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Effect of thyroxine on basal and insulin-stimulated glucose uptake by fast and slow skeletal muscles of rats
Camp. Biochem. Physiol.Vol. loOA,No. 2, PP. 343-345, 1991
0300-%29/91$3.00+ 0.00 0 1991Pergamon Press plc
Printed in Great Britain
EFFECT OF THYROXINE ON BASAL AND INSULIN-STIMULATED GLUCOSE UPTAKE BY FAST AND SLOW SKELETAL MUSCLES OF RATS SHIN’ICHI SHOJI Department of Medicine, Shinshu University School of Medicine, Asahi 3-I-1, Matsumoto 390, Japan. Telephone: 0263-35-4600; Fax: 0263-34-0929 (Received 4 December
1990)
Ah&act--l.
The SCinjection of l-thyroxine (2 mg/kg bw/day) for 8 days produced a significant decrease of body weight gain in young male Wistar rats. 2. In these h~~yroid rats there was a significant decrease in the wet weight of the extensor digitorum longus (EDL) and soleus (Sol) muscles as compared with those of control rats. 3. The basal glucose uptake by the EDL and Sol muscles was unchanged in hyperthyroid rats using
the wet weight of muscle as a reference. 4. In hyperthyroid rats, the insulin-stimulated uptake of glucose by both the EDL and Sol muscles was significantly decreased. This inhibition was stronger in Sol and there was no insulin stimulation of glucose uptake by Sol.
MATERIALS AND METHODS
INTRODUCTION
The blood glucose level is elevated in conditions with an excess of thyroid hormone such as hyperthyroidism or thyrotoxicosis (Renauld et al., 1980; Ikeda et al., 1988). This may be explained by an increase in the inflow of glucose from the GI tract and the liver, and/or a decrease in the outilow of glucose to the liver and peripheral tissue. An increased absorption of glucose from the GI tract (Holdsworth and Besser, 1968) and an increased hepatic glucose output (Okajima and Ui, 1979a; Wennlund et al., 1986) have been reported in hy~~hyroid states. Conveying the decreased outflow of glucose, an impaired glucose tolerance has been reported as a frequent complication of clinical hyperthyroidism (Andersen et al., 1977; Andreani et al., 1977) and of experimental hyperthyroid states (Renauld et al., 1980). The impaired glucose tolerance suggests a decrease in the glucose uptake of skebtal muscle or a diminish~ insulin sensitivity of the tissue. To investigate this phenomenon, the effects of thyroxine administration on the basal and insulin stimulated glucose uptake by the skeletal muscles of rats was studied. Hyperthyroidism produces muscle weakness in about 80% of the patients affected (Havard et af., 1963; Ramsay, 1965) with those most commonly involved being used mainly in the maintenance of posture and during prolonged effect (Ramsay, 1974). It is likely that these are slow-twitch muscles which contain relatively more type I fibers. To evaluate the vulnerability of slow-twitch muscles during experimental thyroid hormone excess, the glucose uptake of slow and fast skeletal muscles in vitro were compared.
Requests for reprints should be addressed to: S. Shoji, Department of Medicine, Shinshu University School of Medicine, Asahi 3-l-1, Matsumoto 390, Japan.
Animals
Male Wistar rats weighing about 5Og were used in this study. They received water and rat chow od lib. Thyroxine
L-Thyroxine solubihzed in 0.01 N NaOH solution (2 mg/ ml) was administered sc at a dose of 2 mg/kg bw/day for 8 days to the test rats. Control rats received the same volume of vehicle (0.01 N NaOH solution) injected sc for 8 days. Muscles The animals were killed by cervical dislocation on day 9. The Sol and EDL muscles were excised together with their proximal and distal tendons after fixing the muscle in a stretched position in a holder in vivo as described previously (Shoji, 1986). Incubation The muscles were incubated in a flask with gentle shaking under continuous aeration with 95% 0,-S% CO, in an incubator at 37°C. The basic medium was Krebs-Henseleit bicarbonate buffer (pH 7.4) containing 5 mM sodium pyruvate, ‘H-labeled 3-0-methylglucose (1.0 @i/ml), 5 mM glucose, and a mixture of i4C-labeled and unlabeled sucrose (1 mM, 0.2 @/ml). In studies using insulin an amount of I~mUnits~ml was added to the medium. Under these conditions the uptake of 3-O-methyl-glucose was linear up to 60 min. Radioactivity
After 30 min incubation the muscles were washed in ice cold physiological saline and the tendons were removed. The muscles were then blotted, weighed, and digested in 0.4 ml of Soluene 350 (Packard Instrument Comp., Inc., Illinois, U.S.A.). After complete digestion, the digests were neutralized with acetic acid. The dual isotope radioactivity of the muscle digests and medium aliquots was determined in Scintisol EX-H (Wake Pure Chemical Industries, Ltd., Osaka, Japan) using a scintillation counter (Packard 3225, Packard Instrument Comp., Inc., Illinois, U.S.A.) after storage overnight in the counter.
343
344
l%IIN’ICHI
Calculations The uptake of 3-U-methylglucose was assessed as the difference between the total 3-O-methylglucose space and the sucrose space (extracellular space). Statistical analysis was done by Student’s t-test with P < 0.05 accepted as statistically significant. RESULTS
SHOJl
muscle wet weight was used as a reference, but it decreased significantly when the whole muscle was used as a reference. The insulin-stimulated glucose uptake did not differ significantly from the basal uptake in the Sol muscles of hyperthyroid rats. The difference between the basal and insulin-stimulated glucose uptake disappeared in the Sol of hyperthyroid rats.
Body weight DISCUSSION
The gain in body weight during the experiment was
significantly less in the hyperthyroid rats than in the controls (30.7 * 5.7 g vs 40.3 f 2.2; P < 0.05). Muscle weight
The weight of both the EDL and Sol muscles was significantly lower in the hyperthyroid rats vs controls (Table 1). Glucose uptake by EDL muscle (Table 2). The basal glucose uptake by the EDL muscle did not differ significantly in the hyperthyroid rats vs controls. The insulin-stimulated uptake of glucose was significantly decreased in the EDL muscle of the hyperthyroid rats. The difference between the basal and insulinstimulated glucose uptake by the EDL muscle was significantly lower in the hyperthyroid rats vs controls. Glucose uptake by Sol muscle (Table 2). The basal glucose uptake by the Sol muscle did not differ significantly from controls in hyperthyroid rats when Table 1. E&t Muscle EDL SO1
of thyroxine on muscle wet weight Control
Thyroxine
37.9 + 2.0 28.4 f 2.ot
35.4 * 2.0’ 26.0 + 3.3tS
Muscle wet weight (mg): mean + SD of 12 muscles Thyroxine: ~-thyroxine (2 mg/kg bw/day) injected sc for 8 days. Control: same volume of vehicle (0.01 N NaOH solution) injected sc for 8 days. ‘P < 0.01 “S control; tP (0.05 “S control; $P < 0.001 vs EDL. Table 2. Effect of thyroxine on muscle glucose uptake EDL Control Basal Insulin Insulin -Basal EDL Thyroxine Basal Insulin Insulin -Basal
A
B
0.80 + 0.05 1.59 +0.12*
30.3 f 3.9 60.3 f 4.6*
0.79 i 0.10
29.9 + 3.8
0.76 + 0.07 1.37 _t 0.08*$
26.9 f 2.5 48.5 f 2.8.t
0.61 f O.OSi
21.6 + 2.8i
1.18 f 0.1811 1.65 f O.IO*
33.5 f 5.1 46.9 f 2.8*1/
0.47 + 0.16ll
13.3 f 4.511
1.04 *0.13 1.12 * 0.15t1\
27.0 k 3.4$3 29.1 k 3.9tII
Sol Control
Basal Insulin Insulin -Basal Sol Thyroxine Basal Insulin Insulin -Basal
0.08 f 0.14t
II
2.1 f 3.7tll
Thyroxine, Control: same as Table 1 legend. Basal: glucose uptake of muscle incubated without insulin. Insulin: glucose uptake of muscle incubated with 100 mUnits/ml insulin. Mean f SD of six muscles (Basal and Insulin) or six pairs of muscle (Insulin-Basal). (A) pmol/gww/hr. (B) nmol/whoIe muscle/hr. *P -z 0.001 vs Basal; fP < 0.001 “S Control; $P < 0.01 “S Control; $P c 0.05 “S Control; 11 P < 0.001 vs EDL; YIP < 0.01 vs EDL.
This study shows that a short-term excess of thyroxine affects the body weight gain, muscle wet weight and the muscle uptake of glucose in rats. The effect on muscle glucose uptake appeared as an inhibition of the insulin-stimulated glucose uptake.
Insulin resistance has been reported in hyperthyroid patients (Bratusch-Marrain et al., 1985; Dimitriades et al., 1985;Shen et al., 1985).The blood insulin level or rate of secretion in hyperthyroidism is reported to be high (Doar et al., 1969; Andreani et al., 1977; Kabadi et al., 1980; Ahren and Lundquist, 1981; Ikeda et al., 1988), or to be low (Malaisse et al., 1967; Andersen et al., 1977; Renauld et al., 1980; Asano et al., 1982; Miiller et al., 1983; Osei et al., 1984). During hypoinsulinemia, the uptake of glucose by skeletal muscle should be decreased. Even during hyperinsulinemia, the diminished sensitivity to insulin of the skeletal muscle revealed in the present study may contribute to the decrease in the outflow of glucose to skeletal muscle. Therefore, this may be one factor responsible for the glucose intolerance and hyperglycemia seen in hyperthyroidism. Chiasson et al. (1981) reported that epinephrine inhibits the insulin-stimulated uptake of glucose in skeletal muscle by the inhibition of glucose phosphorylation. They hypothesized that this inhibition is due to the stimulation of glycogenolysis leading to the accumulation of hexose phosphate which inhibits hexokinase. This may be the mechanism for the diminished sensitivity to insulin in the skeletal muscle of hyperthyroid animals. Since the catecholamines exert their action through the mediation of an adenylate cyclase-cyclic AMP system, it is conceivable that the thyroid hormones, by virtue of their ability to stimulate protein synthesis, may increase the quantity of adenylate cyclase and in this way induce an increase in adrenergic activity (Ingbar et al., 1974). Moreover, epinephrine increases the hyperglycemia seen in hyperthyroid animals (Okajima and Ui, 1979b; Ikeda et al., 1988). The inhibition of insulin-stimulated glucose uptake was significantly more pronounced in slow than in fast muscle, which may thus explain the vulnerability of slow muscle to thyrotoxic myopathy. author thanks Miss Satomi Oosawa for her technical assistance in conducting this investigation. This study was supported by Grant (62-2) from National Center of Neurology and Psychiatry (NCNP) of the Ministry of Health and Welfare, Japan. Acknowledgements-The
REFERENCES
Ahren B. and Lundquist I. (198 1) Insulin secretory response to different secretagogues in hyper- and hypothyroid mice. Acfa Endocrinol. 97, 508-513.
Rat thyrotoxic myopathy Andersen 0. O., Friis T. and Ottessen B. (1977) Glucose intolerance and insulin secretion in hyperthyroidism. Acta Endocrinol. 84, 576-587.
Andreani D., Menziger G., Fallucca F., Alberti G., Tamburrano G. and Cassano C. (1977) Insulin level in thyrotoxicosis and primary myxedema: response to intravenous glucose and glucagon. Diaberologia 6, l-7. Asano T. and Okumura M. (1982) Insulin delivery rate in response to glucose and arginine infusion in hyperthyroidism. Diabelologia 23, 108-l 13. Bratusch-Marain P. R., Komajata M. and Waldhausl W. K. (1985) Glucose metabolism in non-insulin-dependent diabetic patients with experimental hyperthyroidism. J. Clin. Endocrinol. Metab. 60, 1063-1068.
Chiasson J. L., Shikama H., Chu D. T. W. and Exton J. H. (1981) Inhibitory effect of epinephrine on insulin stimulated glucose uptake by rat skeletal muscle. J. Clin. Inoest. 68, 706-713.
Dimitriades G., Baker B., March H., Mandarin0 L., Rizza R., Bergman M., Haymond M. and Gerich J. (1985) Effects of thyroid hormone excess on action, secretion, and metabolism of insulin in humans. Am. J. Physiol. 248, E593-E601. Doar J., Stamp T., Wynn V. and Audhya T. (1969) Effects of oral and intravenous glucose loading in thyrotoxicosis: studies of plasma glucose, free fatty acid, plasma insulin, and blood pyruvate levels. Diabetes 18, 633-639. Havard C. W., Campbell E. D. R., Ross H. B. and Spence A. W. (1963) Elcctromyographic and histological findings in the muscles of patients with thyrotoxicosis. Quart. J. Med. 32, 145-163.
Holdsworth C. D. and Besser G. M. (1968) Influence of gastric emptying rate and insulin response on oral glucose tolerance in thyroid disease. Luncet 1, 700-702. Ikeda T., Mokuda O., Tominaga M. and Mashiba H. (1988) Glucose intolerance in thyrotoxic rats: role of insulin, glucagon, and epinephrine. Am. J. Physiol. 255, E843-E849. Ingbar S. H. and Woeber K. A. (1974) The thyroid gland. In: Textbook of Endocrinology, 5th Edn, pp. 95-232. Saunders, Philadelphia.
345
Kabadi U. M. and Eisenstein A. B. (1980) Glucose intolerance in hyperthyroidism: role of glucagon. J. Clin. Endocrinol. Metab. 50, 392-396.
Malaisse W., Malaisse-Lagae F. and McGraw E. (1967) Effects of thyroid function upon insulin secretion. Diabetes 16, 643-646. Miiller M., Pas&en U. and Seitz H. (1983) Thyroid hormone regulation of glucose homeostasis in the miniature pig. Endocrinology 112, 2025-203 1. Okajima F. and Ui M. (1979a) Metabolism of glucose in hyper- and hypo-thyroid rats in Go. Glucose-turnover values and futile-cycle activities obtained with “C and ‘H-labeled glucose: Biochem. J 182, 565-575. Okaiima F. and Ui M. fl979b) Metabolism of glucose in h&.r- and hypo-thyroid rats in I&O. Relation orcatecholamine actions to thyroid activity in controlling glucose turnover. Biochem. J. 182, 585-592. Osei K., Falko J. M., O’Dorisio T. M. and Adams D. R. (1984) Decreased serum C-peptide/insulin molar ratios after oral glucose ingestion in hyperthyroid patients. Diabetes Care 7, 471-475.
Ramsay I. (1974) Thyroid Disease and Muscle Dysfwrction, 1st edn, pp. l-51. William Heinemann Medical Books Ltd, London. Ramsay I. D. (1965) Electromyography in thyrotoxicosis. Quart. J. Med. 34, 255-276.
Renauld A., Sverdlik R. C. and Garrido D. (1980) Blood sugar, serum insulin and serum free fatty acid responses to slow graded glucose in thyroxine-treated dogs. Acta Diabet. Lat. 17, 189-197.
Shen D. C. and Davidson M. B. (1985) Graves disease causes insulin antagonism. J. Clin. Endocrinol. Merab. 60, 1038-1041.
Shoji S. (1986) Effects of stretch and starvation on glucose uptake of rat soleus and extensor digitorum longus muscles. Muscle Nerve 9, 144-147. Wennlund R. S., Felig P., Hagenfeldt L. and Wahren J. (1986) Hepatic glucose production and splanchnic glucose exchange in hyperthyroidism. J. Clin. Endocrinol. Merab. 62, 174-179.
0300-%29/91$3.00+ 0.00 0 1991Pergamon Press plc
Printed in Great Britain
EFFECT OF THYROXINE ON BASAL AND INSULIN-STIMULATED GLUCOSE UPTAKE BY FAST AND SLOW SKELETAL MUSCLES OF RATS SHIN’ICHI SHOJI Department of Medicine, Shinshu University School of Medicine, Asahi 3-I-1, Matsumoto 390, Japan. Telephone: 0263-35-4600; Fax: 0263-34-0929 (Received 4 December
1990)
Ah&act--l.
The SCinjection of l-thyroxine (2 mg/kg bw/day) for 8 days produced a significant decrease of body weight gain in young male Wistar rats. 2. In these h~~yroid rats there was a significant decrease in the wet weight of the extensor digitorum longus (EDL) and soleus (Sol) muscles as compared with those of control rats. 3. The basal glucose uptake by the EDL and Sol muscles was unchanged in hyperthyroid rats using
the wet weight of muscle as a reference. 4. In hyperthyroid rats, the insulin-stimulated uptake of glucose by both the EDL and Sol muscles was significantly decreased. This inhibition was stronger in Sol and there was no insulin stimulation of glucose uptake by Sol.
MATERIALS AND METHODS
INTRODUCTION
The blood glucose level is elevated in conditions with an excess of thyroid hormone such as hyperthyroidism or thyrotoxicosis (Renauld et al., 1980; Ikeda et al., 1988). This may be explained by an increase in the inflow of glucose from the GI tract and the liver, and/or a decrease in the outilow of glucose to the liver and peripheral tissue. An increased absorption of glucose from the GI tract (Holdsworth and Besser, 1968) and an increased hepatic glucose output (Okajima and Ui, 1979a; Wennlund et al., 1986) have been reported in hy~~hyroid states. Conveying the decreased outflow of glucose, an impaired glucose tolerance has been reported as a frequent complication of clinical hyperthyroidism (Andersen et al., 1977; Andreani et al., 1977) and of experimental hyperthyroid states (Renauld et al., 1980). The impaired glucose tolerance suggests a decrease in the glucose uptake of skebtal muscle or a diminish~ insulin sensitivity of the tissue. To investigate this phenomenon, the effects of thyroxine administration on the basal and insulin stimulated glucose uptake by the skeletal muscles of rats was studied. Hyperthyroidism produces muscle weakness in about 80% of the patients affected (Havard et af., 1963; Ramsay, 1965) with those most commonly involved being used mainly in the maintenance of posture and during prolonged effect (Ramsay, 1974). It is likely that these are slow-twitch muscles which contain relatively more type I fibers. To evaluate the vulnerability of slow-twitch muscles during experimental thyroid hormone excess, the glucose uptake of slow and fast skeletal muscles in vitro were compared.
Requests for reprints should be addressed to: S. Shoji, Department of Medicine, Shinshu University School of Medicine, Asahi 3-l-1, Matsumoto 390, Japan.
Animals
Male Wistar rats weighing about 5Og were used in this study. They received water and rat chow od lib. Thyroxine
L-Thyroxine solubihzed in 0.01 N NaOH solution (2 mg/ ml) was administered sc at a dose of 2 mg/kg bw/day for 8 days to the test rats. Control rats received the same volume of vehicle (0.01 N NaOH solution) injected sc for 8 days. Muscles The animals were killed by cervical dislocation on day 9. The Sol and EDL muscles were excised together with their proximal and distal tendons after fixing the muscle in a stretched position in a holder in vivo as described previously (Shoji, 1986). Incubation The muscles were incubated in a flask with gentle shaking under continuous aeration with 95% 0,-S% CO, in an incubator at 37°C. The basic medium was Krebs-Henseleit bicarbonate buffer (pH 7.4) containing 5 mM sodium pyruvate, ‘H-labeled 3-0-methylglucose (1.0 @i/ml), 5 mM glucose, and a mixture of i4C-labeled and unlabeled sucrose (1 mM, 0.2 @/ml). In studies using insulin an amount of I~mUnits~ml was added to the medium. Under these conditions the uptake of 3-O-methyl-glucose was linear up to 60 min. Radioactivity
After 30 min incubation the muscles were washed in ice cold physiological saline and the tendons were removed. The muscles were then blotted, weighed, and digested in 0.4 ml of Soluene 350 (Packard Instrument Comp., Inc., Illinois, U.S.A.). After complete digestion, the digests were neutralized with acetic acid. The dual isotope radioactivity of the muscle digests and medium aliquots was determined in Scintisol EX-H (Wake Pure Chemical Industries, Ltd., Osaka, Japan) using a scintillation counter (Packard 3225, Packard Instrument Comp., Inc., Illinois, U.S.A.) after storage overnight in the counter.
343
344
l%IIN’ICHI
Calculations The uptake of 3-U-methylglucose was assessed as the difference between the total 3-O-methylglucose space and the sucrose space (extracellular space). Statistical analysis was done by Student’s t-test with P < 0.05 accepted as statistically significant. RESULTS
SHOJl
muscle wet weight was used as a reference, but it decreased significantly when the whole muscle was used as a reference. The insulin-stimulated glucose uptake did not differ significantly from the basal uptake in the Sol muscles of hyperthyroid rats. The difference between the basal and insulin-stimulated glucose uptake disappeared in the Sol of hyperthyroid rats.
Body weight DISCUSSION
The gain in body weight during the experiment was
significantly less in the hyperthyroid rats than in the controls (30.7 * 5.7 g vs 40.3 f 2.2; P < 0.05). Muscle weight
The weight of both the EDL and Sol muscles was significantly lower in the hyperthyroid rats vs controls (Table 1). Glucose uptake by EDL muscle (Table 2). The basal glucose uptake by the EDL muscle did not differ significantly in the hyperthyroid rats vs controls. The insulin-stimulated uptake of glucose was significantly decreased in the EDL muscle of the hyperthyroid rats. The difference between the basal and insulinstimulated glucose uptake by the EDL muscle was significantly lower in the hyperthyroid rats vs controls. Glucose uptake by Sol muscle (Table 2). The basal glucose uptake by the Sol muscle did not differ significantly from controls in hyperthyroid rats when Table 1. E&t Muscle EDL SO1
of thyroxine on muscle wet weight Control
Thyroxine
37.9 + 2.0 28.4 f 2.ot
35.4 * 2.0’ 26.0 + 3.3tS
Muscle wet weight (mg): mean + SD of 12 muscles Thyroxine: ~-thyroxine (2 mg/kg bw/day) injected sc for 8 days. Control: same volume of vehicle (0.01 N NaOH solution) injected sc for 8 days. ‘P < 0.01 “S control; tP (0.05 “S control; $P < 0.001 vs EDL. Table 2. Effect of thyroxine on muscle glucose uptake EDL Control Basal Insulin Insulin -Basal EDL Thyroxine Basal Insulin Insulin -Basal
A
B
0.80 + 0.05 1.59 +0.12*
30.3 f 3.9 60.3 f 4.6*
0.79 i 0.10
29.9 + 3.8
0.76 + 0.07 1.37 _t 0.08*$
26.9 f 2.5 48.5 f 2.8.t
0.61 f O.OSi
21.6 + 2.8i
1.18 f 0.1811 1.65 f O.IO*
33.5 f 5.1 46.9 f 2.8*1/
0.47 + 0.16ll
13.3 f 4.511
1.04 *0.13 1.12 * 0.15t1\
27.0 k 3.4$3 29.1 k 3.9tII
Sol Control
Basal Insulin Insulin -Basal Sol Thyroxine Basal Insulin Insulin -Basal
0.08 f 0.14t
II
2.1 f 3.7tll
Thyroxine, Control: same as Table 1 legend. Basal: glucose uptake of muscle incubated without insulin. Insulin: glucose uptake of muscle incubated with 100 mUnits/ml insulin. Mean f SD of six muscles (Basal and Insulin) or six pairs of muscle (Insulin-Basal). (A) pmol/gww/hr. (B) nmol/whoIe muscle/hr. *P -z 0.001 vs Basal; fP < 0.001 “S Control; $P < 0.01 “S Control; $P c 0.05 “S Control; 11 P < 0.001 vs EDL; YIP < 0.01 vs EDL.
This study shows that a short-term excess of thyroxine affects the body weight gain, muscle wet weight and the muscle uptake of glucose in rats. The effect on muscle glucose uptake appeared as an inhibition of the insulin-stimulated glucose uptake.
Insulin resistance has been reported in hyperthyroid patients (Bratusch-Marrain et al., 1985; Dimitriades et al., 1985;Shen et al., 1985).The blood insulin level or rate of secretion in hyperthyroidism is reported to be high (Doar et al., 1969; Andreani et al., 1977; Kabadi et al., 1980; Ahren and Lundquist, 1981; Ikeda et al., 1988), or to be low (Malaisse et al., 1967; Andersen et al., 1977; Renauld et al., 1980; Asano et al., 1982; Miiller et al., 1983; Osei et al., 1984). During hypoinsulinemia, the uptake of glucose by skeletal muscle should be decreased. Even during hyperinsulinemia, the diminished sensitivity to insulin of the skeletal muscle revealed in the present study may contribute to the decrease in the outflow of glucose to skeletal muscle. Therefore, this may be one factor responsible for the glucose intolerance and hyperglycemia seen in hyperthyroidism. Chiasson et al. (1981) reported that epinephrine inhibits the insulin-stimulated uptake of glucose in skeletal muscle by the inhibition of glucose phosphorylation. They hypothesized that this inhibition is due to the stimulation of glycogenolysis leading to the accumulation of hexose phosphate which inhibits hexokinase. This may be the mechanism for the diminished sensitivity to insulin in the skeletal muscle of hyperthyroid animals. Since the catecholamines exert their action through the mediation of an adenylate cyclase-cyclic AMP system, it is conceivable that the thyroid hormones, by virtue of their ability to stimulate protein synthesis, may increase the quantity of adenylate cyclase and in this way induce an increase in adrenergic activity (Ingbar et al., 1974). Moreover, epinephrine increases the hyperglycemia seen in hyperthyroid animals (Okajima and Ui, 1979b; Ikeda et al., 1988). The inhibition of insulin-stimulated glucose uptake was significantly more pronounced in slow than in fast muscle, which may thus explain the vulnerability of slow muscle to thyrotoxic myopathy. author thanks Miss Satomi Oosawa for her technical assistance in conducting this investigation. This study was supported by Grant (62-2) from National Center of Neurology and Psychiatry (NCNP) of the Ministry of Health and Welfare, Japan. Acknowledgements-The
REFERENCES
Ahren B. and Lundquist I. (198 1) Insulin secretory response to different secretagogues in hyper- and hypothyroid mice. Acfa Endocrinol. 97, 508-513.
Rat thyrotoxic myopathy Andersen 0. O., Friis T. and Ottessen B. (1977) Glucose intolerance and insulin secretion in hyperthyroidism. Acta Endocrinol. 84, 576-587.
Andreani D., Menziger G., Fallucca F., Alberti G., Tamburrano G. and Cassano C. (1977) Insulin level in thyrotoxicosis and primary myxedema: response to intravenous glucose and glucagon. Diaberologia 6, l-7. Asano T. and Okumura M. (1982) Insulin delivery rate in response to glucose and arginine infusion in hyperthyroidism. Diabelologia 23, 108-l 13. Bratusch-Marain P. R., Komajata M. and Waldhausl W. K. (1985) Glucose metabolism in non-insulin-dependent diabetic patients with experimental hyperthyroidism. J. Clin. Endocrinol. Metab. 60, 1063-1068.
Chiasson J. L., Shikama H., Chu D. T. W. and Exton J. H. (1981) Inhibitory effect of epinephrine on insulin stimulated glucose uptake by rat skeletal muscle. J. Clin. Inoest. 68, 706-713.
Dimitriades G., Baker B., March H., Mandarin0 L., Rizza R., Bergman M., Haymond M. and Gerich J. (1985) Effects of thyroid hormone excess on action, secretion, and metabolism of insulin in humans. Am. J. Physiol. 248, E593-E601. Doar J., Stamp T., Wynn V. and Audhya T. (1969) Effects of oral and intravenous glucose loading in thyrotoxicosis: studies of plasma glucose, free fatty acid, plasma insulin, and blood pyruvate levels. Diabetes 18, 633-639. Havard C. W., Campbell E. D. R., Ross H. B. and Spence A. W. (1963) Elcctromyographic and histological findings in the muscles of patients with thyrotoxicosis. Quart. J. Med. 32, 145-163.
Holdsworth C. D. and Besser G. M. (1968) Influence of gastric emptying rate and insulin response on oral glucose tolerance in thyroid disease. Luncet 1, 700-702. Ikeda T., Mokuda O., Tominaga M. and Mashiba H. (1988) Glucose intolerance in thyrotoxic rats: role of insulin, glucagon, and epinephrine. Am. J. Physiol. 255, E843-E849. Ingbar S. H. and Woeber K. A. (1974) The thyroid gland. In: Textbook of Endocrinology, 5th Edn, pp. 95-232. Saunders, Philadelphia.
345
Kabadi U. M. and Eisenstein A. B. (1980) Glucose intolerance in hyperthyroidism: role of glucagon. J. Clin. Endocrinol. Metab. 50, 392-396.
Malaisse W., Malaisse-Lagae F. and McGraw E. (1967) Effects of thyroid function upon insulin secretion. Diabetes 16, 643-646. Miiller M., Pas&en U. and Seitz H. (1983) Thyroid hormone regulation of glucose homeostasis in the miniature pig. Endocrinology 112, 2025-203 1. Okajima F. and Ui M. (1979a) Metabolism of glucose in hyper- and hypo-thyroid rats in Go. Glucose-turnover values and futile-cycle activities obtained with “C and ‘H-labeled glucose: Biochem. J 182, 565-575. Okaiima F. and Ui M. fl979b) Metabolism of glucose in h&.r- and hypo-thyroid rats in I&O. Relation orcatecholamine actions to thyroid activity in controlling glucose turnover. Biochem. J. 182, 585-592. Osei K., Falko J. M., O’Dorisio T. M. and Adams D. R. (1984) Decreased serum C-peptide/insulin molar ratios after oral glucose ingestion in hyperthyroid patients. Diabetes Care 7, 471-475.
Ramsay I. (1974) Thyroid Disease and Muscle Dysfwrction, 1st edn, pp. l-51. William Heinemann Medical Books Ltd, London. Ramsay I. D. (1965) Electromyography in thyrotoxicosis. Quart. J. Med. 34, 255-276.
Renauld A., Sverdlik R. C. and Garrido D. (1980) Blood sugar, serum insulin and serum free fatty acid responses to slow graded glucose in thyroxine-treated dogs. Acta Diabet. Lat. 17, 189-197.
Shen D. C. and Davidson M. B. (1985) Graves disease causes insulin antagonism. J. Clin. Endocrinol. Merab. 60, 1038-1041.
Shoji S. (1986) Effects of stretch and starvation on glucose uptake of rat soleus and extensor digitorum longus muscles. Muscle Nerve 9, 144-147. Wennlund R. S., Felig P., Hagenfeldt L. and Wahren J. (1986) Hepatic glucose production and splanchnic glucose exchange in hyperthyroidism. J. Clin. Endocrinol. Merab. 62, 174-179.