CATTEDRA DI MEDICIN½% COSTITUZIONALE ED ENDOCRINOLOGIA DELL'UNiVERSITA DEGLI STUDI DI ROMA GLUCAGON, INSULIN AN~ GROWTH HORMONE RESPONSE IN OBESE WOMEN
FRANCESCO FALLUCCA
GUIDO MENZINGER
SERGIO TAMBURRANO
SERGIOGAMBAILDELLA
DOMENICO A~REANI
Obesity is associated with elevated basal plasma insulin levels as well as with an exaggerated insulin secretory response to a variety of insulinogenic stimuli 4.8, ~0 The hyperinsulinemia of obesity has genera!ly been regarded as compensatory adaption to the peripheral insulin resistance of the obese state n To fiarther clarify the factors that contribute to hyperinsulinemia vce have investigated in obese women with and w k h o u t carbohydrate intolerance the relations between the behavior of blood glucose, plasma immunoreactive insulin, growth hormone and glucagon in the fasting state and in response to an arginine infusion.
METHODS Two groups of obese women were investigated. One included 7 subjects wi~h a normal response to OGTT (ON), the other 7 women with an abnormal response to OGTT (OD) (latent diabetes according to the criteria of FAJANS and C o ~ s). The body weight of these obese patients ",*'as between 3096 and 90% in excess of the ideal weight (Metropolitan Life Insurance Company Tables, 1959). Seven he£thy normal women within 10% of the ideal weight served as controls (N). The age of aH sabiects studied ranged from 20 to 43 years. For the arginine test (ATT), 30 g azginine a-~onocHoride dissolved in 400 mi of saline were infused during 30 rain at complete bed rest. Blood was drawn at -30, 0, 20, 30, 45, 60, 90 and t20 mid Each specimen was analyzed for blood glucose, pb~ma hnsuHn, growth hormone and plasma irnmunoreactive glucagon. Blood ~ucose (BG), insulin (IRI), and growth hormone (GH) were de,ermined according to the methods indicated in previous workS. Plasma imm~oreactive glucagon (iRG) was assayed by the method described by A~u!~m-P.~.4m~ etal. ~ employing Unger's 30 K antiserum which seems more specific for pancreatic glucagon (nesidioglucagon), Key-words: A~inine; Blood glucose: Carbohydrate intake; Catechdamines; Enterohormones; FFA; GIucagon; Glucose tolerance; Growth hornzone; Insulin; [nsu!i, z resistance; Obesity. Received: Apri! 3, t975. Acta diabet, lat. 12, 239, 1975. 239
GLUCAGON, INSULIN AND GROWTH HORIX/IONE RESPONSE IN OBESE WOMEN
RESULTS No significant difference in blood glucose values was observed between the 3 groups either in the fasting state or during ATT (fig. 1 and tab. 1). Fasting IRI values showed no significant difference in the 3 groups. After arginine, ON showed IRI values significantly higher than N at 60, 90 and 120 rain and OD showed values significantly increased above N at 20, 45, 90 and 120 rain (fig. 1 and tab. 1). There was no difference between ON and OD. tRG levels (fig. 1 and tab. 1) were slightly lower than normal in both obese groups in the fasting state and significantly lower than normal in ON at 20, 30, 90, 120 rain and in OD at 20 and 30 rain during ATT. The IRG values at 90 rain was significantly lower in ON than in OD. GH levels were significantly lower than normal in both obese groups at 120 rain (fig. 1 and tab. 1); no difference was observed between ON and OD. Peak G H levels were significantly lower than normal in both obese groups; no difference was observed between ON and OD (fig. 1 and tab. 1). DISCUSSION The insulin response to arginine was above normal, as reported by others 4, in both obese groups even though biood glucose values in the course of ATT did not differ from normal. This observation might support the hypothesis that the increased insulin production of obesity is not mediated exclusively or principally by increased btood glucose levels. The reduced GH response to arginine observed in both obese groups is in a good accordance with the data found in the literature 12. As to glucagon, in the obese there are conflicting data. WIsE et aI. :~ report IRG values similar to ours. However, normal IRG levds or hypernormal response to arginine are reported respectively by KALk'VqOFF et al. 7 and by TIENGO et al. ,a These discrepancies cannot be satisfactorily explained at the moment, but may be due at least in part to the different selection of patients. Reduced IRG levels and low A-cell responsiveness to specific stimuli in the obese might not be unexpected in obesity in view of other findings such as hyperglycemia, hyperinsulinemia, increased levels of FFA, reduced catecholamine production. In conclusion, our data appear to exclude any contribution of GH and IRG levds to insulin resistance in obesity. A possible explanation for hyperinsulinemia and hypoglucagonem!a in obesity could be found in the increased carbohydrate intake which is common in obese subjects and is Known to induce hyperinsulinemia e and inhibits glucagon secretion 9. ~n this respect previous data ~ of our group have shown that in obese women there is hyperresponsiveness to some enterohormones, such as pancreozymin and secretin, It may be that excessive carbohydrate consumption modifies the 'enteroinsular axis' in such a way that B-ceUs become hyperreactive, while A-celIs respond poorly to the secretory stimuli. 240
F. FALLUCCA~ G. MENZINGER~ S, GAMBARDELLA) S, TANIBURP~MNO~ D. ANDREANt
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F i g 1 - Blood ~ucose (BG), p!asma insulin (IRI), ~ncagon (tRG) and growth hormone (GH) during an arginine test {ATT) in 7 obese women with no_tin,atglucose tolerance (ON), 7 obese women with latent diabetes (OD) and 7 normal control s~zbjects(N).
241
GLUCAGON, INSULIN AND GROWTH HORMONE RESPONSE IN OBESE WONIEN BG time
(rain) peak
--30
0
30
20
45
60
90
N
79-+4
85-+5 93-+6
91-+6
91 _+8
93-+11
75i6
ON
D±11
77±4
92±9
93+_9
88+_6
79i6
76±5
72±4
OD
78±6
74±4
88±3
90±3
91-+3
87-+3
78±4
75-+3
N-ON
n.s.
n.s.
n.s.
n.$.
11.8.
i"1,8,
n.s.
N-OD
n.s.
n,s.
~.s.
I~.$,
g.8,
n,s.
n,s.
12,8,
n.$.
n,s.
n.s.
ON-OD
74-+7
n.$.
I
IRI
N
13-+2
18-+5
41±7
52±9
49+__8
27±3
15"
13-+2
ON
19-+2
2O4-6
54-+9
61-+8
62±14
4519
28j
23-+4
OD
21±5
29±7
85-+15
86-+2t
84--35
47j
27-+5
n,s.
.tl.S.
i3.,$.
t"1.8.
rt,s.
0.025
0.0
0.025
N-OD
n.$.
0.0125
12.8.
0.05
rl.s.
0.0
0.0125
ON-OD
I1.8.
12,8.
t2.8,
IL$.
tt,
P,.s.
N-ON
IRG
N
183±32 i84-+35 422-+34[ 473-+32
396-+62
333-+55
248-+44
~0i20
ON
12I-+19
95+_25 282±441382+_39
303 ± 42
240±28
169-+!9
~0+18
OD
126-+211 D 9 ± 2 9
393+_17
300±26
277±46
~0_--'51
i"1.8.
tl.s.
O.05
?.005
I
0,05
%7%7
N-ON
n.s.
N-OD
n.8.
ri,8.
0105
0it'05
D.8,
I1.8.
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rl.s.
ON-OD
[i.S.
fLS~
P*.8.
n .s.
n,s.
Ii,s,
0,025
i!,s.
t6.4±5.4
19.014.9
1t.2-+2.1
o+i
22.4--+4.4
7.8-+3.2
,..i_ 0 8.4~3.
5.8-+3.6
5±I
8.8-+2.9
5.7±2.5
8.i+__2.6
5.0-+2.1
Ok2
8.6-+2.5
Gt-i
N
2.2--0.4 3 . 5 ± t , 1 7 . 8 ± Z 6
ON
22±091_.±10 07-+02il.8±0.8 2.6-+1.7
3.7-+1,81
OD N-ON N-OD ON-OD
t
n.s,
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n,s.
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1:1.8.
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1 - Blood gJucose (BG), msu!in (IRI), grow~.h hormone (GH) and g!ucagon (IRG) during argin£ne test (30 g i.v. during 30 mini! in 7 normal women (N), 7 obese women with normal glucose tolerance (ON) and 7 obese women with latent diabetes (OD). Table
242
F. EALLIrCCA~ G. MENZINGER~ S. GAMBARDELLA~ 8, TAMBURRANO~ D. ANDRE.~NI
SUMMARY Plasma concentrations o£ insulin, gcowth hormone and glucagon were measured during an arginine test in obese women wi~.h normal (ON) or abnormal (OD) OGTT and in normal, control subjects (N). Plasma insulin levels were higher than normM in both obese groups, while plasma growth hormone and glucagon levels were markedly reduced. REFERENCES 1) AGVJILAe,-PAe,Ana E., EISENT~_rJr A. M., LINGERR. H.: Pancreatic Giucagon Secretion in Normal and Diabetic Subiects - Amer. 7. reed. Sci. 257, 415, 1969, 2) A~VDRE,~'~rD., FALLT:CCaF., MeNZrXGEr~G., GA_Xn3A~DeLLAS., T,~_>:~ZhRF, ANO S., JAwcoLz M.: Insulin and Gtucagon in Obese Subjects - International Symposium on Insulin Synthesis and Secretion, Venezia 1973; p. 42. 3) ANDREANID., FALLUCCAF., TA_MBURR.a G., WEaIENKa L. C., HAXE S., Fo~sua,,a P. H.: Effect o~ Arginine on Serum Levels of Insulin and Growth Hormone in Obese Subjects - Metabolism ld, 485, 1967. 5) F~.j~.as S. S., Coi~¢ J. W,: Approach to Prediction of Diabetes MeIlims by Modi~cation of Glucose Tolerance Test wi~h Cortisone - Diabetes 3, 296, 1954. 6) G~Y N., Kn,NIS D. hi.: Effect of Diet Composition on the Hyperins~xlinemia of Obesiv/ - New Engl. J. Med. 285, 827, 1971. 7) KAL~:,qO~FR. K, Gosse,Ix V, }¢LA.TUTEM. L.: Plasma GIucagon in Obesity - New EngI. J- Med. 289, 465, 1973. 8) tC~m~M G. H., GRODSK~ G. M, F o ~ s ~ P. H.: Excessive Insulin Response to Glucose in Obese Subjects as Measured by Immunochemical Assay - Diabetes 12, 197, 1963. 9) M~rLLEZ W. A., F~_r_OONaG. R., UNOER R. ~ff.: The Influence o£ the Anteceden~ Diet upon G!ucagon and Insulin Secretion - New End. 7. Med. 285, I450, 1971. 10) PERLEY M., KIPNIS D. M.: Plasma Insulin Response to Oral and Intravenous Glucose: Studies in Normal and Diabetic Subjects - 7. din. Invest. 44, 1954, 1967. I1) R~3~-owx~z D., Z~e~n~ K. L.: Forearm Metabolism in Obesib- and its Response to Intrarteriai Insulin: Characterization of Insulin Resistance and Evidence for Adaptive Hyperinst~Iinism - J. din. Invest. 41, 2173, 1962. 12) Tc~o~P,O~aVs_~Y G., ROSSEnZy G., Ass.ca R., Ft~EX'C~E~ P., DgRO~ M.: Growth Iqormone Secretion in Obese Subiects wi~h and without Diabetes - In: VAaWE 7. (Ed.): Physiopatology of Adipose Tissue. Excerpta Medica Foundation, Amsterdam, 1969; p. 269. 13} TIENC-OA., Ass.
FRANCESCO FALLUCCA
GUIDO MENZINGER
SERGIO TAMBURRANO
SERGIOGAMBAILDELLA
DOMENICO A~REANI
Obesity is associated with elevated basal plasma insulin levels as well as with an exaggerated insulin secretory response to a variety of insulinogenic stimuli 4.8, ~0 The hyperinsulinemia of obesity has genera!ly been regarded as compensatory adaption to the peripheral insulin resistance of the obese state n To fiarther clarify the factors that contribute to hyperinsulinemia vce have investigated in obese women with and w k h o u t carbohydrate intolerance the relations between the behavior of blood glucose, plasma immunoreactive insulin, growth hormone and glucagon in the fasting state and in response to an arginine infusion.
METHODS Two groups of obese women were investigated. One included 7 subjects wi~h a normal response to OGTT (ON), the other 7 women with an abnormal response to OGTT (OD) (latent diabetes according to the criteria of FAJANS and C o ~ s). The body weight of these obese patients ",*'as between 3096 and 90% in excess of the ideal weight (Metropolitan Life Insurance Company Tables, 1959). Seven he£thy normal women within 10% of the ideal weight served as controls (N). The age of aH sabiects studied ranged from 20 to 43 years. For the arginine test (ATT), 30 g azginine a-~onocHoride dissolved in 400 mi of saline were infused during 30 rain at complete bed rest. Blood was drawn at -30, 0, 20, 30, 45, 60, 90 and t20 mid Each specimen was analyzed for blood glucose, pb~ma hnsuHn, growth hormone and plasma irnmunoreactive glucagon. Blood ~ucose (BG), insulin (IRI), and growth hormone (GH) were de,ermined according to the methods indicated in previous workS. Plasma imm~oreactive glucagon (iRG) was assayed by the method described by A~u!~m-P.~.4m~ etal. ~ employing Unger's 30 K antiserum which seems more specific for pancreatic glucagon (nesidioglucagon), Key-words: A~inine; Blood glucose: Carbohydrate intake; Catechdamines; Enterohormones; FFA; GIucagon; Glucose tolerance; Growth hornzone; Insulin; [nsu!i, z resistance; Obesity. Received: Apri! 3, t975. Acta diabet, lat. 12, 239, 1975. 239
GLUCAGON, INSULIN AND GROWTH HORIX/IONE RESPONSE IN OBESE WOMEN
RESULTS No significant difference in blood glucose values was observed between the 3 groups either in the fasting state or during ATT (fig. 1 and tab. 1). Fasting IRI values showed no significant difference in the 3 groups. After arginine, ON showed IRI values significantly higher than N at 60, 90 and 120 rain and OD showed values significantly increased above N at 20, 45, 90 and 120 rain (fig. 1 and tab. 1). There was no difference between ON and OD. tRG levels (fig. 1 and tab. 1) were slightly lower than normal in both obese groups in the fasting state and significantly lower than normal in ON at 20, 30, 90, 120 rain and in OD at 20 and 30 rain during ATT. The IRG values at 90 rain was significantly lower in ON than in OD. GH levels were significantly lower than normal in both obese groups at 120 rain (fig. 1 and tab. 1); no difference was observed between ON and OD. Peak G H levels were significantly lower than normal in both obese groups; no difference was observed between ON and OD (fig. 1 and tab. 1). DISCUSSION The insulin response to arginine was above normal, as reported by others 4, in both obese groups even though biood glucose values in the course of ATT did not differ from normal. This observation might support the hypothesis that the increased insulin production of obesity is not mediated exclusively or principally by increased btood glucose levels. The reduced GH response to arginine observed in both obese groups is in a good accordance with the data found in the literature 12. As to glucagon, in the obese there are conflicting data. WIsE et aI. :~ report IRG values similar to ours. However, normal IRG levds or hypernormal response to arginine are reported respectively by KALk'VqOFF et al. 7 and by TIENGO et al. ,a These discrepancies cannot be satisfactorily explained at the moment, but may be due at least in part to the different selection of patients. Reduced IRG levels and low A-cell responsiveness to specific stimuli in the obese might not be unexpected in obesity in view of other findings such as hyperglycemia, hyperinsulinemia, increased levels of FFA, reduced catecholamine production. In conclusion, our data appear to exclude any contribution of GH and IRG levds to insulin resistance in obesity. A possible explanation for hyperinsulinemia and hypoglucagonem!a in obesity could be found in the increased carbohydrate intake which is common in obese subjects and is Known to induce hyperinsulinemia e and inhibits glucagon secretion 9. ~n this respect previous data ~ of our group have shown that in obese women there is hyperresponsiveness to some enterohormones, such as pancreozymin and secretin, It may be that excessive carbohydrate consumption modifies the 'enteroinsular axis' in such a way that B-ceUs become hyperreactive, while A-celIs respond poorly to the secretory stimuli. 240
F. FALLUCCA~ G. MENZINGER~ S, GAMBARDELLA) S, TANIBURP~MNO~ D. ANDREANt
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F i g 1 - Blood ~ucose (BG), p!asma insulin (IRI), ~ncagon (tRG) and growth hormone (GH) during an arginine test {ATT) in 7 obese women with no_tin,atglucose tolerance (ON), 7 obese women with latent diabetes (OD) and 7 normal control s~zbjects(N).
241
GLUCAGON, INSULIN AND GROWTH HORMONE RESPONSE IN OBESE WONIEN BG time
(rain) peak
--30
0
30
20
45
60
90
N
79-+4
85-+5 93-+6
91-+6
91 _+8
93-+11
75i6
ON
D±11
77±4
92±9
93+_9
88+_6
79i6
76±5
72±4
OD
78±6
74±4
88±3
90±3
91-+3
87-+3
78±4
75-+3
N-ON
n.s.
n.s.
n.s.
n.$.
11.8.
i"1,8,
n.s.
N-OD
n.s.
n,s.
~.s.
I~.$,
g.8,
n,s.
n,s.
12,8,
n.$.
n,s.
n.s.
ON-OD
74-+7
n.$.
I
IRI
N
13-+2
18-+5
41±7
52±9
49+__8
27±3
15"
13-+2
ON
19-+2
2O4-6
54-+9
61-+8
62±14
4519
28j
23-+4
OD
21±5
29±7
85-+15
86-+2t
84--35
47j
27-+5
n,s.
.tl.S.
i3.,$.
t"1.8.
rt,s.
0.025
0.0
0.025
N-OD
n.$.
0.0125
12.8.
0.05
rl.s.
0.0
0.0125
ON-OD
I1.8.
12,8.
t2.8,
IL$.
tt,
P,.s.
N-ON
IRG
N
183±32 i84-+35 422-+34[ 473-+32
396-+62
333-+55
248-+44
~0i20
ON
12I-+19
95+_25 282±441382+_39
303 ± 42
240±28
169-+!9
~0+18
OD
126-+211 D 9 ± 2 9
393+_17
300±26
277±46
~0_--'51
i"1.8.
tl.s.
O.05
?.005
I
0,05
%7%7
N-ON
n.s.
N-OD
n.8.
ri,8.
0105
0it'05
D.8,
I1.8.
ms.
rl.s.
ON-OD
[i.S.
fLS~
P*.8.
n .s.
n,s.
Ii,s,
0,025
i!,s.
t6.4±5.4
19.014.9
1t.2-+2.1
o+i
22.4--+4.4
7.8-+3.2
,..i_ 0 8.4~3.
5.8-+3.6
5±I
8.8-+2.9
5.7±2.5
8.i+__2.6
5.0-+2.1
Ok2
8.6-+2.5
Gt-i
N
2.2--0.4 3 . 5 ± t , 1 7 . 8 ± Z 6
ON
22±091_.±10 07-+02il.8±0.8 2.6-+1.7
3.7-+1,81
OD N-ON N-OD ON-OD
t
n.s,
n .s.
n,s.
[IS.
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1:1.8.
S,
n.s.
fl.s,
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025
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1 - Blood gJucose (BG), msu!in (IRI), grow~.h hormone (GH) and g!ucagon (IRG) during argin£ne test (30 g i.v. during 30 mini! in 7 normal women (N), 7 obese women with normal glucose tolerance (ON) and 7 obese women with latent diabetes (OD). Table
242
F. EALLIrCCA~ G. MENZINGER~ S. GAMBARDELLA~ 8, TAMBURRANO~ D. ANDRE.~NI
SUMMARY Plasma concentrations o£ insulin, gcowth hormone and glucagon were measured during an arginine test in obese women wi~.h normal (ON) or abnormal (OD) OGTT and in normal, control subjects (N). Plasma insulin levels were higher than normM in both obese groups, while plasma growth hormone and glucagon levels were markedly reduced. REFERENCES 1) AGVJILAe,-PAe,Ana E., EISENT~_rJr A. M., LINGERR. H.: Pancreatic Giucagon Secretion in Normal and Diabetic Subiects - Amer. 7. reed. Sci. 257, 415, 1969, 2) A~VDRE,~'~rD., FALLT:CCaF., MeNZrXGEr~G., GA_Xn3A~DeLLAS., T,~_>:~ZhRF, ANO S., JAwcoLz M.: Insulin and Gtucagon in Obese Subjects - International Symposium on Insulin Synthesis and Secretion, Venezia 1973; p. 42. 3) ANDREANID., FALLUCCAF., TA_MBURR.a G., WEaIENKa L. C., HAXE S., Fo~sua,,a P. H.: Effect o~ Arginine on Serum Levels of Insulin and Growth Hormone in Obese Subjects - Metabolism ld, 485, 1967. 5) F~.j~.as S. S., Coi~¢ J. W,: Approach to Prediction of Diabetes MeIlims by Modi~cation of Glucose Tolerance Test wi~h Cortisone - Diabetes 3, 296, 1954. 6) G~Y N., Kn,NIS D. hi.: Effect of Diet Composition on the Hyperins~xlinemia of Obesiv/ - New Engl. J. Med. 285, 827, 1971. 7) KAL~:,qO~FR. K, Gosse,Ix V, }¢LA.TUTEM. L.: Plasma GIucagon in Obesity - New EngI. J- Med. 289, 465, 1973. 8) tC~m~M G. H., GRODSK~ G. M, F o ~ s ~ P. H.: Excessive Insulin Response to Glucose in Obese Subjects as Measured by Immunochemical Assay - Diabetes 12, 197, 1963. 9) M~rLLEZ W. A., F~_r_OONaG. R., UNOER R. ~ff.: The Influence o£ the Anteceden~ Diet upon G!ucagon and Insulin Secretion - New End. 7. Med. 285, I450, 1971. 10) PERLEY M., KIPNIS D. M.: Plasma Insulin Response to Oral and Intravenous Glucose: Studies in Normal and Diabetic Subjects - 7. din. Invest. 44, 1954, 1967. I1) R~3~-owx~z D., Z~e~n~ K. L.: Forearm Metabolism in Obesib- and its Response to Intrarteriai Insulin: Characterization of Insulin Resistance and Evidence for Adaptive Hyperinst~Iinism - J. din. Invest. 41, 2173, 1962. 12) Tc~o~P,O~aVs_~Y G., ROSSEnZy G., Ass.ca R., Ft~EX'C~E~ P., DgRO~ M.: Growth Iqormone Secretion in Obese Subiects wi~h and without Diabetes - In: VAaWE 7. (Ed.): Physiopatology of Adipose Tissue. Excerpta Medica Foundation, Amsterdam, 1969; p. 269. 13} TIENC-OA., Ass.
