Clinical Science (1994) 87, 201-206 (Printed in Great Britain)
20 I
Interactions of body fat and muscle mass with substrate
concentrations and fasting insulin levels in adults with
growth hormone deficiency
F. SALOMON, R. C. CUNEO, A. M. UMPLEBY and P. H. SONKSEN
Department of Endocrinology and Chemical Pathology, United Medical and Dental Schools of
Guy’s and St Thomas’s Hospitals, St Thomas’s Hospital, London, U.K.
(Received 13 October 1993/14 March 1994; accepted 18 March 1994)
1. Adults with growth hormone deficiency have an
abnormal body composition. Alterations in body composition are closely related to substrate concentrations and insulin action. The lack of growth
hormone has been associated with increased insulin
sensitivity.
2. We investigated the correlations of body composition with fasting insulin levels and substrate
concentrations in 24 adults with growth hormone
deficiency over a wide range of adiposity (body mass
index 18.8-42.3 kg/m2).
3. Lean body mass was measured by total body
potassium, computer tomography of the thigh and
urinary creatinine excretion. Muscle fibre distribution
was evaluated from vastus lateralis biopsies. Fat
mass was assessed by skinfold thickness measurements, computer tomography of the thigh, and waist
and hip girth.
4. Fasting plasma insulin level increased with fat
mass (r=0.67, P=0.0004) and with waist girth
( r = 0.76, P = 0.0001). Fasting plasma insulin level
increased with fasting plasma glucose level ( r = 0.53,
P = 0.01). Fasting plasma glucose level in turn was
positively correlated with lean body mass ( r = 0.49,
P=O.Ol) and with total thigh muscle area (r=0.54,
P = 0.01). There was no correlation between lean
body mass and fat mass (r=0.17, not significant) nor
between muscle fibre types and fat mass or fat
distribution. Fasting plasma insulin level showed no
correlation with any measurement of lean body mass
or muscle fibre type.
5. These data demonstrate that the presence of obesity is associated with hyperinsulinaemia as the result
of insulin resistance in adults with growth hormone
deficiency, which could contribute to the increased
cardiovascular mortality in adults with growth hormone deficiency.
mass [l-51 with preferential accumulation of turncal fat, especially in women [3, 6). In normal
subjects, central adiposity is associated with increased cardiovascular mortality [7, 81. In patients
with panhypopituitarism on conventional replacement treatment without GH, premature
atherosclerosis and premature mortality due to
cardiovascular disease has been observed [6, 91.
Insulin resistance as a major endocrine feature of
obesity, especially of central obesity [lo], has been
implicated in the pathogenesis of atherosclerosis
[ I l l , but the mechanisms leading to impaired insulin action associated with obesity are unknown. Fat
mass and skeletal muscle are two target organs
of insulin action. Fasting insulin levels are closely
related to overall adiposity as measured by body
mass index (BMI) above the threshold BMI of
27kg/m2 [12], and within the fat compartment
visceral fat mass has the closest association with
fasting insulin levels [ 131. Differences in skeletal
muscle fibre type distribution have also been associated with insulin resistance [I4171 and obesity
[18]. Lean body mass [19], muscle fibre area [14,
15, 171 and the relative amount of type I1 muscle
fibres [14, 171 have been shown to positively correlate with adiposity and with fasting plasma insulin
levels. In simple obesity lean body mass is correlated with fat mass [19, 20, 213 and it is therefore
difficult to separate the effects of these two targets
of insulin action on the development of insulin
resistance.
To gain more insight into the relationship
between body composition, muscle fibre types and
fasting insulin level, we analysed morphological and
metabolic variables from 24 adults with GHD, in
whom there was no relationship between fat mass
and lean body mass.
METHODS
INTRODUCTION
Patients
Adults with growth hormone (GH)deficiency (GHD)
have decreased lean body mass and increased fat
GHD (see Table 1). These patients were later ran-
We investigated 24 adults with longstanding
Key words: body composition, body fat, cardiovascular risk, growth hormone deficiency, insulin, muscle mass, obesity.
Abbreviations: BMI, body mass index; G H , growth hormone; GHD. growth hormone deficiency.
Correspondence: Dr Franco Salomon. Medirinirche Klinik, Departement fur lnnere Medirin, Universitatsspital Zurich, Ramistrasse 100, 8091 Zurich, Switzerland.
202
F. Salornon et al.
domized and took part in a clinical trial of recombinant human G H replacement treatment,
which has been reported previously [ l , 22, 231.
G H D was documented for at least 1 year and was
defined as a peak G H response below 3m-units/l on
an insulin-tolerance test which produced a plasma
glucose nadir equal to or below 2.0mmol/l. All
patients were on appropriate and stable replacement
treatment for at least 12 months before the study.
Nineteen patients had adrenal replacement treatment, the maximal daily dose being either 37.5 mg
of cortisone acetate, 30mg of cortisol, 7mg of
prednisone (or prednisolone) or 0.5 mg of dexamethasone. Twenty-one patients were on thyroid replacement treatment with a maximal dose of 200pg
and the dose was adjusted to normalize plasma
levels of free tri-iodothyronine. Eighteen patients had
gonadal hormone replacement, five patients were on
desmopressin and three patients were taking
fluodrocortisone.
Fasting blood samples were taken after an overnight fast. Hormone replacement was continued in
patients with GHD, cortisone acetate (12.5 mg) was
taken 2 h before blood sampling. Total body potassium was measured in a total body 40K counter
(CRC, Northwick Park Hospital, Harrow, Middx.
U.K.). Skeletal muscle mass of the thigh was measured by computed tomography as described previously [23]. Urinary creatinine excretion was measured in a 24 h urine collection on an unrestricted
diet. Muscle biopsies were taken from the left vastus
lateralis in the afternoon of the next day. Fibre type
areas were quantified as described previously [22].
Relative fibre type area was calculated by multiplying mean fibre type area by the proportion of that
fibre type [22]. Skinfold thickness was expressed as
the sum of five different sites (biceps, triceps, subscapular, abdomen and thigh) taken on the patients
dominant side. Waist circumference was measured
in the upright position at the level of umbilicus, and
the hip girth at the level of the greater trochanter.
Plasma glucose was measured by the glucose
oxidase method. Insulin, C-peptide, free fatty acids,
acetoacetate, 3-hydroxybutyrate, pyruvate and lactate were measured as described previously [24].
Calculations
Lean body mass was calculated assuming
60mmol of K+/kg of lean body mass in female
subjects and 66mmol of K+/kg of lean body mass
in male subjects [25]. The validity of this assumption has been confirmed by tight and superimposable correlation between total body potassium
measurement and total thigh muscle area in adults
with G H D and in normal control subjects, excluding a change in the mean intracellular potassium concentration in G H D [23]. Total body potassium measurements were compared with normal
values based on sex, age, height and weight [26].
Table I.Characteristics of adults with CHD (n=24). Abbreviation:
CT, computed tomography.
Mean fSD Range
Age (years)
Duration of GHD (years)
W t (kg)
Height (cm)
BMI (kglm’)
Lean body mass from total body potassium (kg)
Urinary creatinine excretion (mmol/day)
Total thigh muscle area on CT scan (cm’)
Fat mass from total body potassium (kg)
Percentage body fat from total body potassium
Sum of skinfold thickness (mm)
Total thigh fat area on CT scan (cm’)
Waist girth (cm)
Waist-to-hip ratio
Type I fibre area (pm’)
Type I1 fibre area (pm’)
Percentage type II fibre
Fasting plasma glucose level (mmol/l)
Plasma free fatty acid level (pmol/l)
Plasma ketone body level (pmol/l)
Plasma glycerol (pmol/l)
Plasma lactate (pmol/l)
Fasting plasma insulin level (m-units)
Plasma C-peptide level (pmol/l)
Plasma insulin-like growth factor-I level (m-units)
38f10
8f6
81.7f 18.6
169.7k 10.1
28.3 k 5.7
SO. I 12.6
12.6 f5.0
l32k40
31.5+ 11.8
38.3 f9.0
114.3 f34.3
88f61
94.9f 13.7
21-51
1-25
47.9-124
153-188
18.0-42.3
19.9-71.4
4.7-22. I
57-218
15.7-61.8
23.8-56.4
43.9-178.9
34-273
65.5-118
0.89kO.080.72-1.05
5152f 1219
4020 f I394
53f II
4.8f0.4
423 f I73
199+ 108
&If35
724f340
17.8f22.1
595f360
373f242
30204751
3 127-791 I
33-72
4.1-5.5
I5C-740
35-494
36172
339-1734
3-108
15C-1860
50-960
Lean body mass was calculated from creatinine
excretion using the following formula [27]
Lean body mass (kg)= urinary creatinine
(mmol/day) x 3.3068 7.38
+
Fat mass was calculated as body weight minus lean
body mass. The patients were divided into normal
weight (BMI < 27 kg/m2, n = 12) and overweight
(BMI > 27 kg/m2, n = 12) groups [ 121.
Statistical analysis
The Number Cruncher Statistical System (Dr J.
L. Hintze, Kaysville, UT, U.S.A.) was used for
analysing the data. Student’s t-test was applied for
comparing groups. Correlation analysis was performed with use of Pearson’s correlation coefficient.
Fasting plasma insulin levels and ketone body concentrations were not normally distributed and were
logarithmically transformed before correlation
analysis. For these two variables the MannWhitney test was used to compare normal weight
and overweight patients. P values < 0.05 were considered to indicate statistical significance.
RESULTS
The clinical data of the 24 patients are summarized in Table 1. Adults with G H D were overweight
with reduced lean body mass, as reported previously
[l]. The waist-to-hip ratio was above 0.80 [I71 in
Insulin and body composition in growth hormone deficiency
203
Table 2. Correlation of body composition measurements with plasma insulin, C-peptide and insuliwlike growth factor-I
in adults with GHD. Abbreviation: CT. computed tomography.
Insulin level
Height
C-peptide level
0.19
0.16
Body wt
0.64
P = o.ooo9
0.66
P = o.ooo8
BMI
0.62
P=0.001
P=O.001
0.67
P = o.ooo4
P = O.ooO3
0.76
P=O.OoOl
P = 0.002
0.48
P = 0.03
0.65
P = 0.004
Fat mass
Waist girth
Total thigh fat area on CT scan
0.64
0.70
0.66
0.40
Percentage body fat
0.39
,
Insulin-like growth factor-I level
0.38
0.38
0.20
0.09
0.25
- 0.08
-0.24
, ,-
b b.b!
P = b.07
Sum of skinfold thickness
0.33
0.47
P = 0.0s
0.02
Waist-twhip ratio
0.37
0.18
0.36
Lean body mass from total body potassium
0.31
0.30
0.48
P = 0.04
Total thigh muscle area on CT scan
0.23
0.10
0.42
P = 0.09
Urinary creatinine excretion
0.22
0.1s
0.50
P = 0.03
Type I fibre area
0.37
0.22
0.21
=
Type II fibre area
0.33
0.25
0.40
Percentage type II fibre
0.28
0.32
0.16
six out of eight female patients and higher than 0.9
[28] in seven of the 12 male patients. Muscle fibre
areas were normal [22]. Fasting plasma glucose,
free fatty acids, glycerol, ketone body, lactate and
pyruvate concentrations were in the normal range.
Fasting plasma insulin and C-peptide levels were
increased, and the plasma insulin-like growth factor1 concentration was low [I].
Body composition, muscle fibre types and substrates
Height was positively correlated with lean body
mass (r = 0.79, P = O.OOOOl), which in turn correlated
with type I and type I1 muscle fibre area from
vastus lateralis (r=0.42, P=0.06; r=0.55, P=O.Ol,
respectively). Lean body mass was positively correlated with fasting plasma glucose level (r=0.49,
P = O . O l ) and inversely with plasma ketone body
concentration (r = - 0.60, P = 0.005).
There was no correlation between lean body mass
and fat mass derived from total body potassium
(r=0.17, not significant) or between any of the other
measurements of lean body mass and fat cornpartment.
Insulin, C-peptide and insulin-like growth factor-I
(Table 2)
Fasting plasma glucose was positively correlated
with fasting plasma insulin (r =0.53, P=O.Ol) and
C-peptide (r =0.48, P =0.02) levels, but not with
total plasma insulin-like growth factor-1 level
(r =0.20, not significant).
Fasting plasma insulin level increased with body
weight, BMI and fat mass, but the thightest
correlation was observed with waist circumference
(r=0.76, P=O.OOOl) (Fig. 1). There was a weak or
no association of fasting insulin level with the waistto-hip ratio, percentage body fat and the sum of
skinfold measurements (Table 2). The correlation of
plasma C-peptide level with measurements of adiposity were similar (Table 2). There was no correlation of total plasma insulin-like growth factor-I
level with any measurement of adiposity (Table 2),
but lean body mass was positively correlated with
plasma insulin-like growth factor-I level (r =0.48,
P=O.O4). There was no correlation of plasma insulin or C-peptide levels with insulin-like growth
factor- 1 level.
Normal weight versus overweight GHD patients (Tables
3 and 4)
Total body potassium, expressed as percentage of
expected values, was lower in normal weight than in
overweight patients. In normal weight GHD
patients the measured total body potassium was
significantly lower than the expected value
F. Salomon et al.
204
.c
-
3
._
I
60
80
100
I20
Waist circumference (crn)
Fig. I . Correlation of waist circumference with fasting plasma insuand overweight (A) adults with
lin level in normal weight (0)
CHD. r=0.76, P=O.OOOl.
( P =0.0002), but failed to reach statistical significance in the overweight group ( P =0.08). The differences between normal weight and overweight GHD
patients in total muscle area of the thigh were of the
same order of magnitude as seen in total body
potassium. Lean body mass, calculated from urinary
creatinine excretion, was in the same range as
derived from total body potassium in normal weight
adults with GHD, but lower in the overweight
patients. There was no difference in the sum of
skinfolds, percentage body fat and waist-to-hip ratio
between normal weight and overweight GHD
patients (Table 3). Despite the larger fat mass in
overweight patients fasting plasma glycerol, free
fatty acids and ketone body concentrations were
similar in normal weight and overweight GHD
(Table 4). Fasting plasma insulin level was higher in
the overweight GHD patients (Table 4).
DISCUSSlON
The changes in body composition are crucial to
the understanding of the metabolic effects brought
about by longstanding GHD. We have previously
shown that adults with GHD have a decreased lean
body mass for age, sex, height and weight [l]. In
the present study the changes in body composition
assessed by the five independent methods were
concordant in showing that adults with GHD and
BMI below 27 kg/m2 were more affected by the lack
of GH, with lower lean body mass and higher
relative fat mass. The reason for this difference is
not clear. A methodological error seems unlikely
given the consistent results from the different
approaches used to measure lean body mass and fat
mass. In patients with a BMI above 27kg/m2 the
lack of the anabolic effect of GH may have been
compensated in part by the higher fasting insulin
levels.
Fasting plasma insulin levels increased with fasting plasma glucose concentration [14, 191 and with
adiposity [12, 14, 15, 17, 19, 203 as in normal
subjects with obesity-associated insulin resistance.
Hyperinsulinaemia in adults with GHD was the
result of incieased insulin secretion, as documented
by the parallel increase in plasma C-peptide levels.
Increasing fasting insulin and C-peptide levels with
fat mass in the presence of normal fasting plasma
glucose concentration are a hallmark of obesityassociated insulin resistance. Elevated fasting plasma
insulin levels are well correlated with more sophisticated measurements of insulin resistance [29, 301
and may be an even better indicator of insulin
resistance in obese subjects due to the hyperbolic
correlation between fasting insulin levels and insulin
sensitivity [31]. In adults with GHD, fasting insulin
levels were not associated with body fat distribution
or relative adiposity, but with absolute fat mass,
especially with waist girth, a measure of visceral fat
mass [13]. With a BMI below 27kg/m2 the
increased relative amount of fat and the accumulation of visceral fat was not sufficient in adults with
GHD to induce obesity-associated insulin resistance.
An absolute increase in fat mass in relation to lean
body mass with a BMI above 27 kg/m2 was necessary to be associated with elevated plasma insulin
concentrations, as observed in normal subjects [ 123.
The occurrence of insulin resistance in adults with
GHD is at odds with the frequently mentioned
increased insulin sensitivity in the absence of GH in
the textbooks [32]. Formal investigations of sensitivity to exogenous insulin in GHD performed by the
insulin-tolerance test have shown the initial fall and
nadir of glucose during an insulin-tolerance test in
GHD patients to be normal 1133, 341, indicating
normal insulin sensitivity [35]. Recovery from hypoglycaemia, however, was delayed, representing
impaired hypoglycaemic responsiveness [33, 341,
which is determined by insulin antagonistic hormones and substrate availability [36]. The present
data demonstrated that, in adults with GHD,
obesity-associated insulin resistance can occur. The
presence of hyperinsulinaemia could be a factor
contributing to the premature atherosclerosis and
premature mortality due to cardiovascular disease
in adults with GHD [6, 91.
Probably due to the divergence of lean body mass
and fat mass we have been unable to find a
correlation of fasting insulin levels with muscle fibre
type area or body mass in adults with GHD. In
normal subjects lean body mass and fat mass are
closely related [19, 211 and fasting insulin levels
correlate with lean body mass and fat mass. When,
however, this usual correlation between lean body
mass and fat mass was uncoupled in normal subjects, the relationship between lean body mass and
Insulin and body composition in g r o w t h hormone deficiency
205
Table 3. Characteristics of normal weight (BMI <27kg/m*) and overweight (BMI >27kg/m’) adults with GHD. Abbreviations: CT. computed tomography; NS, not significant. Values are means fSD.
Sex (M/f)
Age (years)
Duration of GHD (years)
Wt. (kg)
Height (cm)
Normal weight
(n= 12)
Overweight
(n= 12)
9: 3
39f II
9f6
67.3 f 11.6
167.8+ 10.2
7.5
37f 10
8f7
96.0 I I .7
171.Sf 10.1
8141 (lillml)
14.1-C1.9
39.1 41.j
Total body potassium (percentage of expected value)
Lean body mass from total body potassium (kg)
Urinary creatinine (mmol/day)
Lean body mass from urinary creatinine (kg)
Total thigh muscle area on CT scan (cm’)
Type I fibre area (pm’)
Type II fibre area (pm’)
Percentage type I1 fibre
Sum of skinfold thickness (mm)
Total thigh fat area on CT scan (cm’)
Percentage body fat from total body potassium
Expected percentage body fat from total body potassium
Percentage body fat from urinary creatinine
Fat mass from total body potassium (kg)
Fat mass from urinary creatinine (kg)
Waist girth (cm)
Waist-twhip ratio
88.3 +_ 5.7
43. I k 8.6
I l.4rf: 3.9
45.2 f 12.7
111f24
4937 f I277
4736 k I398
50f 10
110.2 f37.2
66 f28
36f6
28+7
35f 10
23.8 5.4
23.2 f6. I
86.2 f 12.0
0.89 f0. I I
95.2 +_ 8.2
57.2 f 12.2
13.7f5.9
52.7 f 19.5
153244
5366 f I I89
4919f 1460
55f 12
118.9f31.9
110+77
4of II
39+9
45f I9
38.3 f 12.0
32.3 f 18.8
103.4f8.6
0.90 f0.06
P
NS
NS
NS
0.03
0.004
NS
NS
0.017
NS
NS
NS
NS
0. I
NS
0.002
NS
0.002
0.004
0.002
NS
Table 4. Substrate concentrations in normal weight (BMI <27kg/m*) and overweight (BMI >27 kg/m*) adults with
GHD. Abbreviation: NS. not significant. Values are means +SD.
fasting plasma glucose level (mmol/l)
Plasma free fatty acid level (pmol/l)
Plasma ketone body level (pmol/l)
Plasma glycerol level (pmol/l)
Plasma lactate level (pmolll)
Plasma pyruvate level (pmol/l)
Fasting plasma insulin level (m-units)
Plasma C-peptide level (pmol/l)
Plasma insulin-like growth factor-I level (m-units)
fasting insulin levels was also no longer present
[37]. Despite the lack of correlation between lean
body mass and fat mass in adults with GHD the
other correlations present in normal subjects
between fasting plasma glucose and insulin levels
[14, 191, fasting plasma glucose level and lean body
mass [19] or muscle fibre area [14, 161, and fasting
plasma insulin level and fat mass [12, 19, 201 could
all be found in adults with GHD. Therefore the
association of fasting plasma insulin levels with lean
body mass 1191 and with muscle fibre area and fibre
types [14, 15, 171 observed in normal subjects may
merely be a reflection of the close association of fat
mass with lean body mass [14, 17, 213.
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NS
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