Effects of an adenosine-receptor antagonist on insulin-resistance in soleus muscle from obese Zucker rats

Challis, R. A. John; Budohoski, L; McManus, Bronwyn; Newsholme, Eric A.

doi:10.1042/bj2210915

Cited by 55 publications

(36 citation statements)

References 14 publications

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“…Increased AMP concentration might lead to extra adenosine formation (affecting glucose uptake) (11)(12)(13) as well as activation of ATP synthesis mediated by AMP-activated protein kinase (47,48). The latter, however, is hindered by inhibition of adenine nucleotide translocator by long-chain fatty acyl-CoA esters.…”

Section: Resultsmentioning

confidence: 99%

“…The increase in AMP concentration should promote formation of adenosine, which in turn was reported to have both inhibitory and stimulatory effects on insulin-dependent glucose uptake (11)(12)(13). It was hypothesized that an increased extracellular adenosine concentration could explain such pathophysiological features of type 2 diabetes as elevated levels of uric acid, increased sympathetic activity, and expansion of extracellular volume (9).…”

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confidence: 99%

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Modular Kinetic Analysis of the Adenine Nucleotide Translocator–Mediated Effects of Palmitoyl-CoA on the Oxidative Phosphorylation in Isolated Rat Liver Mitochondria

Čiapaitė

Eikenhorst

Bakker³

et al. 2005

Diabetes

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To test whether long-chain fatty acyl-CoA esters link obesity with type 2 diabetes through inhibition of the mitochondrial adenine nucleotide translocator, we applied a system-biology approach, dual modular kinetic analysis, with mitochondrial membrane potential (⌬) and the fraction of matrix ATP as intermediates. We found that 5 mol/l palmitoyl-CoA inhibited adenine nucleotide translocator, without direct effect on other components of oxidative phosphorylation. Indirect effects depended on how oxidative phosphorylation was regulated. When the electron donor and phosphate acceptor were in excess, and the mitochondrial "work" flux was allowed to vary, palmitoyl-CoA decreased phosphorylation flux by 38% and the fraction of ATP in the medium by 39%. ⌬ increased by 15 mV, and the fraction of matrix ATP increased by 46%. Palmitoyl-CoA had a stronger effect when the flux through the mitochondrial electron transfer chain was maintained constant: ⌬ increased by 27 mV, and the fraction of matrix ATP increased 2.6 times. When oxidative phosphorylation flux was kept constant by adjusting the rate using hexokinase, ⌬ and the fraction of ATP were not affected. Palmitoyl-CoA increased the extramitochondrial AMP concentration significantly. The effects of palmitoyl-CoA in our model system support the proposed mechanism linking obesity and type 2 diabetes through an effect on adenine nucleotide translocator. Diabetes 54:944 -951, 2005 O besity is a common finding in patients with type 2 diabetes (1-3). Numerous studies suggest that the oversupply of lipid to nonadipose tissues might result in lipotoxicity and contribute to the development of the insulin resistance syndrome and type 2 diabetes (4,5). The molecular mechanisms responsible for lipotoxicity, insulin resistance, and ␤-cell dysfunction are not fully understood. It is particularly confusing that so many processes appear to be affected at the same time, but not always to the same extent, and often in paradoxical ways.It has been hypothesized that inhibition of the mitochondrial adenine nucleotide translocator by long-chain fatty acyl-CoA esters, the active form of fatty acids, may be an important link between obesity and type 2 diabetes (6,7). Adenine nucleotide translocator is an enzyme that catalyzes the exchange of mitochondrial ATP for cytosolic ADP (8). It was shown that long-chain fatty acyl-CoA esters are potent inhibitors of adenine nucleotide translocator from both the cytosolic and the matrix side of the inner mitochondrial membrane (9). It was proposed that accumulation of long-chain fatty acyl-CoA esters in the cell and subsequent inhibition of adenine nucleotide translocator could lead to an increase in the matrix ATP-to-ADP ratio, membrane potential (⌬; i.e., electric potential across the inner mitochondrial membrane [out minus in]), and oxygen free radical production. In ␤-cells, like in other cells (10), an initial increase in O 2 ⅐ Ϫ (superoxide anion radical) production could stimulate cell growth and contribute to compensatory hyperinsulinemia. Later ...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Modular Kinetic Analysis of the Adenine Nucleotide Translocator–Mediated Effects of Palmitoyl-CoA on the Oxidative Phosphorylation in Isolated Rat Liver Mitochondria

Čiapaitė

Eikenhorst

Bakker³

et al. 2005

Diabetes

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“…Furthermore, the stimulation of the rate of glycogen synthesis by insulin in the muscle can be metabolically independent of the effect of insulin on glucose transport, since glycogen synthase catalyses a flux-generating step [45]. Thus, adenosine receptor antagonists have previously been shown to increase the sensitivity of glucose transport and glycolysis to insulin without affecting the sensitivity of glycogen synthesis [46].…”

Section: Resultsmentioning

confidence: 99%

Effects of hypothyroidism on the sensitivity of glycolysis and glycogen synthesis to insulin in the soleus muscle of the rat

Dimitriadis

Leighton

Parry-Billings

et al. 1989

Biochemical Journal

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1. The effects of hypothyroidism on the sensitivity of glycolysis and glycogen synthesis to insulin were investigated in the isolated, incubated soleus muscle of the rat. 2. Hypothyroidism, which was induced by administration of propylthiouracil to the rats, decreased fasting plasma levels of free fatty acids and increased plasma levels of glucose but did not significantly change plasma levels of insulin. 3. The sensitivity of the rates of glycogen synthesis to insulin was increased at physiological, but decreased at supraphysiological, concentrations of insulin. 4. The rates of glycolysis in the hypothyroid muscles were decreased at all insulin concentrations studied and the EC50 for insulin was increased more than 8-fold; the latter indicates decreased sensitivity of this process to insulin. However, at physiological concentrations of insulin, the rates of glucose phosphorylation in the soleus muscles of hypothyroid rats were not different from controls. This suggests that hypothyroidism affects glucose metabolism in muscle not by affecting glucose transport but by decreasing the rate of glucose 6-phosphate conversion to lactate and increasing the rate of conversion of glucose 6-phosphate to glycogen. 5. The rates of glucose oxidation were decreased in the hypothyroid muscles at all insulin concentrations. INTRODUCTIONPrevious studies have suggested that thyroid hormones influence the effect of insulin on the rate of glucose metabolism: in hyperthyroidism, the sensitivity of the rate of glucose production to insulin is decreased [1][2][3][4][5][6] whereas that of glucose uptake by skeletal muscle is increased [4,7]; in hypothyroidism, the rate of glucose production from the liver is decreased [8][9][10][11]. However, the effects of hypothyroidism on the sensitivity and responsiveness of glucose utilization to insulin have not been systematically studied. In hypothyroid patients, after administration of either intravenous glucose or insulin, and in the perfused rat hindquarter, the rate of utilization of glucose is either normal or decreased [11][12][13][14][15][16]. The effects of insulin on glucose utilization in isolated adipocytes from hypothyroid patients or rats are variable: the rate of glucose utilization is reported to be normal, decreased or increased [17][18][19]. The effects of insulin on glucose utilization in skeletal muscle have been investigated in only one study: markedly decreased rates of glycolysis and glycogen synthesis in soleus muscles isolated from hypothyroid rats were reported [19]. However, these experiments were performed in the presence of supraphysiological concentrations of insulin. The glycogen content is increased in soleus muscles isolated from hypothyroid rats [20,21] and it is normal in skeletal muscle of hypothyroid patients [22,23] which does not suggest that hypothyroidism should markedly decrease the sensitivity of the rate of this process to insulin. In view of the variability of the results in the above studies, it was decided to investigate the sensitivity of glucose u...

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“…In the periphery, interstitial adenosine may be involved in insulin-mediated glucose metabolism, although controversy exists as to whether adenosine exerts opposing effects in adipose tissue and skeletal muscle. Some studies have reported adenosine to increase insulin-mediated glucose metabolism in adipose tissue (5,31) and to decrease metabolism in skeletal muscle (32). Others have recorded decreased skeletal muscle glucose uptake with degradation or blocking of adenosine (33,34), indicating uniform effects of adenosine on (insulin-mediated) glucose metabolism in fat and muscle.…”

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confidence: 99%

Caffeine Can Decrease Insulin Sensitivity in Humans

Keijzers¹,

Galan²,

Tack³

et al. 2002

Diabetes Care

303

205

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OBJECTIVE -Caffeine is a central stimulant that increases the release of catecholamines. As a component of popular beverages, caffeine is widely used around the world. Its pharmacological effects are predominantly due to adenosine receptor antagonism and include release of catecholamines. We hypothesized that caffeine reduces insulin sensitivity, either due to catecholamines and/or as a result of blocking adenosine-mediated stimulation of peripheral glucose uptake.RESEARCH DESIGN AND METHODS -Hyperinsulinemic-euglycemic glucose clamps were used to assess insulin sensitivity. Caffeine or placebo was administered intravenously to 12 healthy volunteers in a randomized, double-blind, crossover design. Measurements included plasma levels of insulin, catecholamines, free fatty acids (FFAs), and hemodynamic parameters. Insulin sensitivity was calculated as whole-body glucose uptake corrected for the insulin concentration. In a second study, the adenosine reuptake inhibitor dipyridamole was tested using an identical protocol in 10 healthy subjects.RESULTS -Caffeine decreased insulin sensitivity by 15% (P Ͻ 0.05 vs. placebo). After caffeine administration, plasma FFAs increased (P Ͻ 0.05) and remained higher than during placebo. Plasma epinephrine increased fivefold (P Ͻ 0.0005), and smaller increases were recorded in plasma norepinephrine (P Ͻ 0.02) and blood pressure (P Ͻ 0.001). Dipyridamole did not alter insulin sensitivity and only increased plasma norepinephrine (P Ͻ 0.01).CONCLUSIONS -Caffeine can decrease insulin sensitivity in healthy humans, possibly as a result of elevated plasma epinephrine levels. Because dipyridamole did not affect glucose uptake, peripheral adenosine receptor antagonism does not appear to contribute to this effect. Diabetes Care 25:364 -369, 2002C affeine is one of the most widely consumed "drugs" in the world. The average daily intake per capita in the western world is ϳ300 mg (1), and most of it comes from dietary sources such as coffee, tea, cola drinks, and chocolate. Caffeine is a methylxanthine derivative and a potent adenosine receptor antagonist that exerts its effects both centrally and peripherally because it crosses the blood-brain barrier. Systemic effects of caffeine include an increase in blood pressure and stimulation of the release of catecholamines, particularly epinephrine (2). Local effects of caffeine stem from interaction with interstitial adenosine (3).Data from animal studies have indicated that methylxanthines are involved in insulin-mediated glucose handling and insulin responsiveness in adipose and muscular tissue. In obese Zucker rats, the caffeine-related adenosine receptor antagonist 1,3 dipropyl-8-(acrylic) phenylxanthine was found to inhibit glucose uptake in adipose tissue, whereas the reverse was observed in skeletal muscle (4).Both effects were attributed to adenosine receptor antagonism at the tissue site because the compound does not cross the blood-brain barrier. Studies showing that adenosine or adenosine agonists increase insulin sensitivity in adipos...

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Effects of an adenosine-receptor antagonist on insulin-resistance in soleus muscle from obese Zucker rats

Cited by 55 publications

References 14 publications

Modular Kinetic Analysis of the Adenine Nucleotide Translocator–Mediated Effects of Palmitoyl-CoA on the Oxidative Phosphorylation in Isolated Rat Liver Mitochondria

Modular Kinetic Analysis of the Adenine Nucleotide Translocator–Mediated Effects of Palmitoyl-CoA on the Oxidative Phosphorylation in Isolated Rat Liver Mitochondria

Effects of hypothyroidism on the sensitivity of glycolysis and glycogen synthesis to insulin in the soleus muscle of the rat

Caffeine Can Decrease Insulin Sensitivity in Humans

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