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Institutes of Endocrinology (L.D.M., A.B., A.M., R.G., M.P., A.G., T.P., L.T., A.F.) and Clinical Surgery (R.M.T.), Catholic University School of Medicine, 00168 Rome, Italy; and Eli Lilly & Co. (D.V.), 50122 Florence, Italy
Address all correspondence and requests for reprints to: Laura De Marinis, M.D., Via Cassia, 901, 00189 Rome, Italy. E-mail: laurademarinis{at}yahoo.it.
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Abstract |
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Introduction |
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In human obesity, the GH/IGF-I axis is altered at different levels. 1) Basal GH secretion is blunted, with reduced GH half-life, frequency of secretory episodes, and daily production rate (1). GH secretion is impaired in response to all stimuli acting at the hypothalamus and to direct stimulation by exogenous GHRH (2). 2) The plasma levels of the high affinity GH-binding protein are increased, with a positive correlation between serum levels of this molecule and both BMI and percent body fat mass (FM) (3, 4, 5). 3) Plasma IGF-I levels could be normal, low, or high despite high serum levels of the free fraction of IGF-I (3, 4, 6, 7). 4) IGF-binding protein-1 (IGFBP-1) and IGFBP-2 plasma levels are blunted due to inhibition by insulin, which is generally increased in overweight subjects (7). IGFBP-3 levels are normal or high (8, 9). 5) Binding of IGF-I to its receptor is decreased (4). Thus, human obesity may be seen as a condition characterized by an increase in both sensitivity to GH and resistance to IGF-I. In contrast, in obese human subjects, the leptin axis is also altered. Leptin, the ob gene product, is strictly related to body weight [measured by body mass index (BMI) or percent body fat]. Leptin levels adapt to changes in nutritional status. Although leptin concentrations increase during overfeeding or weight gain (10), they decrease during fasting or weight loss (10, 11).
Several studies have reported leptin changes during diet-induced weight loss. Maffei et al. (12) showed that dieting in 14 obese females caused a decrease in leptin levels. Considine et al. (11) reported a leptin reduction after 10% body weight loss. Scholtz et al. (13) showed an uncoupled decrease in leptin and body weight during a long-term hypocaloric diet. Sinha et al. (14) showed a 50% drop in free plasma leptin levels after short-term fasting (24 h). The study by De Marinis et al. (15) was the only one performed on nonfasting subjects. In this study, a decrease in leptin and insulin plasma levels in nonfasting subjects was found in the period following surgically induced weight loss.
Human obesity is characterized by high plasma leptin levels, suggesting that leptin resistance, rather than leptin production, may contribute to the development of obesity (16, 17). As (even when in high amounts) leptin is secreted normally, a wide range of mechanisms have been hypothesized to explain this condition: 1) a transport system defect at the level of the blood-brain barrier (18, 19), 2) a receptor defect (20, 21), 3) a postreceptorial defect of signal transduction (18), and 4) an impaired reaction to peripheral signals, such as glucocorticoids (22, 23). ob gene mutations, such as those found in mice, are extremely rare in humans (24).
The aim of our study was to further explore the interactions between the GH/IGF axis, leptin, insulin levels, and body composition in a group of nonfasting, morbidly obese subjects (undergoing a normal high mean energy intake diet) before and after BPD and to identify factors influencing leptin and GH secretion pattern in these subjects.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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This study protocol was approved by the ethical committee of our institution. All participating subjects signed an informed consent. We studied 15 females, aged 23–54 yr (mean age, 42.7 ± 2.6 yr), with a mean BMI of 44.02 ± 1.45 kg/m2 (range, 32.46–54.57); these were morbidly obese patients who underwent therapeutic BPD (pre-BPD subjects). When studied 16–24 months after having undergone successful BPD (post-BPD subjects), their body weight (BW) was found to have returned partially or completely to normal (mean BMI, 28.29 ± 0.89 kg/m2). All patients were studied in a phase of stabilized BW (±2% variation in BW in the 6 months before testing). One patient was postmenopausal; the others were normally menstruating or exhibited slight irregularities (oligomenorrhea) and were tested in the follicular phase of the menstrual cycle.
BPD consisted of partial gastrectomy with Roux-en-Y reconstruction. Gastric volumes resected ranged from 200–400 ml. The lengths of the alimentary and common tracts were 200 and 50 cm, respectively. As a consequence, nutrition was not subject to the normal action of biliary and pancreatic secretions in the alimentary tract. The patients therefore developed fat malabsorption (75% of ingested) and a partial starch malabsorption while maintaining normal absorption of monodisaccharides (19% of ingested starch plus mono- and disaccharides). Protein absorption remained normal as well (25). The demonstrated metabolic and hormonal results (25, 26, 27) include 1) the reversal of insulin resistance; 2) an increase in diet-induced thermogenesis; and 3) modifications of gut hormones, such as gastrin, enteroglucagon, neurotensin, and cholecystokinin. Despite the above-described malabsorption patterns, calorimetric and body composition analyses demonstrated no signs of malnutrition, as the preservation of lean body mass (LBM) persisted similar to that in the control subjects (28).
The control group consisted of 15 normal female subjects, aged 18–59 yr (mean age, 40.8 ± 2.3 yr), with a mean BMI of 27.52 ± 0.53 kg/m2 (range, 25.71–29.74 kg/m2). No patients were taking medications known to affect GH secretion. Moreover, no patients suffered from diabetes mellitus, thyroid diseases, or chronic diseases. Two subjects were postmenopausal; the others were tested during the follicular phase of the menstrual cycle.
Study design
All groups were studied during their usual diet, and energy intake was determined using a 1-wk food diary. In pre-BPD subjects, the reported mean energy intake was 2500 ± 894 kcal/24 h (composed of 47 ± 7% carbohydrates, 13 ± 6% proteins, and 39 ± 10% lipids). In post-BPD subjects, the reported mean energy intake was 2940 ± 1018 kcal/24 h (63 ± 16% carbohydrates, 11 ± 4% proteins, and 26 ± 4% lipids). In normal subjects, on the other hand, the reported mean energy intake was 1860 ± 360 kcal/24 h (55 ± 5% carbohydrates, 13.6 ± 2.8% proteins, and 30.6 ± 4.1% lipids). Thus, despite weight loss, an augmented caloric intake was observed in post-BPD patients.
At 0800 h, after overnight fasting, we performed the following in all study subjects (controls and pre- and post-BPD patients): 1) evaluation of the GH response to a GHRH bolus (1 µg/kg BW, iv) and collection of blood samples at 0-, 15-, 30-, 60-, and 90-min intervals; 2) basal samples of IGF-I, IGFBP-3, leptin, insulin, glucose, and free fatty acids (FFA); 3) assessment of insulin resistance measured by homeostasis model assessment (HOMA; calculated as glucose (millimoles per liter) x insulin (milliinternational units per liter)/22.5, as described by Matthews et al. (29, 30, 31), where high HOMA scores denote low insulin sensitivity (insulin resistance); and 4) evaluation of total body mass, LBM, and FM, determined by dual energy x-ray absorptiometry (DEXA). GHRH-(1–29) was furnished by Serono (Milan, Italy).
Hormone assays
Plasma GH levels were measured in duplicate by immunoradiometric assay with reagents purchased from Radim (Pomezia, Italy). The intraassay coefficient of variation ranged from 2.5–3.9%, and the interassay coefficient of variation ranged from 5.8–8.5%. Normal basal plasma GH levels ranged from 46.5–232.5 pmol/liter.
Plasma IGF-I was measured with the immunoradiometric assay method using kits from Medgenix Diagnostix SA (Fleurus, Belgium). Soluble IGF-I was separated from interfering binding proteins using the acid-ethanol procedure of Daughaday et al. (32). In our laboratory, normal plasma values, matched for age and sex, of IGF-I ranged from 10.46–43.13 nmol/liter, and the inter- and intraassay coefficients of variations (CVs) were 9.6% and 4.1%, respectively.
Plasma IGFBP-3 was measured by RIA using commercial kits (Mediagnost, Tubingen, Germany) as previously described by Blum et al. (33) and in our laboratory ranged from 49.5–161.7 nmol/liter (matched for age and sex). All samples from each individual subject were analyzed in duplicate and in the same assay; the inter- and intraassay CVs were 6.5% and 3.5%, respectively.
We assumed 30.5 kDa as the molar weight of IGFBP-3 (34) for the molar comparison between IGF-I and IGFBP-3.
Leptin was assayed by RIA for human leptin (Phoenix Pharmaceuticals, Inc., Phoenix, AZ). Intra- and interassay CVs were, respectively, 4.2% and 4.5%. The sensitivity of the method was 0.5 µg/liter. Insulin was assayed by RIA using kits from Abbott Diagnostics (Milan, Italy). Intra- and interassay CVs were, respectively, 4.5% and 5.6%. Normal basal plasma insulin levels ranged from 34.42–137.68 pmol/liter.
Body composition study
All patients were evaluated before and after BPD by anthropometry (weight, height, and BMI), hematochemical parameters, and DEXA. DEXA (Lunar DPX, Lunar Europe, Everberg, Belgium) with photon emissions of 40 and 70 keV was used for a whole body rectilinear scan; it can estimate segmental mass (left and right arms, leg, and trunk), LBM, and FM; it is also able to analyze the complete patient body in the case of massive obesity, scanning separately the two halves of the body. The DEXA system was calibrated weekly with seven bags of ground beef in which the fat content (based on chemical analysis) ranged between 3–83% (35). The reproducibility of percent fat by DEXA ranged from 0.97–0.99 in human subjects measured five times and was 0.99 in phantom studies (35). The total radiation energy dose equivalent was less than 0.03 milliSievert. The CV was 4% for FM and 1.9% for LBM. Despite the high degree of adiposity in very obese patients, DEXA can be a reliable method to estimate body composition in such individuals (36, 37, 38).
Statistics
All results are expressed as the mean ± SEM. Plasma GH concentrations were also expressed as the area under the curve (GH AUC) relative to zero, calculated by trapezoidal rule, and compared in the same way.
The distribution of the data was tested (Kolmogorov-Smirnov test), and it was found that data were not normally distributed. Statistical analysis was performed using the Wilcoxon rank-sum test when comparing pre- and post-BPD subjects and using the Mann-Whitney U test when comparing data from different groups. For correlation and regression analyses, body composition variables and serum analytes were log-transformed to produce a normal distribution. Linear regression analysis was used to identify independent effects of other hormonal (insulin, IGF-I, and IGFBP-3) and body composition (FM and LBM) parameters on leptin and GH secretion (GH peak and GH AUC) in each group (controls, pre-BPD, and post-BPD). Stepwise multiple linear regression analysis was used, grouping pre- and post-BPD patients, to identify variables that best predicted serum leptin and GH secretion pattern. Multiple linear regression analysis was performed, also grouping the two groups of subjects, to identify independent effects from other hormonal (insulin, IGF-I, and IGFBP-3) and body composition (FM and LBM) parameters on serum leptin and GH secretion pattern. The level of statistical significance was set at P < 0.05. We used the software package Statistica (Statsoft, Inc., Tulsa, OK; release 5.0, 1996, for Windows 95) for statistical evaluation.
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Results |
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The results are shown in Table 1
. The plasma GH levels after stimulation were blunted in pre-BPD patients. The GH peak and GH AUC were significantly lower than in the controls (P < 0.0001). IGF-I and IGFBP-3 were also lower than in the control group (P < 0.0001). The GH response to GHRH was severely increased in post-BPD subjects compared with pre-BPD patients (P < 0.0001) and the control group (P < 0.02).
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Biochemical data
The results are shown in Table 1
. In pre-BPD subjects the leptin levels were significantly higher than in the controls (P < 0.0001). Average leptin levels after BPD showed a significant decrease vs. preoperative levels and vs. controls (P < 0.0001).
Pre-BPD patients exhibited higher plasma levels of insulin and FFA as well as higher HOMA scores compared with control subjects (P < 0.0001). After BPD, insulin and FFA levels as well as HOMA scores showed a significant decrease (P < 0.0001). HOMA scores and insulin levels were also lower than those in the control group (P < 0.007 and P < 0.0002, respectively).
Body composition
After surgery (16–24 months), all patients had experienced a significant reduction of BW (mean BMI, 28.29 ± 0.89 vs. 44.02 ± 1.45 kg/m2; P < 0.0001). Post-BPD FM was significantly lower than pre-BPD FM (50.34 ± 2.03 vs. 80.05 ± 3.57 kg; P < 0.0001), and the LBM was physiological (24.42 ± 1.07 vs. 37.38 ± 1.63; P < 0.0001 vs. pre-BPD; not significant vs. control group).
Relationships between hormonal parameters and body composition
Linear regression analysis performed in each group (controls, pre-BPD, and post-BPD) between leptin or GH peak or GH AUC as dependent variables, and insulin, FM, LBM, IGF-I, and IGFBP-3 as independent variables, showed only in pre-BPD a positive significantly correlation between leptin and insulin (P = 0.001; r2 = 0.61), leptin and FM (P = 0.0001; r2 = 0.75), and leptin and LBM (P = 0.0001; r2 = 0.76).
Considering all subjects (pre-BPD, post-BPD, and controls), correlation analysis showed a strong positive correlation between insulin and leptin, and a negative correlation between insulin and GH peak and between insulin and GH AUC (Table 2 and Fig. 1).
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). When IGF-I and IFGBP-3 were excluded from the analysis, the contribution of insulin remained unchanged. Multiple linear regression analysis also showed that in our model insulin is independently related to leptin (P = 0.02), GH peak (P = 0.002), and GH AUC (P = 0.01; Table 4). When IGF-I and IFGBP-3 were excluded from the analysis, the contribution of insulin remained unchanged.
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Discussion |
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After BPD (18–24 months after surgery), we observed a significant reduction in BW. BMI, FM, and LBM were significantly lower than during the pre-BPD period. Furthermore, we observed a decrease in leptin, insulin, and FFA levels as well as in the HOMA score. In contrast, there was a significant increase in the GH response to GHRH in the fasting state, whereas IGF-I and IGF-BP3 remained unchanged. Moreover, our data showed a significant positive correlation between insulin and leptin levels as well as a strong negative correlation between insulin and GH secretion pattern.
Although we tried to describe the interactions among the GH/IGF axis, leptin, insulin levels, and body composition in a small group of morbidly obese subjects before and after BPD, and we hypothesized that insulin status could be the main factor influencing leptin and GH secretion pattern in our subjects, previous studies also support a possible causal interrelation among insulin, leptin, and GH secretion modifications.
The reduced GH response to GHRH in pre-BPD obese fasting patients seems to be caused by both central and peripheral factors. Among central factors, impairment of endogenous GHRH tone or augmented somatostatin release has been hypothesized (40, 41). It has been also suggested that the defect resides in the pituitary gland, with enhanced somatostatin release being responsible for the blunted GH response (42). Among the peripheral factors, the role of increased bioavailability of IGF-I, measured by the IGF-I/IGFBP-3 ratio, and its possible increased negative feedback action on somatotroph cells have been underlined (43). However, insulin and FFA levels seem to be the most important factors involved (42, 44). Insulin is able to reduce GH release from rat pituitary in vitro, suggesting an IGF-I-like effect (45). Massive weight loss, inducing a decrease in insulin secretion, seems to be directly involved in the restoration of a normal 24-h GH profile (46). A recent study has shown that the blunted GH response to GHRH in obese subjects is reverted after Acipimox treatment by a decrease in FFA levels (47). In models such as polycystic ovary syndrome or old normal subjects, where the GH response to GHRH is similar to that in obese subjects, it has been shown that a pharmaceutical decrease in FFA levels can reestablish a normal GH response (48, 49).
During the post-BPD period, there is a net improvement in the metabolic parameters: normalization of insulin levels, principally caused by a decrease in FFA levels (44), in turn caused by lipid malabsorption, as well as a decrease in leptin levels, as described in previous studies (15). Therefore, the first pathophysiological phenomenon seems to be the lipid malabsorption that has been argued to be the cause of insulin resistance reversion (44). The same phenomenon paired with the decrease in FM would also explain the reduction in leptin levels. Finally, the increased insulin sensitivity could contribute to the reduction of leptin levels (15). Despite lipid malabsorption, calorimetric and body composition analyses demonstrate no signs of malnutrition in our patients (28), and LBM is preserved as in the control group.
In the present study insulin levels, beyond normalization, exhibit values lower than controls, suggesting an increased sensitivity to insulin itself. The reversion of multiple mechanisms, both prereceptorial (gut hormones and FFA) and postreceptorial (glucose transporter-4 expression enhancement, reduced expression of uncoupling protein-2 and -3, and reduced phosphodiesterase kinase-4 expression) (50, 51, 52) could explain these phenomena. However, only studies of longer duration can clarify whether this hormonal pattern is permanent or is an index of a dynamic adaptation to surgery. The same considerations can be made concerning leptin levels, which are significantly related to insulin levels, as below discussed.
The changes in insulin and FFA levels also seem to be determinant factors for GH secretion in post-BPD patients. It is known that in obese patients, high insulin levels cause an increase in the hepatic GH receptor with IGF-I-preserved synthesis, decreases in IGFBP-1 and -2, and subsequent increased negative feedback of pituitary GH secretion (3, 4, 5, 53). Insulin can act directly at the pituitary level on GH secretion, through interaction with the IGF-I receptor, thus incrementing the negative feedback (4, 5, 6). Interestingly, in post-BPD patients, despite an increase in GH after GHRH levels, IGF-I and IGFBP-3 remain similar to pre-BPD values. This is probably due both to the insulin-mediated reduction in the GH hepatic receptor and to a paired increase in IGFBP-1 and -2 levels (inversely correlated to insulin levels) (7, 8), suggesting that the restored insulin sensitivity underlies both the augmented GH secretion and the postoperative condition of GH resistance.
Recent studies have tried to show the effects of GH and leptin on each other without reaching unequivocal results. The administration of GH both in vivo and in vitro reduces or terminates the secretion of leptin by adipose cells (54, 55, 56). In patients affected by GHD, the administration of rhGH as a substitute therapy seems to determine a lower leptin release, but no change in BMI (57, 58). In contrast, in normal subjects the administration of a single GH bolus induces a sharp and rapid increase in leptin levels, followed by a fall in leptin levels. Another recent study (59) performed on patients affected by GH insensitivity, has shown that high leptin levels, characteristic of this pathology, remained unchanged after brief recombinant human GH treatment.
On the other hand, leptin increases GH secretion. Leptin seems to act as a metabolic sign for GH secretion in a population of children, aged 6–17 yr, in whom there exists a positive correlation between leptin and fat as well as a negative one between leptin and GH secretion (60). Finally, Casanueva et al. (24) have shown that in obese subjects with hyperleptinemia and in obese subjects with homo- and heterozygote mutations of the leptin gene, there is no difference in GH secretion, which is lower than the norm in both populations.
The influence of insulin on leptin secretion is more clear. A recent study has shown that a short-term treatment with metformin in normal subjects induces a decrease in both leptin and insulin levels without affecting BMI and body composition (61). One of our previous studies (15) showed an association between a significant decrease in insulin and leptin levels in the immediate post-BPD period, even before the decrease in BMI. Moreover, direct evidence of the influence of glucose homeostasis on leptin secretion does exist. Similarly, competitive inhibition of glucose transport has been shown to decrease leptin secretion and mRNA content in cultured rat adipocytes (62). Leptin concentration dose-dependently increases during euglycemic hyperinsulinemic clamp experiments and is attenuated during hypoglycemic clamps (63, 64, 65).
Finally, complex mechanisms can interfere with absorptive dynamics, such as direct modifications of gastrointestinal anatomy, and alterations in gastrointestinal hormones, such as reduction of the upper small intestinal hormones, motilin and gastric inhibitory polypeptide, have been found after different kinds of bariatric surgery. Conversely, the ileal hormones, neurotensin and enteroglucagon, have been found to be elevated after surgery. This pattern is consistent with the known distribution of these hormones. Variations in response due to surgical differences have been noted for gastrin and cholecystokinin, which have been more markedly disturbed after BPD compared with other technique. More recent data concern ghrelin, the potent appetite stimulant produced by the stomach, which has been shown to be decreased in obesity (66) and elevated in anorexia nervosa (67), but its possible regulator role in energy balance after bariatric surgery remains unknown. A recent study (68) showed that patients who lose weight by restricting caloric intake experience an increase in fasting and postprandial ghrelin levels, but the same researchers observed reduced ghrelin concentrations in a group of obese patients after gastric bypass.
In conclusion, surgical treatment of severe obesity after stabilization of body weight decreases BMI and FM while preserving normal LBM as well as positively influencing insulin sensitivity and thus aiding the normalization of leptin levels. The decrease in insulin secretion may be mainly involved in the GH response to GHRH through central and peripheral mechanisms while decreasing the peripheral sensitivity to GH itself, as shown by the stable nature of the IGF-I and IGFBP-3 values. Although further studies are necessary to explore the complex interaction among insulin, leptin, and the GH/IGF-I axis, our findings suggest that the changes in insulin levels are the starting point for the changes in both leptin levels and the somatotrope axis after BPD.
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Footnotes |
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Received August 16, 2002.
Accepted September 29, 2003.
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reduction and GLUT4 expression enhancement. Int J Obes Relat Metab Disord 26:1165–1172[CrossRef][Medline]
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, Control subjects; 
, pre-BPD (obese subjects before surgery); 
, post-BPD (18–24 months after surgery).