Biomedical subjects

J P Kirwan

Publications and source records attributed to J P Kirwan.

At least 19 recordsLinked to original sources

PubMed2006

In vitro evidence that hyperglycemia stimulates tumor necrosis factor-alpha release in obese women with polycystic ovary syndrome.

Women with polycystic ovary syndrome (PCOS) are often insulin resistant and have chronic low-level inflammation. The purpose of this study was to determine the effects of hyperglycemia in vitro on tumor necrosis factor (TNF)-alpha release from mononuclear cells (MNC) in PCOS. Twelve reproductive-age women with PCOS (six lean, six obese) and 12 age-matched controls (six lean, six obese) were studied. Insulin sensitivity (IS(HOMA)) was estimated from fasting levels of glucose and insulin and percent truncal fat was determined by dual energy absorptiometry (DEXA). TNFalpha release was measured from MNC cultured under euglycemic and hyperglycemic conditions. IS(HOMA) was higher in obese women with PCOS than in lean women with PCOS (student's t-test; 73.7 +/- 14.8 vs 43.1 +/- 8.6, P < 0.05), but similar to that of obese controls. IS(HOMA) was positively correlated with percent truncal fat (r=0.57, P < 0.04). Obese women with PCOS exhibited an increase in the percent change in TNFalpha release from MNC in response to hyperglycemia compared with obese controls (10 mM, 649 +/- 208% vs 133 +/- 30%, P < 0.003; 15 mM, 799 +/- 347% vs 183 +/- 59%, P < 0.04). The TNFalpha response directly correlated with percent truncal fat (r=0.45, P < 0.03) and IS(HOMA) (r=0.40, P < 0.05) for the combined groups, and with plasma testosterone (r=0.60, P < 0.05) for women with PCOS. MNC of obese women with PCOS exhibit an increased TNFalpha response to in vitro physiologic hyperglycemia. MNC-derived TNFalpha release may contribute to insulin resistance and hyperandrogenism, particularly when the combination of PCOS and increased adiposity is present.

Abdominal Fat↗

PubMed2003

Insulin signalling, exercise and cellular integrity.

Although the effects of exercise on insulin sensitivity are generally positive, eccentric exercise presents a paradox because it induces a transient state of insulin resistance that persists for up to 48 h after the exercise bout. Excessive eccentric contractions, such as prolonged downhill running, or marathon running, causes muscle damage and disruption of the integrity of the cell. Down-regulation of insulin receptor tyrosine phosphorylation and subsequent steps in the insulin signalling pathway, including insulin receptor substrate-1 (IRS-1)-associated phosphoinositide 3-kinase (PI3K), Akt kinase serine phosphorylation and activity and glucose transporter (GLUT-4) protein content, are evident in skeletal muscle after eccentric exercise. Furthermore, increased tumour necrosis factor alpha (TNF-alpha) secretion from monocytes is associated with the decrease in PI3K activity after this type of exercise. Recent studies have shown that TNF-alpha can increase IRS-1 serine/threonine phosphorylation, which impairs IRS-1 docking to the insulin receptor, and this inhibits insulin signalling. Thus a unifying hypothesis to explain insulin resistance after eccentric exercise may include inflammation arising from the disruption of muscle-cell integrity, leading to an acute-phase response that includes TNF-alpha, with the latter inhibiting insulin signalling and subsequent metabolic events. In contrast, exercise training increases insulin signalling and GLUT-4 expression, decreases TNF-alpha expression in skeletal muscle, and is associated with enhanced insulin sensitivity. These observations highlight the complexity of the cellular and molecular adaptations to exercise. Understanding these adaptations is essential in order to establish a sound theoretical basis for recommending exercise as a therapeutic intervention for insulin resistance and type 2 diabetes.

Exercise↗

PubMed2001

Maternal factors that determine neonatal size and body fat.

These data are a review of previously published data. Initially, body composition was estimated in 186 neonates. Fat- free mass (FFM), which constituted 86% of birth weight, accounted for 83% of the variance in birth weight; fat mass (FM), which constituted 14% of birth weight, accounted for 46% of the variance in birth weight. Male neonates were an average of 175 g heavier than females. FFM was greater among males compared with females (P = 0.0001). Using stepwise logistic regression, 29% of the variance in birth weight, 30% in FFM, and 17% in FM was accounted for. Independent variables included maternal height, pregravid weight, weight gain during pregnancy, education, parity, paternal height and weight, neonatal sex, and gestational age. Including maternal insulin sensitivity explained 48% of the variance in birth weight, 53% in FFM, and 46% in FM. There was a positive correlation between weight gain and birth weight in control subjects but a negative correlation in subjects with gestational diabetes mellitus. Lastly, the roles of insulin, insulin-like growth factors, and leptin were examined in relation to fetoplacental growth and body composition. The assessment of fetal/neonatal body composition may improve the understanding of the effect of differential factors on fetal growth. Factors associated with accretion of fetal adipose tissue in late gestation are less well understood compared with birth weight and FFM. Additional studies of maternal glucose and lipid metabolism are needed to better evaluate fetal growth.

Adipose Tissue↗

PubMed2001

Effects of moderate and high glycemic index meals on metabolism and exercise performance.

The purpose of this study was to determine whether pre-exercise ingestion of meals with moderate and high glycemic indexes (GI) affects glucose availability during exercise and exercise performance time. Six male volunteers (22 +/- 1 years; 80.4 +/- 3.7 kg; VO(2peak), 54.3 +/- 1.2 ml. kg(-1). min(-1)) ingested 75 g of carbohydrate in the form of 2 different breakfast cereals, rolled oats (moderate GI, approximately 61; MOD-GI) or puffed rice (high GI, approximately 82; HI-GI), combined with 300 mL of water; or water alone (control). The trials were randomized, and the meals were ingested 45 minutes before the subjects performed cycling exercise (60% VO(2peak)) to exhaustion. Venous blood samples were drawn to measure glucose, free fatty acids (FFAs), glycerol, insulin (INS), epinephrine (EPI) and norepinephrine (NE) concentrations. A muscle biopsy specimen was obtained from the vastus lateralis before the meal and immediately after exercise for glycogen determination. Before exercise, both test meals elicited significant (P <.05) hyperglycemia and hyperinsulinemia compared with control. The glycemic response was higher (P <.05) at the start of exercise after the HI-GI meal than after the control. During exercise, plasma glucose levels were higher (P <.05) at 60 (5.2 +/- 0.1, 4.2 +/- 0.2, and 4.6 +/- 0.1 mmol. L(-1)) and 90 (4.8 +/- 0.1, 4.1 +/- 0.1, and 4.3 +/- 0.1 mmol. L(-1)) minutes after the MOD-GI meal than after either the HI-GI or control. Total carbohydrate oxidation was greater (P <.05) during the MOD-GI trial than in control and was directly correlated with exercise performance time (r =.95, P <.0001). Pre-exercise plasma FFA levels were suppressed (P <.05) 30 and 45 minutes after ingestion of the HI-GI meal and 45 minutes after the MOD-GI meal compared with control. At 30, 60, and 120 minutes of exercise, FFAs remained suppressed (P <.05) for both test meals compared with control. At exhaustion, plasma glucose, INS, FFA, glycerol, EPI, and NE levels and muscle glycogen use were not different for all trials. Exercise time was prolonged (P <.05) after the MOD-GI meal compared with control, but the HI-GI trial was not different from control (MOD-GI, 165 +/- 11; HI-GI, 141 +/- 8; control, 134 +/- 13 minutes). Thus, in contrast to the HI-GI meal or control, the MOD-GI breakfast cereal ingested 45 minutes before exercise enhanced performance time, maintained euglycemia for a longer period during exercise, and resulted in greater total carbohydrate oxidation during the exercise bout. We conclude that a MOD-GI meal provides a significant performance and metabolic advantage when consumed 45 minutes before exercise.

Adult↗

PubMed2001

Effects of a moderate glycemic meal on exercise duration and substrate utilization.

PURPOSE: To determine whether eating a breakfast cereal with a moderate glycemic index could alter substrate utilization and improve exercise duration. METHODS: Six active women (age, 24 +/- 2 yr; weight, 62.2 +/- 2.6 kg; VO(2peak), 46.6 +/- 3.8 mL x kg(-1) x min(-1)) ate 75 g of available carbohydrate in the form of regular whole grain rolled oats (RO) mixed with 300 mL of water or water alone (CON). The trials were performed in random order and the meal or water was ingested 45 min before performing cycling exercise to exhaustion (60% of VO(2peak)). Blood samples were drawn for glucose, glucose kinetics, free fatty acids (FFA), glycerol, insulin, epinephrine (EPI), and norepinephrine (NE) determination. A muscle biopsy was obtained from the vastus lateralis muscle before the trial and immediately after exercise for glycogen determination. Glucose kinetics (Ra) were determined using a [6,6-(2)H] glucose tracer. RESULTS: Compared with CON, plasma FFA and glycerol levels were suppressed (P < 0.05) during the first 120 min of exercise for the RO trial. Respiratory exchange ratios (RER) were also higher (P < 0.05) for the first 120 min of exercise for the RO trial. At exhaustion, glucose, insulin, FFA, glycerol, EPI, NE, RER, and muscle glycogen were not different between trials. Glucose Ra was greater (P < 0.05) during the RO trial compared with CON (2.36 +/- 0.22 and 1.92 +/- 0.27 mg x kg(-1) x min(-1), respectively). Exercise duration was 5% longer during RO, but the mean times were not significantly different (253.6 +/- 6 and 242.0 +/- 15 min, respectively). CONCLUSIONS: Increased hepatic glucose output before fatigue provides some evidence of glucose sparing after the breakfast cereal trial. However, exercise duration was not significantly altered, possibly because of the sustained suppression of lipid metabolism and increased carbohydrate utilization throughout much of the exercise period.

Adult↗

PubMed2001

Physiological and metabolic characteristics of elite tug of war athletes.

OBJECTIVE: To determine the aerobic power (VO(2)MAX), body composition, strength, muscular power, flexibility, and biochemical profile of an elite international squad of tug of war athletes. METHODS: Sixteen male competitors (mean (SEM) age 34 (2) years) were evaluated in a laboratory. For comparative purposes, data were analysed relative to normative data for our centre and to a group of 20 rugby forwards from the Irish international squad. RESULTS: The tug of war participants were lighter (83.6 (3.0) v 104.4 (1.8) kg, p<0.0001) and had less lean body mass (69.4 (2.1) v 86.2 (1.2) kg) than the rugby players and had lower than normal body fat (16.7 (0.9)%); all values are mean (SEM). Aerobic power measured during a treadmill test was 55.8 (1.6) ml/kg/min for the tug of war participants compared with 51.1 (1.4) ml/kg/min for the rugby forwards (p<0.03). A composite measure of strength derived from (sum of dominant and non-dominant grip strength and back strength)/lean body mass yielded a strength/mass ratio that was 32% greater (p<0.0001) for the tug of war group than the rugby group. Dynamic leg power was lower for the tug of war group than the rugby forwards (4659.8 (151.6) v 6198.2 (105) W respectively; p<0.0001). Leg flexibility was 25.4 (2.0) cm for the tug of war group. Back flexibility was 28.6 (1.4) cm which was lower (p<0.02) than the rugby forwards 34.2 (1.5) cm. Whereas blood chemistry and haematology were normal, packed cell volume, haemoglobin concentration, and erythrocyte volume were lower in the tug of war group than in the rugby players (p<0.05). All three haematological measures correlated with muscle mass (packed cell volume, r(2) = 0.37, p<0.0001; haemoglobin concentration, r(2) = 0.13, p<0.05; erythrocyte volume, r(2) = 0.21, p<0.01). CONCLUSIONS: The data indicate that international level tug of war participants have excellent strength and above average endurance relative to body size, but have relatively low explosive leg power and back flexibility. The data provide reference standards for the sport and may be useful for monitoring and evaluating current and future participants.

Adolescent↗

PubMed2001

Human aging is associated with altered TNF-alpha production during hyperglycemia and hyperinsulinemia.

Changes in tumor necrosis factor-alpha (TNF-alpha) may provide a mechanism to explain impaired glucose metabolism with advancing age. Hyperglycemic clamps (180 min, 10 mM) were performed on seven older [67 +/- 2 yr; body mass index (BMI) 24.7 +/- 1.0 kg/m(2)] and seven younger (22 +/- 1 yr; BMI 21.8 +/- 1.3 kg/m(2)) healthy sedentary males with normal glucose tolerance. TNF-alpha production at basal and at the end of 180 min of hyperglycemia and hyperinsulinemia was measured ex vivo from lipopolysaccharide-stimulated (1 ng/ml) peripheral blood mononuclear cells. Plasma glucose, insulin, and C-peptide levels were similar in both groups at basal and during the last 30 min of the hyperglycemic clamp. Glucose infusion rates were lower (P < 0.004) in the older group compared with the young, indicating decreased insulin action among the older subjects. Basal TNF-alpha secretion was similar in older and younger subjects. TNF-alpha was suppressed (P < 0.02) in the younger group (230 +/- 46 vs. 126 +/- 49 pg/ml; basal vs. clamp) but not in the older group (153 +/- 37 vs. 182 +/- 42 pg/ml), with significant group differences in response (P < 0.05). A significant correlation was observed between the level of suppression in TNF-alpha production and insulin action (Kendall's rank, tau = 0.40, P < 0.05). Furthermore, the TNF-alpha response during the clamp was related to fat mass (r = 0.88, P < 0.001) and abdominal fat (r = 0.81, P < 0.003). In conclusion, these findings suggest a possible mechanism by which TNF-alpha may modulate glucose metabolism in younger people. Aging and modest increases in adiposity prevent the "normal" suppression of TNF-alpha production after a sustained postprandial-like hyperglycemic-hyperinsulinemic stimulus, which may contribute in part to the decline in insulin sensitivity in older men.

Adult↗

PubMed2001

Euglycemic clamp study in clozapine-induced diabetic ketoacidosis.

OBJECTIVE: To describe the fifth case of clozapine-induced diabetic ketoacidosis (DKA) with complete resolution of abnormal glucose metabolism after discontinuation of clozapine as assessed by oral glucose tolerance testing (OGTT) and the first to be serially studied with markers of pancreatic autoimmunity; to demonstrate insulin resistance using the euglycemic clamp study and reduced pancreatic insulin reserve using intravenous glucose tolerance testing (IVGTT) in clozapine-induced diabetes mellitus and DKA, when the OGTT was normal; and to systematically review the previously described cases of clozapine-induced diabetes mellitus and DKA. CASE SUMMARY: A 33-year-old white man without past or family history of diabetes mellitus presented with DKA after eight months of clozapine therapy (50 mg twice daily). After treatment of DKA and discontinuation of clozapine, glucose tolerance and concurrent serum insulin concentrations reverted to normal as measured by two OGTT performed 60 and 320 days after resolution of DKA. DISCUSSION: Antiislet-cell antibodies, antiglutamic acid decarboxylase antibodies, and human insulin antibody were negative on two separate occasions. Euglycemic clamp study demonstrated insulin resistance manifested by a glucose disposal rate of approximately 55% of mean normal values. IVGTT demonstrated a low rate of glucose disappearance (KG = 0.95) and diminished first-phase insulin response when OGTT was normal, indicating impairment in insulin sensitivity and reduction in beta cell function 323 days after discontinuance of clozapine. This adverse reaction is considered probable according to the Naranjo probability scale. CONCLUSIONS: The occurrence of cases of DKA and new or worsening diabetes mellitus in patients using clozapine suggests a causal relationship. We hypothesize that the mechanism by which clozapine may produce glucose intolerance may require a preexisting latent defect in insulin secretion and insulin action. With the administration of clozapine, some of these patients may develop worsening insulin resistance and may fail to mount an appropriate compensatory beta cell insulin secretion for the degree of insulin resistance. As a consequence, hyperglycemia develops and its persistence results in glucose toxicity, further suppressing beta cell insulin secretion. Such combined defects in insulin secretion and sensitivity are known to be synergistic, leading to the development of abnormal glucose tolerance, which can be clinically manifested as a spectrum ranging from impaired glucose tolerance through severe hyperglycemia to DKA. Patients being started on clozapine should be carefully followed for the development or worsening of diabetes mellitus, regardless of the dose of the drug.

Adult↗

PubMed2001

Clinically useful estimates of insulin sensitivity during pregnancy: validation studies in women with normal glucose tolerance and gestational diabetes mellitus.

OBJECTIVE: We examined whether selected indexes of insulin sensitivity derived from an oral glucose tolerance test (IS(OGTT)) or fasting glucose/insulin levels (IS(QUICKI) and IS(HOMA)) can be used to predict insulin sensitivity in women before and during pregnancy. RESEARCH DESIGN AND METHODS: A 2-h euglycemic-hyperinsulinemic clamp (5 mmol/l glucose, 40 mU. m(-2). min(-1) insulin) and a 120-min oral glucose tolerance test (75 g load pregravid, 100 g pregnant) were repeated on 15 women (10 with normal glucose tolerance [NGT] and 5 with gestational diabetes mellitus [GDM]) pregravid and during both early (12-14 weeks) and late (34-36 weeks) pregnancy. An index of insulin sensitivity derived from the clamp (IS(CLAMP)) was obtained from glucose infusion rates adjusted for change in fat-free mass and endogenous glucose production measured using [6,6(-2)H(2)]glucose. RESULTS: Univariate analysis using combined groups and periods of pregnancy resulted in significant correlations between IS(CLAMP) and IS(OGTT) (r(2) = 0.74, P < 0.0001), IS(QUICKI) (r(2) = 0.64, P < 0.0001), and IS(HOMA) (r(2) = 0.53, P < 0.0001). The IS(OGTT) provided a significantly better correlation (P < 0.0001) than either IS(QUICKI) or IS(HOMA.) Multivariate analysis showed a significant group effect (P < 0.0003) on the prediction model, and separate equations were developed for the NGT (r(2) = 0.64, P < 0.0001) and GDM (r(2) = 0.85, P < 0.0001) groups. When subdivided by period of pregnancy, the correlation between IS(CLAMP) and IS(OGTT) pregravid was r(2) = 0.63 (P = 0.0002), during early pregnancy was r(2) = 0.80 (P < 0.0001), and during late pregnancy was r(2) = 0.64 (P = 0.0002). CONCLUSIONS: Estimates of insulin sensitivity from the IS(OGTT) during pregnancy were significantly better than from fasting glucose and insulin values. However, separate prediction equations are necessary for pregnant women with NGT and women with GDM.

Analysis of Variance↗

PubMed2000

Muscle damage impairs insulin stimulation of IRS-1, PI 3-kinase, and Akt-kinase in human skeletal muscle.

Physiological stress associated with muscle damage results in systemic insulin resistance. However, the mechanisms responsible for the insulin resistance are not known; therefore, the present study was conducted to elucidate the molecular mechanisms associated with insulin resistance after muscle damage. Muscle biopsies were obtained before (base) and at 1 h during a hyperinsulinemic-euglycemic clamp (40 mU x kg(-1) x min(-1)) in eight young (age 24+/-1 yr) healthy sedentary (maximal O(2) consumption, 49.7+/-2.4 ml x kg(-1) x min(-1)) males before and 24 h after eccentric exercise (ECC)-induced muscle damage. To determine the role of cytokines in ECC-induced insulin resistance, venous blood samples were obtained before (control) and 24 h after ECC to evaluate ex vivo endotoxin-induced mononuclear cell secretion of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1beta. Glucose disposal was 19% lower after ECC (P<0.05). Insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation was 45% lower after ECC (P<0.05). Insulin-stimulated phosphatidylinositol (PI) 3-kinase, Akt (protein kinase B) serine phosphorylation, and Akt activity were reduced 34, 65, and 20%, respectively, after ECC (P < 0.05). TNF-alpha, but not IL-6 or IL-1beta production, increased 2.4-fold 24 h after ECC (P<0.05). TNF-alpha production was positively correlated with reduced insulin action on PI 3-kinase (r = 0.77, P = 0.04). In summary, the physiological stress associated with muscle damage impairs insulin stimulation of IRS-1, PI 3-kinase, and Akt-kinase, presumably leading to decreased insulin-mediated glucose uptake. Although more research is needed on the potential role for TNF-alpha inhibition of insulin action, elevated TNF-alpha production after muscle damage may impair insulin signal transduction.

Adult↗

PubMed2000

Regular exercise enhances insulin activation of IRS-1-associated PI3-kinase in human skeletal muscle.

Insulin action in skeletal muscle is enhanced by regular exercise. Whether insulin signaling in human skeletal muscle is affected by habitual exercise is not well understood. Phosphatidylinositol 3-kinase (PI3-kinase) activation is an important step in the insulin-signaling pathway and appears to regulate glucose metabolism via GLUT-4 translocation in skeletal muscle. To examine the effects of regular exercise on PI3-kinase activation, 2-h hyperinsulinemic (40 mU. m(-2). min(-1))-euglycemic (5.0 mM) clamps were performed on eight healthy exercise-trained [24 +/- 1 yr, 71.8 +/- 2.0 kg, maximal O(2) uptake (VO(2 max)) of 56.1 +/- 2.5 ml. kg(-1). min(-1)] and eight healthy sedentary men and women (24 +/- 1 yr, 64.7 +/- 4.4 kg, VO(2 max) of 44.4 +/- 2.7 ml. kg(-1). min(-1)). A [6, 6-(2)H]glucose tracer was used to measure hepatic glucose output. A muscle biopsy was obtained from the vastus lateralis muscle at basal and at 2 h of hyperinsulinemia to measure insulin receptor substrate-1(IRS-1)-associated PI3-kinase activation. Insulin concentrations during hyperinsulinemia were similar for both groups (293 +/- 22 and 311 +/- 22 pM for trained and sedentary, respectively). Insulin-mediated glucose disposal rates (GDR) were greater (P < 0.05) in the exercise-trained compared with the sedentary control group (9.22 +/- 0.95 vs. 6.36 +/- 0.57 mg. kg fat-free mass(-1). min(-1)). Insulin-stimulated PI3-kinase activation was also greater (P < 0.004) in the trained compared with the sedentary group (3.8 +/- 0.5- vs. 1.8 +/- 0.2-fold increase from basal). Endurance capacity (VO(2 max)) was positively correlated with PI3-kinase activation (r = 0.53, P < 0.04). There was no correlation between PI3-kinase and muscle morphology. However, increases in GDR were positively related to PI3-kinase activation (r = 0.60, P < 0.02). We conclude that regular exercise leads to greater insulin-stimulated IRS-1-associated PI3-kinase activation in human skeletal muscle, thus facilitating enhanced insulin-mediated glucose uptake.

Adult↗

PubMed2000

Insulin and exercise differentially regulate PI3-kinase and glycogen synthase in human skeletal muscle.

The purpose of this study was to determine the separate and combined effects of exercise and insulin on the activation of phosphatidylinositol 3-kinase (PI3-kinase) and glycogen synthase in human skeletal muscle in vivo. Seven healthy men performed three trials in random order. The trials included 1) ingestion of 2 g/kg body wt carbohydrate in a 10% solution (CHO); 2) 75 min of semirecumbent cycling exercise at 75% of peak O(2) consumption; followed by 5 x 1-min maximal sprints (Ex); and 3) Ex, immediately followed by ingestion of the carbohydrate solution (ExCHO). Plasma glucose and insulin were increased (P < 0.05) at 15 and 30 (Post-15 and Post-30) min after the trial during CHO and ExCHO, although insulin was lower for ExCHO. Hyperinsulinemia during recovery in CHO and ExCHO led to an increase (P < 0.001) in PI3-kinase activity at Post-30 compared with basal, although the increase was lower (P < 0. 004) for ExCHO. Furthermore, PI3-kinase activity was suppressed (P < 0.02) immediately after exercise (Post-0) during Ex and ExCHO. Area under the insulin response curve for all trials was positively associated with PI3-kinase activity (r = 0.66, P < 0.001). Glycogen synthase activity did not increase during CHO but was increased (P < 0.05) at Post-0 and Post-30 during Ex and ExCHO. Ingestion of the drink increased (P < 0.05) carbohydrate oxidation during CHO and ExCHO, although the increase after ExCHO was lower (P < 0.05) than CHO. Carbohydrate oxidation was directly correlated with PI3-kinase activity for all trials (r = 0.63, P < 0.001). In conclusion, under resting conditions, ingestion of a carbohydrate solution led to activation of the PI3-kinase pathway and oxidation of the carbohydrate. However, when carbohydrate was ingested after intense exercise, the PI3-kinase response was attenuated and glycogen synthase activity was augmented, thus facilitating nonoxidative metabolism or storage of the carbohydrate. Activation of glycogen synthase was independent of PI3-kinase.

Adult↗

PubMed1999

TNF-alpha impairs insulin signaling and insulin stimulation of glucose uptake in C2C12 muscle cells.

Physiological stressors such as sepsis and tissue damage initiate an acute immune response and cause transient systemic insulin resistance. This study was conducted to determine whether tumor necrosis factor-alpha (TNF-alpha), a cytokine produced by immune cells during skeletal muscle damage, decreases insulin responsiveness at the cellular level. To examine the molecular mechanisms associated with TNF-alpha and insulin action, we measured insulin receptor substrate (IRS)-1- and IRS-2-mediated phosphatidylinositol 3-kinase (PI 3-kinase) activation, IRS-1-PI 3-kinase binding, IRS-1 tyrosine phosphorylation, and the phosphorylation of two mitogen-activated protein kinases (MAPK, known as p42(MAPK) and p44(MAPK)) in cultured C2C12 myotubes. Furthermore, we determined the effects of TNF-alpha on insulin-stimulated 2-deoxyglucose (2-DG) uptake. We observed that TNF-alpha impaired insulin stimulation of IRS-1- and IRS-2-mediated PI 3-kinase activation by 54 and 55% (P < 0.05), respectively. In addition, TNF-alpha decreased insulin-stimulated IRS-1 tyrosine phosphorylation by 40% (P < 0.05). Furthermore, TNF-alpha repressed insulin-induced p42(MAPK) and p44(MAPK) tyrosine phosphorylation by 81% (P < 0.01). TNF-alpha impairment of insulin signaling activation was accompanied by a decrease (P < 0.05) in 2-DG uptake in the muscle cells (60 +/- 4 vs. 44 +/- 6 pmol. min-1. mg-1). These data suggest that increases in TNF-alpha may cause insulin resistance in skeletal muscle by inhibiting IRS-1- and IRS-2-mediated PI 3-kinase activation as well as p42(MAPK) and p44(MAPK) tyrosine phosphorylation, leading to impaired insulin-stimulated glucose uptake.

Calcium-Calmodulin-Dependent Protein Kinases↗

PubMed1998

Age-related differences in the pancreatic beta-cell response to hyperglycemia after eccentric exercise.

Eccentric exercise (ECC) causes muscle damage, insulin resistance, and increased pancreatic beta-cell secretion in young individuals. However, the effects of age on the pancreatic beta-cell response to glucose after ECC are unknown. Hyperglycemic clamps (180 min, 10.0 mM) were performed on eight young (age 22 +/- 1 yr) and eight older (age 66 +/- 2 yr) healthy sedentary males without exercise (CONT) and 48 h after ECC. ECC increased (P < 0.02) muscle soreness ratings and plasma creatine kinase concentrations in both groups. Insulin and C-peptide secretions were similar between young and older subjects during CONT clamps. ECC increased (P < 0.05) first-phase (0-10 min) C-peptide area under the curve in young (4.2 +/- 0.4 vs. 3.7 +/- 0.6 nM . min; ECC vs. CONT, respectively) but not in older subjects (3.2 +/- 0.7 vs. 3.5 +/- 0.7 nM . min; ECC vs. CONT), with significant group differences (P < 0.02). Indeed, ECC repressed (P < 0.05) first-phase peak C-peptide concentrations in older subjects (0. 93 +/- 0.16 vs. 1.12 +/- 0.11 nM; ECC vs. CONT). Moreover, first-phase C-peptide-to-insulin molar ratios suggest age-related differences (P < 0.05) in insulin/C-peptide clearance after ECC. Furthermore, the observed C-peptide response after ECC was related to abdominal adiposity [r = -0.62, P < 0.02, and r = -0.66, P < 0. 006, for first and second (10-180 min) phases, respectively]. In conclusion, older individuals did not exhibit the compensatory increase in beta-cell secretion observed among young individuals after ECC. Thus, with increasing age, the pancreatic beta-cell may be less responsive to the physiological stress associated with ECC.

Activity Cycles↗

PubMed1998

A moderate glycemic meal before endurance exercise can enhance performance.

The purpose of this study was to determine whether presweetened breakfast cereals with various fiber contents and a moderate glycemic index optimize glucose availability and improve endurance exercise performance. Six recreationally active women ate 75 g of available carbohydrate in the form of breakfast cereals: sweetened whole-grain rolled oats (SRO, 7 g of dietary fiber) or sweetened whole-oat flour (SOF, 3 g of dietary fiber) and 300 ml of water or water alone (Con). The meals were provided 45 min before semirecumbent cycle ergometer exercise to exhaustion at 60% of peak O2 consumption (VO2peak). Diet and physical activity were controlled by having the subjects reside in the General Clinical Research Center for 2 days before each trial. Blood samples were drawn from an antecubital vein for glucose, free fatty acid (FFA), glycerol, insulin, epinephrine, and norepinephrine determination. Breath samples were obtained at 15-min intervals after meal ingestion and at 30-min intervals during exercise. Muscle glycogen concentration was determined from biopsies taken from the vastus lateralis muscle before the meal and immediately after exercise. Plasma FFA concentrations were lower (P < 0.05) during the SRO and SOF trials for the first 60 and 90 min of exercise, respectively, than during the Con trial. Respiratory exchange ratios were higher (P < 0.05) at 90 and 120 min of exercise for the SRO and SOF trials, respectively, than for the Con trial. At exhaustion, glucose, insulin, FFA, glycerol, epinephrine, and norepinephrine concentrations, respiratory exchange ratio, and muscle glycogen use in the vastus lateralis muscle were similar for all trials. Exercise time to exhaustion was 16% longer (P < 0.05) during the SRO than during the Con trial: 266.5 +/- 13 and 225.1 +/- 8 min, respectively. There was no difference in exercise time for the SOF (250.8 +/- 12) and Con trials. We conclude that eating a meal with a high dietary fiber content and moderate glycemic index 45 min before prolonged moderately intense exercise significantly enhances exercise capacity.

Adult↗

PubMed1997

A single bout of concentric resistance exercise increases basal metabolic rate 48 hours after exercise in healthy 59-77-year-old men.

BACKGROUND: It has been shown that basal metabolic rate (BMR) decreases with age. The extent to which some of the decrease can be reversed by exercise in older men and women is unclear. Resistance exercise has been shown to significantly increase muscle mass in older individuals, and because muscle is a highly active metabolic tissue there is potential to increase BMR as a secondary outcome to the training adaptation. METHODS: Twelve healthy men aged 59-77 years performed single-leg knee extension exercise (right and left leg) and bench press lifts (16 sets, 10 reps/set with timed recovery between sets) at 75% of the individual's 3RM. Subjects only performed the concentric phase of the lift. BMR was measured on two separate occasions, once after a nonexercise control period and again 48 hrs after a bout of resistance exercise. RESULTS: BMR was significantly increased (p < .006) 48 hrs after exercise (EX) compared to control (CON) (284.0 +/- 34.0 vs 274.9 +/- 34.0 kJ/hr, respectively). Calculated over a 24-hour period, the energy expenditure corresponded to 1570 +/- 193 and 1627 +/- 193 kcal/24 hr (p < .0002) for the CON and EX measures, respectively. VO2 (L/min) was higher (p < .0002) 48 hrs after the EX bout compared to 48 hrs post-CON (0.232 +/- 0.03 vs 0.225 +/- 0.03 L/min, respectively). CONCLUSION: We conclude that in healthy 59-77-year-old men, an acute bout of resistance exercise causes a sustained increase in BMR that persists for up to 48 hours after exercise.

Aged↗

PubMed1993

Endurance exercise training reduces glucose-stimulated insulin levels in 60- to 70-year-old men and women.

BACKGROUND: Aging is frequently associated with development of insulin resistance and deterioration of glucose tolerance. Plasma glucose and insulin concentrations tend to be higher than in young people, even in those older individuals whose glucose tolerance is within the normal range. A sedentary life style could play a role in the development of insulin resistance and hyperinsulinemia with advancing age. METHODS: We evaluated the effect of 9 mo of vigorous endurance exercise training (approximately 80% of maximal heart rate) on the glucose-stimulated insulin response and glucose disposal rate, using the hyperglycemic clamp procedure, in 12 people aged 65 +/- 1 yr (mean +/- SE) with normal glucose tolerance. The post-training hyperglycemic clamps were performed approximately 16 h after a usual exercise session. RESULTS: VO2max increased approximately 23% in response to the exercise program. The plasma insulin concentration (I) during hyperglycemia (180 mg.dL-1) was significantly lower (mean 36 +/- 6 microU.mL-1 before vs 26 +/- 5 microU.mL-1 after; p < .05) after the exercise program. Insulin action was improved by the exercise, as the glucose disposal rate (M) during hyperglycemia was unchanged despite the blunted insulin response, resulting in an increase in the M/I ratio from 24 +/- 5 to 30 +/- 5 (p < .05), a value similar to the M/I ratio of 33 +/- 4 found in normally active young subjects. CONCLUSION: These results provide evidence that regular exercise is effective in reducing hyperinsulinemia and improving insulin action in 65-yr-olds to levels typical of young people.

Age Factors↗

PubMed1993

Relationship between glucose tolerance and glucose-stimulated insulin response in 65-year-olds.

BACKGROUND: Decreased insulin secretion may contribute to the deterioration of glucose tolerance associated with aging. METHODS: We studied the insulin response to a 3-hour hyperglycemic clamp (10 mM) of 19 young (24 +/- 1 y) subjects with normal glucose tolerance and 60 older (65 +/- 1 y) subjects with various levels of glucose tolerance. RESULTS: The noninsulin dependent diabetic (NIDDM) group had a diminished first phase immunoreactive (IR)-insulin response compared to young and nondiabetic older groups (p < .05). The older groups had a lower rate of change in IR insulin concentration during the third hour of hyperglycemia compared to the young group (p < .05). This was not, however, a universal finding, because a decreased third hour response was not seen in a subgroup of older subjects whose glucose tolerance was similar to that of the young group. Another subgroup of older subjects with a decrease in glucose tolerance mild enough to be considered normal by the National Diabetes Group Criteria tended to have both an increase in the early insulin response and a decrease in the third hour response. More severe decreases in glucose tolerance were associated with blunting of the early response. CONCLUSION: Aberrations in early and late phase glucose-stimulated insulin responses appear to be present in older subjects with even mildly decreased glucose tolerance. Some individuals, however, show no evidence of deterioration of glucose tolerance or insulin response to glucose with aging, at least up to age 70 years.

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