Improvement in glucose tolerance and skeletal muscle glucose transport in broiler chickens treated with PPARγ agonist troglitazone.
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Abstract:
Carbohydrate metabolism in chickens is character ized by hyperglycemia and insulin resistance compared to that observed in mammals. We previously reported that although gene of GLUT4 (an insulin-responsive glucose transporter ) is deficient in chickens (Seki et al., 2003), GLUT1 and GLUT8 are expressed, to a very small extent, in skeletal muscles (Kono et al., 2005). Fur thermore, it has been evidenced that glucose transpor t across the plasma membrane of skeletal muscles is stimulated by insulin injection in growing chicks (Tokushima et al., 2005). In the insulin-mediated glucose transport in mammals, peroxisome prolifer ator-activated receptor-gamma (PPAR ) plays a crucial role. The present study was under taken to assess the involvement of PPAR in the glucose toler ance and skeletal muscle glucose transport in chickens by using troglitazone, a PPAR agonist. Broiler chickens aged 1 to 2 week were orally administered with troglitazone (50 mg/kg body weight/day) 2 times a day for 17-22 days. Plasma glucose and NEFA concentr ations were decreased, to a small extent, by troglitazone administration for 22 days. In an oral glucose toler ance test, troglitazone suppressed an increase in plasma glucose concentr ations following glucose loading (2 g glucose/kg BW). A decrease in the plasma glucose concentration in insulin-injected (40 g/kg BW) chickens was par tly intensified by troglitazone administr ation for 22 days. Troglitazone administr ation for 17 days augmented insulin-mediated glucose transport, being determined by 2DG uptake, in skeletal muscles (extensor digitorum longus (EDL), pectoral superficialis and pectoral profundus) of chickens. These results suggest that PPAR is involved in the regulation of carbohydrate metabolism species-specific to chickens and troglitazone improves insulin resistance through modulation of skeletal muscle glucose transport.Keywords:
Troglitazone
GLUT4
Carbohydrate Metabolism
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Insulin and glucose stimulate glucose uptake in human muscle by different mechanisms. Insulin has well-known effects on glucose transport, glycogen synthesis, and glucose oxidation, but the effects of hyperglycemia on the intracellular routing of glucose are less well characterized. We used euglycemic and hyperglycemic clamps with leg balance measurements to determine how hyperglycemia affects skeletal muscle glucose storage, glycolysis, and glucose oxidation in normal human subjects. Glycogen synthase (GS) and pyruvate dehydrogenase complex (PDHC) activities were determined using muscle biopsies. During basal insulin replacement, hyperglycemia (11.6 +/- 0.31 mM) increased leg muscle glucose uptake (0.522 +/- 0.129 vs. 0.261 +/- 0.071 mumol.min-1 x 100 ml leg tissue-1, P < 0.05), storage (0.159 +/- 0.082 vs. -0.061 +/- 0.055, P < 0.05), and oxidation (0.409 +/- 0.080 vs. 0.243 +/- 0.085, P < 0.05) compared with euglycemia (6.63 +/- 0.33 mM). The increase in basal glucose oxidation due to hyperglycemia was associated with increased muscle PDHC activity (0.499 +/- 0.087 vs. 0.276 +/- 0.049, P < 0.05). However, the increase in leg glucose storage was not accompanied by an increase in muscle GS activity. During hyperinsulinemia, hyperglycemia (11.9 +/- 0.49 mM) also caused an additional increase in leg glucose uptake over euglycemia (6.14 +/- 0.42 mM) alone (5.75 +/- 1.25 vs. 3.75 +/- 0.58 mumol.min-1 x 100 ml leg-1, P < 0.05). In this case the major intracellular effect of hyperglycemia was to increase glucose storage (5.03 +/- 1.16 vs. 2.39 +/- 0.37, P < 0.05). At hyperinsulinemia, hyperglycemia had no effect on muscle GS or PDHC activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Hyperinsulinemia
Basal (medicine)
Carbohydrate Metabolism
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GLUT4
Homeostasis
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GLUT4
Carbohydrate Metabolism
Hexokinase
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The regulation of liver and skeletal muscle glycogen synthase by plasma insulin and glucose has not been investigated in vivo at physiological blood glucose concentrations. We have,therefore, used the glucose clamp technique to investigate the effects of these variables independently in rats. Short-term streptozocin-(0.15 g/kg) diabetic animals were used in addition to normal rats to avoid endogenous insulin secretion during hyperglycemic clamps. In normal and diabetic animals, 3 h of hyperinsulinemia without change in blood glucose concentrations caused only a small increase in liver glycogen synthase activity (+ 34%), whereas hyperglycemic clamps at 6.0 and 10.0 mmol/L resulted in marked increases (+ 268 and +394% of basal, P < 0.001). Liver glycogen concentrations at the end of the clamps reflected these changes. In skeletalmuscle, glycogen synthase was increased by +58% by the euglycemic hyperinsulinemic clamp and was not increased significantly further by hyperglycemia. Similarly, muscle glycogen concentration increased with the 4.0-mmol/L clamp but during the hyperglycemic clamps was only raised more indirect proportion to blood glucose concentrations. The results confirm that blood glucose concentration is the major short-term regulator of glycogen synthase activity in the liver but that insulin is of prime importance in skeletal muscle.
Hyperinsulinemia
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Glycogenesis
Glucose clamp technique
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Glycogen is an important component of whole-body glucose metabolism. MGSKO mice lack skeletal muscle glycogen due to disruption of the GYS1 gene, which encodes muscle glycogen synthase. MGSKO mice were 5–10% smaller than wild-type littermates with less body fat. They have more oxidative muscle fibers and, based on the activation state of AMP-activated protein kinase, more capacity to oxidize fatty acids. Blood glucose in fed and fasted MGSKO mice was comparable to wild-type littermates. Serum insulin was lower in fed but not in fasted MGSKO animals. In a glucose tolerance test, MGSKO mice disposed of glucose more effectively than wild-type animals and had a more sustained elevation of serum insulin. This result was not explained by increased conversion to serum lactate or by enhanced storage of glucose in the liver. However, glucose infusion rate in a euglycemic-hyperinsulinemic clamp was normal in MGSKO mice despite diminished muscle glucose uptake. During the clamp, MGSKO animals accumulated significantly higher levels of liver glycogen as compared with wild-type littermates. Although disruption of the GYS1 gene negatively affects muscle glucose uptake, overall glucose tolerance is actually improved, possibly because of a role for GYS1 in tissues other than muscle.
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The glucose utilization by different skeletal muscle tissues of short-term streptozotocin treated Wistar rats was studied both in vivo and in vitro. The findings permit the following statements: The reduced metabolic conversion of glucose is mainly the result of the diminished transport of glucose into the muscle cells. The utilization of the glucose taken up by the muscle cells for synthesis of glycogen is unchanged in the diabetic animals and can be stimulated by insulin correspondingly as in normal rats. The conversion of the glucose metabolized by the cells to lactate and the time course of the specific activity of glycogen and lactate lead to the conclusion that glycogenolysis in the muscles of streptozotocin diabetic rats during the incubation is enhanced.
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Abstract. The effects of growth hormone (GH) administration to rats in vivo on the sensitivity of the rate of glucose utilization to insulin were studied in soleus muscles isolated from these rats. A single injection of GH did not increase the rate of glucose transport within 1–2 h. However, 12 h after, the rate of glucose transport was increased at 10 mU insulin l ‐1 and was accompanied by a similar increase in the rate of lactate formation but no change in the rate of glycogen synthesis. Prolonged treatment with GH decreased the rate of glucose transport and glycogen synthesis and increased the content of glucose 6‐phosphate at physiological levels of insulin but did not affect the rate of lactate formation. These results suggest that: (a) GH does not increase the rate of glucose transport acutely; however, after several hours, the sensitivity of glucose transport and glycolysis to insulin are increased; (b) prolonged elevations of the level of GH in plasma decrease the sensitivity of the rate of glucose transport and glycogen synthesis to insulin. However, redirection of glucose residues away from the pathway of glycogen synthesis towards that of glycolysis and a possible increase in the rate of glycogenolysis maintain a normal rate of lactate formation, although the rate of glucose transport is decreased.
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To elucidate cellular mechanisms of insulin resistance induced by excess dietary fat, we studied conscious chronically high-fat–fed (HFF) and control chow diet-fed rats during euglycemic-hyperinsulinemic (560 pmol/1 plasma insulin) clamps. Compared with chow diet feeding, fat feeding significantly impaired insulin action (reduced whole body glucose disposal rate, reduced skeletal muscle glucose metabolism, and decreased insulin suppressibility of hepatic glucose production [HGP]). In HFF rats, hyperinsulinemia significantly suppressed circulating free fatty acids but not the intracellular availability of fatty acid in skeletal muscle (long chain fatty acyl-CoA esters remained at 230% above control levels). In HFF animals, acute blockade of β-oxidation using etomoxir increased insulin-stimulated muscle glucose uptake, via a selective increase in the component directed to glycolysis, but did not reverse the defect in net glycogen synthesis or glycogen synthase. In clamp HFF animals, etomoxir did not significantly alter the reduced ability of insulin to suppress HGP, but induced substantial depletion of hepatic glycogen content. This implied that gluconeo-genesis was reduced by inhibition of hepatic fatty acid oxidation and that an alternative mechanism was involved in the elevated HGP in HFF rats. Evidence was then obtained suggesting that this involves a reduction in hepatic glucokinase (GK) activity and an inability of insulin to acutely lower glucose-6-phos-phatase (G-6-Pase) activity. Overall, a 76% increase in the activity ratio G-6-Pase/GK was observed, which would favor net hepatic glucose release and elevated HGP in HFF rats. Thus in the insulin-resistant HFF rat 1) acute hyperinsulinemia fails to quench elevated muscle and liver lipid availability, 2) elevated lipid oxidation opposes insulin stimulation of muscle glucose oxidation (perhaps via the glucose-fatty acid cycle) and suppression of hepatic gluconeogenesis, and 3) mechanisms of impaired insulin-stimulated glucose storage and HGP suppressibility are not dependent on concomitant lipid oxidation; in the case of HGP we provide evidence for pivotal involvement of G-6-Pase and GK in the regulation of HGP by insulin, independent of the glucose source.
Hyperinsulinemia
Glucose clamp technique
Gluconeogenesis
Carbohydrate Metabolism
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Rats fed a high-fat diet display blunted insulin-stimulated skeletal muscle glucose uptake. It is not clear whether this is due solely to a defect in glucose transport, or if glucose delivery and phosphorylation are also impaired. To determine this, rats were fed standard chow (control rats) or a high-fat diet (HF rats) for 4 wk. Experiments were then performed on conscious rats under basal conditions or during hyperinsulinemic euglycemic clamps. Rats received primed constant infusions of 3- O-methyl-[ 3 H]glucose (3- O-MG) and [1- 14 C]mannitol. Total muscle glucose concentration and the steady-state ratio of intracellular to extracellular 3- O-MG concentration [which distributes based on the transsarcolemmal glucose gradient (TSGG)] were used to calculate glucose concentrations at the inner and outer sarcolemmal surfaces ([G] im and [G] om , respectively) in soleus. Total muscle glucose was also measured in two fast-twitch muscles. Muscle glucose uptake was markedly decreased in HF rats. In control rats, hyperinsulinemia resulted in a decrease in soleus TSGG compared with basal, due to increased [G] im . In HF rats during hyperinsulinemia, [G] im also exceeded zero. Hyperinsulinemia also decreased muscle glucose in HF rats, implicating impaired glucose delivery. In conclusion, defects in extracellular and intracellular components of muscle glucose uptake are of major functional significance in this model of insulin resistance.
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Carbohydrate Metabolism
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