05), HMW adiponectin (P<0.05), and VO2max (P<0.05). ROS production during the OGTT was reduced following exercise training (P<0.05). HMW adiponectin was increased after the exercise program and the increase was positively correlated with the increase in liver PUI (r=0.52, P=0.05). Body weight remained stable during the program (P>0.05).Conclusion:Short-term exercise can target hepatic lipid composition, which may reduce the risk of NAFLD progression. The improvement in hepatic lipid composition may be driven by adiponectin.
    The Journal of clinical endocrinology and metabolism 04/2013; · 6.50 Impact Factor
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    ABSTRACT: Increased hepatocyte apoptosis is a hallmark of nonalcoholic fatty liver disease (NAFLD) and contributes to the profibrogenic state responsible for the progression to nonalcoholic steatohepatitis (NASH). Strategies aimed at reducing apoptosis may result in better outcomes for individuals with NAFLD. We therefore examined the effect of a short-term exercise program on markers of apoptosis-plasma cytokeratin 18 (CK18) fragments, alanine aminotransferase (ALT), aspartate aminotransferase (AST), soluble Fas (sFas), and sFas ligand (sFasL)-in 13 obese individuals with NAFLD [body mass index 35.2 ± 1.2 kg/m(2), >5% intrahepatic lipid (IHL) assessed by (1)H-MR spectroscopy]. Exercise consisted of treadmill walking for 60 min/day on 7 consecutive days at ∼85% of maximal heart rate. Additionally, subjects underwent an oral glucose tolerance test and a maximal oxygen consumption (Vo(2max)) test before and after the exercise intervention. The Matsuda index was used to assess insulin sensitivity. We observed significant decreases in CK18 fragments (558.4 ± 106.8 vs. 323.4 ± 72.5 U/l, P < 0.01) and ALT (30.2 ± 5.1 vs. 24.3 ± 4.8 U/l, P < 0.05), and an increase in whole body fat oxidation (49.3 ± 6.1 vs. 69.4 ± 7.1 mg/min, P < 0.05), while decreases in circulating sFasL approached statistical significance (66.5 ± 6.0 vs. 63.0 ± 5.7 pg/ml, P = 0.06), as did the relationship between percent change in circulating CK18 fragments and ALT (r = 0.55, P = 0.05). We also observed a significant correlation between changes in fat oxidation and circulating sFasL (rho = -0.65, P < 0.05). There was no change in IHL following the intervention (18.2 ± 2.5 vs. 17.5 ± 2.1%, NS). We conclude that short-term exercise reduces a circulatory marker of hepatocyte apoptosis in obese individuals with NAFLD and propose that changes in the proapoptotic environment may be mediated through improved insulin sensitivity and increased oxidative capacity.
    Journal of Applied Physiology 05/2012; 113(1):1-6. · 3.48 Impact Factor
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    ABSTRACT: High-molecular weight (HMW) adiponectin is the biologically active form of adiponectin and is related to enhanced insulin sensitivity and metabolic function. Previously, we found that 7 d of exercise improves insulin sensitivity in obese subjects; however, whether short-term exercise training affects HMW adiponectin in obese persons is unknown. We examined the effect of seven consecutive days of supervised vigorous exercise (60 min · d(-1), 85% HRmax) on HMW adiponectin and leptin secretion in 17 obese individuals (age = 55 ± 3 yr; body mass index = 33.7 ± 0.9 kg · m(-2)). Insulin sensitivity was calculated from an oral glucose tolerance test (ISIOGTT) using the Matsuda Index. Fasting plasma HMW adiponectin and leptin were quantified from blood samples obtained before the ISIOGTT. Glucose and insulin measures were obtained before and every 30 min during the test. Dual-energy x-ray absorptiometry was used to determine body composition, and indirect calorimetry was used to assess fat oxidation. After the intervention, there was a significant increase in HMW adiponectin (3202 ± 543 vs 3878 ± 682 ng · mL(-1), P = 0.02) and a decrease in leptin (36.8 ± 5.1 vs 31.1 ± 4.2 μg · mL(-1), P = 0.03). Further, we observed an increase in ISIOGTT (1.7 ± 0.3 vs 2.1 ± 0.3, P = 0.04) and a decrease in glucose area under the curve (30,871 ± 2105 vs 28,469 ± 1657 mg · dL(-1) for 3 h, P = 0.01). The increase in HMW adiponectin was positively associated with the increase in basal fat oxidation (r = 0.57, P = 0.03), consistent with an improvement in adipose tissue metabolic function. The data suggest that 7 d of exercise is sufficient not only to improve insulin sensitivity and fat oxidation but also to favorably alter adipokine secretion, independent of changes in body weight or composition.
    Medicine and science in sports and exercise 06/2011; 44(1):69-74. · 4.48 Impact Factor
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    ABSTRACT: To examine the effects of acute altitude-induced hypoxia on the hormonal and metabolic response to ingested glucose, 8 young, healthy subjects (5 men and 3 women; age, 26 +/- 2 years; body mass index, 23.1 +/- 1.0 kg/m(2)) performed 2 randomized trials in a hypobaric chamber where a 75-g glucose solution was ingested under simulated altitude (ALT, 4300 m) or ambient (AMB, 362 m) conditions. Plasma glucose, insulin, C-peptide, epinephrine, leptin, and lactate concentrations were measured at baseline and 30, 60, 90, and 120 minutes after glucose ingestion during both trials. Compared with AMB, the plasma glucose response to glucose ingestion was reduced during the ALT trial (P = .04). There were no differences in the insulin and C-peptide responses between trials or in insulin sensitivity based on the homeostasis model assessment of insulin resistance. Epinephrine and lactate were both elevated during the ALT trial (P < .05), whereas the plasma leptin response was reduced compared with AMB (P < .05). The data suggest that the plasma glucose response is suppressed at ALT, but this is not due to insulin per se because insulin and C-peptide levels were similar for both trials. Elevated plasma epinephrine and lactate during ALT are indicative of increased glycogenolysis, which may have masked the magnitude of the reduced glucose response. We conclude that, during acute altitude exposure, there is a rapid metabolic response that is accompanied by a shift in the hormonal milieu that appears to favor increased glucose utilization.
    Metabolism: clinical and experimental 09/2009; 59(2):200-5. · 3.10 Impact Factor