Clinical characteristics of severely obese subjects with low IGF-1 SDS
We next examined clinical characteristics of severely obese patients with low- IGF-1 levels. We compared metabolic and clinical parameters between severely obese subjects with and without low IGF-1 levels (IGF-1 SDS ≤ -2.0: the low IGF-1 group). Since all subjects without low IGF-1 levels were in the − 2.0 < IGF-1 SDS < 2.0 range, we refer to this population as the standard IGF-1 group. Contrary to our expectations, there were no statistically significant differences in body weight or BMI between the two groups (Table 1). Interestingly, however, body fat mass (57.6 [50.7, 64.8] vs. 45.8 [42.2, 55,4] kg, P = 0.043) and body fat percentage (53.5 [50.7, 54.5] vs. 46.9 [41.9, 49.9] %, P = 0.0026) were significantly higher in the low IGF-1 group (Table 1) (Data hereafter shown as low IGF-1 vs. standard IGF-1 group with P-value). Thus, despite similar BMI, the low IGF-1 group showed higher adiposity than the standard IGF group.
Table 1
Clinical parameters in low IGF-1 and standard IGF-1 groups.
|
low IGF-1 group (n = 17)
|
standard IGF-1 group (n = 47)
|
P value
|
all subjects (n = 64)
|
Sex (male/female)
|
5/12
|
21/26
|
0.39
|
26/38
|
Age (years)
|
39.0 [30.0, 43.0]
|
40.0 [33.5, 55.0]
|
0.39
|
39.0 [32.8, 52.0]
|
IGF-1 (ng/mL)
|
72.0 [47.0, 91.0]
|
134.0 [118.0, 156.5]
|
< 0.001
|
124.0 [91.0, 143.0]
|
IGF-1 SDS
|
-2.7 [-3.4, -2.4]
|
-0.9 [-1.3, -0.3]
|
< 0.001
|
-1.3 [-2.0, -0.6]
|
GH (ng/mL)
|
0.4 [0.3, 0.5]
|
0.5 [0.1, 0.7]
|
0.42
|
0.14 [0.08, 0.53]
|
Body weight on admission (kg)
|
106.2 [96.1, 126.0]
|
109.1 [97.1, 120.1]
|
0.82
|
108.8 [96.8, 121.7]
|
Body weight at discharge (kg)
|
100.6 [92.1, 115.5]
|
103.1 [91.7, 115.2]
|
0.85
|
101.6 [91.8, 115.3]
|
BMI (kg/m2)
|
41.5 [37.1, 49.7]
|
40.0 [37.1, 45.5]
|
0.27
|
40.2 [37.1, 46.5]
|
Systolic blood pressure (mmHg)
|
136.5 [125.5, 146.5]
|
133.6 [122.0, 146.0]
|
0.60
|
135.7 [124.5, 146.0]
|
Diastolic blood pressure (mmHg)
|
83.2 [74.0、97.0]
|
84.2 [77.0, 90.0]
|
0.80
|
83.9 [77.0, 91.5]
|
Body fat mass (kg)
|
57.6 [50.7, 64.8]
|
45.8 [42.2, 55.4]
|
0.043
|
50.3 [43.4, 58.35]
|
Body fat percentage (%)
|
53.5 [50.7, 54.5]
|
46.9 [41.9, 49.9]
|
0.0026
|
48.0 [43.4, 58.4]
|
Skeletal muscle mass index (kg/m2)
|
10.8 [10.5, 13.1]
|
11.6 [10.7, 12.2]
|
0.78
|
11.6 [10.7, 12.4]
|
AST (U/L)
|
28.0 [19.0, 43.0]
|
23.0 [17.0, 36.5]
|
0.44
|
24.0 [17.5, 39.0]
|
ALT (U/L)
|
32.0 [12.0, 43.0]
|
32.0 [17.5, 44.0]
|
0.99
|
32.0 [16.8, 43.8]
|
Creatinine (mg/dL)
|
0.6 [0.5, 0.7]
|
0.7 [0.5, 0.8]
|
0.20
|
0.65 [0.53, 0.77]
|
eGFR (mL/min/1.73m2)
|
103.0 [90.5, 113.0]
|
92.0 [75.0, 107.0]
|
0.11
|
93.0 [80.3, 107.8]
|
HbA1c (%)
|
6.8 [6.2, 10.1]
|
6.7 [5.9, 9.5]
|
0.44
|
6.7 [6.0, 9.9]
|
Fasting blood glucose (mg/dL)
|
98.0 [96.0, 116.0]
|
105.0 [88.0, 127.0]
|
0.83
|
99.5 [88.0, 125.3]
|
Ιnsulin (µIU/mL)
|
13.8 [8.6, 27.5]
|
13.9 [8.1, 18.5]
|
0.59
|
13.9 [8.5, 20.1 ]
|
CPR (ng/mL)
|
3.1 [2.3, 4.5]
|
3.1 [2.1, 3.8]
|
0.40
|
3.1 [2.1, 4.0]
|
Natural log-transformed HS-CRPa
|
-0.16 [-0.62, -0.01]
|
-0.65 [-0.95, -0.25]
|
0.016
|
-0.54 [-0.87, -0.14]
|
Diabetes b
|
12 (70.6%)
|
34 (72.3%)
|
1.00
|
46 (71.9%)
|
Dyslipidemia b
|
16 (94.1%)
|
30 (63.8%)
|
0.025
|
46 (71.9%)
|
Hyperuricemia b
|
15 (88.2%)
|
19 (40.4%)
|
< 0.001
|
34 (53.1%)
|
Hypertension b
|
14 (82.4%)
|
28 (59.6%)
|
0.26
|
44 (68.8%)
|
a Data was transformed as necessary to maintain assumptions of normality for the purposes of the analyses |
b Values are the number (%). |
Abbreviations: IGF-1, Insulin like growth factor-1; SDS, standard deviation scores; GH, growth hormone; BMI, body mass index; AST, aspartate aminotransferase; ALT, alanine aminotransferase; eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c; CPR, connecting-peptide immunoreactivity; HS-CRP, high-sensitivity C-reactive protein |
Otherwise, as shown in Table 1, the liver enzyme levels (aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels), parameters reflecting kidney function (including creatinine and eGFR) and glucose metabolism (including fasting plasma glucose, insulin levels and serum C-peptide immunoreactivity) did not differ between the two groups. Additionally, there were no differences in the parameters reflecting the hypothalamic–pituitary–adrenal (HPA), the hypothalamic–pituitary–thyroid (HPT), or the renin-angiotensin-aldosterone (RAA) axis (Supplementary Table 1), suggesting low IGF-1 levels to be minimally associated with dysregulation of other endocrinological axes. In addition, uric acids and lipid profiles, such as triglycerides, total cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol levels, did not differ between the two groups (Supplementary Table 1). Similarly, atherosclerosis parameters, such as the ankle brachial index (ABI), cardio ankle vascular index (CAVI) and max intima-media thickness (IMT) were also similar in the two groups (Supplementary table 1). On the other hand, interestingly, natural log-transformed high-sensitivity C-reactive protein (HS-CRP) was significantly elevated in the low IGF-1 group (-0.16 [-0.62, -0.01] vs. -0.65 [-0.95, -0.25] mg/dL, P = 0.016). Thus, low IGF-1 levels are strongly linked to increased inflammation in subjects with severe obesity.
We additionally analyzed the frequencies of commonly occurring obesity-related metabolic comorbidities (e.g. diabetes, dyslipidemia, hyperuricemia and hypertension) as shown in Table 1. We defined these metabolic comorbidities based on each of the relevant guidelines 17–20. We also included patients who had a history and/or diagnosis of these metabolic disorders according to their medical records as having these comorbidities. The frequencies of dyslipidemia (16 (94.1%) vs. 30 (63.8%), P = 0.025) and hyperuricemia (15 (88.2%) vs. 19 (40.4%), P < 0.001) were significantly higher in the low than in the standard IGF-1 group. The frequency of hypertension tended to be high in the low IGF-1 group (14 (82.4%) vs. 28 (59.6%), P = 0.26), while that of diabetes was not increased (12 (70.6%) vs. 34 (72.3%), P = 1.00).
Collectively, these observations indicate that, despite their similar BMI, severely obese subjects with low IGF-1 levels are markedly more predisposed to have multiple metabolic abnormalities, such as increased adiposity, inflammation, dyslipidemia and hyperuricemia than subjects in the standard IGF-1 range.
Increased adiposity, increased inflammation and high metabolic comorbidities were also confirmed in severely obese subjects who had low IGF-1 levels without diabetes
In addition to obesity, hyperglycemia and uncontrolled diabetes are applied as caveats when assessing GH-IGF-1 axis function in adults 1,8,21. Since this study was conducted on inpatients managed at the Department of Diabetes and Metabolism in our hospital, the subjects included a high proportion (71.9%) of patients with diabetes. Therefore, we additionally conducted a similar analysis of the subjects without diabetes. We searched for any history of diabetes in clinical records and relied on the Japanese guideline 20. Subjects already diagnosed as having diabetes on admission were also excluded.
We found that the histogram reflecting the number of subjects without diabetes showed a similar shape with IGF-1 SDS values peaking around − 1.5. In addition, the percentage of low IGF-1 SDS subjects was 27.8% (Fig. 2), similar to that of the entire subjects (26.6%).
In the subjects without diabetes (Table 2), body fat percentage (53.5 [50.8, 53.5] vs. 45.1 [41.2, 48.0] %, P = 0.0083), blood glucose level (97.0 [97.0, 97.0] vs. 85.0 [82.0, 93.0] mg/dL, P = 0.038) and natural log-transformed HS-CRP (-0.11 [-0.17, -0.01] vs. -0.80 [-1.02, -0.30] mg/dL, P = 0.043) were significantly higher in the low IGF-1 than in the standard IGF-1 group. In addition, the frequency of dyslipidemia tended to be higher in the low IGF-1 group (5 (100.0%) vs. 7 (38.9%), P = 0.11). Notably, higher fasting glucose levels were identified as another significant parameter. In contrast, no significant differences were seen in the parameters reflecting the HPA, the HPT, or the RAA axis (Supplementary Table 2). These findings clearly suggest low IGF-1 levels to be associated with increased adiposity, inflammation and high comorbidities involving metabolic diseases in patients with severe obesity, whether they have diabetes or not, independently from other endocrinological axes.
Table 2
Clinical characteristics of severely obesity patients according to the existence of serum IGF-1 levels.
|
low IGF-1 group
(n = 5)
|
standard IGF-1 group (n = 13)
|
P value
|
all subjects (n = 18)
|
Sex (male/female)
|
1/4
|
7/6
|
0.31
|
8/10
|
Age (years)
|
30.0 [30.0, 37.0]
|
35.0 [28.0, 44.0]
|
0.62
|
34 [29.3, 39.0]
|
IGF-1 (ng/mL)
|
95.0 [95.0, 110.0]
|
128.0 [112.0, 146.0]
|
0.030
|
117.5 [97.8, 145.0]
|
IGF-1 SDS
|
-2.8 [-3.4, -2.6]
|
-1.4 [-1.5, -1.0]
|
0.0013
|
-1.5 [-2.1, -1.2]
|
GH (ng/mL)
|
0.5 [0.4, 0.5]
|
0.4 [0.1, 1.2]
|
0.91
|
0.4 [0.3, 0.7]
|
Body weight on admission (kg)
|
105.7 [104.8, 110.6]
|
118.6 [110.0, 128.8]
|
0.35
|
111.2 [115.0, 128.0]
|
Body weight at discharge (kg)
|
100.6 [100.0, 108.6]
|
115.1 [99.8, 132.2]
|
0.59
|
106.3 [79.3, 129.5]
|
BMI (kg/m2)
|
42.1 [39.7, 46.3]
|
41.9 [38.7, 48.7]
|
0.66
|
42.0 [38.9, 48.3]
|
Systolic blood pressure (mmHg)
|
122.8 [107.0, 134.0]
|
134.0 [121.0、143.0]
|
0.26
|
130.9 [12.03, 142.8]
|
Diastolic blood pressure (mmHg)
|
76.0 [71.0, 84.0]
|
80.1 [77.0, 84.0]
|
0.55
|
78.9 [74.0, 84.0]
|
Body fat mass (kg)
|
57.6 [51.0, 59.0]
|
47.0 [43.3, 55.3]
|
0.19
|
51.0 [44.4, 57.6]
|
Body fat percentage (%)
|
53.5 [50.8, 53.5]
|
45.1 [41.2, 48.0]
|
0.0083
|
48.2 [44.2, 52.5]
|
Skeletal muscle mass index (kg/m2)
|
14.9 [12.8, 17.1]
|
12.1 [11.1, 13.3]
|
0.31
|
11.7 [10.8, 13.0]
|
AST (U/L)
|
13.0 [13.0, 19.0]
|
26.0 [16.0, 34.0]
|
0.13
|
21.0 [14.3, 33.8]
|
ALT (U/L)
|
11.0 [10.0, 12.0]
|
23.0 [18.0, 37.0]
|
0.068
|
21.0 [12.0, 36.8]
|
Creatinine (mg/dL)
|
0.6 [0.6, 0.7]
|
0.7 [0.7, 0.9]
|
0.14
|
0.7 [0.6, 0.8]
|
eGFR (mL/min/1.73m2)
|
93.0 [84.0, 103.0]
|
87.0 [77.0, 107.0]
|
0.43
|
89.0 [80.3, 106.0]
|
HbA1c (%)
|
6.1 [5.9, 6.2]
|
5.5 [5.5, 5.9]
|
0.18
|
5.9 [5.5, 6.1]
|
Fasting blood glucose (mg/dL)
|
97.0 [97.0, 97.0]
|
85.0 [82.0, 93.0]
|
0.038
|
90.0 [83.5, 97.0]
|
Ιnsulin (µIU/mL)
|
17.0 [15.4, 28.7]
|
14.1 [9.8, 23.4]
|
0.52
|
16.0 [10.1, 23.9]
|
CPR (ng/mL)
|
3.4 [3.1, 4.5]
|
3.4 [2.8, 3.8]
|
0.52
|
3.4 [2.8, 3.8]
|
Natural log-transformed HS-CRPa
|
-0.11 [-0.17, -0.01]
|
-0.80 [-1.02, -0.30]
|
0.043
|
-0.58 [-0.92, -0.12]
|
Dyslipidemiaa
|
5 (100.0)
|
7 (38.9)
|
0.11
|
12 (66.7)
|
Hyperuricemiaa
|
3 (60.0)
|
6 (33.3)
|
1.00
|
9 (50.0)
|
Hypertensiona
|
3 (60.0)
|
10 (55.6)
|
0.58
|
13 (72.2)
|
a Values are the number (%) |
Abbreviations: IGF-1, Insulin like growth factor-1; SDS, standard deviation scores; GH, growth hormone; BMI, body mass index; AST, aspartate aminotransferase; ALT, alanine aminotransferase; eGFR, estimated-glomerular filtration rate; HbA1c, hemoglobin A1c; CPR, connecting-peptide immunoreactivity; HS-CRP, high-sensitivity C-reactive protein |
The forward-backward stepwise variable selection procedure reveals adiposity to be a strong predictor of low IGF-1 levels
Next, using the entire subjects of this study, we aimed at identifying the factor most strongly associated with low IGF-1 levels among those showing statistically significant relevance (i.e., increased adiposity, dyslipidemia, hyperuricemia and increased inflammation). Four reliable variables associated with the low IGF-1 group (P < 0.05) (body fat percentage, dyslipidemia, hyperuricemia and natural log-transformed HS-CRP) were enrolled and we applied the forward-backward stepwise variable selection procedure. Body fat mass was excluded from this analysis because of strong correlation with body fat percentage. Based on the analysis, solely body fat percentage was solely selected (P = 0.0087), while other factors were eliminated (Table 3). When the analysis including HS-CRP instead of natural log-transformed HS-CRP was also performed, the same result showing that only body fat percentage was selected (P = 0.041) was obtained (Supplementary Table 3). Thus, increased adiposity is a more significant predictor of low IGF-1 levels than increased inflammation and multiple comorbidities. These findings suggest that low IGF-1 levels are primarily associated with increased adiposity, which may consequently exacerbate inflammation and induce multiple metabolic disorders.
Table 3
Results of the forward-backward stepwise selection procedure for the low IGF-1 group a.
|
|
Stepwise Model
|
Possible Factors
|
Unadjusted Odds Ratio [95%CI]
|
Wald-statistics
|
P-value
|
Body fat percentage (%)
|
1.34 [1.10–1.67]
|
6.89
|
0.0087
|
Natural log-transformed HS-CRP
|
1.69 [0.84–3.60]
|
-
|
-
|
Dyslipidemia (Ref; No)
|
9.07 [1.62-170.74]
|
-
|
-
|
Hyperuricemia (Ref; No)
|
11.05 [2.71–75.43]
|
-
|
-
|
a Forward-backward stepwise variable selection procedure was conducted with clinical parameters with P-value < 0.05 as the statistical significance entry criterion. |
Abbreviation: HS-CRP, high-sensitivity C-reactive protein |