Effects of subbasal insulin infusion on resting and exercise-induced glucose turnover in depancreatized dogs

1993 ◽  
Vol 264 (3) ◽  
pp. E334-E341 ◽  
Author(s):  
Z. Q. Shi ◽  
A. Giacca ◽  
K. Yamatani ◽  
S. J. Fisher ◽  
H. L. Lickley ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Insulin Infusion ◽  
Glucose Turnover ◽  
Acid Oxidation ◽  
Minimal Amount ◽  
Adrenergic Blockade ◽  
Metabolic Clearance ◽  
Diabetic Dogs ◽  
Exercise Induced

beta-Adrenergic blockade suppressed lipolysis and normalized the exercise-induced increments in glucose uptake (GlcU) and metabolic clearance rate (MCR) in alloxan-diabetic dogs with residual insulin, but not in insulin-deprived depancreatized dogs even when combined with methylpalmoxirate (MP), which suppresses fatty acid oxidation. The effects of a minimal amount of insulin (as in the alloxan-diabetic dog), were studied in depancreatized, 24-h insulin-deprived dogs during rest and treadmill exercise (6 km/h, 10% slope) using a 1/4 basal insulin infusion (50 microU.kg-1.min-1, insulin, n = 6) alone, or with MP (20 mg.kg-1.day orally, 2.5 days, MP+insulin, n = 6). At rest, insulin decreased circulating fatty acids (31%) and Glc (13%) and increased GlcU and MCR (86 and 72%). Glc production was unaffected. MP plus insulin markedly suppressed hepatic fatty acid oxidation, decreased Glc (44%) and Glc production (50%), and markedly increased MCR (128%). The exercise-induced increments in MCR were markedly improved only by MP plus insulin but were still lower than in the propranolol-treated alloxan-diabetic dogs. Plasma Glc inversely correlated with the exercise-induced increase in MCR (r = -0.86). We conclude that 1) acute infusion of subbasal insulin improved GlcU in depancreatized dogs at rest but not during exercise; 2) inhibition of fatty acid oxidation combined with subbasal insulin improved the exercise-induced increase in MCR; and 3) the difference in GlcU and MCR between the MP plus insulin-treated depancreatized dogs and the beta-blockade-treated alloxan-diabetic dogs suggests a difference between acute and chronic effects of insulin.

Impact of in vivo fatty acid oxidation blockade on glucose turnover and muscle glucose metabolism during low-dose AICAR infusion

2006 ◽  
Vol 291 (5) ◽  
pp. E1131-E1140 ◽  
Author(s):  
Michael Christopher ◽  
Christian Rantzau ◽  
Zhi-Ping Chen ◽  
Rodney Snow ◽  
Bruce Kemp ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Glucose Metabolism ◽  
Fatty Acid Oxidation ◽  
Low Dose ◽  
Whole Body ◽  
Glucose Turnover ◽  
Acid Oxidation ◽  
Metabolic Clearance ◽  
The Impact

AMPK plays a central role in influencing fuel usage and selection. The aim of this study was to analyze the impact of low-dose AMP analog 5-aminoimidazole-4-carboxamide-1-β-d-ribosyl monophosphate (ZMP) on whole body glucose turnover and skeletal muscle (SkM) glucose metabolism. Dogs were restudied after prior 48-h fatty acid oxidation (FAOX) blockade by methylpalmoxirate (MP; 5 × 12 hourly 10 mg/kg doses). During the basal equilibrium period (0–150 min), fasting dogs ( n = 8) were infused with [3-3H]glucose followed by either 2-h saline or AICAR (1.5–2.0 mg·kg−1·min−1) infusions. SkM was biopsied at completion of each study. On a separate day, the same protocol was undertaken after 48-h in vivo FAOX blockade. The AICAR and AICAR + MP studies were repeated in three chronic alloxan-diabetic dogs. AICAR produced a transient fall in plasma glucose and increase in insulin and a small decline in free fatty acid (FFA). Parallel increases in hepatic glucose production (HGP), glucose disappearance (Rd tissue), and glycolytic flux (GF) occurred, whereas metabolic clearance rate of glucose (MCRg) did not change significantly. Intracellular SkM glucose, glucose 6-phosphate, and glycogen were unchanged. Acetyl-CoA carboxylase (ACC∼pSer221) increased by 50%. In the AICAR + MP studies, the metabolic responses were modified: the glucose was lower over 120 min, only minor changes occurred with insulin and FFA, and HGP and Rd tissue responses were markedly attenuated, but MCRg and GF increased significantly. SkM substrates were unchanged, but ACC∼pSer221 rose by 80%. Thus low-dose AICAR leads to increases in HGP and SkM glucose uptake, which are modified by prior FAox blockade.

Effects of the oral hypoglycemic agent methyl palmoxirate on exercise capacity of rats

1984 ◽  
Vol 62 (7) ◽  
pp. 815-818 ◽  
Author(s):  
J. C. Young ◽  
J. E. Bryan ◽  
S. H. Constable ◽  
G. F. Tutwiler ◽  
J. O. Holloszy
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Exercise Capacity ◽  
Liver Glycogen ◽  
Oral Hypoglycemic Agent ◽  
Strenuous Exercise ◽  
Acid Oxidation ◽  
Hypoglycemic Agent ◽  
Minimal Treatment ◽  
Exercise Induced

The effect of the oral hypoglycemic agent methyl palmoxirate (methyl 2-tetradecylglycidate, McN-3716), a selective inhibitor of long chain fatty acid oxidation, on the exercise capacity of normal rats was evaluated. Daily administration of 2.5 mg/kg for 7 days, or of a single dose of 10 mg/kg, of methyl palmoxirate did not affect the ability of rats to perform strenuous exercise of an intensity that caused exhaustion in less than 30 min. The ability to perform prolonged, moderately strenuous exercise of an intensity that could be maintained for more than 60 min was decreased slightly (17%) in the methyl palmoxirate treated rats. This effect appeared to be mediated by a significant reduction in initial liver glycogen content in the methyl palmoxirate treated rats. As a consequence, the methyl palmoxirate treated rats became hypoglycemic during prolonged exercise. Inhibition of fatty acid oxidation in skeletal muscle was minimal. Treatment with methyl palmoxirate protected against the development of exercise-induced ketosis. It appears that the liver is the major site of action of methyl palmoxirate when given in low dosage.

Excess body fat in men decreases plasma fatty acid availability and oxidation during endurance exercise

2004 ◽  
Vol 286 (3) ◽  
pp. E354-E362 ◽  
Author(s):  
Bettina Mittendorfer ◽  
David A. Fields ◽  
Samuel Klein
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Body Fat ◽  
Fat Mass ◽  
Total Fatty Acid ◽  
Acid Oxidation ◽  
Acid Uptake ◽  
Plasma Fatty Acids ◽  
Exercise Induced

The effect of relative body fat mass on exercise-induced stimulation of lipolysis and fatty acid oxidation was evaluated in 15 untrained men (5 lean, 5 overweight, and 5 obese with body mass indexes of 21 ± 1, 27 ± 1, and 34 ± 1 kg/m2, respectively, and %body fat ranging from 12 to 32%). Palmitate and glycerol kinetics and substrate oxidation were assessed during 90 min of cycling at 50% peak aerobic capacity (V̇o2 peak) by use of stable isotope-labeled tracer infusion and indirect calorimetry. An inverse relationship was found between %body fat and exercise-induced increase in glycerol appearance rate relative to fat mass ( r2 = 0.74; P < 0.01). The increase in total fatty acid uptake during exercise [(μmol/kg fat-free mass) × 90 min] was ∼50% smaller in obese (181 ± 70; P < 0.05) and ∼35% smaller in overweight (230 ± 71; P < 0.05) than in lean (354 ± 34) men. The percentage of total fatty acid oxidation derived from systemic plasma fatty acids decreased with increasing body fat, from 49 ± 3% in lean to 39 ± 4% in obese men ( P < 0.05); conversely, the percentage of nonsystemic fatty acids, presumably derived from intramuscular and possibly plasma triglycerides, increased with increasing body fat ( P < 0.05). We conclude that the lipolytic response to exercise decreases with increasing adiposity. The blunted increase in lipolytic rate in overweight and obese men compared with lean men limits the availability of plasma fatty acids as a fuel during exercise. However, the rate of total fat oxidation was similar in all groups because of a compensatory increase in the oxidation of nonsystemic fatty acids.

Effect of adrenodemedullation on decline in muscle malonyl-CoA during exercise

1993 ◽  
Vol 74 (5) ◽  
pp. 2548-2551 ◽  
Author(s):  
W. W. Winder ◽  
R. W. Braiden ◽  
D. C. Cartmill ◽  
C. A. Hutber ◽  
J. P. Jones
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Treadmill Running ◽  
Acid Oxidation ◽  
Sham Operation ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Malonyl Coa ◽  
Exercise Induced ◽  
Rate Limiting

Malonyl-CoA is an inhibitor of carnitine palmitoyltransferase, a rate-limiting enzyme of fatty acid oxidation. Previous studies have indicated that muscle malonyl-CoA declines in rats during treadmill running. This decrease may be important for allowing an increased rate of fatty acid oxidation during prolonged exercise. This study was designed to determine whether epinephrine is essential for inducing the decline in muscle malonyl-CoA during exercise. Male Sprague-Dawley rats underwent adrenodemedullation (ADM) or sham operation. After allowing 3 wk for recovery, rats were killed (pentobarbital anesthesia) at rest or after running at 21 m/min up a 15% grade for 60 min. Red quadriceps malonyl-CoA decreased from 2.6 +/- 0.3 to 0.8 +/- 0.07 nmol/g in sham-operated rats and from 2.2 +/- 0.3 to 0.8 +/- 0.1 nmol/g in ADM rats. White quadriceps malonyl-CoA decreased to similar levels during exercise in both sham-operated and ADM rats. A second experiment on 24-h fasted rats also showed no impairment in the exercise-induced decline in red quadriceps malonyl-CoA as a result of adrenodemedullation. The hormones of the adrenal medulla are therefore unessential for inducing the decline in malonyl-CoA during exercise.

Muscle malonyl-CoA decreases during exercise

1989 ◽  
Vol 67 (6) ◽  
pp. 2230-2233 ◽  
Author(s):  
W. W. Winder ◽  
J. Arogyasami ◽  
R. J. Barton ◽  
I. M. Elayan ◽  
P. R. Vehrs
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Plasma Catecholamines ◽  
Male Rats ◽  
Acid Oxidation ◽  
Glycogen Depletion ◽  
Carnitine Acyltransferase ◽  
Malonyl Coa ◽  
Important Regulator ◽  
Exercise Induced

Malonyl-CoA, the inhibitor of carnitine acyltransferase I, is an important regulator of fatty acid oxidation and ketogenesis in the liver. Muscle carnitine acyltransferase I has previously been reported to be more sensitive to malonyl-CoA inhibition than is liver carnitine acyltransferase I. Fluctuations in malonyl-CoA concentration may therefore be important in regulating the rate of fatty acid oxidation in muscle during exercise. Male rats were anesthetized (pentobarbital via venous catheters) at rest or after 30 min of treadmill exercise (21 m/min, 15% grade). The gastrocnemius/plantaris muscles were frozen at liquid N2 temperature. Muscle malonyl-CoA decreased from 1.66 +/- 0.17 to 0.60 +/- 0.05 nmol/g during the exercise. This change was accompanied by a 31% increase in cAMP in the muscle. The decline in malonyl-CoA occurred before muscle glycogen depletion and before onset of hypoglycemia. Plasma catecholamines, corticosterone, and free fatty acids were all significantly increased during the exercise. This exercise-induced decrease in malonyl-CoA may be important for allowing the increase in muscle fatty acid oxidation during exercise.

scholarly journals The role of hepatocellular eNOS in NAFLD development and hepatic mitochondrial adaptations to exercise

2020 ◽  
Author(s):  
◽  
Rory P. Cunningham
Keyword(s):  
Nitric Oxide ◽  
Fatty Acid ◽  
Hepatic Steatosis ◽  
Fatty Acid Oxidation ◽  
Whole Body ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid ◽  
Exercise Induced ◽  
Mitochondrial Adaptations

Whole body loss of endothelial nitric oxide synthase (eNOS) worsens hepatic mitochondrial function and exacerbates nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) development and progression. However, the precise role of eNOS in hepatocytes in the contribution to NAFLD has not been established. Here, we use gain- and loss- of-function approaches including a hepatocyte-specific eNOS knockout mouse model (eNOShep-/-), and lifestyle interventions (diet and exercise), to investigate the role of hepatocellular eNOS in NAFLD/NASH development and hepatic mitochondrial adaptations to exercise. Ablation of hepatocellular eNOS via genetic and viral knockout exacerbated hepatic steatosis and inflammation, decreased hepatic mitochondrial fatty acid oxidation and respiration, and impaired mitophagy. Conversely, overexpressing hepatocellular eNOS via viral approaches increased hepatocyte respiration, markers of mitophagy, while attenuating NASH progression. Interestingly, these detriments were not rescued by BNIP3 overexpression or nitric oxide (NO) donors in eNOS deficient hepatocytes. In addition, elevated H2O2 emission and hepatic steatosis in eNOShep-/- mice was completely ablated with 10 weeks of voluntary wheel running exercise. Interestingly, eNOShep-/- male mice had a blunted exercise-induced increase in hepatic fatty acid oxidation. eNOShep-/- mice also had impaired markers of energy sensing ability of the cell and attenuated activation of the autophagy initiating factor ULK1. While mitochondrial respiration and markers of mitochondrial content were not increased with exercise, female mice showed markers of mitochondrial biogenesis. Collectively, these data uncover the important and novel role of hepatocellular eNOS in exercise-induced hepatic mitochondrial adaptations, and help to further the understanding behind the mechanistic role of eNOS in NAFLD development.

Exercise, FGF21, and PGC-1 : roles in hepatic metabolism

2014 ◽  
Author(s):  
◽  
Justin Andrew Fletcher
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Gene Transcription ◽  
Fibroblast Growth Factor 21 ◽  
Acid Oxidation ◽  
Wild Type ◽  
Hepatic Fatty Acid ◽  
Exercise Induced ◽  
Hepatic Fatty Acid Oxidation ◽  
Mitochondrial Adaptations

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] The liver is instrumental in maintaining euglycemia during times of fasting and exercise, and in-turn exercise is a stimulus that challenges the liver and results in hepatic mitochondrial adaptations. Mechanisms responsible for these improvements in mitochondrial function are not currently known. Fibroblast growth factor 21 (FGF21), a powerful metabolic regulator, is one potential mechanism responsible for exercise- induced hepatic mitochondrial adaptations. Previous studies show that FGF21 modulates hepatic fatty acid oxidation (FAO), gluconeogenesis, ketogenesis, and TCA cycle flux, in addition to gene transcription of proteins important to these processes. The purpose of the first objective in the current study was to examine whether FGF21 is necessary for exercise to induce hepatic mitochondrial adaptations in mice. A second objective was to determine if PGC--1? is responsible for the upregulation of genes important to metabolic processes in response to FGF21 signaling. We mechanistically assessed the necessity of FGF21 for exercise-induced hepatic mitochondrial adaptations by providing wild-type and FGF21 knockout mice with running wheels for 8 weeks to promote physical activity. A major finding in the current study is that the FGF21KO mice experience a hepatic fatty acid oxidation deficit compared to the wild-type group and that 8 weeks of voluntary wheel running normalized FAO in the FGF21KO mice. The role of PGC-1[alpha] in FGF21 regulation of gene transcription was also assessed by continuously administering FGF21 (1 mg/kg), or saline into wild-type or liver specific PGC--1[alpha] heterozygous mice (LPGC--1[alpha]) for 4 weeks. It was found that female mice did not express a phenotype effect; however, in male mice hepatic FAO was significantly blunted in the LPGC-1[alpha] mice, yet FGF21 administration was able to elevate FAO regardless in both genotypes. Collectively, this data suggests that FGF21 is necessary for the expression and content of certain genes or proteins, but that VWR is able to circumvent the absence of FGF21 and normalize hepatic FAO. Furthermore, a reduction in hepatic PGC-1[alpha] does not appear to influence the ability of FGF21 to regulate hepatic FAO.

Glucose, glucagon, and insulin during adrenergic blockade in exercising sheep

1982 ◽  
Vol 52 (2) ◽  
pp. 315-319 ◽  
Author(s):  
R. P. Brockman ◽  
R. Halvorson
Keyword(s):  
Sympathetic Innervation ◽  
Glucagon Secretion ◽  
Glucose Turnover ◽  
Adrenergic Blockade ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Insulin And Glucagon Secretion ◽  
Propranolol Administration ◽  
Exercise Induced ◽  
Glucagon And Insulin

The interrelationships of glucagon and insulin with the sympathetic system on glucose turnover during exercise were examined in sheep. Six sheep were run for 45 min on a treadmill with and without alpha- and/or beta-adrenergic blockade. The exercise-induced increase in glucose appearance, as assessed by infusion of [2–3H]glucose, was reduced during the first 25 min of exercise by phentolamine administration. The metabolic clearance rate of glucose also was greater during exercise with phentolamine treatment than without. Phentolamine was associated with a rise in insulin concentrations and appeared to delay the exercise-induced rise in glucagon. Propranolol administration had no effect on glucose turnover and plasma glucagon and insulin. Nor did it have any effect on the changes in glucose, insulin, or glucagon induced by phentolamine administration. These observations are consistent with the alpha-adrenergic mediation of the sympathetic influences on insulin and glucagon secretion, which may account in part for the glucose adaptations to exercise in sheep. However, direct affects of circulating catecholamines on and increased stimulation of sympathetic innervation to the liver cannot be ruled out.

PGC-1α-induced improvements in skeletal muscle metabolism and insulin sensitivityThis paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 34 (3) ◽  
pp. 307-314 ◽  
Author(s):  
Arend Bonen
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Fatty Acid Oxidation ◽  
Insulin Signalling ◽  
Metabolic Effects ◽  
Zucker Rats ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid ◽  
Exercise Induced

The peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α), a nuclear encoded transcriptional coactivator, increases the expression of many genes in skeletal muscle, including those involved with fatty acid oxidation and oxidative phosphorylation. Exercise increases the expression of PGC-1α, and the exercise-induced upregulation of many genes is attributable, in part, to the preceding activation and upregulation of PGC-1α. Indeed, PGC-1α overexpression, like exercise training, increases exercise performance. PGC-1α reductions in humans have been observed in type 2 diabetes, while, in cell lines, PGC-1α mimics the exercise-induced improvement in insulin sensitivity. However, unexpectedly, in mammalian muscle, PGC-1α overexpression contributed to the development of diet-induced insulin resistance. This may have been related to the massive overexpression of PGC-1α, which induced the upregulation of the fatty acid transporter FAT/CD36 and led to an increase in intramuscular lipids, which interfere with insulin signalling. In contrast, when PGC-1α was overexpressed modestly, within physiological limits, mitochondrial fatty acid oxidation was increased, GLUT4 expression was upregulated, and insulin-stimulated glucose transport was increased. More recently, similar PGC-1α-induced improvements in the insulin-resistant skeletal muscle of obese Zucker rats have been observed. These studies suggest that massive PGC-1α overexpression, but not physiologic PGC-1α overexpression, induces deleterious metabolic effects, and that exercise-induced improvements in insulin sensitivity are induced, in part, by the exercise-induced upregulation of PGC-1α.

Time course of exercise-induced decline in malonyl-CoA in different muscle types

1990 ◽  
Vol 259 (2) ◽  
pp. E266-E271 ◽  
Author(s):  
W. W. Winder ◽  
J. Arogyasami ◽  
I. M. Elayan ◽  
D. Cartmill
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Time Course ◽  
Exercise Bout ◽  
Male Rats ◽  
Acid Oxidation ◽  
Type I ◽  
Malonyl Coa ◽  
Exercise Induced ◽  
Cpt I

Malonyl-CoA is a potent inhibitor of carnitine palmitoyltransferase I (CPT-I), the rate-limiting enzyme for fatty acid oxidation in mitochondria from liver of fed rats. Malonyl-CoA has also been demonstrated to inhibit skeletal muscle CPT-I. This study was designed to determine the rate of decline in malonyl-CoA in muscle during the course of a prolonged exercise bout. Adult male rats were anesthetized (pentobarbital sodium, intravenously) at rest or after running for 5, 10, 20, 30, 60, or 120 min on a treadmill (21 m/min, 15% grade). Malonyl-CoA was then quantitated in the soleus (type I fibers) and in the superficial white (type IIB) and deep red (type IIA) regions of the quadriceps. Malonyl-CoA decreased in red quadriceps from 2.8 +/- 0.2 to 1.4 +/- 0.2 pmol/mg after 5 min and to 0.9 +/- 0.1 pmol/mg after 20 min of exercise. The concentration of malonyl-CoA remained at this level for the duration of the exercise bout (120 min). In white quadriceps, resting values of malonyl-CoA were lower than in red quadriceps, and a significant decline was not observed until 30 min of exercise. A significant decrease in the soleus was observed after 20 min of exercise. This decline in muscle malonyl-CoA may be an important signal for allowing increased fatty acid oxidation during long-term exercise.

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