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Fasting Glucagon-like Peptide-1 and Its Relation to Insulin in Obese Children Before and After Weight Loss

Reinehr, Thomas*; de Sousa, Gideon*; Roth, Christian L

Journal of Pediatric Gastroenterology and Nutrition: May 2007 - Volume 44 - Issue 5 - p 608–612
doi: 10.1097/MPG.0b013e3180406a24
Original Articles: Hepatology & Nutrition

Objective: To study the relationships between glucagon-like peptide-1 (GLP-1), weight status, insulin, and insulin resistance in the fasting state.

Patients and Methods: Fasting GLP-1, glucose and insulin concentrations, insulin resistance index as homeostasis model assessment (HOMA), body mass index (BMI), and percentage body fat based on skinfold thickness measurements were determined in 42 obese (median age 11 years) and in 16 lean children of the same age. The HOMA model was used to calculate degree of insulin resistance. Furthermore, the changes in GLP-1, glucose, insulin, and HOMA in the course of 1 year were analyzed in the 42 obese children participating in an obesity intervention.

Results: GLP-1 concentrations did not differ significantly between obese and lean children. In multiple linear regression analyses, GLP-1 was significantly related to insulin (P = 0.028) and HOMA (P = 0.019) but not to glucose, age, sex, pubertal stage, BMI, or percentage body fat. The 15 obese children with substantial weight reduction demonstrated significantly (P < 0.05) decreased GLP-1, insulin, and HOMA levels, whereas these parameters did not change in 27 obese children without substantial weight loss. Changes in GLP-1 correlated significantly with changes in insulin (r = 0.46, P = 0.001) and HOMA (r = 0.28, P = 0.036) but not with changes in glucose, BMI, or percentage of body fat.

Conclusions: In children, fasting GLP-1 concentrations are independent of age, sex, and pubertal stage. Although GLP-1 did not differ between lean and obese children, weight loss was associated with decreasing GLP-1. Inasmuch as GLP-1 levels were related to insulin concentrations in both cross-sectional and longitudinal analyses, we hypothesize a relationship between GLP-1 and insulin in the fasting state.

*Vestische Hospital for Children and Adolescents Datteln, University of Witten/Herdecke

Department of Pediatrics, University of Bonn, Germany

Received 9 November, 2006

Accepted 22 January, 2007

Address correspondence and reprint requests to Dr Thomas Reinehr, Vestische Hospital for Children and Adolescents Datteln, University of Witten/Herdecke, Dr F. Steiner Str 5, 45711 Datteln, Germany (e-mail:

Supported by the Bonfor Research Foundation, University of Bonn, Germany, and by NIH RR0163 and DK 62202.

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Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone that is synthesized and secreted in 2 major molecular forms with equipotent biological activity—GLP-1(7-36)amide and GLP-1(7-37)—from enteroendocrine L cells of the small bowel and large bowel (1). Endogenous concentration is low in the fasting state and increases in response to a meal (1). GLP-1 is believed to be the most potent insulinotropic hormone known to date (1,2). Furthermore, GLP-1 suppresses glucagon secretion and inhibits gastric emptying and acid secretion (1,2).

An attenuated GLP-1 response is suggested to contribute to the impaired insulin response in patients with type 2 diabetes mellitus (1,3). Insulin resistance is associated with an impaired GLP-1 response to a mixed meal (4). GLP-1 receptor—null mice demonstrated glucose intolerance and an attenuated insulin response to oral glucose loading (5). GLP-1 was found to normalize both the fasting and the postprandial glucose levels in humans with type 2 diabetes (6). The insulinotropic effect of GLP-1 has been demonstrated in animal models (7,8): GLP-1 stimulated insulin secretion in a glucose-dependent manner, and it stimulated β-cell proliferation and differentiation (7).

Like many other peptides of the brain-gut axis, GLP-1 is involved in control of food intake (1,2). Recently, GLP-1 has been shown to reduce energy intake and enhance satiety, most likely via delay of gastric emptying and via specific GLP-1 receptors within the central nervous system (1,9). However, the role of GLP-1 in obesity is poorly understood. Some authors have reported an attenuated response of GLP-1 to meals in obese individuals (10,11), whereas others have found no differences in fasting and stimulated GLP-1 levels between normal-weight and obese individuals (12,13). In obese humans losing weight increasing (10,14), decreasing (15), and unchanged fasting and stimulated GLP-1 levels (16) have been reported.

Since the development of GLP-1 analogues as new therapeutic approaches in diabetes and obesity (1,8), it has been interesting to study the relationships between GLP-1, weight status, insulin, and insulin resistance not only postprandially but also in the fasting state. To our knowledge, no studies have been published concerning the relationship between GLP-1, weight status, and insulin levels in children. The advantage of examining children is that potential confusion with further chronic diseases or medication is limited. Therefore, and because studies in obese adults are conflicting, we analyzed fasting GLP-1 and insulin concentrations, insulin resistance, and their changes during 1 year in obese children participating in an obesity intervention program. We compared these parameters with those of lean children. The aim of this study was to analyze whether fasting GLP-1 concentrations are related to weight status, insulin, and/or insulin resistance.

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We examined anthropometric markers, GLP-1, glucose, and insulin concentrations in 42 obese and 16 lean, healthy white children (Table 1). Furthermore, the same parameters were analyzed in the obese children before and after they participated in a 1-year obesity intervention program. Children with endocrine disorders or syndromal obesity were excluded from the study. Obesity was defined according to the definition of the International Obesity Taskforce (17).



The degree of overweight was quantified by Cole's least mean squares method, which normalized the body mass index (BMI), skewed distribution in childhood, and expressed BMI as a standard deviation score (SDS-BMI) (18). Reference data for German children were used (19). Triceps and subscapularis skinfold thickness was measured in duplicate with a caliper and averaged to calculate the percentage of body fat by use of a skinfold thickness equation with the following formulas (20): boys: body fat % = 0.783 × (subscapularis skinfold thickness + triceps skinfold thickness in mm) + 1.6; girls: body fat % = 0.546 × (subscapularis skinfold thickness + triceps skinfold thickness in mm) + 9.7.

The pubertal developmental stage was determined according to Marshall and Tanner and categorized into 2 groups (prepubertal: boys with pubic hair and gonadal stage I, girls with pubic hair stage and breast stage I; pubertal: boys with pubic hair or gonadal stage ≥II, girls with pubic hair stage or breast stage ≥II).

Blood sampling was performed while participants were in the fasting state at 8 AM. Serum GLP-1 concentrations were measured by a high-specific enzyme-linked immunosorbent assay (human active GLP-1 ELISA Kit, Linco Research, St. Charles, Missouri, USA) for GLP-1(7-36)amide and GLP-1(7-37) without cross-reactions to glucagon or to other forms of GLP-1. All values of GLP-1 are composed of GLP-1(7-36)amide and GLP-1(7-37). The sensitivity stated by the manufacturer was 2 pmol/L, whereas we determined a sensitivity of 0.5 pmol/L. Insulin concentrations were measured by microparticle enhanced immunometric assay (MEIA, Abbott, Wiesbaden, Germany). Glucose levels were determined by colorimetric test with a Vitros analyzer (Ortho Clinical Diagnostics, Neckargemuend, Germany). Intraassay and interassay coefficients of variation were <5% in all methods apart from GLP-1 (<13%). Homeostasis model assessment (HOMA) was used to detect the degree of insulin resistance (21): The resistance can be assessed from the fasting glucose and insulin concentrations by the formula: resistance (HOMA) = (insulin [mU/L] × glucose [mmol/L]/22.5).

The obesity intervention program, Obeldicks, has been described in detail elsewhere (22). Briefly, the program was based on physical exercise, nutrition education, and behavior therapy, including individual psychological care of the child and the family. The nutritional course was based on a fat-reduced and sugar-reduced diet compared with the everyday nutrition of German children (22): The diet contained 30% fat, 15% protein, and 55% carbohydrates, including 5% sugar. Substantial weight loss during the 1-year intervention was defined by a reduction in SDS-BMI of 0.5 or more because with a reduction of <0.5 SDS-BMI, no improvement of insulin resistance and cardiovascular risk factors could be measured in obese children (23,24).

Statistical analysis was performed with the Winstat software package. Apart from GLP-1, all variables were normally distributed tested by the Kolmogorov-Smirnov test. Therefore, GLP-1 was log transformed. Differences were tested with χ2 tests, t tests, Mann-Whitney U tests, or Wilcoxon test as appropriate. Pearson and partial correlations adjusted for SDS-BMI were used. Direct multivariate linear regression analyses were conducted for the dependent variable GLP-1, including age, sex, pubertal stage, BMI, glucose, and insulin or HOMA instead of glucose and insulin as independent variables. Sex and pubertal stage were used as classified variables in these models. P < 0.05 was considered significant. Written informed consent was obtained from all of the children and their parents. The study was approved by the local ethics committee of the University of Witten/Herdecke.

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The age, stage of puberty, sex, degree of overweight, insulin resistance index (HOMA), insulin, and glucose concentrations of the 42 obese and 16 lean children are shown in Table 1. The obese children demonstrated significantly higher insulin resistance index (HOMA) and insulin than did the lean children, whereas the lean and obese children did not significantly differ in terms of age, sex, pubertal status, glucose, or GLP-1 concentrations.

In the 58 obese and normal-weight children, log transformed GLP-1 did not significantly correlate to the degree of overweight (SDS-BMI) (r = 0.17; P = 0.097) or percentage body fat (r = 0.01; P = 0.464). In partial correlation adjusted to SDS-BMI, log transformed GLP-1 correlated significantly to insulin (r = 0.30; P = 0.011) but not to glucose (r = 0.01; P = 0.476), HOMA (r = 0.12; P = 0.168), or age (r = −0.10; P = 0.236). Insulin correlated significantly to SDS-BMI (r = 0.47; P < 0.001) and percentage body fat (r = 0.44; P = 0.001). In direct multivariate linear regression analysis (r2 = 0.33), GLP-1 correlated significantly to insulin (coefficient 0.37, 95% CI 0.05–0.70; P = 0.027) but not to BMI (P = 0.179), glucose (P = 0.479), age (P = 0.679), sex (P = 0.988), and pubertal stage (P = 0.628). The use of HOMA instead of insulin and glucose in the multivariate linear regression analysis also demonstrated a significant relationship between HOMA and GLP-1 (coefficient 1.8, 95% CI 0.3–3.3; P = 0.019).

The changes in insulin resistance index (HOMA), insulin, glucose, and GLP-1 concentrations during the 1-year period in the 15 obese children with substantial weight loss and the 27 obese children without substantial weight loss are shown in Table 2. Substantial weight loss led to a significant decrease in percentage body fat, insulin concentration, insulin resistance index (HOMA), and GLP-1 levels. We found no significant changes in the obese children without change of weight status. Five (33%) children with substantial weight loss and 9 (33%) children without substantial weight loss entered into puberty. At baseline, there were no significant differences in sex (P = 0.750), percentage body fat (P = 0.443), and SDS-BMI (P = 0.944) between the obese children with and without substantial weight loss, whereas the obese children with substantial weight loss were significantly (P = 0.001) younger and more frequently prepubertal (P = 0.027). Glucose (P = 0.246), insulin (P = 0.216), HOMA (P = 0.143), and GLP-1 concentrations (P = 0.589) did not significantly differ between the children with and without substantial weight loss at baseline.



In the 1-year follow-up, changes in GLP-1 concentrations were significantly correlated to changes in insulin (r = 0.46, P = 0.001) (Fig. 1) and HOMA (r = 0.28; P = 0.036), whereas there were no significant correlations between glucose and GLP-1 (r = 0.14; P = 0.180) by use of partial correlations adjusted to changes in SDS-BMI. Furthermore, changes in GLP-1 were not significantly correlated to changes in percentage body fat (r = −0.13; P = 0.277) or SDS-BMI (r = −0.01; P = 0.476).

FIG. 1

FIG. 1

At baseline, GLP-1 levels in the 29 girls (median 2.9 interquartile range [IQR] 1.5–5.8 pmol/L) did not significantly (P = 0.681) differ from the GLP-1 concentrations in the 29 boys (median 3.0 IQR 1.3–7.5 pmol/L). Boys and girls did not differ with respect to age (P = 0.626), pubertal stage (P = 0.174), or SDS-BMI (P = 0.648).

The GLP-1 levels in the 33 prepubertal children (median 3.4 IQR 1.4–6.7 pmol/L) did not significantly (P = 0.345) differ from the GLP-1 concentrations in the 25 pubertal children (median 2.2 IQR 1.2–7.4 pmol/L). Prepubertal and pubertal children did not differ with respect to sex (P = 0.189) or SDS-BMI (P = 0.899).

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To our knowledge, this is the first study analyzing the cross-sectional and longitudinal relationships between fasting GLP-1, insulin, insulin resistance index, and weight status in childhood. In both cross-sectional and longitudinal analyses GLP-1 was significantly correlated to insulin in the fasting state. Furthermore, the longitudinal relationship between GLP-1 and insulin was stronger than that between GLP-1 and the insulin resistance index (HOMA), and GLP-1 was not related to glucose as a parameter of the insulin resistance index. Therefore, we hypothesize a direct relationship between GLP-1 and insulin concentrations in the fasting state.

The mechanism of this relationship between fasting insulin and GLP-1 seems to be different from that in the postprandial state. GLP-1 stimulated postprandial insulin secretion in a glucose-dependent manner (7,8), whereas fasting GLP-1 was not related to glucose. Furthermore, postprandial GLP-1 concentrations were reported to be impaired in insulin resistance (4), whereas insulin resistance index was not negatively associated with GLP-1 in our fasting study. Probably other factors like leptin, which stimulates GLP-1 secretion from intestinal L cells (25), are involved in the regulation of fasting GLP-1.

However, our findings do not support a direct relationship between GLP-1 and weight status. GLP-1 concentrations did not differ between obese and lean children, in accord with other studies (12,13). Conversely, the relationship between GLP-1 and weight status seems to be more complicated than was anticipated. In our study weight loss was associated with a decrease of GLP-1 concentrations, in accord with a study based on a low–energy intake diet (15). Inasmuch as GLP-1 is a satiety signal, the decrease of GLP-1 concentrations in weight loss could probably, at least in part, explain some of the difficulties in long-term maintenance of weight loss based on dieting.

The decrease of GLP-1 in obese children losing weight substantially may be explained in part by decreasing leptin concentration in weight loss (26). Leptin stimulates GLP-1 secretion from rodents and human intestinal L cells (25). Furthermore, the decrease of GLP-1 in obese children losing weight substantially was probably a consequence of the intervention program. GLP-1 concentrations are reported to be influenced by the manner of dieting and by physical exercise (1,2,15,27). Because exercise therapy and dieting were performed together in our intervention program, we cannot distinguish the possible effects of these 2 factors on GLP-1 concentrations.

The conflicting findings with increasing GLP-1 levels in obese humans losing weight in other studies (28–30) can probably be explained by the small sample sizes and by the effects of gastric surgery in these studies. It is difficult to distinguish between the effects of surgery and weight reduction on the levels of gastrointestinal hormones because the change of GLP-1 release after surgery on the gastrointestinal tract may also be in part due to the absence of gastric and duodenal food stimuli, vagal injury, or lower blood glucose, which mainly regulate GLP-1 secretion (1).

This study has a few potential limitations. First, BMI percentiles and skinfold measurements were used to classify overweight. Although these are good measurements of overweight, one needs to be aware of their limitations as an indirect measure of fat mass. Second, the children with substantial weight loss were younger and more frequently prepubertal than were the obese children without change of weight status. Inasmuch as GLP-1 concentrations were independent of age, sex, and pubertal stage, it seems unlikely that these factors could have influenced our findings. Third, the HOMA model is only an assessment of insulin resistance, and clamp studies are the gold standard for the analysis of insulin resistance. Given that the HOMA model correlated to clamp studies, it is a good method to study insulin resistance in field studies (31). Finally, our study design did not permit us to distinguish between causes and consequences. Therefore, it remains unclear whether fasting GLP-1 stimulates insulin secretion or vice versa.

In summary, fasting GLP-1 levels were independent of weight status, age, sex, and pubertal stage, whereas weight loss was associated with a decrease of GLP-1 concentrations in childhood. Inasmuch as fasting GLP-1 concentrations were related to fasting insulin levels both in cross-sectional and in longitudinal analyses, we hypothesize a relationship between GLP-1 and insulin in the fasting state. Further prospective research is required to examine the relationship between GLP-1 and insulin concentrations in humans.

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The authors thank Ms R. Maslak, Children's Hospital, University of Bonn; Ms P. Niklowitz, Children's Hospital, Datteln, University of Witten/Herdecke; and Ms M. Schmidt, Department of Clinical Biochemistry, University of Bonn, for assistance in the laboratory, and Dr R. Reinehr, University of Düsseldorf, for assistance with data analysis.

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Glucagon-like peptide-1; Insulin; Obesity; Children; Weight loss

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