565
Short Communications prove to be more useful therapeu tically than somatostatin in controlling the hyperglycemia of human diabctics, as suggested (Raptis, Zoupas, Maier, Beischer and Rosenthai 1978). No overt clinical evidence of untoward side effects, such as steatorrhea or weight loss, was observed in any dog during and after the three days of treatment with either analog as might be expected considering the inhibitory actions of unmodified somatostatin upon gastrointestinal functions (Pointner, Hengl, Bayer and Flegel 1977; Wahren and Felig 1976). The data obtained in this study suggests that these analogs may have potential therapeu tic usefulness in human j uvenileonset diabetics. Acknowledgemen ts This work was supported by VA lnstitutional Research Support Grant 549 -8000-01; NIH Grants AM-0270016 and AM-18811; National Foundation Grant 1-411; The Salk Institute Texas Research Foundation.
References
Eggstein, M., F.H. Kreutz: 1. Klin. Wschr. 44: 262-273 (l966) Faloona, G.R., R.H. Unger: In Methods in Hormone Radioimmunoassay. laffe, B.M. and Behrman, H.R., Eds. New York, Academic Press, pp. 201-204 (l974) Gerich, J.E., M. Lorenzi, V. Schneider, J.H. Karam, J. Rivier, R. Guillemin, P.H. Forsham: N. Eng!. J. Med. 291: 544547 (1974) Meissner, c., Ch. Thum, W. Beischer, G. Winkler, K.E. Schroder, E.F. Pfeiffer: Diabetes 24, 988-996 (1975) Pointner, H., G. Hengl, P.M. Bayer, U. Flegel: Wien, KIin. Wschr. 89: 224-226 (1977) Rap/is, S., Ch. Zoupas, V. Maier, W. Beischer, J. Rosenthai: Acta Endocrinol. (Kbh.) Suppt. 215: 64 (1978) Raskin, P., R.H. Unger: Clin. Res. 24: 486A (1976) Unger, R.H.: Diabetes 25: 136-151 (1976) Wahren,J.,P. Felig: Laneet I: 1213-1216 (1976)
Horm. Metab. Res. 10 (1978) 565-566
Growth Hormone Secretion and Diazoxide Induced Hyperglycaemia L. Henningsen and K. Johansen Medical Department F. Glostrup Hospital, 2600 Glostrup, Denmark
~
Diazoxide (3-methyl-7-chloro-l,2,4 benzothiazine-I, I-dioxide) hyperglycaemia is accompanied by inhibition of insulin release from the B-cells (Fajans, Floyd, Knopf, Rull, Guntsche and Conn 1963). Tabachnick, Gulbenkian and Seidman (1964) have shown that diazoxide can cause hyperglycaemia in depancreatized dogs and alloxanized mice. lt has been suggested that at least some of the effeets of diazoxide may be mediated by endogenous sympathetic stimulation. The hyperglyeaemie effeet of diazoxide in adrenalectomized mice treated with cortisol is, however, comparable to that seen in normal animals (Tabachnick, Gulbenkian and Seidman 1965). When diazoxide is administered to hypophysectomized mice the usual hyperglycaemia is not observed (Tabachnick, Gulbenkian and Seidman 1964). lt is, therefore, probable that diazoxide indueed hyperglycaemia in man require the release of growth hormone. The present study was initiated in order to see if oral administration of diazoxide in doses of 200 and 400 mg per day for I week augments the growth hormone response to insulin induced hypoglycaemia.
100
Material and Methods
80
Eleven males (20-28 years, weight 63-86 kg) were studied. Blood glucose (BG) and serum growth hormone (GH) concentrations were measured before and every 10 min for I hr after intravenous bolus injection of .1 unit of insulin Aetrapid®per kg of body weight. Seven were studied before and after 200 mg diazoxide and six before and after 400 mg per day for I week. GH was measured with a radioimmunoassay (fPrskov Thomsen and Yde 1968), BG with a hexokinase method (Neeley 1972).
Received: 3 June 1977
Accepted: 14 Aug. 1978
0018-5043/78
805.00
1132-0565
t 100
SERUM
o ~
BO
INSULIN
~
GROWTH
OIAZOXIDE
200 mg 400 mg
-,,-,,-
+
PER
Kg i.v.
HORMONE - ng Iml
BEFORE
MEAN
60
ACTRAPID®O.l UNITS
1 S.O.
40 20 0
~
oJ; CwSJ
BLOOO
~
GLUCOSE - mg 1100 ml
60 40 20 0
0
10
~~~ 20
30
40
50
60
MINUTES
Fig. I GH and BG responses to insulin-induced hypoglycaemia before and after I week of oral administration of diazoxide.
© 1978 Georg Thieme Publishers
Downloaded by: NYU. Copyrighted material.
Requests for reprints should be addressed to: Dr. Roger H. Unger, VA Hospital, 4500 South Lancaster Dallas, Texas 75216 (USA)
566
Short Communications
Results ud Discussion
References
Figure 1 shows that diazoxide in 200 and 400 mg doses per day for 1 week does not change fasting GH level or the GH response to hypoglycaemia in normal subjects. Fasting BG level was significantly higher (p < 0.01, Wilcoxon) after I week treatment with 400 mg diazoxide compared to before diazoxide but the degree of maximal hypoglycaemia was identical. The increased fasting BG level after diazoxide is, thus attained despite unchanged fasting GH level and unchanged GH response to hypoglycaemia. The results seem to exclude GH hypersecretion as a major factor in the pathogenesis of diazoxide induced hyperglycaemia.
Fajans, S., J. Floyd, R. Knopf, J. Rull, E. Guntsche, I. Conn: I. Clin. Invest. 45: 481 (1966) Tabachnick, I.I.A., A. GulbenkÜln, F. Seidman: Diabetes 13: 408 (1964) Tabachnick,I.J.A., A. Gulbenkian, F. Seidman: I. Pharm. and Experiment. Therapeutics ISO: 455 (965) fJ,skov,H., H.G. Thomsen, H. Yde: Nature (London) 219: 193 (968) Nee/ey, W.E.: Clin Chem. 18: 509 (1972)
Requests for reprints should be addressed to: Klaus 10hansen, Dept. of Internal Medicine and Endocrinology, Herlev Hospital, 2730 Herlev (Denmark) Horm. Metab. Res. 10 (1978) 566-567
Peripheral Metabolism of T4 , T 3 , Reverse T 3 , 3' ,5' Diiodothyronine and 3,3' Diiodothyronine in Liver Cirrhosis I.B. Lumholtz, J. Faber, M. Buch Stfrensen, C. Kirkegaard, K. Siersbcek-Nielsen and Th. Friis
nines labelled with radioactive iodine and specific radioimIt is weIl known that serum 3,5,3'-triiodothyronine (T3) is munoassays developed in our laboratory (Lumho/tz et a1' in decreased and serum 3,3',S'-triiodothyronine (reverse T3, press, Faber et a1' to be published). rT 3) increased in patients with hepatic cirrhosis. In a group of patients with liver cirrhosis and normal thyroid function Chopra (976) has recently shown th~t these changes were Results due to a decreased production of T3, while the production of Absorption of 1-T4 in the patient with Iiver cirrhosis was 68% rT 3 was unaltered. In order to avoid the influence of the not differing from the controls (49-95, mean 71 %). Serum thyroid gland we have studied the peripheral metaqolism of concentrations, metabolic clearance rates (MCR) and producthyroxine (T 4), T3, rT 3\3/-diiodothyronine (3,3 -Tl) and tion rates (PR) are given in the table. Conversion rate~ (
Short Communications prove to be more useful therapeu tically than somatostatin in controlling the hyperglycemia of human diabctics, as suggested (Raptis, Zoupas, Maier, Beischer and Rosenthai 1978). No overt clinical evidence of untoward side effects, such as steatorrhea or weight loss, was observed in any dog during and after the three days of treatment with either analog as might be expected considering the inhibitory actions of unmodified somatostatin upon gastrointestinal functions (Pointner, Hengl, Bayer and Flegel 1977; Wahren and Felig 1976). The data obtained in this study suggests that these analogs may have potential therapeu tic usefulness in human j uvenileonset diabetics. Acknowledgemen ts This work was supported by VA lnstitutional Research Support Grant 549 -8000-01; NIH Grants AM-0270016 and AM-18811; National Foundation Grant 1-411; The Salk Institute Texas Research Foundation.
References
Eggstein, M., F.H. Kreutz: 1. Klin. Wschr. 44: 262-273 (l966) Faloona, G.R., R.H. Unger: In Methods in Hormone Radioimmunoassay. laffe, B.M. and Behrman, H.R., Eds. New York, Academic Press, pp. 201-204 (l974) Gerich, J.E., M. Lorenzi, V. Schneider, J.H. Karam, J. Rivier, R. Guillemin, P.H. Forsham: N. Eng!. J. Med. 291: 544547 (1974) Meissner, c., Ch. Thum, W. Beischer, G. Winkler, K.E. Schroder, E.F. Pfeiffer: Diabetes 24, 988-996 (1975) Pointner, H., G. Hengl, P.M. Bayer, U. Flegel: Wien, KIin. Wschr. 89: 224-226 (1977) Rap/is, S., Ch. Zoupas, V. Maier, W. Beischer, J. Rosenthai: Acta Endocrinol. (Kbh.) Suppt. 215: 64 (1978) Raskin, P., R.H. Unger: Clin. Res. 24: 486A (1976) Unger, R.H.: Diabetes 25: 136-151 (1976) Wahren,J.,P. Felig: Laneet I: 1213-1216 (1976)
Horm. Metab. Res. 10 (1978) 565-566
Growth Hormone Secretion and Diazoxide Induced Hyperglycaemia L. Henningsen and K. Johansen Medical Department F. Glostrup Hospital, 2600 Glostrup, Denmark
~
Diazoxide (3-methyl-7-chloro-l,2,4 benzothiazine-I, I-dioxide) hyperglycaemia is accompanied by inhibition of insulin release from the B-cells (Fajans, Floyd, Knopf, Rull, Guntsche and Conn 1963). Tabachnick, Gulbenkian and Seidman (1964) have shown that diazoxide can cause hyperglycaemia in depancreatized dogs and alloxanized mice. lt has been suggested that at least some of the effeets of diazoxide may be mediated by endogenous sympathetic stimulation. The hyperglyeaemie effeet of diazoxide in adrenalectomized mice treated with cortisol is, however, comparable to that seen in normal animals (Tabachnick, Gulbenkian and Seidman 1965). When diazoxide is administered to hypophysectomized mice the usual hyperglycaemia is not observed (Tabachnick, Gulbenkian and Seidman 1964). lt is, therefore, probable that diazoxide indueed hyperglycaemia in man require the release of growth hormone. The present study was initiated in order to see if oral administration of diazoxide in doses of 200 and 400 mg per day for I week augments the growth hormone response to insulin induced hypoglycaemia.
100
Material and Methods
80
Eleven males (20-28 years, weight 63-86 kg) were studied. Blood glucose (BG) and serum growth hormone (GH) concentrations were measured before and every 10 min for I hr after intravenous bolus injection of .1 unit of insulin Aetrapid®per kg of body weight. Seven were studied before and after 200 mg diazoxide and six before and after 400 mg per day for I week. GH was measured with a radioimmunoassay (fPrskov Thomsen and Yde 1968), BG with a hexokinase method (Neeley 1972).
Received: 3 June 1977
Accepted: 14 Aug. 1978
0018-5043/78
805.00
1132-0565
t 100
SERUM
o ~
BO
INSULIN
~
GROWTH
OIAZOXIDE
200 mg 400 mg
-,,-,,-
+
PER
Kg i.v.
HORMONE - ng Iml
BEFORE
MEAN
60
ACTRAPID®O.l UNITS
1 S.O.
40 20 0
~
oJ; CwSJ
BLOOO
~
GLUCOSE - mg 1100 ml
60 40 20 0
0
10
~~~ 20
30
40
50
60
MINUTES
Fig. I GH and BG responses to insulin-induced hypoglycaemia before and after I week of oral administration of diazoxide.
© 1978 Georg Thieme Publishers
Downloaded by: NYU. Copyrighted material.
Requests for reprints should be addressed to: Dr. Roger H. Unger, VA Hospital, 4500 South Lancaster Dallas, Texas 75216 (USA)
566
Short Communications
Results ud Discussion
References
Figure 1 shows that diazoxide in 200 and 400 mg doses per day for 1 week does not change fasting GH level or the GH response to hypoglycaemia in normal subjects. Fasting BG level was significantly higher (p < 0.01, Wilcoxon) after I week treatment with 400 mg diazoxide compared to before diazoxide but the degree of maximal hypoglycaemia was identical. The increased fasting BG level after diazoxide is, thus attained despite unchanged fasting GH level and unchanged GH response to hypoglycaemia. The results seem to exclude GH hypersecretion as a major factor in the pathogenesis of diazoxide induced hyperglycaemia.
Fajans, S., J. Floyd, R. Knopf, J. Rull, E. Guntsche, I. Conn: I. Clin. Invest. 45: 481 (1966) Tabachnick, I.I.A., A. GulbenkÜln, F. Seidman: Diabetes 13: 408 (1964) Tabachnick,I.J.A., A. Gulbenkian, F. Seidman: I. Pharm. and Experiment. Therapeutics ISO: 455 (965) fJ,skov,H., H.G. Thomsen, H. Yde: Nature (London) 219: 193 (968) Nee/ey, W.E.: Clin Chem. 18: 509 (1972)
Requests for reprints should be addressed to: Klaus 10hansen, Dept. of Internal Medicine and Endocrinology, Herlev Hospital, 2730 Herlev (Denmark) Horm. Metab. Res. 10 (1978) 566-567
Peripheral Metabolism of T4 , T 3 , Reverse T 3 , 3' ,5' Diiodothyronine and 3,3' Diiodothyronine in Liver Cirrhosis I.B. Lumholtz, J. Faber, M. Buch Stfrensen, C. Kirkegaard, K. Siersbcek-Nielsen and Th. Friis
nines labelled with radioactive iodine and specific radioimIt is weIl known that serum 3,5,3'-triiodothyronine (T3) is munoassays developed in our laboratory (Lumho/tz et a1' in decreased and serum 3,3',S'-triiodothyronine (reverse T3, press, Faber et a1' to be published). rT 3) increased in patients with hepatic cirrhosis. In a group of patients with liver cirrhosis and normal thyroid function Chopra (976) has recently shown th~t these changes were Results due to a decreased production of T3, while the production of Absorption of 1-T4 in the patient with Iiver cirrhosis was 68% rT 3 was unaltered. In order to avoid the influence of the not differing from the controls (49-95, mean 71 %). Serum thyroid gland we have studied the peripheral metaqolism of concentrations, metabolic clearance rates (MCR) and producthyroxine (T 4), T3, rT 3\3/-diiodothyronine (3,3 -Tl) and tion rates (PR) are given in the table. Conversion rate~ (
