GERALD J.M. TEVAARWERK, BA, MD, FRCP[C]; CAROLYN J. HURST, RT; PEET UKSIK, RT, B Sc; LIONEL REESE, MD, CM, FRCS[C], FRCP[C], FACS

The effect of Insulin-induced hypoglycemia on serum thyroid hormone concentrations was studied in nine healthy individuals. Before, during and after the hypoglycemia blood samples were taken for measurement of the concentrations of glucose, thyroxine (Ti, triiodothyronine (T,), reverse triiodothyronine (rTj, catecholamines and pituitary hormones. There was no change in the mean serum T4 level (± the standard error of the mean) of 67 ± 2 .'g/l. However, the T3 concentrations rose from a mean basal level of 1.86 ± 0.06 .'g/l to a mean peak of 2.51 ± 0.21 Mg/I (P < 0.01) at 45 minutes after the insulin injection, and the rT3 concentrations fell from a mean basal level of 0.184 ± 0.008 Mg/I to a mean nadir of 0.171 ± 0.022 Mg/I (not a significant change). The mean peak epinephrine level was 545 ± 103 ng/l and it occurred between 30 and 45 minutes after the insulin injection; the mean peak norepinephrine level was 584 ± 114 ng/l and it occurred between 30 and 90 minutes after the injection. The growth hormone levels reached a mean peak of 26.1 ± 4.8 Mg/I and the plasma cortisol levels rose to 215 ± 9 Mg/I. The mean basal prolactin level was 8.5 ± 0.9 Mg/I; in five subjects there was a rise to a mean peak of 50.6 ± 14.6 Mg/I, whereas in the remaining four no significant increase occurred. No correlation was found between the changes in the serum T, concentration and any of the other factors studied. It was concluded that acute hypoglycemia is associated with a rapid increase in the serum T3 concentration. L.effet de l.hypoglycemie provoquee par l.insuline sur les concentrations s6riques d'hormones thyroidiennes a ete etudie chez neuf sujets sains. Avant, pendant et apres l'hypoglycemie des echantillons de sang ont ete preleves pour Ia mesure des concentrations de glucose, de thyroxine (Ti, de trilodothyronine (T,), de triiodothyronine inversee (IT,), de catecholamines et d'hormones hypophysaires. On n'a observe aucun changement dans le taux serique moyen de T4 (± erreur type) de 67 ± 2 Mg/I. Toutefois, les concentrations de T, ont augment6 d'un niveau basal moyen de 1.86 ± 0.06 Mg/I A une concentration maximum moyenne de 2.51 ± 0.21 Mg/I (P < 0.01) 45 minutes apres l'injection d'insuline, et les concentrations de iT, se sont abaissees d'une moyenne basale de 0.184 ± 0.008 /Ag/I a un nadir moyen de 0.171 ± 0.022 Mg/I (un changement non significatif). La concentration maximum moyenne d'epinephrine fut de 545 ± 103 ng/l et est apparue entre 30 et 45 minutes apres l'injection d'insuline; Ia concentration maximum moyenne de norepinephrine fut de 584 ± 114 ng/l et est

From the departments of medicine and nuclear medicine, St. Joseph's Hospital and the University of Western Ontario, London Reprint requests to: Dr. Gerald J.M. Tevaarwerk, St. Joseph's Hospital, 268 Grosvenor St., London, Ont. N6A 4V2 1090

CMA JOURNAL/OCTOBER 20, 1979/VOL. 121

apparue entre 30 et 90 minutes apres l'injection. Les taux d'hormone de croissance ont atteint un maximum moyen de 26.1 ± 4.8 Mg/I et les taux plasmatiques de cortisol se sont eleves a 215 ± 9 ,.g/I. Le niveau basal moyen de prolactine etait de 8.5 ± 0.9 Mg/I; chez cinq sujets il y eut une augmentation A un maximum moyen de 50.6 ± 14.6 Mg/I, alors que chez les quatre autres aucune augmentation significative n'est survenue. Aucune correlation n'a ete observee entre les changements des concentration seriques en T3 et aucun des autres facteurs etudies. On conclut que l'hypoglycemie aigue est associee A une augmentation rapide de Ia concentration serique de F,.

Since the demonstration that thyroxine (T4) can be converted to 3,3',5-triiodothyronine (T3) outside the thyroid gland' it has been found that T4 may also be deiodinated peripherally to an inactive form of thyroid hormone: 3,3',5'-triiodothyronine (reverse T3 or Indeed, it has been proposed that T4 serves as a prohormone that is peripherally converted to either the active hormone T3 by 5'-monodeiodination or the inactive rT, by 5-monodeiodination.'4 Various factors have been found to affect these two competing deiodination pathways, and this has led to the suggestion that the peripheral metabolism of T4 may be an important mechanism of thyrometabolic regulation in the tissues.7-'7 The purpose of the study reported in this paper was to determine if acute hypoglycemia affects T3 and rT, levels, and to determine if the change occurs sufficiently rapidly that it might affect tissue metabolism. Concentrations of pituitary hormones and catecholamines were also measured in a search for possible mediating factors Subjects and methods Nine healthy individuals, five men and four women aged 24 to 40 years with no history of thyroid, renal or hepatic disease and within 10% of their ideal weight, were studied. None were taking medications and informed consent was obtained. After an overnight fast blood samples were taken for 2 hours, through an indwelling catheter, from an antecubital vein. Regular insulin, 0.1 U/kg body weight, was then given intravenously and blood samples were drawn for a further 2 hours. The serum was separated and stored at -200C until the time of assay. Urine samples were taken immediately before and 2 hours after insulin administration for measurement of the free cortisol concentration.

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iy by measuring the total plasma and urinary free cortisol responses. The mean plasma cortisol concentration rose from a basal value of 157 ± 6 .g/l to a peak of 215 ± 9 p.g/l (P < 0.01) between 30 and 90 minutes after the insulin injection. The mean basal urinary free cortisol concentration, expressed as a fraction of the creatinine content of the urine sample, rose significantly (P < 0.001), from 99 ± 12.4 .g/g creatinine immediately before the insulin injection to 205 ± 21.0 .g/g creatinine 2 hours after the injection. From calculations involving peak and integrated responses no correlation was found between the serum T3 response and the changes in any of the other factors studied. Discussion

In our study insulin-induced hypoglycemia was accompanied by an increase in the serum T3 concentration. There was no change in the serum T4 concentration, which suggests that the increase in the T3 concentration was of peripheral, not thyroid, origin, although, since thyrotropin levels were not measured during hypoglycemia, an altered T4/T3 ratio of secreted products has not been ruled out. The increase in the T3 concentration was presumably due to increased 5'monodeiodinase activity, which would also increase the rate of disposal of rT3 by increasing the rate of removal of iodine in the 5' position. The lesser effect on the serum rT3 level in this study may be explained by a decrease in the rate of production of rT3. Indeed, it has recently been shown that 5- and 5'-deiodination of T4 can be varied independently.8 Alterations in serum T3 levels have been described in association with energy deprivation,7-9 wasting illnesses,10 the neonatal period11 and the use of such drugs as propylthiouracil," dexamethasone14 and propranolol.1117 An increase in the serum T3 level has been reported in response to long-term growth hormone administration in growth-hormone-deficient children.12 Fasting appears to inhibit 5'-monodeiodination, causing a decrease in the rate of conversion of T4 to T3 and an increase in the rT. concentration.9 The drugs just mentioned are thought to have a similar effect, increasing the production of rT3. Growth hormone is thought to stimulate the removal of iodine at the 5' position, thus causing a rise in the serum T3 concentration.'2 The release of catecholamines, pituitary hormones and corticotropin-mediated cortisol during acute hypoglycemia indicates a possible link between these hormones and the increase in the serum T3 levels. The previously demonstrated decrease in the T3 concentration and reciprocal increase in the rT3 concentration caused by propranolol administration led us to suggest that catecholamines may cause an increase in the conversion of T4 to T3 by induction of the 5'-monodeiodinase enzyme system?' The present study, however, did not show any direct relation between changes in the epinephrine or norepinephrine concentration and changes in thyroid hormone concentrations. However, this does not rule out an indirect cause-and-effect relationship. It is possible that catecholamines may induce 5'-monodeiodinase activity directly but that changes 1092 CMA JOURNAL/OCTOBER 20, 1979/VOL. 121

in the serum T3 concentration may be delayed and altered in degree by such factors as distribution spaee and rate of disposal.9 In a review of the literature we did not find any reports on the effects of catecholamine administration on serum T2 and rT3 levels. However, Galton21 has demonstrated that the urinary excretion of iodine-i 31 following an injection of 1211-T4 in rats is increased by the administration of epinephrine. Galton also showed that epinephrine administered in vivo caused an increase in the deiodinating activity of homogenates of mouse liver. Other possible mediators for the changes found include corticotropin and cortisol, prolactin and growth hormone. We were unable to find any reports on the direct effect of corticotropin on thyroid hormones, but glucocorticoids have been shown to decrease serum T3 concentrations.14 Prolactin release following intravenous administration of insulin has been shown to be mediated via intracellular glucopenia,2' presumably of the hypothalamus or higher brain centres. However, we found no correlation between the increases in the prolactin and T3 levels. Indeed, the T3 increases were seen even in subjects without a prolactin response. Growth hormone is perhaps a more likely candidate, as all subjects had a growth hormone response to hypoglycemia, although no direct correlation was found. However, the same arguments used for catecholamines must be considered here. For instance, it has been shown by Sato and colleagues12 that long-term administration of growth hormone to growth-hormonedeficient individuals causes an increase in the serum T3 concentration. It is necessary to examine the effect of pituitary hormones and catecholamines on the peripheral metabolism of thyroid hormones in vivo and in vitro to determine whether any cause-and-effect relationships exist. Finally, it is possible that insulin, or the effect it has on intracellular glucose, affects the conversion of T4 to T3. For instance, Danforth and associates27 have observed in humans that the serum T3 concentration varies directly with the carbohydrate content of the diet. Balsam, Sexton and Ingbar28 reported that homogenates of the liver of diabetic rats converted less T4 to T3 than those of healthy rats. The administration of insulin to the diabetic rats corrected the abnormality. Harris and colleagues,29 also using rat liver homogenates, found that the administration of carbohydrate or amino acids, but not lipids, significantly increased the T3 generation above that observed in starved rats. Interestingly, although the serum glucose levels were similar in the three nutrient groups, the insulin concentrations were significantly higher in the groups given carbohydrate or amino acids. Recently Burman and coworkers30 observed that, in fasted humans, refeeding with glucose was associated with an increase in the mean serum T3 concentration and a decrease in the mean serum rT. concentration. These findings and ours are compatible with the idea that insulin increases the intracellular concentration of glucose and that the latter modulates the conversion of T4 to T3. It is concluded that insulin-induced hypoglycemia causes a change in the peripheral metabolism of thyroid hormones and that the change can occur suf-

ficiently rapidly to play a role in thyrometabolic adaptation in the tissues. Further studies are needed to elucidate the importance and mechanism of the peripheral regulation of thyroid hormone concentrations and the effect of these hormones on the tissues.

effect of propyithiouracil and evidence supporting the concept that triiodothyronine is the active thyroid hormone. J Cliii Invest 51: 2493, 1972 14. CHOPRA IJ, WILLIAMS DE, ORGIAZZI J, et al: Opposite effects of dexamethasone on serum concentrations of 3.3',5'-triiodothyronine (reverse T3) and 3,3',5-triiodothyronine (173). J Cliii Endocrinol Metab 41: 911, 1975

We thank Dr. M. Binns Smith and Mr. C. MacDonald, department of medical biochemistry, St. Joseph's Hospital, London, Ont., for their help in measuring the plasma catecholamine concentrations, and Ms. C. Voorhaar for typing the manuscript. Antibodies to human triiodothyronine and prolactin were kindly donated by Drs. C. Burke, of Oxford, and H.G. Friesen, of Winnipeg, respectively.

15. ROSZKOWSKA K, NAUMAN J, NAUMAN A: Influence of propranolol on levels of thyroxine and triiodothyronine in hyperthyreotic patients. Mater Med PcI 6: 178, 1974 16. TEVAARWERK GJM, BOYD D: Propranolol pretreatment and thyroid hoimone levels during subtotal thyroidectomy for Graves' disease (abstr). A liii R Coil Physicians Surg Can 10: 42, 1977 17. TEVAARWERK GJM, MALIK MH, BOYD D: Preliminary report on the use of propranolol in thyrotoxicosis: I. Effect on serum thyroxine, triiodothyronine and reverse triiodothyronine concentrations. Can Med Assoc J 119: 350, 1978 18. HWANG P, GUYDA GJ, FRIESEN HG: A radioimmunoassay for human prolactin. Proc NatI Acad Sci USA 68: 1902, 1971 19. TEVAARWERK GJM, BOYLE DA, HURST CJ, et al: Double antibody solid phase radioimmunoassay: a simplified phase separation procedure applied to various ligands. J NucI Med (in press) 20. NUGENT CA, MAYES DM: Plasma corticosteroids determined by use of corticosteroid-binding globulin and dextran-coated charcoal. J Cliii Endocrinol Metab 26: 1116, 1966 21. MURPHY BEP, HOOD AB, PAlTEE CJ: Clinical studies utilizing a new method for the serial determination of plasma corticoids. Can Med Assoc J 90: 755, 1964 22. PEULER JD, JOHNSON GA: Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine. Life Sci 21: 625, 1977 23. COLTON 17: Statistics in Mediciiie, Little, Boston, 1974, pp 219-27 24. TEVAARWERK GJM, BOYD D: Propranolol in thyrotoxicosis: II. Serum thyroid hormone concentrations during subtotal thyroidectomy. Can J Surg 22: 264, 1979 25. GALTON VA: Thyroid hormone-catecholamine interrelationships. Endocriiiology 77: 278, 1965 26. WOOLF PD, LEE LA, LEEBAW W, et al: Intracellular glucopenia causes prolactin release in man. J Cliii Endo-

References 1. BRAvERMAN LE, INGBAR SH, STERLING K: Conversion of thyroxine (T4) to triiodothyronine (T3) in athyreotic human subjects. J Clin invest 49: 855, 1970 2. CHOPRA IJ: A radioimmunoassay for measurement of 3,3',5'-triiodothyronine (reverse T3). J CIi,z invest 54: 583, 1974 3. CHOPRA IJ, SOLOMON DH, CHUA TECO GN: Thyroxine: just a prohormone or a hormone too? J Clin Endocrinol Metab 36: 1050, 1973 4. BURMAN KD, DIMOND RC, WRIGHT FD, et al: A radioimmunoassay for 3,3',5'-L-triiodothyronine (reverse-T3) assessment of thyroid gland content and serum measurement in conditions of normal and altered thyroidal economy and following administration of thyrotropin releasing hormone (TRH) and thyrotropin (TSH). J Clin Endocrinol Metab 44: 660, 1977 5. GAVIN L, CASTLE J, MCMAHON F, et al: Extrathyroidal conversion of thyroxine to 3,-3',5'-triiodothyronine (reverse-T3) and to 3,-5,3'-triiodothyronine (p3) in humans. Ibid, p 733 6. SCHWARTZ HL, SURKS MI, OPPENHEIMER JH: Quantitation of extrathyroidal conversion of L-thyrOXine to 3,5,3'triiodo-L-thyronine in the rat. J Clin invest 50: 1124, 1971 7. VAGENAKIS AG, BURGER A, PORTNAY GI, et al: Diversion of peripheral thyroxine metabolism from activating to inactivating pathways during complete fasting. J Cliii

Endocrinol Metab 41: 191, 1975 8. EISENSTEIN Z, HAGG 5, VAGENAKIS AG, et al: Effect of starvation on the production and peripheral metabolism of 3,3',5'-triiodothyronine in euthyroid obese subjects.

J Clin Endocrinol Metab 47: 889, 1978 9. SUDA AK, PFrTMAN C, SHIMIZER T, et al: Production and metabolism of 3,5,3'-triidothyronine and 3,3',5'-triiodothyronine in normal and fasting subjects. Ibid, p 1311 10. BURKE CW, EASTMAN CJ: Thyroid hormones. Br Med Bull 30: 93, 1974 11. LARSEN PR: Direct immunoassay of triiodothyronine in

human serum. J Clin invest 51: 1939, 1972 12. SATO T, SUZUKI Y, TAKETANI T, et al: Enhanced peripheral conversion of thyroxine to triiodothyronine during hGH therapy in GH deficient children. J Cliii Endocrinol

Metab 45: 324, 1977 13. OPPENHEIMER JH, SCHWARTZ HL, SURKS MI: Propylthiouracil inhibits the conversion of L-thyroxine to Ltriiodothyronine. An explanation of the antithyroxine

Biofeedback therapy for migraine Some migraine sufferers are using biofredback therapy to relieve their migraine attacks. Hand warming and muscle control exercises and relaxation are among the biofeedback methods taught at one Chicago clinic. Twelve of these patients were interviewed by Dr. Nathan M. Szajnberg, a Chicago psychiatrist. All but one of the patients reported improvements in their social and vocational functioning, and seven reported

crinol Metab 45: 377, 1977 27. DANFORTH E, TYZBIR ED, HORTON ES, et al: Reciprocal changes in serum triiodothyronine .T3) and reverse 173 (r173) induced by altering the carbohydrate content of the diet (abstr). Clin Res 25: 294A, 1977 28. BALSAM A, SEXTON FC, INGBAR SH: In vitro generation of 173 from 174 by rat liver: reversible inhibition induced by starvation and diabetes mellitus. Presented at 52nd meeting of American Thyroid Association, Toronto, June 12, 1975 29. HARRIS ARC, FANG S-L, VAGENAKIS AG, et al: Effect of starvation, nutriment replacement, and hypothyroidism on in vitro hepatic 174 to 173 conversion in the rat. Metabolism 27: 1680, 1978 30. BURMAN KD, DIMOND RC, HARVEY GS, et al: Glucose modulation of alterations in serum iodothyronine concentrations induced by fasting. Metabolism 28: 291. 1979

sufferers may be a mixed blessing

continuing relief from headaches. However, Dr. Szajnberg found that despite the sense of well-being three of the patients had since acquired disorders such as memory lapses, backaches, abdominal pains and sinusitis. Another three had become depressed and two described an ability to influence the thoughts of others U CMA JOURNAL/OCTOBER 20, 1979/VOL. 121

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Effect of insulin-induced hypoglycemia on the serum concentrations of thyroxine, triiodothyronine and reverse triiodothyronine.

GERALD J.M. TEVAARWERK, BA, MD, FRCP[C]; CAROLYN J. HURST, RT; PEET UKSIK, RT, B Sc; LIONEL REESE, MD, CM, FRCS[C], FRCP[C], FACS The effect of Insul...
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