pii: jc- 00308-15http://dx.doi.org/10.5664/jcsm.5672
S CI E NT IF IC IN VES TIGATIONS
IGF-1 Levels are Inversely Associated With Metabolic Syndrome in Obstructive Sleep Apnea Suelem Izumi, MD¹; Fernando F. Ribeiro-Filho, MD, PhD2; Gláucia Carneiro, MD, PhD¹; Sônia M. Togeiro, MD, PhD³; Sérgio Tufik, MD, PhD³; Maria T. Zanella, MD, PhD¹ ¹Department of Endocrinology, Universidade Federal de São Paulo, SP, Brazil; ²Department of Endocrinology, Universidade Federal do Pará, PA, Brazil; ³Department of Psycobiology, Sleep Disorders Center, Universidade Federal de São Paulo, SP, Brazil
Study Objectives: This study examined insulin-like growth factor-1 (IGF-1) production and its association with the metabolic syndrome (MS) in men with obstructive sleep apnea (OSA). Methods: In total, 47 overweight and obese men who had been referred for suspected OSA underwent polysomnography and were classified based on the apnea-hypopnea index (AHI) into three groups: no OSA, < 5 events/h (n = 11); mild OSA, ≥ 5 to < 15 events/h (n = 8); and moderate-severe OSA, ≥ 15 events/h (n = 28). The assessment of the somatotropic axis function included IGF-1 measurement. MS was diagnosed according to the National Cholesterol Education Program guidelines. Results: IGF-1 level in the moderate-severe OSA group was lower than in the no-OSA group (156.8 ± 54.3 µg/L versus 225.5 ± 80.5 µg/L; p = 0.013). IGF-1 level was negatively correlated with body mass index, waist circumference (WC), AHI, and sleep duration with oxygen (O2) saturation < 90% and positively correlated with the average and minimum O2 saturation (p = 0.027). In a multivariable linear regression, considering WC and minimum O2 saturation as independent variables, only the minimum O2 saturation was a predictor of low IGF-1 levels. The proportions of patients with MS were different between the three groups (18.2% in no OSA; 25% in mild OSA, and 57.1% in moderate-severe OSA; p = 0.047). Furthermore, in the lowest tertile of IGF-1 value, 66.7% of patients were affected by MS (p = 0.049). Hemoglobin (Hb)A1c correlated negatively with the minimum O2 saturation and IGF-1 levels. However, in multivariable linear regression only IGF-1 levels were a predictor of HbA1c levels. Conclusion: The occurrence of OSA is associated with a reduction in IGF-1 levels. IGF-1 alterations in OSA also seem to be associated with a higher prevalence of MS. Keywords: GH/IGF-1 axis, IGF-1, insulin-like growth factor-1, metabolic syndrome, obstructive sleep apnea Citation: Izumi S, Ribeiro-Filho FF, Carneiro G, Togeiro SM, Tufik S, Zanella MT. IGF-1 levels are inversely associated with metabolic syndrome in obstructive sleep apnea. J Clin Sleep Med 2016;12(4):487–493.
I N T RO D U C T I O N
BRIEF SUMMARY
Current Knowledge/Study Rationale: OSA has been associated with reduced secretion of growth hormone (GH) and IGF-1. Moreover, a growing body of evidence suggests that OSA may contribute to the development of metabolic syndrome. This study examined IGF-1 production and its association with the MS in men with OSA. Study Impact: The association between OSA and MS has been demonstrated in several studies, and therefore it is important to understand the influence of the GH/IGF-1 system on metabolic changes among patients with OSA. This study aims to understand the independent association of reduced IGF-1 production with increased incidence of MS in patients with OSA.
Obstructive sleep apnea (OSA) has been associated with reduced secretion of growth hormone (GH) and insulinlike growth factor-1 (IGF-1).1 However, the GH/IGF-1 axis is disrupted in OSA by mechanisms that are not yet fully understood.2,3 Obesity has been associated with increasing OSA severity, and weight gain represents the most important risk factor for OSA.4,5 It is also recognized that obesity results in reduced GH secretion and subnormal IGF-I levels.6,7 The exact mechanisms responsible for the association between obesity and dysregulation of GH/IGF-1 levels have yet to be clarified.8,9 Neuroendocrine changes in growth hormone-releasing hormone (GHRH), somatostatin and ghrelin pathways have been associated with low plasma GH levels in obesity. Hyperinsulinemia, probably by stimulating greater hypothalamic somatostatin release, can also contribute to reduced GH secretion and may affect IGF-1 levels, which are associated with insulin resistance.10 Factors derived from excess ectopic fat, including proinflammatory mediators and free fatty acids, can affect IGF-1 secretion and bioactivity independently or in concert.11 Finally, some authors
have suggested that OSA may mediate the negative association between obesity and the GH/IGF-1 axis.12 Metabolic syndrome (MS), which is a commonly used term for the clustering of obesity, insulin resistance, hypertension, and dyslipidemia, affects millions of people worldwide and is associated with an increased risk of type 2 diabetes. A growing body of evidence suggests that OSA may contribute to the development of MS and diabetes. Despite substantial evidence from studies to suggest an independent link between 487
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total cholesterol, triglycerides, high-density lipoprotein (HDL), very-low-density lipoprotein (VLDL), and liver function tests. A standard 75-g oral glucose tolerance test (OGTT) was performed by measuring fasting and 2-h plasma glucose levels. IGF-1 levels were measured at the first visit. Single blood samples were drawn between 08:00 and 09:00 following the sleep period. Serum samples were stored at –70°C until assessment.
OSA and metabolic abnormalities, the issue still remains controversial.13–17 One hypothesis to explain the metabolic changes found in patients with OSA is somatotropic axis dysfunction. Growth hormone deficiency (GHD) may predispose adults to the development of type 2 diabetes mellitus because it is characterized by a tendency toward obesity with visceral adiposity.18 The structural homology of IGF-1 with insulin also appears to play a key role in glucose homeostasis in these patients.19 Reduction in IGF-1 level leads to reduced peripheral glucose uptake and increased hepatic glucose production, thus inducing insulin resistance.20–22 Some investigators have evaluated the relationship between OSA and MS; however, the mechanisms have yet to be clarified.13–17 Moreover, studies suggest that OSA may contribute to reduced secretion of GH and IGF-1,12,23,24 which could be the mechanism involved in the association between OSA and MS. The aim of the current study was to examine IGF-1 production and its association with the MS in men with OSA.
Polysomnographic Parameters
PSG was performed using a digital system (EMBLA S7000, Embla Systems, Inc, Broomfield, CO, USA). The following physiological variables were monitored simultaneously and continuously: four channels for the electroencephalogram (EEG); two channels for the electrooculogram; four channels for the surface electromyogram (submental region, anterior tibialis muscle, masseter region, and seventh intercostal space); one channel for an electrocardiogram; airflow detection via two channels through a thermocoupler (one channel); nasal pressure (one channel); respiratory effort of the thorax (one channel) and of the abdomen (one channel) using inductance plethysmography; snoring (one channel) and body position (one channel); oxy-hemoglobin (Hb) saturation (SpO2); and pulse rate. All of the sleep studies were scored in a blinded fashion. Trained technicians recorded the polysomnographic data according to standardized criteria for sleep investigation.27 EEG arousals were scored according to the criteria established by The American Academy of Sleep Medicine Manual for Scoring Sleep and Associated Events.28 Analysis of SpO2 was performed to obtain a profile of average and minimum oxygen saturation as well as the percentage of total sleep time, during which SpO2 was < 90%. Apneas were considered when there was a decrease in the amplitude of airflow ≥ 90% from baseline lasting ≥ 10 sec. An obstructive apnea was classified by continued/increased inspiratory effort during the event and a central apnea was characterized by absent inspiratory effort during the event. Only patients with obstructive apnea were selected. Hypopneas were recorded when there was a 30% reduction in the amplitude of airflow lasting ≥ 10 sec followed by a ≥ 3% decrease in arterial oxygen saturation or an EEG arousal.28 The number of apnea and hypopnea episodes per hour of sleep (AHI) was calculated.
METHODS
Population
Between January 2013 and November 2014, 47 men age 18– 60 y with a body mass index (BMI) of 25 to 45 kg/m 2 were referred for polysomnography (PSG) for suspected OSA and selected for the study. Patients were classified according to their apnea-hypopnea index (AHI) into three groups: No OSA (AHI < 5 events/h), (n = 11); mild OSA (AHI between 5–14.9 events/h), (n = 8); or moderate to severe OSA (AHI ≥ 15 events/h), (n = 28). Exclusion criteria included a history of smoking, sleep apnea treatment, cardiovascular and pulmonary diseases, malignant tumors, untreated thyroid disease, severe depression, diabetes mellitus, metformin therapy, chronic kidney disease, liver failure, and changes in antihypertensive class drugs in the past 3 mo. Because there are differences in OSA severity between men and women, only men were considered for evaluation.25 This study was approved by the Ethics Committee of the Universidade Federal de São Paulo, and written informed consent was obtained from all of the participants.
Laboratory Analyses
Clinical, Anthropometric, and Biochemical Parameters
Plasma glucose, total cholesterol, triglyceride, HDL-cholesterol, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels were measured using an ADVIA 2400 Chemistry System (Siemens, Tarrytown, NY, USA). Glucose was analyzed by hexokinase. The detection limit was 0 mg/dL, and the average within-assay coefficient of variation was 0.7%. Total cholesterol, HDL-cholesterol, and triglycerides were analyzed by enzymatic colorimetric methods. The detection limits were: cholesterol 10 mg/dL, HDL-cholesterol 20 mg/dL, triglycerides 0 mg/dL, and the average within-assay coefficients of variation were: cholesterol 0.6%, HDL-cholesterol 0.4%, triglycerides 0.6%. Low-density lipoprotein (LDL) levels were calculated using the Friedewald formula.29 AST and ALT were analyzed according to the International Federation of Clinical Chemistry (IFCC) method (detection limits: AST 0 UI/L, ALT
A questionnaire was used to document patient personal and medical history as well as drug therapy. A physical examination was performed, and anthropometric measurements including weight (in kilograms), height (in meters) and waist circumference (in centimeters) were recorded. Waist circumference was measured at the midpoint between the last rib and the iliac crest at the end of a normal expiration.26 BMI was calculated by dividing weight by height squared. Waking blood pressure was measured between 08:00 and 11:00 in the supine position after a 5-min rest period and was recorded as the mean of three measurements taken at 1-min intervals. Blood specimens were obtained after a 12-h overnight fast from all of the subjects for the measurement of plasma glucose, Journal of Clinical Sleep Medicine, Vol. 12, No. 4, 2016
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Table 1—Clinical, anthropometrical, and biochemical characteristics of all subjects. Characteristics Age, y BMI, kg/m² WC, cm SBP, mmHg DBP, mmHg Metabolic and Hormonal Profile Fasting glucose, mg/dL 2-h glucose during OGTT, mg/dL HbA1c, % AST, IU/L ALT, IU/L Total cholesterol, mg/dL LDL-cholesterol, mg/dL HDL-cholesterol, mg/dL Triglycerides, mg/dL IGF-1, µg/L
No OSA (n = 11) 42.3 ± 8.3 31.9 ± 2.9 105.4 ± 8.5 124.5 ± 14.4 83.6 ± 8.1 No OSA (n = 11) 96.1 ± 8.1 113.4 ± 28.1 5.5 ± 0.3 24.7 ± 5.1 34.7 ± 17.8 201.7 ± 33.9 128.4 ± 68.7 47.7 ± 8.1 126.8 ± 68.7 225.5 ± 80.5
Mild OSA (n = 8) 46.7 ± 6.7 34.6 ± 6.2 113.4 ± 11.7 131.2 ± 17.3 85.0 ± 7.5 Mild OSA (n = 8) 94.4 ± 9.4 112.4 ± 33.5 5.9 ± 0.3 26.2 ± 5.7 33.2 ± 14.2 187.7 ± 29.9 110.2 ± 23.9 56.0 ± 52.6 108.4 ± 52.6 177.2 ± 41.4
Moderate-Severe OSA (n = 28) 48.0 ± 7.3 33.0 ± 3.2 110.1 ± 8.8 124.6 ± 10.7 83.9 ± 6.3 Moderate-Severe OSA (n = 28) 99.2 ± 13.0 122.6 ± 43.9 5.9 ± 0.4* 27.3 ± 6.5 38.6 ± 15.2 195.6 ± 32.9 124.7 ± 26.0 43.9 ± 7.5 151.1 ± 81.2 156.8 ± 54.3*
p value 0.107 0.324 0.168 0.419 0.906 p value 0.516 0.711 0.033 0.500 0.619 0.657 0.262 0.060 0.315 0.013
Values are presented as mean ± standard deviation. Analysis of variance was used. *p < 0.05 moderate-severe OSA versus no OSA. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; DBP, diastolic blood pressure; HDL, high-density lipoprotein; Hb, hemoglobin; IGF-1, insulin-like growth factor-1; LDL, low-density lipoprotein; OGTT, oral glucose tolerance test; OSA, obstructive sleep apnea; SBP, systolic blood pressure; ; WC, waist circumference.
0 UI/L, and average within-assay coefficient of variation: AST 2.3%, ALT 2%). HbA1c levels were measured by high performance liquid chromatography (HPLC) (2.2 Tosoh Plus A1C, Tosoh Corporation, Tokyo, Japan). Serum IGF-1 levels were measured using a chemiluminescent enzyme immunoassay system (DiaSorin, Saluggia, Italy) and a commercially available kit (LIAISON IGF-I, Saluggia, Italy). Assay sensitivity was 3 µg/L. The interassay and intraassay coefficients of variation were 5.6–9.6% and 3.0–5.1%, respectively. Samples were assayed in a single large batch, and quality assessment samples were well within the manufacturers’ defined ranges. All of the biochemical assays were performed in the Sleep Institute Laboratory.
or the Spearman test. Multivariate linear regression analysis was used to identify associations between polysomnographic, anthropometric, and metabolic parameters with IGF-1 and HbA1c levels. IGF-1 levels were divided into tertiles, and the prevalence of MS in the lowest tertile (tertile 1) was compared with the prevalence in the highest tertile (tertile 3). Continuous variables were compared between tertile 1 and tertile 3 using unpaired Student t-test or the Mann-Whitney U test. A value of p < 0.05 was considered to be statistically significant. Data analysis was performed using Statistical Package for Social Sciences for Windows version 20.0 (SPSS Inc, Chicago, IL). R ES U LT S
Metabolic Syndrome
MS was diagnosed according to the National Cholesterol Education Program (NCEP) guidelines.30 Patients had MS if they had three or more of the following risk factors: waist circumference > 102 cm, triglycerides ≥ 150 mg/dL, HDL cholesterol < 40 mg/dL, blood pressure ≥ 130/85 mmHg or current use of antihypertensive drugs, and fasting plasma glucose level ≥ 100 mg/dL.
The general, laboratory, and polysomnographic characteristics of all subjects are summarized in Table 1. There were no significant differences in age, BMI, waist circumference (WC), and blood pressure between the three groups. However, the moderate-severe OSA group had marginally lower HDLcholesterol levels than the mild OSA group. As expected, significant differences in the following polysomnographic parameters were observed: AHI, arousal index per hour of sleep, duration of stages 1 and 3 sleep, average and minimum oxygen saturation, and sleep period with SpO2 < 90% (Table 2). IGF-1 levels in the moderate-severe OSA group (156.8 ± 54.3 µg/L) were significantly lower than in the no-OSA group (225.5 ± 80.5 µg/L; p = 0.013). IGF-1 values were significantly negatively correlated with BMI (r = −0.340; p = 0.019), WC (r = −0.291; p = 0.047), AHI (r = −0.312; p = 0.033) and with the sleep period with SpO2 < 90% (r = −0.308; p = 0.035) whereas a positive and significant correlation was observed with
Statistical Analysis
The data are expressed as the mean (standard deviation) or the median (interquartile range). Clinical, anthropometrical, biochemical, and polysomnographic characteristics were compared between no OSA, mild OSA, and moderate-severe OSA groups using analysis of variance or the Kruskal-Wallis test. To assess the differences between categorical variables, we used chi-square statistics. Correlations between variables of interest were determined using the linear correlation test 489
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Table 2—Polysomnographic characteristics of all subjects. Characteristics Polysomnographic parameters Total sleep time, h Sleep efficiency, % AHI, events/h # Arousal index, events/h # Stage 1 sleep duration, % Stage 2 sleep duration, % Stage 3 sleep duration, % REM sleep, % Average oxygen saturation, % Minimum oxygen saturation, % # Sleep period with SpO2 < 90%, % #
No OSA (n = 11)
Mild OSA (n = 8)
6.1 ± 1.6 80.4 ± 9.7 1.6 (0.8–3.5) 10.0 (6.5–16.4) 11.5 ± 7.5 47.2 ± 10.2 26.1 ± 8.7 15.1 ± 4.5 94.8 ± 2.2 90 (87–93) 0.1 (0.0–1.3)
7.2 ± 1.3 85.7 ± 8.6 7.7 (5.6–13.1) 9.5 (6.7–15.2) 8.9 ± 4.9 45.5 ± 11.4 23.7 ± 8.1 21.9 ± 8.8 94.3 ± 1.4 83.0 (78.2–85.5) 1.5 (0.5–3.2)
Moderate-Severe OSA (n = 28) 6.6 ± 1.4 82.7 ± 9.8 50.7 (17.5–51.3) 83.0 (78.2–85.5) 20.3 ± 13.5* 43.4 ± 8.4 17.3 ± 9.0* 19.0 ± 6.4 92.7 ± 2.2* 76.5 (69.2–81.7) 6.3 (3.0–20.0)
p value 0.454 0.130 < 0.001 < 0.001 0.019 0.501 0.014 0.083 0.015 < 0.001 < 0.001
Values are presented as mean ± standard deviation or median (interquartile range). Analysis of variance was used, except the Kruskal-Wallis test was used for non-normally distributed variables (indicated by # ). *p < 0.05 moderate-severe OSA versus no OSA. AHI, apnea-hypopnea index; OSA, obstructive sleep apnea; REM, rapid eye movement; SpO2, oxy-hemoglobin saturation.
Table 3—Linear regression analysis of insulin-like growth factor-1 level predictors. Waist circumference, cm Minimum oxygen saturation, %
β -0.211 0.301
Table 4—Linear regression analysis of hemoglobin A1c predictors.
p value 0.144 0.035
Insulin-like growth factor-1, µg/L Waist circumference, cm Minimum oxygen saturation, %
Adjusted for age.
p value 0.023 0.147 0.622
tertile of IGF-1 values are summarized in Tables 5 and 6. The subgroup with the lowest tertile of IGF-1 values had higher BMI, WC, HbA1c, AHI, and sleep period with SpO2 < 90%, whereas HDL-cholesterol and average and minimum oxygen saturation were lower than in the subgroup with the highest IGF-1 levels.
average (r = 0.329; p = 0.024) and minimum oxygen saturation (r = 0.323; p = 0.027) (Figure 1A). There was no significant correlation between IGF-1 levels and stage 3 sleep duration (p = 0.254). The association of central obesity and OSA with IGF-1 levels was assessed. In a subsequent multivariable linear regression (Table 3) in which WC and minimum oxygen saturation were the independent variables, and IGF-1 level was the dependent variable, only the minimum oxygen saturation was associated with lower IGF-1 levels. HbA1c levels in the moderate-severe OSA group (5.9 ± 0.4%) were significantly higher than in the no OSA group (5.5 ± 0.3%; p = 0.033) (Table 1). Moreover, HbA1c levels negatively correlated with the minimum oxygen saturation (r = −0.306; p = 0.025) and IGF-1 levels (r = −0.408, p = 0.004) (Figure 1B). However, in a subsequent multivariable linear regression in which IGF-1, WC, and minimum oxygen saturation were the independent variables, and HbA1c was the dependent variable; only IGF-1 levels was associated with HbA1c levels (Table 4). The proportions of patients with MS were different between the three patients groups (18.2% in no OSA; 25% in mild OSA and 57.1% in moderate-severe OSA; p = 0.047). Furthermore, in the whole group, there was an association between IGF-1 levels and MS. In the lowest tertile of IGF-1 values (IGF-1 ≤ 148.0 µg/L), 66.7% of patients were affected by MS compared with 31.2% in the subgroup of IGF-1 levels ≥ 203.0 µg/L (p = 0.049) (Table 5). The general, laboratory, and polysomnographic characteristics of the subgroups with the lowest tertile and the highest Journal of Clinical Sleep Medicine, Vol. 12, No. 4, 2016
β -0.351 -0.218 -0.498
D I SCUS S I O N This study demonstrated that hypoxemia induced by OSA is associated with reduced IGF-1 levels and reduced IGF-1 is in turn associated with higher HbA1c values regardless of the severity of obesity. GH secretion is strongly related to sleep and is mainly released during slow wave sleep.31 Thus, individuals with sleep apnea, who demonstrate polysomnographic reduction of slow wave sleep, may also display alterations in GH secretion. However, studies on the somatotropic axis in patients with OSA has revealed mixed results, possibly reflecting different methodologies used or patients with different degrees of OSA.12,23,24 Our study demonstrated that somatotropic dysfunction in the moderate-severe OSA group was characterized by low IGF-1 levels compared to the no- OSA group. Reduced plasma IGF-1 levels in OSA has also been demonstrated in previous studies.24,32 Intermittent hypoxemia seen in OSA has been associated with decreased IGF-1 levels.33 Previous animal studies already demonstrated that chronic hypoxemia may decrease IGF-1 levels.2 Consistent with this finding, in experiments with 490
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Figure 1—Insulin-like growth factor levels.
AB
Correlation between insulin-like growth factor-1 levels and (A) minimum oxygen saturation, (B) hemoglobin (Hb)A1c levels.
Table 5—Clinical, anthropometrical, and biochemical characteristics of all subjects according to insulin-like growth factor-1 tertile. Characteristics Metabolic syndrome, % Age, y BMI, kg/m² WC, cm SBP, mmHg DBP, mmHg Metabolic and Hormonal Profile Fasting glucose, mg/dL 2-h glucose during OGTT, mg/dL HbA1c, % AST, IU/L ALT, IU/L Total cholesterol, mg/dL LDL-cholesterol, mg/dL HDL-cholesterol, mg/dL Triglycerides, mg/dL
IGF-1 Tertile 1 (n = 15) IGF-1 ≤ 148.0 µg/L 66.7 46.4 ± 7.3 35.4 ± 4.3 115.1 ± 9.7 126.6 ± 11,7 84.0 ± 6.3 IGF-1 Tertile 1 (n = 15) IGF-1 ≤ 148.0 µg/L 102.4 ± 15.7 133.8 ± 47.5 5.9 ± 0.5 26.0 ± 6.7 36.9 ± 15.3 198.0 ± 25.8 124.4 ± 19.5 42.7 ± 5.7 153.9 ± 72.4
IGF-1 Tertile 3 (n = 16) IGF-1 ≥ 203.0 µg/L 31.2 45.7 ± 8.4 31.0 ± 2.6 106.2 ± 8.8 126.2 ± 15.8 84.4 ± 8.1 IGF-1 Tertile 3 (n = 16) IGF-1 ≥ 203.0 µg/L 95.0 ± 6.6 105.1 ± 29.1 5.5 ± 0.2 27.0 ± 6.6 38.6 ± 18.8 168.8 ± 33.4 123.3 ± 26.7 50.2 ± 9.8 144.5 ± 88.6
p value 0.049 0.084 0.002 0.012 0.935 0.888 p value 0.111 0.055 0.006 0.660 0.786 0.913 0.896 0.016 0.750
Values are presented as mean ± standard deviation. The p values were obtained by the chi-square test or Student t-test. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; DBP, diastolic blood pressure; HDL, high-density lipoprotein; Hb, hemoglobin; IGF-1, insulin-like growth factor-1; LDL, low-density lipoprotein; OGTT, oral glucose tolerance test; ; SBP, systolic blood pressure; WC, waist circumference.
rats, hyperoxia increased IGF-1 and GH receptor expression.34 Additionally, Ursavas et al.12 demonstrated that the low- circulating IGF-1 levels in patients with OSA were correlated with several PSG parameters, such as AHI, arousal index, average desaturation, and oxygen desaturation index. However, Grunstein et al.33 highlighted the role of hypoxemia, which was a more important contributor than sleep fragmentation in the pathogenesis of this hormonal change. Our findings are in line with the prior studies that have suggested an important role for hypoxemia for reduction in IGF-1 level in patients with OSA. Although several studies have reported a significant association between obesity and the reduced GH and IGF-1 levels, the exact mechanisms remain unclear.8–11 Importantly, many
prior studies exploring the relationship between obesity and somatotropic dysfunction did not account for the presence and severity of OSA. A few investigators have indeed shown an important association between OSA severity and IGF-1 levels independent of obesity.12,24 In fact, in our study, although low serum IGF-1 level was also associated with various measures of adiposity (i.e., BMI and WC), the association seemed to be more dependent on OSA-induced hypoxemia. As in our study, the association between OSA and metabolic syndrome has been demonstrated in several studies and seems to be responsible for many of the features of this syndrome. Men with OSA have a higher prevalence of both insulin resistance and MS than men with a similar BMI but without OSA.13–17 491
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Table 6—Polysomnographic characteristics of all subjects according to insulin-like growth factor-1 tertile. Characteristics Polysomnographic parameters AHI, events/h # Arousal index, events/h # Stage 1 sleep duration, % Stage 2 sleep duration, % Stage 3 sleep duration, % REM sleep, % Average oxygen saturation, % Minimum oxygen saturation, % # Sleep period with SpO2 < 90%, % #
IGF-1 tertile 1 (n = 15) IGF-1 ≤ 148.0 ng/L
IGF-1 tertile 3 (n = 16) IGF-1 ≥ 203.0 ng/L
p value
33.6 (18.5–66.9) 19.9 (14.6–51.3) 18.5 ± 15.2 45.6 ± 9.1 19.3 ± 10.7 16.6 ± 6.8 92.4 ± 2.1 80.0 (70.0–85.0) 6.2 (3.8–23.2)
6.2 (1.9–41.0) 17.2 (10.9–41.0) 12.4 ± 7.5 47.1 ± 9.8 23.1 ± 8.5 17.4 ± 4.9 94.5 ± 1.6 85.5 (76.7–89.5) 1.2 (0.3–3.2)
0.041 0.379 0.163 0.669 0.277 0.724 0.003 0.045 0.006
Values are presented as mean ± standard deviation or median (interquartile range). The p values were obtained by Student t-test, except the Mann-Whitney U test was used for nonnormally distributed variables (indicated by # ). AHI, apnea-hypopnea index; IGF-1, insulin-like growth factor-1; REM, rapid eye movement; SpO2, oxy-hemoglobin saturation.
Somatotropic dysfunction may partially explain the higher prevalence of MS in these patients with OSA. Verhelst et al.35 demonstrated that MS is highly prevalent in hypopituitary patients with adult-onset GH deficiency. Consistently, MS in patients with GH deficiency is partially reversed by GH replacement therapy.36 GH-deficient patients have increased central adiposity, reduced lean body mass, and impaired insulin sensitivity. In our study, 66.7% of the individuals in the lowest tertile of IGF-1 levels (< 148.0 µg/L) were also affected by MS compared with 31.2% of those in the highest tertile of IGF-1 levels. Studies suggest that IGF-1 decreases insulin secretion and increases glucose disposal, and thus plays an important role in glucose metabolism.37 Insulin and IGF-1 have significant homology and interact with differing affinity on the same receptors. Thus, insulin resistance, which is a component of MS, may partially result from low IGF-1 levels. This explains why the higher HbA1c values in the moderate-severe OSA group correlated with IGF-1 levels in our study. Some investigators also reported that low circulating IGF-1 levels are independently associated with hyperglycemia in adults.38–40 Reduced levels of GH and/or IGF-1 in patients with OSA may be an important mechanism responsible for the higher prevalence and incidence of type 2 diabetes seen in patients with OSA. Our study has some limitations including a small sample size and the fact that the study results cannot be generalized to women. The small sample size limits our ability to adjust for some important confounders in our statistical models. Last, the cross-sectional nature of the study does not address the direction of causality. Indeed, only rigorously designed intervention studies will provide causal evidence and insights into mechanisms by which OSA may lead to somatotropic dysfunction. Despite the aforementioned limitations, our results indicate that the of OSA severity, particularly hypoxemia, is associated with reduced in IGF-1 levels. Furthermore, alterations in IGF-1 levels in OSA seem to be associated with higher prevalence of MS. Strengths of our study include measurement of fasting and postprandial glucose levels as well as objective assessment of sleep and OSA by using in-laboratory PSG. Undoubtedly, further studies are needed to clarify the mechanisms that are Journal of Clinical Sleep Medicine, Vol. 12, No. 4, 2016
involved in the GH/IGF-1 axis alteration in patients with OSA as well as to evaluate the effect of positive airway pressure on neuroendocrine dysregulation. A B B R E V I AT I O N S AHI, apnea-hypopnea index ALT, alanine aminotransferase AST, aspartate aminotransferase BMI, body mass index EEG, electroencephalogram GH, growth hormone GHD, growth hormone deficiency GHRH, growth hormone-releasing hormone Hb, hemoglobin HDL, high-density lipoprotein HPLC, high performance liquid chromatography IFCC, international federation of clinical chemistry IGF-1, insulin-like growth factor-1 LDL, low-density lipoprotein MS, metabolic syndrome NCEP, national cholesterol education program OGTT, oral glucose tolerance test OSA, obstructive sleep apnea O2 , oxygen PSG, polysomnography SpO2, oxy-hemoglobin saturation VLDL, very-low-density lipoprotein WC, waist circumference R E FE R E N CES 1. Lanfranco F, Motta G, Minetto MA, Ghigo E, Maccario M. Growth hormone/ insulin-like growth factor-I axis in obstructive sleep apnea syndrome: an update. J Endocrinol Invest 2010;33:192–6. 2. Bernstein D, Jasper JR, Rosenfeld RG, Hintz RL. Decreased serum insulin like growth factor-I associated with growth failure in newborn lambs with experimental cyanotic heart disease. J Clin Invest 1992;89:1128–32.
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S Izumi, FF Ribeiro-Filho, G Carneiro et al. IGF-1 and Obstructive Sleep Apnea 3. Gronfier C, Luthringer R, Follenius M, et al. A quantitative evaluation of the relationships between growth hormone secretion and delta wave electroencephalographic activity during normal sleep and after enrichment delta waves. Sleep 1996;19:817–24. 4. Newman AB, Foster G, Givelber R, et al. Progression and regression of sleepdisordered breathing with changes in weight: the Sleep Heart Health Study. Arch Intern Med 2005;165:2408–13. 5. Young T, Peppard PE, Taheri S. Excess weight and sleep disordered breathing. J Appl Physiol 2005;99:1592–9. 6. Lanfranco F, Motta G, Minetto MA, et al. Neuroendocrine alterations in obese patients with sleep apnea syndrome. Int J Endocrinol 2010;2010:474518. 7. Rasmussen MH. Obesity, growth hormone and weight loss. Mol Cell Endocrinol 2010;316:147–53. 8. Maccario M, Ramunni J, Oleandri SE, et al. Relationship between IGF-I and age, gender, body mass, fat distribution, metabolic and hormonal variables in obese patients. Int J Obesity 1999;23:612–8. 9. Minuto F, Barreca A, Del Monte P, et al. Spontaneous growth hormone and somatomedin-C/insulin like growth factor-I secretion in obese subjects during puberty. J Endocrinol Invest 1988;11:489–95. 10. Savastano S, Di Somma C, Barrea L, Colao A. The complex relationship between obesity and the somatotropic axis: the long and winding road. Growth Horm IGF Res 2014;24:221–6. 11. Tarantino G, Savastano S, Colao A. Hepatic steatosis, low-grade chronic inflammation and hormone/growth factor/adipokine imbalance. World J Gastroenterol 2010;16:4773–83. 12. Ursavas A, Karadag M, Ilcol YO, et al. Low level of IGF-1 in obesity may be related to obstructive sleep apnea syndrome. Lung 2007;185:309–14. 13. Coughlin SR, Mawdsley L, Mugarza JA, Calverley PM, Wilding JP. Obstructive sleep apnoea is independently associated with an increased prevalence of metabolic syndrome. Eur Heart J 2004;25:735–41. 14. Gruber A, Horwood F, Sithole J, Ali NJ, Idris I. Obstructive sleep apnoea is independently associated with the metabolic syndrome but not insulin resistance state. Cardiovasc Diabetol 2006;5:22. 15. Lam JC, Lam B, Lam CL, et al. Obstructive sleep apnea and the metabolic syndrome in community based Chinese adults in Hong Kong. Respir Med 2006;100:980–7. 16. Sasanabe R, Banno K, Otake K, et al. Metabolic syndrome in Japanese patients with obstructive sleep apnea syndrome. Hypertens Res 2006;29:315–22. 17. Parish JM, Adam T, Facchiano L. Relationship of metabolic syndrome and obstructive sleep apnea. J Clin Sleep Med 2007;3:467–72. 18. Abs R, Mattsson AF, Thunander M, et al. Prevalence of diabetes mellitus in 6050 hypopituitary patients with adult-onset GH deficiency before GH replacement: a KIMS analysis. Eur J Endocrinol 2013;168:297–305. 19. Friedrich N, Thuesen B, Jørgensen T, et al. The association between IGF-1 and insulin resistance. Diabetes Care 2012;35:768–73. 20. Boulware SD, Tamborlane WV, Rennert NJ, Gesundheit N, Sherwin RS. Comparison of the metabolic effects of recombinant human insulin-like growth factor-I and insulin. Dose-response relationships in healthy young and middleaged adults. J Clin Invest 1994;93:1131–9. 21. Sesti G, Sciacqua A, Cardellini M, et al. Plasma concentration of IGF-1 is independently associated with insulin sensitivity in subjects with different degrees of glucose tolerance. Diabetes Care 2005;28:132–7. 22. Sandhu MS, Heald AH, Gibson JM, Cruickshank JK, Dunger DB, Wareham NJ. Circulating concentrations of insulin like growth factor-I and development of glucose intolerance: a prospective observational. Lancet 2002;359:1740–5. 23. Gianotti L, Pivetti S, Lanfranco F, et al. Concomitant impairment of growth hormone secretion and peripheral sensitivity in obese patients with obstructive sleep apnea syndrome. J Clin Endocrinol Metab 2002;87:5052–7. 24. Makino S, Fujiwara M, Handa H, et al. Plasma dehydroepiandrosterone sulfate and insulin-like growth factor I levels in obstructive sleep apnoea syndrome. Clin Endocrinol 2012;76:593–601. 25. Heinzer R, Vat S, Marques-Vidal P, et al. Prevalence of sleep-disordered breathing in the general population: the HypnoLaus study. Lancet Respir Med 2015;3:310–8. 26. World Health Organization. WHO STEPwise approach to surveillance (STEPS): guide to physical measurements. 2008. Accessed 22 May 2015. Available at http://www.who.int/chp/steps/Part3_Section3.pdf.
27. Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Los Angeles: UCLA Brain Information Service/Brain Research Institute, 1968. 28. Berry RB, Budhiraja R, Gottlieb D J, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2012;8:597–619. 29. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499–502. 30. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome. A Joint Interim Statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120:1640–5. 31. Van Cauter E, Latta F, Nedeltcheva A, et al. Reciprocal interactions between the GH axis and sleep. Growth Horm IGF Res 2004;14 Suppl A:S10–7. 32. McArdle N, Hillman D, Beilin L, Watts G. Metabolic risk factors for vascular disease in obstructive sleep apnea. Am J Respir Crit Care Med 2007;175:190–5. 33. Grunstein RR, Handelsman DJ, Lawrence SJ, Blackwell C, Caterson ID, Sullivan CE. Neuroendocrine dysfunction in sleep apnea: reversal by continuous positive airways pressure therapy. J Clin Endocrinol Metab 1989;68:352–8. 34. Han RN, Han VKM, Buch S, Freeman BA, Post M, Tanswell AK. Insulin-like growth factor binding proteins in air and 85% oxygen-exposed adult rat lung. Am J Physiol 1998;274:L647–56. 35. Verhelst J, Mattsson AF, Luger A, et al. Prevalence and characteristics of the metabolic syndrome in 2479 hypopituitary patients with adult-onset GH deficiency before GH replacement: a KIMS analysis. Eur J Endocrinol 2011;165:881–9. 36. Akanji AO, Smith RJ. The insulin-like growth factor system, metabolic syndrome, and cardiovascular disease risk. Metab Syndr Relat Disord 2012;10:3–13. 37. Ren J, Anversa P. The insulin-like growth factor I system: physiological and pathophysiological implication in cardiovascular diseases associated with metabolic syndrome. Biochem Pharmacol 2015;93:409–17. 38. Berryman DE, Glad CA, List EO, Johannsson G. The GH/IGF-1 axis in obesity: pathophysiology and therapeutic considerations. Nat Rev Endocrinol 2013;9:346–56. 39. Scott RA, Lagou V, Welch RP, et al. Large scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nat Genet 2012;44:991–1005. 40. Teppala S, Shankar A. Association between serum IGF-1 and diabetes among U.S. adults. Diabetes Care 2010;33:2257–9.
ACK N O W L E D G M E N T S This study was supported by the Conselho Nacional de Pesquisa (CNPq) and the AFIP (Associação Fundo de Incentivo à Pesquisa).
SUBM I SSI O N & CO R R ESPO NDENCE I NFO R M ATI O N Submitted for publication July, 2015 Submitted in final revised form November, 2015 Accepted for publication November, 2015 Address correspondence to: Suelem Izumi, MD, Department of Endocrinology, Universidade Federal de São Paulo, Rua Leandro Dupret 365, 04025-011, São Paulo/SP, Brazil; Tel: 55 11 59040423; Fax: 55 11 59040401; Email: suelem.i.l@ hotmail.com
D I SCLO S U R E S TAT E M E N T This was not an industry supported study. The authors have indicated no financial conflicts of interest.
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S CI E NT IF IC IN VES TIGATIONS
IGF-1 Levels are Inversely Associated With Metabolic Syndrome in Obstructive Sleep Apnea Suelem Izumi, MD¹; Fernando F. Ribeiro-Filho, MD, PhD2; Gláucia Carneiro, MD, PhD¹; Sônia M. Togeiro, MD, PhD³; Sérgio Tufik, MD, PhD³; Maria T. Zanella, MD, PhD¹ ¹Department of Endocrinology, Universidade Federal de São Paulo, SP, Brazil; ²Department of Endocrinology, Universidade Federal do Pará, PA, Brazil; ³Department of Psycobiology, Sleep Disorders Center, Universidade Federal de São Paulo, SP, Brazil
Study Objectives: This study examined insulin-like growth factor-1 (IGF-1) production and its association with the metabolic syndrome (MS) in men with obstructive sleep apnea (OSA). Methods: In total, 47 overweight and obese men who had been referred for suspected OSA underwent polysomnography and were classified based on the apnea-hypopnea index (AHI) into three groups: no OSA, < 5 events/h (n = 11); mild OSA, ≥ 5 to < 15 events/h (n = 8); and moderate-severe OSA, ≥ 15 events/h (n = 28). The assessment of the somatotropic axis function included IGF-1 measurement. MS was diagnosed according to the National Cholesterol Education Program guidelines. Results: IGF-1 level in the moderate-severe OSA group was lower than in the no-OSA group (156.8 ± 54.3 µg/L versus 225.5 ± 80.5 µg/L; p = 0.013). IGF-1 level was negatively correlated with body mass index, waist circumference (WC), AHI, and sleep duration with oxygen (O2) saturation < 90% and positively correlated with the average and minimum O2 saturation (p = 0.027). In a multivariable linear regression, considering WC and minimum O2 saturation as independent variables, only the minimum O2 saturation was a predictor of low IGF-1 levels. The proportions of patients with MS were different between the three groups (18.2% in no OSA; 25% in mild OSA, and 57.1% in moderate-severe OSA; p = 0.047). Furthermore, in the lowest tertile of IGF-1 value, 66.7% of patients were affected by MS (p = 0.049). Hemoglobin (Hb)A1c correlated negatively with the minimum O2 saturation and IGF-1 levels. However, in multivariable linear regression only IGF-1 levels were a predictor of HbA1c levels. Conclusion: The occurrence of OSA is associated with a reduction in IGF-1 levels. IGF-1 alterations in OSA also seem to be associated with a higher prevalence of MS. Keywords: GH/IGF-1 axis, IGF-1, insulin-like growth factor-1, metabolic syndrome, obstructive sleep apnea Citation: Izumi S, Ribeiro-Filho FF, Carneiro G, Togeiro SM, Tufik S, Zanella MT. IGF-1 levels are inversely associated with metabolic syndrome in obstructive sleep apnea. J Clin Sleep Med 2016;12(4):487–493.
I N T RO D U C T I O N
BRIEF SUMMARY
Current Knowledge/Study Rationale: OSA has been associated with reduced secretion of growth hormone (GH) and IGF-1. Moreover, a growing body of evidence suggests that OSA may contribute to the development of metabolic syndrome. This study examined IGF-1 production and its association with the MS in men with OSA. Study Impact: The association between OSA and MS has been demonstrated in several studies, and therefore it is important to understand the influence of the GH/IGF-1 system on metabolic changes among patients with OSA. This study aims to understand the independent association of reduced IGF-1 production with increased incidence of MS in patients with OSA.
Obstructive sleep apnea (OSA) has been associated with reduced secretion of growth hormone (GH) and insulinlike growth factor-1 (IGF-1).1 However, the GH/IGF-1 axis is disrupted in OSA by mechanisms that are not yet fully understood.2,3 Obesity has been associated with increasing OSA severity, and weight gain represents the most important risk factor for OSA.4,5 It is also recognized that obesity results in reduced GH secretion and subnormal IGF-I levels.6,7 The exact mechanisms responsible for the association between obesity and dysregulation of GH/IGF-1 levels have yet to be clarified.8,9 Neuroendocrine changes in growth hormone-releasing hormone (GHRH), somatostatin and ghrelin pathways have been associated with low plasma GH levels in obesity. Hyperinsulinemia, probably by stimulating greater hypothalamic somatostatin release, can also contribute to reduced GH secretion and may affect IGF-1 levels, which are associated with insulin resistance.10 Factors derived from excess ectopic fat, including proinflammatory mediators and free fatty acids, can affect IGF-1 secretion and bioactivity independently or in concert.11 Finally, some authors
have suggested that OSA may mediate the negative association between obesity and the GH/IGF-1 axis.12 Metabolic syndrome (MS), which is a commonly used term for the clustering of obesity, insulin resistance, hypertension, and dyslipidemia, affects millions of people worldwide and is associated with an increased risk of type 2 diabetes. A growing body of evidence suggests that OSA may contribute to the development of MS and diabetes. Despite substantial evidence from studies to suggest an independent link between 487
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total cholesterol, triglycerides, high-density lipoprotein (HDL), very-low-density lipoprotein (VLDL), and liver function tests. A standard 75-g oral glucose tolerance test (OGTT) was performed by measuring fasting and 2-h plasma glucose levels. IGF-1 levels were measured at the first visit. Single blood samples were drawn between 08:00 and 09:00 following the sleep period. Serum samples were stored at –70°C until assessment.
OSA and metabolic abnormalities, the issue still remains controversial.13–17 One hypothesis to explain the metabolic changes found in patients with OSA is somatotropic axis dysfunction. Growth hormone deficiency (GHD) may predispose adults to the development of type 2 diabetes mellitus because it is characterized by a tendency toward obesity with visceral adiposity.18 The structural homology of IGF-1 with insulin also appears to play a key role in glucose homeostasis in these patients.19 Reduction in IGF-1 level leads to reduced peripheral glucose uptake and increased hepatic glucose production, thus inducing insulin resistance.20–22 Some investigators have evaluated the relationship between OSA and MS; however, the mechanisms have yet to be clarified.13–17 Moreover, studies suggest that OSA may contribute to reduced secretion of GH and IGF-1,12,23,24 which could be the mechanism involved in the association between OSA and MS. The aim of the current study was to examine IGF-1 production and its association with the MS in men with OSA.
Polysomnographic Parameters
PSG was performed using a digital system (EMBLA S7000, Embla Systems, Inc, Broomfield, CO, USA). The following physiological variables were monitored simultaneously and continuously: four channels for the electroencephalogram (EEG); two channels for the electrooculogram; four channels for the surface electromyogram (submental region, anterior tibialis muscle, masseter region, and seventh intercostal space); one channel for an electrocardiogram; airflow detection via two channels through a thermocoupler (one channel); nasal pressure (one channel); respiratory effort of the thorax (one channel) and of the abdomen (one channel) using inductance plethysmography; snoring (one channel) and body position (one channel); oxy-hemoglobin (Hb) saturation (SpO2); and pulse rate. All of the sleep studies were scored in a blinded fashion. Trained technicians recorded the polysomnographic data according to standardized criteria for sleep investigation.27 EEG arousals were scored according to the criteria established by The American Academy of Sleep Medicine Manual for Scoring Sleep and Associated Events.28 Analysis of SpO2 was performed to obtain a profile of average and minimum oxygen saturation as well as the percentage of total sleep time, during which SpO2 was < 90%. Apneas were considered when there was a decrease in the amplitude of airflow ≥ 90% from baseline lasting ≥ 10 sec. An obstructive apnea was classified by continued/increased inspiratory effort during the event and a central apnea was characterized by absent inspiratory effort during the event. Only patients with obstructive apnea were selected. Hypopneas were recorded when there was a 30% reduction in the amplitude of airflow lasting ≥ 10 sec followed by a ≥ 3% decrease in arterial oxygen saturation or an EEG arousal.28 The number of apnea and hypopnea episodes per hour of sleep (AHI) was calculated.
METHODS
Population
Between January 2013 and November 2014, 47 men age 18– 60 y with a body mass index (BMI) of 25 to 45 kg/m 2 were referred for polysomnography (PSG) for suspected OSA and selected for the study. Patients were classified according to their apnea-hypopnea index (AHI) into three groups: No OSA (AHI < 5 events/h), (n = 11); mild OSA (AHI between 5–14.9 events/h), (n = 8); or moderate to severe OSA (AHI ≥ 15 events/h), (n = 28). Exclusion criteria included a history of smoking, sleep apnea treatment, cardiovascular and pulmonary diseases, malignant tumors, untreated thyroid disease, severe depression, diabetes mellitus, metformin therapy, chronic kidney disease, liver failure, and changes in antihypertensive class drugs in the past 3 mo. Because there are differences in OSA severity between men and women, only men were considered for evaluation.25 This study was approved by the Ethics Committee of the Universidade Federal de São Paulo, and written informed consent was obtained from all of the participants.
Laboratory Analyses
Clinical, Anthropometric, and Biochemical Parameters
Plasma glucose, total cholesterol, triglyceride, HDL-cholesterol, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels were measured using an ADVIA 2400 Chemistry System (Siemens, Tarrytown, NY, USA). Glucose was analyzed by hexokinase. The detection limit was 0 mg/dL, and the average within-assay coefficient of variation was 0.7%. Total cholesterol, HDL-cholesterol, and triglycerides were analyzed by enzymatic colorimetric methods. The detection limits were: cholesterol 10 mg/dL, HDL-cholesterol 20 mg/dL, triglycerides 0 mg/dL, and the average within-assay coefficients of variation were: cholesterol 0.6%, HDL-cholesterol 0.4%, triglycerides 0.6%. Low-density lipoprotein (LDL) levels were calculated using the Friedewald formula.29 AST and ALT were analyzed according to the International Federation of Clinical Chemistry (IFCC) method (detection limits: AST 0 UI/L, ALT
A questionnaire was used to document patient personal and medical history as well as drug therapy. A physical examination was performed, and anthropometric measurements including weight (in kilograms), height (in meters) and waist circumference (in centimeters) were recorded. Waist circumference was measured at the midpoint between the last rib and the iliac crest at the end of a normal expiration.26 BMI was calculated by dividing weight by height squared. Waking blood pressure was measured between 08:00 and 11:00 in the supine position after a 5-min rest period and was recorded as the mean of three measurements taken at 1-min intervals. Blood specimens were obtained after a 12-h overnight fast from all of the subjects for the measurement of plasma glucose, Journal of Clinical Sleep Medicine, Vol. 12, No. 4, 2016
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Table 1—Clinical, anthropometrical, and biochemical characteristics of all subjects. Characteristics Age, y BMI, kg/m² WC, cm SBP, mmHg DBP, mmHg Metabolic and Hormonal Profile Fasting glucose, mg/dL 2-h glucose during OGTT, mg/dL HbA1c, % AST, IU/L ALT, IU/L Total cholesterol, mg/dL LDL-cholesterol, mg/dL HDL-cholesterol, mg/dL Triglycerides, mg/dL IGF-1, µg/L
No OSA (n = 11) 42.3 ± 8.3 31.9 ± 2.9 105.4 ± 8.5 124.5 ± 14.4 83.6 ± 8.1 No OSA (n = 11) 96.1 ± 8.1 113.4 ± 28.1 5.5 ± 0.3 24.7 ± 5.1 34.7 ± 17.8 201.7 ± 33.9 128.4 ± 68.7 47.7 ± 8.1 126.8 ± 68.7 225.5 ± 80.5
Mild OSA (n = 8) 46.7 ± 6.7 34.6 ± 6.2 113.4 ± 11.7 131.2 ± 17.3 85.0 ± 7.5 Mild OSA (n = 8) 94.4 ± 9.4 112.4 ± 33.5 5.9 ± 0.3 26.2 ± 5.7 33.2 ± 14.2 187.7 ± 29.9 110.2 ± 23.9 56.0 ± 52.6 108.4 ± 52.6 177.2 ± 41.4
Moderate-Severe OSA (n = 28) 48.0 ± 7.3 33.0 ± 3.2 110.1 ± 8.8 124.6 ± 10.7 83.9 ± 6.3 Moderate-Severe OSA (n = 28) 99.2 ± 13.0 122.6 ± 43.9 5.9 ± 0.4* 27.3 ± 6.5 38.6 ± 15.2 195.6 ± 32.9 124.7 ± 26.0 43.9 ± 7.5 151.1 ± 81.2 156.8 ± 54.3*
p value 0.107 0.324 0.168 0.419 0.906 p value 0.516 0.711 0.033 0.500 0.619 0.657 0.262 0.060 0.315 0.013
Values are presented as mean ± standard deviation. Analysis of variance was used. *p < 0.05 moderate-severe OSA versus no OSA. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; DBP, diastolic blood pressure; HDL, high-density lipoprotein; Hb, hemoglobin; IGF-1, insulin-like growth factor-1; LDL, low-density lipoprotein; OGTT, oral glucose tolerance test; OSA, obstructive sleep apnea; SBP, systolic blood pressure; ; WC, waist circumference.
0 UI/L, and average within-assay coefficient of variation: AST 2.3%, ALT 2%). HbA1c levels were measured by high performance liquid chromatography (HPLC) (2.2 Tosoh Plus A1C, Tosoh Corporation, Tokyo, Japan). Serum IGF-1 levels were measured using a chemiluminescent enzyme immunoassay system (DiaSorin, Saluggia, Italy) and a commercially available kit (LIAISON IGF-I, Saluggia, Italy). Assay sensitivity was 3 µg/L. The interassay and intraassay coefficients of variation were 5.6–9.6% and 3.0–5.1%, respectively. Samples were assayed in a single large batch, and quality assessment samples were well within the manufacturers’ defined ranges. All of the biochemical assays were performed in the Sleep Institute Laboratory.
or the Spearman test. Multivariate linear regression analysis was used to identify associations between polysomnographic, anthropometric, and metabolic parameters with IGF-1 and HbA1c levels. IGF-1 levels were divided into tertiles, and the prevalence of MS in the lowest tertile (tertile 1) was compared with the prevalence in the highest tertile (tertile 3). Continuous variables were compared between tertile 1 and tertile 3 using unpaired Student t-test or the Mann-Whitney U test. A value of p < 0.05 was considered to be statistically significant. Data analysis was performed using Statistical Package for Social Sciences for Windows version 20.0 (SPSS Inc, Chicago, IL). R ES U LT S
Metabolic Syndrome
MS was diagnosed according to the National Cholesterol Education Program (NCEP) guidelines.30 Patients had MS if they had three or more of the following risk factors: waist circumference > 102 cm, triglycerides ≥ 150 mg/dL, HDL cholesterol < 40 mg/dL, blood pressure ≥ 130/85 mmHg or current use of antihypertensive drugs, and fasting plasma glucose level ≥ 100 mg/dL.
The general, laboratory, and polysomnographic characteristics of all subjects are summarized in Table 1. There were no significant differences in age, BMI, waist circumference (WC), and blood pressure between the three groups. However, the moderate-severe OSA group had marginally lower HDLcholesterol levels than the mild OSA group. As expected, significant differences in the following polysomnographic parameters were observed: AHI, arousal index per hour of sleep, duration of stages 1 and 3 sleep, average and minimum oxygen saturation, and sleep period with SpO2 < 90% (Table 2). IGF-1 levels in the moderate-severe OSA group (156.8 ± 54.3 µg/L) were significantly lower than in the no-OSA group (225.5 ± 80.5 µg/L; p = 0.013). IGF-1 values were significantly negatively correlated with BMI (r = −0.340; p = 0.019), WC (r = −0.291; p = 0.047), AHI (r = −0.312; p = 0.033) and with the sleep period with SpO2 < 90% (r = −0.308; p = 0.035) whereas a positive and significant correlation was observed with
Statistical Analysis
The data are expressed as the mean (standard deviation) or the median (interquartile range). Clinical, anthropometrical, biochemical, and polysomnographic characteristics were compared between no OSA, mild OSA, and moderate-severe OSA groups using analysis of variance or the Kruskal-Wallis test. To assess the differences between categorical variables, we used chi-square statistics. Correlations between variables of interest were determined using the linear correlation test 489
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Table 2—Polysomnographic characteristics of all subjects. Characteristics Polysomnographic parameters Total sleep time, h Sleep efficiency, % AHI, events/h # Arousal index, events/h # Stage 1 sleep duration, % Stage 2 sleep duration, % Stage 3 sleep duration, % REM sleep, % Average oxygen saturation, % Minimum oxygen saturation, % # Sleep period with SpO2 < 90%, % #
No OSA (n = 11)
Mild OSA (n = 8)
6.1 ± 1.6 80.4 ± 9.7 1.6 (0.8–3.5) 10.0 (6.5–16.4) 11.5 ± 7.5 47.2 ± 10.2 26.1 ± 8.7 15.1 ± 4.5 94.8 ± 2.2 90 (87–93) 0.1 (0.0–1.3)
7.2 ± 1.3 85.7 ± 8.6 7.7 (5.6–13.1) 9.5 (6.7–15.2) 8.9 ± 4.9 45.5 ± 11.4 23.7 ± 8.1 21.9 ± 8.8 94.3 ± 1.4 83.0 (78.2–85.5) 1.5 (0.5–3.2)
Moderate-Severe OSA (n = 28) 6.6 ± 1.4 82.7 ± 9.8 50.7 (17.5–51.3) 83.0 (78.2–85.5) 20.3 ± 13.5* 43.4 ± 8.4 17.3 ± 9.0* 19.0 ± 6.4 92.7 ± 2.2* 76.5 (69.2–81.7) 6.3 (3.0–20.0)
p value 0.454 0.130 < 0.001 < 0.001 0.019 0.501 0.014 0.083 0.015 < 0.001 < 0.001
Values are presented as mean ± standard deviation or median (interquartile range). Analysis of variance was used, except the Kruskal-Wallis test was used for non-normally distributed variables (indicated by # ). *p < 0.05 moderate-severe OSA versus no OSA. AHI, apnea-hypopnea index; OSA, obstructive sleep apnea; REM, rapid eye movement; SpO2, oxy-hemoglobin saturation.
Table 3—Linear regression analysis of insulin-like growth factor-1 level predictors. Waist circumference, cm Minimum oxygen saturation, %
β -0.211 0.301
Table 4—Linear regression analysis of hemoglobin A1c predictors.
p value 0.144 0.035
Insulin-like growth factor-1, µg/L Waist circumference, cm Minimum oxygen saturation, %
Adjusted for age.
p value 0.023 0.147 0.622
tertile of IGF-1 values are summarized in Tables 5 and 6. The subgroup with the lowest tertile of IGF-1 values had higher BMI, WC, HbA1c, AHI, and sleep period with SpO2 < 90%, whereas HDL-cholesterol and average and minimum oxygen saturation were lower than in the subgroup with the highest IGF-1 levels.
average (r = 0.329; p = 0.024) and minimum oxygen saturation (r = 0.323; p = 0.027) (Figure 1A). There was no significant correlation between IGF-1 levels and stage 3 sleep duration (p = 0.254). The association of central obesity and OSA with IGF-1 levels was assessed. In a subsequent multivariable linear regression (Table 3) in which WC and minimum oxygen saturation were the independent variables, and IGF-1 level was the dependent variable, only the minimum oxygen saturation was associated with lower IGF-1 levels. HbA1c levels in the moderate-severe OSA group (5.9 ± 0.4%) were significantly higher than in the no OSA group (5.5 ± 0.3%; p = 0.033) (Table 1). Moreover, HbA1c levels negatively correlated with the minimum oxygen saturation (r = −0.306; p = 0.025) and IGF-1 levels (r = −0.408, p = 0.004) (Figure 1B). However, in a subsequent multivariable linear regression in which IGF-1, WC, and minimum oxygen saturation were the independent variables, and HbA1c was the dependent variable; only IGF-1 levels was associated with HbA1c levels (Table 4). The proportions of patients with MS were different between the three patients groups (18.2% in no OSA; 25% in mild OSA and 57.1% in moderate-severe OSA; p = 0.047). Furthermore, in the whole group, there was an association between IGF-1 levels and MS. In the lowest tertile of IGF-1 values (IGF-1 ≤ 148.0 µg/L), 66.7% of patients were affected by MS compared with 31.2% in the subgroup of IGF-1 levels ≥ 203.0 µg/L (p = 0.049) (Table 5). The general, laboratory, and polysomnographic characteristics of the subgroups with the lowest tertile and the highest Journal of Clinical Sleep Medicine, Vol. 12, No. 4, 2016
β -0.351 -0.218 -0.498
D I SCUS S I O N This study demonstrated that hypoxemia induced by OSA is associated with reduced IGF-1 levels and reduced IGF-1 is in turn associated with higher HbA1c values regardless of the severity of obesity. GH secretion is strongly related to sleep and is mainly released during slow wave sleep.31 Thus, individuals with sleep apnea, who demonstrate polysomnographic reduction of slow wave sleep, may also display alterations in GH secretion. However, studies on the somatotropic axis in patients with OSA has revealed mixed results, possibly reflecting different methodologies used or patients with different degrees of OSA.12,23,24 Our study demonstrated that somatotropic dysfunction in the moderate-severe OSA group was characterized by low IGF-1 levels compared to the no- OSA group. Reduced plasma IGF-1 levels in OSA has also been demonstrated in previous studies.24,32 Intermittent hypoxemia seen in OSA has been associated with decreased IGF-1 levels.33 Previous animal studies already demonstrated that chronic hypoxemia may decrease IGF-1 levels.2 Consistent with this finding, in experiments with 490
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Figure 1—Insulin-like growth factor levels.
AB
Correlation between insulin-like growth factor-1 levels and (A) minimum oxygen saturation, (B) hemoglobin (Hb)A1c levels.
Table 5—Clinical, anthropometrical, and biochemical characteristics of all subjects according to insulin-like growth factor-1 tertile. Characteristics Metabolic syndrome, % Age, y BMI, kg/m² WC, cm SBP, mmHg DBP, mmHg Metabolic and Hormonal Profile Fasting glucose, mg/dL 2-h glucose during OGTT, mg/dL HbA1c, % AST, IU/L ALT, IU/L Total cholesterol, mg/dL LDL-cholesterol, mg/dL HDL-cholesterol, mg/dL Triglycerides, mg/dL
IGF-1 Tertile 1 (n = 15) IGF-1 ≤ 148.0 µg/L 66.7 46.4 ± 7.3 35.4 ± 4.3 115.1 ± 9.7 126.6 ± 11,7 84.0 ± 6.3 IGF-1 Tertile 1 (n = 15) IGF-1 ≤ 148.0 µg/L 102.4 ± 15.7 133.8 ± 47.5 5.9 ± 0.5 26.0 ± 6.7 36.9 ± 15.3 198.0 ± 25.8 124.4 ± 19.5 42.7 ± 5.7 153.9 ± 72.4
IGF-1 Tertile 3 (n = 16) IGF-1 ≥ 203.0 µg/L 31.2 45.7 ± 8.4 31.0 ± 2.6 106.2 ± 8.8 126.2 ± 15.8 84.4 ± 8.1 IGF-1 Tertile 3 (n = 16) IGF-1 ≥ 203.0 µg/L 95.0 ± 6.6 105.1 ± 29.1 5.5 ± 0.2 27.0 ± 6.6 38.6 ± 18.8 168.8 ± 33.4 123.3 ± 26.7 50.2 ± 9.8 144.5 ± 88.6
p value 0.049 0.084 0.002 0.012 0.935 0.888 p value 0.111 0.055 0.006 0.660 0.786 0.913 0.896 0.016 0.750
Values are presented as mean ± standard deviation. The p values were obtained by the chi-square test or Student t-test. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; DBP, diastolic blood pressure; HDL, high-density lipoprotein; Hb, hemoglobin; IGF-1, insulin-like growth factor-1; LDL, low-density lipoprotein; OGTT, oral glucose tolerance test; ; SBP, systolic blood pressure; WC, waist circumference.
rats, hyperoxia increased IGF-1 and GH receptor expression.34 Additionally, Ursavas et al.12 demonstrated that the low- circulating IGF-1 levels in patients with OSA were correlated with several PSG parameters, such as AHI, arousal index, average desaturation, and oxygen desaturation index. However, Grunstein et al.33 highlighted the role of hypoxemia, which was a more important contributor than sleep fragmentation in the pathogenesis of this hormonal change. Our findings are in line with the prior studies that have suggested an important role for hypoxemia for reduction in IGF-1 level in patients with OSA. Although several studies have reported a significant association between obesity and the reduced GH and IGF-1 levels, the exact mechanisms remain unclear.8–11 Importantly, many
prior studies exploring the relationship between obesity and somatotropic dysfunction did not account for the presence and severity of OSA. A few investigators have indeed shown an important association between OSA severity and IGF-1 levels independent of obesity.12,24 In fact, in our study, although low serum IGF-1 level was also associated with various measures of adiposity (i.e., BMI and WC), the association seemed to be more dependent on OSA-induced hypoxemia. As in our study, the association between OSA and metabolic syndrome has been demonstrated in several studies and seems to be responsible for many of the features of this syndrome. Men with OSA have a higher prevalence of both insulin resistance and MS than men with a similar BMI but without OSA.13–17 491
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S Izumi, FF Ribeiro-Filho, G Carneiro et al. IGF-1 and Obstructive Sleep Apnea
Table 6—Polysomnographic characteristics of all subjects according to insulin-like growth factor-1 tertile. Characteristics Polysomnographic parameters AHI, events/h # Arousal index, events/h # Stage 1 sleep duration, % Stage 2 sleep duration, % Stage 3 sleep duration, % REM sleep, % Average oxygen saturation, % Minimum oxygen saturation, % # Sleep period with SpO2 < 90%, % #
IGF-1 tertile 1 (n = 15) IGF-1 ≤ 148.0 ng/L
IGF-1 tertile 3 (n = 16) IGF-1 ≥ 203.0 ng/L
p value
33.6 (18.5–66.9) 19.9 (14.6–51.3) 18.5 ± 15.2 45.6 ± 9.1 19.3 ± 10.7 16.6 ± 6.8 92.4 ± 2.1 80.0 (70.0–85.0) 6.2 (3.8–23.2)
6.2 (1.9–41.0) 17.2 (10.9–41.0) 12.4 ± 7.5 47.1 ± 9.8 23.1 ± 8.5 17.4 ± 4.9 94.5 ± 1.6 85.5 (76.7–89.5) 1.2 (0.3–3.2)
0.041 0.379 0.163 0.669 0.277 0.724 0.003 0.045 0.006
Values are presented as mean ± standard deviation or median (interquartile range). The p values were obtained by Student t-test, except the Mann-Whitney U test was used for nonnormally distributed variables (indicated by # ). AHI, apnea-hypopnea index; IGF-1, insulin-like growth factor-1; REM, rapid eye movement; SpO2, oxy-hemoglobin saturation.
Somatotropic dysfunction may partially explain the higher prevalence of MS in these patients with OSA. Verhelst et al.35 demonstrated that MS is highly prevalent in hypopituitary patients with adult-onset GH deficiency. Consistently, MS in patients with GH deficiency is partially reversed by GH replacement therapy.36 GH-deficient patients have increased central adiposity, reduced lean body mass, and impaired insulin sensitivity. In our study, 66.7% of the individuals in the lowest tertile of IGF-1 levels (< 148.0 µg/L) were also affected by MS compared with 31.2% of those in the highest tertile of IGF-1 levels. Studies suggest that IGF-1 decreases insulin secretion and increases glucose disposal, and thus plays an important role in glucose metabolism.37 Insulin and IGF-1 have significant homology and interact with differing affinity on the same receptors. Thus, insulin resistance, which is a component of MS, may partially result from low IGF-1 levels. This explains why the higher HbA1c values in the moderate-severe OSA group correlated with IGF-1 levels in our study. Some investigators also reported that low circulating IGF-1 levels are independently associated with hyperglycemia in adults.38–40 Reduced levels of GH and/or IGF-1 in patients with OSA may be an important mechanism responsible for the higher prevalence and incidence of type 2 diabetes seen in patients with OSA. Our study has some limitations including a small sample size and the fact that the study results cannot be generalized to women. The small sample size limits our ability to adjust for some important confounders in our statistical models. Last, the cross-sectional nature of the study does not address the direction of causality. Indeed, only rigorously designed intervention studies will provide causal evidence and insights into mechanisms by which OSA may lead to somatotropic dysfunction. Despite the aforementioned limitations, our results indicate that the of OSA severity, particularly hypoxemia, is associated with reduced in IGF-1 levels. Furthermore, alterations in IGF-1 levels in OSA seem to be associated with higher prevalence of MS. Strengths of our study include measurement of fasting and postprandial glucose levels as well as objective assessment of sleep and OSA by using in-laboratory PSG. Undoubtedly, further studies are needed to clarify the mechanisms that are Journal of Clinical Sleep Medicine, Vol. 12, No. 4, 2016
involved in the GH/IGF-1 axis alteration in patients with OSA as well as to evaluate the effect of positive airway pressure on neuroendocrine dysregulation. A B B R E V I AT I O N S AHI, apnea-hypopnea index ALT, alanine aminotransferase AST, aspartate aminotransferase BMI, body mass index EEG, electroencephalogram GH, growth hormone GHD, growth hormone deficiency GHRH, growth hormone-releasing hormone Hb, hemoglobin HDL, high-density lipoprotein HPLC, high performance liquid chromatography IFCC, international federation of clinical chemistry IGF-1, insulin-like growth factor-1 LDL, low-density lipoprotein MS, metabolic syndrome NCEP, national cholesterol education program OGTT, oral glucose tolerance test OSA, obstructive sleep apnea O2 , oxygen PSG, polysomnography SpO2, oxy-hemoglobin saturation VLDL, very-low-density lipoprotein WC, waist circumference R E FE R E N CES 1. Lanfranco F, Motta G, Minetto MA, Ghigo E, Maccario M. Growth hormone/ insulin-like growth factor-I axis in obstructive sleep apnea syndrome: an update. J Endocrinol Invest 2010;33:192–6. 2. Bernstein D, Jasper JR, Rosenfeld RG, Hintz RL. Decreased serum insulin like growth factor-I associated with growth failure in newborn lambs with experimental cyanotic heart disease. J Clin Invest 1992;89:1128–32.
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ACK N O W L E D G M E N T S This study was supported by the Conselho Nacional de Pesquisa (CNPq) and the AFIP (Associação Fundo de Incentivo à Pesquisa).
SUBM I SSI O N & CO R R ESPO NDENCE I NFO R M ATI O N Submitted for publication July, 2015 Submitted in final revised form November, 2015 Accepted for publication November, 2015 Address correspondence to: Suelem Izumi, MD, Department of Endocrinology, Universidade Federal de São Paulo, Rua Leandro Dupret 365, 04025-011, São Paulo/SP, Brazil; Tel: 55 11 59040423; Fax: 55 11 59040401; Email: suelem.i.l@ hotmail.com
D I SCLO S U R E S TAT E M E N T This was not an industry supported study. The authors have indicated no financial conflicts of interest.
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