Propranoloi Effect on Plasma Glucose, Free Fatty Acid, Insulin, and Growth Hormone in Graves' Disease Jos~ Luis Ortigosa, Fernando Mendoza, Rosa Maria Argote, Guadalupe Garcia, Carlos Cervantes, and Adalberto Parra A 3-hr oral glucose tolerance test was performed in 12 thyrotoxic patients before and after propranolol treatment for 30 days ( 120 mg/day). Plasma glucose, free fatty acid, insulin, and growth hormone levels were determined on each test and compared to each other and against nine clinically healthy volunteers. In eight thyrotoxic patients (subgroup A) an improvement in carbohydrate tolerance was observed after propranolol treatment, along with a fall in the previously elevated fasting FFA; no change in plasma insulin levels was observed. Plasma growth hormone levels were higher than normal both before and after propranolol; however, a 46% glucose-induced suppression was seen in both instances, in the other four patients (subgroup B) (who had had a marked and rapid weight loss) a deterioration of the previously normal glucose tolerance was seen after propranolol administration without signifi-
cant changes in insulin levels. Elevated fasting plasma free fatty acids remained so despite propranolol treatment. Plasma growth hormone was higher than normal before and after propranolol; a late suppression {at 120 min) and no suppression at all were seen, respectively. After propranolol treatment, subgroup B had higher plasma free fatty acid than subgroup A in the fasting state and at 30 and 180 min. It is proposed that the improvement or deterioration in carbohydrate tolerance after propranolol treatment might be related to whether or not a satisfactory propranolol-induced lipolytic blockade is achieved, leading to a decrease in plasma free fatty acid levels, improved insulin sensitivity, and better peripheral glucose utilization. Therefore, a uniform dose of propranolol w i l l not always be sumcient to obtain adequate lipolytic blockade, particularly if the thyrotoxic patient has had a marked and rapid weight loss.
N THE PAST 2 YR, propranolol (a B-blocking agent) has demonstrated its usefulness in the control of the prominent cardiovascular manifestations of thyrotoxicosis.~,2 This benefit seems to be achieved by decreasing the sympathetic hyperactivity or hyperresponsiveness present in this disease 3 and not by affecting plasma catecholamine levels, which have been reported to be low. 4 The sympathetic hyperactivity has also been postulated to be the cause of the decreased pancreatic insulin response to an oral glucose load, and thus is at least partially responsible for the abnormal carbohydrate tolerance observed in thyrotoxic patients. 5 Since propranolol and epinephrine have a synergistic action in blocking pancreatic insulin release, 6,7 theoretically one would expect a deterioration of the carbohydrate tolerance in the thyrotoxic patient treated with propranolol.
I
From the Department o f Endocrinology, Centro Mbdico La Raza and the Seccibn de Hormonas Protbicas, Divisibn de Biologia de la Reproduccibn, Unldad de lnvestigacibn Cientifica, Centro Mbdico Nacional, Instituto Mexicano del Seguro Social, Mbxico City, Mexico. Received for publication October 20, 1975. Supported in part by a grant from the Ford Foundation. Reprint requests should be addressed to A dalberto Parra, M.D., Unidad de Investigacibn Cientifica, Centro Mbdico Nacional, Instituto Mexicano del Seguro Social, Apartado 73-032, Mbxico 73, D.F., Mexico. 9 1976 by Grune & Stratton, Inc.
Metabolism,Vol. 25, No. 11 (November), 1976
1201
1202
ORTIGOSA ET AL. Table 1. Clinical and Laboratory Data Actual
Weight loss before
Ideal
Evolu-
Age
Height
Weight
study
Weight
tion
T3 uptake
Serum T4
Sex
(yr)
(cm)
(kg)
(kg)
(kg)
(mo)
(%)
(#g/100 rnl)
6 hr
24 hr
(m~/day)
1 2
F F
20 20
153 157
61.4 60.5
12 3
51.8 54.0
5 7
47,6 49.4
25,0 34,6
68,4 97.4
74.2 84.6
120 120
3
F
39
155
54.0
6
58.1
6
49.7
25.0
56.4
74,3
120
4
M
43
168
57.0
9
68.1
8
45.0
30.1
74.6
87.7
120
5 6
F F
49 16
158 152
64.5 51.0
2 9
66,2 49.5
3 6
50.1 52.4
24,7 19.8
93.8 60.2
70.7 92.4
120 120
Patient No.
131 I Thyroid Uptake
Propranolol
7
F
42
142
34.0
10
54.0
8
43.2
25.0
85.5
94.3
120
8
F
34
150
60.0
8
59.0
10
54.3
25.0
80.2
75.5
120
9
F
18
172
69.0
5
62.7
5
49.4
17.4
58.9
80.4
120
10
F
34
144
51.0
8
54.8
7
50.2
19.8
42.6
72.3
120
11
F
38
157
62.0
8
59.2
12
47.8
30.1
71,4
81.0
120
12
F
36
162
53,5
10
61.7
10
54.3
28.6
80.2
75,5
120
A c c o r d i n g l y , t h e p r e s e n t s t u d y w a s u n d e r t a k e n in a n a t t e m p t t o s t u d y p l a s m a glucose, free fatty acid, insulin, and growth hormone levels, during an oral g l u c o s e t o l e r a n c e t e s t , in p a t i e n t s w i t h G r a v e s ' d i s e a s e b e f o r e a n d a f t e r p r o pranolol treatment. MATERIALS A N D METHODS
Patients Thyrotoxic group. Twelve subjects with Graves' disease (all but one were female) 16-49 yr of age were included in this group. The diagnosis of thyrotoxicosis was based on clinical manifestations, as well as on the abnormality of the following tests: Serum T4, 8 T3-binding capacity, 9 and 6- and 24-hr 1311 thyroid uptake (Table 1).* The criteria for selecting the patients were: (1) no known family history of diabetes mellitus; (2) absence of any concomitant disease; and (3) absence of extremely severe thyrotoxicosis needing immediate control. Controlgroup. This group consisted of nine clinically healthy, nonobese volunteers, 18-29 yr of age, with no family history of diabetes mellitus and no personal history of drug ingestion during the past 6 too.
Procedures At admission to the study, each patient was instructed to consume a carbohydrate intake of at least 250 g/day during 3 days prior to study. The fourth day, and after a 10 12-hr overnight fast, a 3-hr oral glucose tolerance test (1.75 g/kg body weight, maximum 100 g) was performed. Thereafter, each thyrotoxic patient received propranolol tablets 40 mg t.i.d, for 30 days. During this period all patients engaged in their usual activity and were followed at weekly intervals on an out-patient basis. Pulse rates ranged between 75 and 85/min, and in no instance were below 70. No electrocardiographic abnormalities were observed. The morning after the last dose of propranolol, an oral glucose tolerance test was again performed in all thyrotoxic patients in a fashion identical to the first test. During each test, heparinized blood samples were obtained at -15, 0, 30, 60, 120, and 180 min and duplicate determinations of plasma immunoreactive insulin (IRI), 1~growth hormone (HGH), 11 glucose, 12 and free fatty acid (FFA) 13 were performed on each sample. The values obtained on the two basal samples ( - 1 5 and 0 rain) were averaged and expressed as mean fasting values at time "zero." The oral glucose tolerance test was identically performed once in each member of the control group (who received no treatment) and the same plasma determinations were carried out. Statistical analysis was performed by means of the Student's t test (thyrotoxic versus control)
*Normal values in our laboratory: s e r u m T 4 = 5.3-14.5 #g/100 ml; T3-binding capacity = 2 5 ~ 35~o; 1311 thyroid uptake at 6 hr = 10~o-35~, and at 24 hr = 20~-50~o.
PROPRANOL EFFECT
1203
and the paired t analysis (thyrotoxic before versus after propranolol). The values in the text and figures represent the mean • SEM.
RESULTS
Based on plasma glucose levels, two types of response to propranolol were observed in the thyrotoxic group: In eight patients (cases 2-6, 8, 9, and 11), the oral glucose tolerance test improved after propranolol treatment; this group will be referred as subgroup A. In the other four patients (cases 1, 7, 10, and 12) the glucose tolerance test deteriorated on propranolol therapy; this group will be named subgroup B. These four patients had had a marked and rapid weight loss prior to the study. 200-
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cant changes in insulin levels. Elevated fasting plasma free fatty acids remained so despite propranolol treatment. Plasma growth hormone was higher than normal before and after propranolol; a late suppression {at 120 min) and no suppression at all were seen, respectively. After propranolol treatment, subgroup B had higher plasma free fatty acid than subgroup A in the fasting state and at 30 and 180 min. It is proposed that the improvement or deterioration in carbohydrate tolerance after propranolol treatment might be related to whether or not a satisfactory propranolol-induced lipolytic blockade is achieved, leading to a decrease in plasma free fatty acid levels, improved insulin sensitivity, and better peripheral glucose utilization. Therefore, a uniform dose of propranolol w i l l not always be sumcient to obtain adequate lipolytic blockade, particularly if the thyrotoxic patient has had a marked and rapid weight loss.
N THE PAST 2 YR, propranolol (a B-blocking agent) has demonstrated its usefulness in the control of the prominent cardiovascular manifestations of thyrotoxicosis.~,2 This benefit seems to be achieved by decreasing the sympathetic hyperactivity or hyperresponsiveness present in this disease 3 and not by affecting plasma catecholamine levels, which have been reported to be low. 4 The sympathetic hyperactivity has also been postulated to be the cause of the decreased pancreatic insulin response to an oral glucose load, and thus is at least partially responsible for the abnormal carbohydrate tolerance observed in thyrotoxic patients. 5 Since propranolol and epinephrine have a synergistic action in blocking pancreatic insulin release, 6,7 theoretically one would expect a deterioration of the carbohydrate tolerance in the thyrotoxic patient treated with propranolol.
I
From the Department o f Endocrinology, Centro Mbdico La Raza and the Seccibn de Hormonas Protbicas, Divisibn de Biologia de la Reproduccibn, Unldad de lnvestigacibn Cientifica, Centro Mbdico Nacional, Instituto Mexicano del Seguro Social, Mbxico City, Mexico. Received for publication October 20, 1975. Supported in part by a grant from the Ford Foundation. Reprint requests should be addressed to A dalberto Parra, M.D., Unidad de Investigacibn Cientifica, Centro Mbdico Nacional, Instituto Mexicano del Seguro Social, Apartado 73-032, Mbxico 73, D.F., Mexico. 9 1976 by Grune & Stratton, Inc.
Metabolism,Vol. 25, No. 11 (November), 1976
1201
1202
ORTIGOSA ET AL. Table 1. Clinical and Laboratory Data Actual
Weight loss before
Ideal
Evolu-
Age
Height
Weight
study
Weight
tion
T3 uptake
Serum T4
Sex
(yr)
(cm)
(kg)
(kg)
(kg)
(mo)
(%)
(#g/100 rnl)
6 hr
24 hr
(m~/day)
1 2
F F
20 20
153 157
61.4 60.5
12 3
51.8 54.0
5 7
47,6 49.4
25,0 34,6
68,4 97.4
74.2 84.6
120 120
3
F
39
155
54.0
6
58.1
6
49.7
25.0
56.4
74,3
120
4
M
43
168
57.0
9
68.1
8
45.0
30.1
74.6
87.7
120
5 6
F F
49 16
158 152
64.5 51.0
2 9
66,2 49.5
3 6
50.1 52.4
24,7 19.8
93.8 60.2
70.7 92.4
120 120
Patient No.
131 I Thyroid Uptake
Propranolol
7
F
42
142
34.0
10
54.0
8
43.2
25.0
85.5
94.3
120
8
F
34
150
60.0
8
59.0
10
54.3
25.0
80.2
75.5
120
9
F
18
172
69.0
5
62.7
5
49.4
17.4
58.9
80.4
120
10
F
34
144
51.0
8
54.8
7
50.2
19.8
42.6
72.3
120
11
F
38
157
62.0
8
59.2
12
47.8
30.1
71,4
81.0
120
12
F
36
162
53,5
10
61.7
10
54.3
28.6
80.2
75,5
120
A c c o r d i n g l y , t h e p r e s e n t s t u d y w a s u n d e r t a k e n in a n a t t e m p t t o s t u d y p l a s m a glucose, free fatty acid, insulin, and growth hormone levels, during an oral g l u c o s e t o l e r a n c e t e s t , in p a t i e n t s w i t h G r a v e s ' d i s e a s e b e f o r e a n d a f t e r p r o pranolol treatment. MATERIALS A N D METHODS
Patients Thyrotoxic group. Twelve subjects with Graves' disease (all but one were female) 16-49 yr of age were included in this group. The diagnosis of thyrotoxicosis was based on clinical manifestations, as well as on the abnormality of the following tests: Serum T4, 8 T3-binding capacity, 9 and 6- and 24-hr 1311 thyroid uptake (Table 1).* The criteria for selecting the patients were: (1) no known family history of diabetes mellitus; (2) absence of any concomitant disease; and (3) absence of extremely severe thyrotoxicosis needing immediate control. Controlgroup. This group consisted of nine clinically healthy, nonobese volunteers, 18-29 yr of age, with no family history of diabetes mellitus and no personal history of drug ingestion during the past 6 too.
Procedures At admission to the study, each patient was instructed to consume a carbohydrate intake of at least 250 g/day during 3 days prior to study. The fourth day, and after a 10 12-hr overnight fast, a 3-hr oral glucose tolerance test (1.75 g/kg body weight, maximum 100 g) was performed. Thereafter, each thyrotoxic patient received propranolol tablets 40 mg t.i.d, for 30 days. During this period all patients engaged in their usual activity and were followed at weekly intervals on an out-patient basis. Pulse rates ranged between 75 and 85/min, and in no instance were below 70. No electrocardiographic abnormalities were observed. The morning after the last dose of propranolol, an oral glucose tolerance test was again performed in all thyrotoxic patients in a fashion identical to the first test. During each test, heparinized blood samples were obtained at -15, 0, 30, 60, 120, and 180 min and duplicate determinations of plasma immunoreactive insulin (IRI), 1~growth hormone (HGH), 11 glucose, 12 and free fatty acid (FFA) 13 were performed on each sample. The values obtained on the two basal samples ( - 1 5 and 0 rain) were averaged and expressed as mean fasting values at time "zero." The oral glucose tolerance test was identically performed once in each member of the control group (who received no treatment) and the same plasma determinations were carried out. Statistical analysis was performed by means of the Student's t test (thyrotoxic versus control)
*Normal values in our laboratory: s e r u m T 4 = 5.3-14.5 #g/100 ml; T3-binding capacity = 2 5 ~ 35~o; 1311 thyroid uptake at 6 hr = 10~o-35~, and at 24 hr = 20~-50~o.
PROPRANOL EFFECT
1203
and the paired t analysis (thyrotoxic before versus after propranolol). The values in the text and figures represent the mean • SEM.
RESULTS
Based on plasma glucose levels, two types of response to propranolol were observed in the thyrotoxic group: In eight patients (cases 2-6, 8, 9, and 11), the oral glucose tolerance test improved after propranolol treatment; this group will be referred as subgroup A. In the other four patients (cases 1, 7, 10, and 12) the glucose tolerance test deteriorated on propranolol therapy; this group will be named subgroup B. These four patients had had a marked and rapid weight loss prior to the study. 200-
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