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

Abstract

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...

K⁺ Transport and Volume Regulatory Response by NKCC in Resting Rat Hindlimb Skeletal Muscle

“…It remains to be determined if this IP-3 signal is downregulated postexercise, thus promoting an insulin-mediated increase in muscle cell volume and anabolic state. In support, the finding that other diuretics like furosemide and hydrochorothiazide that reduce cellular Cl -conductance decrease the sensitivity of skeletal muscle cells to insulin, suggests that the NKCC does play a role in maintaining an elevated insulin sensitivity in skeletal muscle [33]. While insulin also increases Na,K ATPase activity in skeletal muscle, it remains unclear if this is a direct effect or indirectly mediated through increases in intracellular [Na + ] resulting from increased Na + entry into the cell via the NKCC or glucose transporters [34].…”

Hypothyroidism in rats decreases peripheral glucose utilisation, a defect partially corrected by central leptin infusion

“…Thus, several investigations have demonstrated a stimulatory effect of T3 on insulin-stimulated glucose transport and/or phosphorylation in muscle [4,5], on the insulin-sensitive muscle/fat glucose transporter, GLUT4 [4,6], and on glycolysis in isolated muscle [5]. Other data showed decreased insulinstimulated glucose transport and/or phosphorylation, as well as a lower rate of glycolysis in isolated muscles from hypothyroid animals, as induced by propylthiouracil (PTU) administration [5,7]. Similar findings were obtained when studying isolated adipocytes from hypothyroid patients, as these cells exhibited decreased insulin responsiveness with regard to glucose utilisation.…”

Furosemide decreases the sensitivity of glucose transport to insulin in skeletal muscle in vitro

“…In these experiments, to investigate the effects of furosemide on the sensitivity of glucose transport to insulin, three concentrations of insulin were considered sufficient: a basal concentration, one which is close to the K m for this muscle preparation and a maximal concentration (16,19,23). The concentration of 10 000 mU/l insulin was used as maximal since higher concentrations of insulin (100 000 mU/l) were shown not to increase further the rate of glucose utilization in the soleus muscle (11).…”

“…Skeletal muscle is quantitatively most important for glucose disposal in response to insulin (10). In this tissue, furosemide impairs the sensitivity of glycolysis to insulin (11). Although this may be caused, at least in part, by a decrease in the activity of key glycolytic enzymes (12), the possibility that furosemide inhibits glucose transport has never been examined.…”