Insulinogenic index at 15 min as a marker of stable eating behavior in bulimia nervosa

ARTICLE IN PRESS Clinical Nutrition (2004) 23, 711–720

www.elsevier.com/locate/clnu

ORIGINAL ARTICLE

Insulinogenic index at 15 min as a marker of stable eating behavior in bulimia nervosa Daisuke Yasuhara, Yoshiki Tatebe, Takashi Nakayama, Tetsuro Muranaga, Shin-ichi Nozoe, Tetsuro Naruo* Division of Behavioral Medicine, Department of Social and Behavioral Medicine, Course for Health Science, Kagoshima University Graduate School of Medicine and Dental Science, 8-35-1 Sakuragaoka, Kagoshima-City 890-8520, Japan Received 15 August 2003; accepted 3 December 2003

KEYWORDS Bulimia nervosa; Eating behavior; Insulinogenic index; Oral glucose tolerance test; Vomiting; Body weight maintenance

Summary Background & aims: The aim of this study was to determine the relationship between insulinogenic index at 15 min (II15 min), body weight maintenance, and the presence of vomiting in patients with bulimia nervosa. Methods: Forty-eight bulimic inpatients and 14 controls underwent an oral glucose tolerance test on the seventh hospital day. We calculated II15 min and other biological markers, including serum amylase concentrations. During the first week after admission, we monitored the frequency of vomiting and calculated changes in body weight. Patients were divided into 4 subgroups according to the presence of vomiting and weight loss. Results: Two-factor analysis of variance of the II15 min value revealed significant main effects of vomiting and body weight change (Po0:001 for both). The II15 min values for controls and bulimic patients with weight loss and no vomiting were lower than those of other bulimic groups. The II15 min values were positively correlated with serum amylase concentrations (r ¼ 0.37, Po0.01), body weight change (r ¼ 0.35, Po0.05), and frequencies of vomiting (r ¼ 0.49, Po0.05). Conclusions: These findings suggest that II15 min values may be a useful marker for assessing the stability of eating behavior in patients with bulimia nervosa. & 2004 Elsevier Ltd. All rights reserved.

Introduction Bulimia nervosa (BN) is characterized by binge eating/vomiting cycles, purging behavior, and various physical/mental complications;1,2 and the increasing prevalence of this disorder (1–1.5%) is a *Corresponding author. Tel.: þ 81-99-275-5751; fax: þ 81-99275-5749. E-mail address: [email protected] (T. Naruo).

serious problem in young female populations.3 Bulimic patients follow a chaotic eating behavior pattern, with periods of severe energy restriction, binge eating, and compensatory vomiting.4 For these patients, evaluations of the stability of eating behavior should be made in the course of treatment. However, in most cases, patients with BN are secretive with regard to their eating behavior, and clinicians have difficulties assessing a patient’s status accurately using interviews or self-reported questionnaires.5 Although several markers of

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nutritional status or vomiting have been reported,6–18 few useful biological markers can be used to assess the stability of eating behavior in BN. Previous studies of carbohydrate metabolism in patients with BN have revealed a wide range of responses to the oral glucose tolerance test (OGTT) and suggested a close relationship between OGTT results and the presence of unstable eating habits.19–21 Recently, our studies have revealed that very early phase insulin metabolism, especially insulinogenic index at 15 min (II15 min), correlates well with nutritional improvement and eating behavior in patients with anorexia nervosa (AN).22,23 It is possible that II15 min may also be a useful biological marker of stable eating behavior in patients with BN. To assess the stability of eating behavior, we considered that weekly changes in body weight (BW), which mirrored patient’s nutritional progress or energy restriction,22 and the frequency of vomiting were of particular importance. The aim of this study was to determine the relationship between II15 min, BW maintenance, and the presence of vomiting in patients with BN.

Procedure

Methods

Delta BW ¼ BW on the seventh day ðkgÞ  BW on the first day ðkgÞ:

We treated patients with eating disorders in our inpatient unit using a multidisciplinary program consisting of a structured meal plan, nutritional counseling, group therapy, family therapy, and cognitive behavioral therapy.22,23,26 During the first week after admission (observation period), each patient was served meals totaling 8370 kJ (or 2000 kcal) per day. Activity was restricted and patients were only permitted to walk within the unit under staff observation; no excessive exercise was allowed. No further energy intake was permitted and no further behavioral intervention was applied during this period. Our staff observed the eating behavior of the patients directly, including watching patients for at least 2 h after meals. They evaluated the presence and frequency of vomiting (episodes/week), and recorded total amounts of daily energy intake of served meals. BW was measured at 0700 h on the first day and the seventh day, and changes in body weight during the first week after admission (delta BW) were calculated to assess BW maintenance:

Subjects Sixty-two women participated in this study. Fourteen were healthy control subjects and 48 were patients with BN who were admitted to our department for inpatient treatment of an eating disorder between January 1999 and December 2001. Informed consent was obtained from all subjects and controls before they began participating in this research, in accordance with the principles of the Declaration of Helsinki. All patients presented BN (binge eating/purging type). Diagnoses were carried out by trained interviewers using the Mini-International Neuropsychiatric Interview24 according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV).25 All patients used vomiting as a method of compensating for binges. None of the patients had a history of diabetes mellitus (DM) or alcoholic or other metabolic diseases that might affect glucose metabolism. The 14 controls were recruited by local advertisements and assessed by clinical interview; all were found to be mentally and physically healthy and suitable for participating in the study. Control subjects ate a normal diet and did not show any weight changes for at least 2 weeks before participation. In addition, they did not habitually use any medications, and had no personal or family history of DM or other metabolic disease.

Patients were divided into 4 subgroups according to the presence of vomiting and weight loss (delta BWo0 kg/week): (1) weight loss with vomiting (vomiting present, delta BWo0 kg/week); (2) weight loss without vomiting (no vomiting, delta BWo0 kg/week); (3) stable weight (or weight gain) with vomiting (vomiting present, delta BWX0 kg/ week); and (4) stable weight (or weight gain) without vomiting (no vomiting, delta BWX0 kg/ week). A standard OGTT was administered to each bulimic subject on the seventh day after admission, and control subjects underwent the OGTT in the outpatient unit of our department. Control subjects were advised to undergo no energy restriction, no excessive exercise, and no alcohol consumption for at least 3 days before participation. Blood samples were collected starting at 0700 h, after subjects had fasted overnight. To collect blood samples efficiently, a butterfly needle was inserted into a forearm vein, and the catheter was kept patent by a saline infusion with heparin as an anticoagulant. Subjects then drank a solution of 75-g glucose (Trelan G75, Shimizu Pharmaceutical Co., Ltd., Shizuoka, Japan) dissolved in 225 ml water for 3 min. Blood samples were collected at conventional OGTT times (0, 30, 60, 120 min) and also at 15 min after glucose administration. The

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blood samples were collected in tubes containing an antiglycolysis agent (NaF method), mixed well, and stored at 41C until the blood glucose concentrations could be measured with a glucose autoanalyzer (Hitachi 7170 Autoanalyzer, Hitachi Ltd., Tokyo, Japan). Centrifugal separation (2000  g for 5 min at room temperature) was performed and the plasma portions were stored at –201C until the serum insulin concentrations could be measured by radioimmunoassay. In addition to serum amylase concentrations, serum potassium and serum aspartate aminotransferase concentrations that might affect glucose metabolism were measured before glucose loading. No alcohol consumption was permitted during hospitalization. During testing, all participants rested in a recumbent position, and no other activity or eating was permitted.

Evaluation of early phase insulin metabolism To evaluate additional insulin secretion after eating, we calculated the insulinogenic index at 30 min (II30 min) during the OGTT. Some researchers have reported that, in patients with type 2 DM, II30 min values decrease to 0.4 with a 75-g glucose load, and that this index can be useful for evaluating the initial insulin secretion after glucose administration.27 The insulin secretion after eating consists of early (p30 min after loading) and late phases that arise in response to increased and peak blood glucose concentrations, respectively.28,29 Recently, our studies have indicated that very early phase (15 min after glucose loading) insulin metabolism correlated well with nutritional improvement in patients with AN.22 Therefore, to evaluate the very early phase insulin metabolism, we calculated the II15 min during the OGTT as follows: II15 min ¼ 0:0077  ðinsulin15 min ðpmol=lÞ insulin0

min

ðpmol=lÞÞ=ðblood glucose15

blood glucose0

min ðmmol=lÞ

min ðmmol=lÞÞ:

Evaluation of other glucose markers We evaluated glucose/insulin metabolism during the OGTT by measuring fasting serum insulin and blood glucose concentrations, the insulin area under the curve between 0 and 120 min, and the homeostasis model assessment for insulin resistance (HOMA-IR):30 HOMA-IR ¼ 2:48  ðblood glucose0  insulin0

min

min

ðmmol=lÞ

ðpmol=lÞ=405Þ:

Statistical analysis Data were generated using the Statviewt software program, version 5.0 (SAS Institute Inc., Cary, North Carolina). To evaluate demographic data, biological markers and glucose markers on the OGTT, including the II15 min value, were compared between subjects with BN and controls using one-factor analysis of variance (ANOVA) followed by post hoc Bonferroni correction. Two-factor ANOVA (vomiting  BW change) was used to analyze the results of all variables among BN subjects. Correlation coefficients of the II15 min value and frequencies of vomiting were calculated by linear regression analysis among bulimic patients with vomiting, and those of the II15 min value and other variables were calculated among all bulimic subjects. For glucose and insulin response curves, the main effects and interactions of the group (each BN subgroup and controls) and the time course (0, 15, 30, 60, 120 min) for both blood glucose and serum insulin concentration were evaluated among each BN subgroup and controls by two-factor repeated-measure ANOVA. When interaction (the group  the time course) was significant, one-factor ANOVA followed by post hoc Bonferroni correction evaluated the differences in blood glucose and insulin concentrations between group means at each time point on the OGTT. The results of subgroup analysis for demographics, glucose markers, and response curves on the OGTT were considered significant at Po0.01. All other results were considered significant at Po0.05.

Results All patients completed the study, resulting in a study population of 48 patients with BN (mean age, 21.573.4 years; mean BMI, 19.8 7 2.0 kg/m2) and 14 healthy controls (mean age, 23.171.5 years; mean BMI, 21.571.1 kg/m2). The 48 bulimic subjects were divided into 4 subgroups: 13 patients had weight loss and vomiting, 14 had weight loss with no vomiting, 10 had stable weight (or weight gain) with vomiting, and 11 had stable weight (or weight gain) and no vomiting.

Demographic and clinical data Table 1 shows the demographic and clinical variables of patients and controls. Two-factor ANOVA of biological markers revealed significant differences in the main effects for vomiting among bulimic subjects, with patients with vomiting showing significantly higher serum amylase concentrations

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Table 1

D. Yasuhara et al.

Demographic characteristics of bulimic patients and controls.n Stable weight

Age (yr) BMI (kg/m2)w,z Duration (yr)y Energyz,: Delta BW,ww,zz Potassiumyy,zz Amylase88, Aminotransferasewww

Weight loss

Controls

Vomiting n ¼ 10

No vomiting n ¼ 11

Vomiting n ¼ 13

No vomiting n ¼ 14

n ¼ 14

21.273.9 19.372.8 4.771.9 13607460 0.570.8 4.170.3 115.6741.1 16.577.0

20.873.3 20.471.9 3.171.6 15367304 1.170.6 4.270.3 92.3724.3 19.7710.2

21.973.8 19.471.6 4.672.0 12927472 1.270.6 3.970.4 103.3745.9 17.677.9

21.973.0 20.072.0 4.172.1 11037289 1.571.0 4.170.2 82.6727.0 17.976.2

23.171.5 21.571.1 F F F F F F

n

Data are mean7S.D. Body mass index (weight in kg/height in square meters) at 7th hospital day. z Significant differences among bulimic groups and controls, Po0:05 (one-factor ANOVA). y Duration of disease prior to admission. z Mean value of energy intake per day during first week after admission (kcal/day). : Significant main effect for body weight change, Po0:05 (two-factor ANOVA). nn Change values of body weight during first week after admission (kg/week). ww Significant main effect for body weight change, Po0:0001 (two-factor ANOVA). zz Significant interaction between vomiting and body weight change, Po0:05 (two-factor ANOVA). yy Serum potassium concentrations at 7th hospital day (normal range, 3.3–4.8 mmol/l). zz Significant main effect for vomiting, Po0:05 (two-factor ANOVA). 88 Serum amylase concentrations at 7th hospital day (normal range, 40–125 IU/l). nnn Significant main effect for vomiting, Po0:05 (two-factor ANOVA). www Serum aspartate aminotransferase concentrations at 7th hospital day (normal range, 11–29 IU/l). w

and lower serum potassium concentrations than patients with no vomiting. For mean values of daily energy intake during first week, a significant main effect was detected for BW change, with patients with weight loss showing a significantly lower daily energy intake than patients without weight loss. For delta BW values, significant interactions and main effects for BW change were detected. For BMI values, one-factor ANOVA detected a significant difference among subjects, but subgroup analysis by post hoc Bonferroni correction did not detect any differences. No other significant differences were seen between bulimic subjects and controls.

Glucose and insulin response curves during the OGTT Fig. 1 shows the pattern of blood glucose and serum insulin concentrations over the course of the OGTT in bulimic subjects and healthy controls. For blood glucose concentrations, analysis of variance (the group  the time course) showed no significant interaction and no main effect for the group, but revealed a significant main effect for the time course. For serum insulin concentrations, there was no significant interaction and no significant difference in the main effect for the group. There was a significant main effect for the time course. Very

early phase serum insulin concentrations, 15 min after glucose load, of bulimic subjects with stable weight (or weight gain) and weight loss who presented vomiting were significantly higher than those of other groups.

Glucose markers including the II15 min values Fig. 2 displays II15 min values for BN subjects and controls. Two-factor ANOVA of the II15 min values (vomiting  BW change) revealed that there were significant main effects for vomiting and BW change (Po0.001 for both), and no significant interaction. One-factor ANOVA of the II15 min values detected a significant difference among bulimic subjects and controls (Po0.0001), and the II15 min values for controls and bulimic patients with weight loss and no vomiting were found to be significantly lower than those of other groups. Table 2 displays the values for other glucose markers, showing that there were no significant differences among bulimic subjects and controls.

Relationship of the II15 min values and other biological/clinical variables Fig. 3 displays relationship of the II15 min values, serum potassium, and serum amylase concentra-

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Serum glucose concentration (mmol/L)

Insulinogenic index in bulimia nervosa

10 9

715

Weight loss with vomiting Stable weight with vomiting Weight loss with no vomiting Stable weight with no vomiting controls

8 7 6 5 4

Serum insulin concentration (pmol/L)

0

15

30 60 Time (minutes)

120

700 600 500 400 300

*

200

** **

100

† †

**

0 0

15

30

60

120

Time (minutes)

Figure 1 Blood glucose (top) and serum insulin (bottom) response curves during the oral glucose tolerance test in bulimic patients and 14 healthy controls (D) (means7SE). Patients were classified into 4 groups: 13 patients had weight loss and vomiting (K), 14 had weight loss and no vomiting (’), 10 had stable weight (or weight gain) and vomiting (J), and 11 had stable weight (or weight gain) and no vomiting (&). For blood glucose concentrations, analysis of variance (ANOVA) showed no significant interaction (P ¼ 0.67) and no main effect for the group (P ¼ 0.76), and revealed significant main effect for the time course (Po0.0001). For serum insulin concentrations, there was no significant interaction (P ¼ 0.36) and no significant difference in the main effect for the group (P ¼ 0.12). There was a significant main effect for the time course (Po0.0001). Subgroup analysis was performed by one-factor ANOVA followed by Bonferroni correction. *Po0.005 vs. patients with weight loss and vomiting. wPo0.005 vs. patients with stable weight (or weight gain) and vomiting. **Po0.0005 vs. patients with weight loss and vomiting.

tions in bulimic subjects. The II15 min values positively correlated with serum amylase values (r ¼ 0.37, Po0.01), whereas there were no significant correlations between the II15 min values and serum potassium concentrations. Fig. 4 displays the relationship of the II15 min value, body weight change, and frequencies of vomiting in bulimic subjects. The II15 min values were positively correlated with body weight change and frequencies of vomiting (r ¼ 0.35, Po0.05; r ¼ 0.49, Po0.05, respectively).

Discussion The major findings of this study were that (1) the II15 min values closely correlated with BW mainte-

nance and vomiting episodes; this index increased in patients with vomiting and decreased with weight loss, and (2) the II15 min values were positively correlated with serum amylase concentrations, BW change, and frequencies of vomiting. Our recent studies have shown that II15 min values correlate with weight gain during nutritional rehabilitation in patients with both subtypes of AN.22,23 In the current study, we observed similar findings of BW change in BN, suggesting that II15 min values were a good marker of BW maintenance despite marked differences in body mass index between patients with AN and BN. In addition, the very early phase insulin metabolism played an important role in bulimic symptoms involving vomiting in the present study as well as in nutritional improvement in AN,22,23 which would

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Insulinogenic index at 15 min

2.0

**, ††

1.8 1.6 1.4

*, †

*, †

1.2 1.0 0.8 0.6 0.4 0.2 0

Stable weight with vomiting

Weight loss with vomiting

Stable weight with no vomiting

Weight loss with no vomiting

Controls

Figure 2 Insulinogenic index at 15 min in patients with bulimia nervosa and 14 healthy controls. Patients were classified into 4 groups: 13 patients had weight loss and vomiting, 14 had weight loss and no vomiting, 10 had stable weight (or weight gain) and vomiting, and 11 had stable weight (or weight gain) and no vomiting. Two-factor analysis of variance (ANOVA) (vomiting  body weight change) revealed significant main effects for vomiting and body weight change (Po0.001 for both), and no significant interaction between vomiting and body weight change (P ¼ 0.86). Subgroup analysis was performed by one-factor ANOVA followed by Bonferroni correction. *Po0.005 vs. controls. w Po0.005 vs. patients with weight loss and no vomiting **Po0.0001 vs. controls. wwPo0.0001 vs. patients with weight loss and no vomiting.

Table 2

Other glucose markers in bulimic patients and controls.n Stable weight

FBGw FIRIz HOMA-IRy AUCz II30 min:

Weight loss

Controls

Vomiting n ¼ 10

No vomiting n ¼ 11

Vomiting n ¼ 13

No vomiting n ¼ 14

n ¼ 14

4.4370.55 42.12715.82 1.1670.48 792.977313.52 1.2670.58

4.4170.38 34.54713.70 0.9470.42 748.967523.64 0.8770.44

4.3070.55 36.64720.22 0.9970.58 893.067506.74 1.2571.01

4.3970.70 35.84722.42 1.0370.90 603.507480.23 0.9170.83

4.5670.53 37.33713.87 1.0670.46 692.757276.16 0.7270.44

n

Data are mean7SD. Fasting blood glucose concentration (mmol/l). z Fasting serum insulin concentration (pmol/l). y Homeostasis model assessment for insulin resistance (mmol pmol/l2). z Insulin area under the curve (h pmol/l). : Insulinogenic index at 30 min. w

indicate that very early phase insulin metabolism is noteworthy when assessing eating behavior in patients with eating disorders. Some researchers in BN have reported markers of vomiting, such as serum/urine electrolytes, urine pH, the ratio of urine sodium to urine chloride, and serum amylase concentrations,6–15 and others revealed those of nutritional status, such as T lymphocyte subsets, insulin-like growth factor 1, and plasma leptin concentrations.16–18 However, few studies had revealed the effects of both BW maintenance and abnormal eating behavior on each marker, making it difficult to assess the stability of eating behavior in patients with BN. In this study,

we examined serum potassium and serum amylase concentrations, which were reported to be strong markers for vomiting,6–8,10–14 and observed that both variables were good markers for vomiting, but not for BW maintenance. With regard to glucose markers, compared with the II15 min values, other variables in this study appeared to be insufficient to differentiate our subjects. These findings suggest that the II15 min value, which could assess chaotic eating patterns with periods of energy restriction and vomiting, was a useful factor; it is possible that this index was influenced by several gastrointestinal and nutritional factors, such as gastrointestinal mobility and gut hormones.22

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Insulinogenic index at 15 min

Insulinogenic index in bulimia nervosa

717

3.0 2.5 2.0 1.5 1.0 0.5 0 20

40

60

80

100

120

140

160

180

200

Insulinogenic index at 15 min

Serum amylase concentration (IU/L) 3.0 2.5 2.0 1.5 1.0 0.5 0 3.0

3.2

3.4

3.6

3.8

4.0

4.2

4.4

4.6

4.8

Serum potassium concentration (mmol/L) Figure 3 Relationship of the insulinogenic index at 15 min (II15 min) values, serum amylase (top) and serum potassium (bottom) concentrations in bulimic subjects. The II15 min values were positively correlated with serum amylase concentrations (r ¼ 0.37, Po0.01). There were no correlations between the II15 min value and serum potassium concentrations (P ¼ 0.24).

Metabolic aspects of abnormal eating behaviors have been reported in several studies on BN. Russell et al.21 reported that patients with BN who binged and vomited frequently had a blunted insulin response during the OGTT, and those who binged and vomited less often had exaggerated response patterns. These responses were normalized after treatment. Johnson et al.20 reported that bulimic subjects showed a dramatic reduction in both insulin and glucose concentrations after purging, with hypoglycemia playing an especially important role in binge/purge cycles. Casper et al.19 reported that, given BW maintenance and adequate nutrition, bulimic patients showed normal glucose tolerance after glucose load. These reports suggest the existence of a close relationship among the OGTT results, BW maintenance, and binge eating/vomiting cycles in bulimics. Our findings, in which the II15 min values correlated with BW maintenance and frequency of vomiting, were consistent with these previous studies.

Some researchers in BN have reported that several factors influenced glucose/insulin metabolism, such as gastrointestinal function,31 pancreatic B-cell function,32 and gut hormones.33 The current study was limited, as it did not examine these factors, and we could not determine the mechanism of the II15 min values. Recently, our studies revealed a close relationship between binge/purge cycles and plasma ghrelin concentrations in patients with BN;34 the mean plasma ghrelin levels in bulimics (purging type) were higher than those in both bulimics (non-purging type) and controls; in addition, there were positive correlations between plasma ghrelin concentrations and frequencies of binge/purge cycles. Ghrelin interacts with insulin secretion and is influenced by nutritional status.35,36 Therefore, we think that the ghrelin–insulin axis might play an important role in the mechanism of II15 min values. Further studies are needed to confirm these relationships.

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3.0 2.5 2.0 1.5 1.0 0.5 0 -4

-3

-2

-1

0

1

2

3

Insulinogenic index at 15 min

Body weight change (kg/week) 3.0 2.5 2.0 1.5 1.0 0.5 0 0

1

2

3

4

5

6

7

8

Frequency of vomiting (episodes/week) Figure 4 Relationship of the insulinogenic index at 15 min (II15 min) values, body weight change (top), and frequencies of vomiting (bottom) in bulimic subjects. The II15 min values were positively correlated with body weight change and frequencies of vomiting (r ¼ 0.35, Po0.05; r ¼ 0.49, Po0.05, respectively).

There were several limitations to the current study. Although we found that the frequency of vomiting and weight gain lead to increased II15 min values in bulimics, it is possible that this index could not differentiate patients with weight loss and vomiting from those with stable weight (or weight gain) and no vomiting. When assessing clinical status in bulimics using II15 min values, clinicians should consider that both of the foregoing factors mirror this index. We suggest that, in addition to our index, evaluations of other compensatory variables, such as serum amylase concentrations that appear to be positively correlated with II15 min values, are helpful for interpreting the II15 min values. Another limitation of this study was that we could not investigate a relationship between II15 min values and binge eating, despite the fact that binge eating is one of the core symptoms of BN. Close relationships between binge eating/vomiting cycles and the OGTT results have been suggested in previous BN studies,20,21 and thus we deemed that

II15 min values would relate to binge eating as well as to vomiting. In the current study, we observed that BN patients with larger amounts of daily energy intake (stable weight or weight gain groups) presented higher II15 min values compared with those with decreased energy intake (weight loss groups). Therefore, we speculated that bulimic patients with binge eating might show higher II15 min values than those with energy restriction or normal energy intake. Further research is needed to investigate the relationship between II15 min values and binge eating, which would be helpful for the assessment of eating behavior in patients with binge eating disorders, obesity, and other nutritional disorders. In summary, the II15 min values appeared to be a useful marker to assess the stability of eating behavior in patients with BN. Our findings also suggest that very early phase insulin metabolism plays an important role in eating patterns in patients with BN. This marker is easily obtained, and it takes only 15 min to get the results. Thus we

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think II15 min values could aid in the assessment of patients’ status during treatment for BN.

Acknowledgements This work was supported by a research grant from the Japanese Ministry of Health, Labor and Welfare. The authors thank Junko Tsutsui, Rie Isechi and Rumiko Takahashi for their assistance with preparation of this manuscript. We would like to thank Dr. D. Blake Woodside, University of Toronto, for his helpful comments on the manuscript.

References 1. Russell G. Bulimia nervosa: an ominous variant of anorexia nervosa. Psychol Med 1979;9:429–48. 2. Hall RCW, Hoffman RS, Beresford TP, Wooley B, Hall AK, Kubasak L. Physical illness encountered in patients with eating disorders. Psychosomatics 1989;30:174–91. 3. Fairburn CG, Beglin SJ. Studies of the epidemiology of bulimia nervosa. Am J Psychiatry 1990;147:401–8. 4. Beumont PJV, Beumont CC, Touyz SW, Williams H. Nutritional counseling and supervised exercise. In: Garner DM, Garfinkel PE, editors. Handbook of treatment for eating disorders. New York: Guilford Press; 1997. p. 178–87. 5. Vitousek KB, Daly J, Heiser C. Reconstructing the internal world of the eating-disordered individual: overcoming denial and distortion in self-report. Int J Eat Disord 1991;10: 647–66. 6. Pyle RL, Mitchell JE, Eckert ED. Bulimia: a report of 34 cases. J Clin Psychiatry 1981;42:60–4. 7. Greenfeld D, Mickley D, Quinlan DM, Roloff P. Hypokalemia in outpatients with eating disorders. Am J Psychiatry 1995;152:60–2. 8. Crow SJ, Salisbury JJ, Crosby RD, Mitchell JE. Serum electrolytes as markers of vomiting in bulimia nervosa. Int J Eat Disord 1997;21:95–8. 9. Crow SJ, Rosenberg ME, Mitchell JE, Thuras P. Urine electrolytes as markers of bulimia nervosa. Int J Eat Disord 2001;30(3):279–87. 10. Mitchell JE, Pyle RL, Eckert ED, Hatsukami D, Lentz R. Electrolyte and other physiological abnormalities in patients with bulimia. Psychol Med 1983;13:273–8. 11. Humphries LL, Adams LJ, Eckfeldt JH, Levitt MD, McClain CJ. Hyperamylasemia in patients with eating disorders. Ann Intern Med 1987;106:50–2. 12. Gwirtsman HE, Kaye WH, George DT, Carosella NW, Greene RC, Jimerson DC. Hyperamylasemia and its relationship to binge-purge episodes: development of a clinically relevant laboratory test. J Clin Psychiatry 1989;50:196–204. 13. Kronvall P, Fahy TA, Isaksson A, Theander S, Russell GFM. The clinical relevance of salivary amylase monitoring in bulimia nervosa. Biol Psychiatry 1992;32:156–63. 14. Kinzl J, Biebl W, Herold M. Significance of vomiting for hyperamylasemia and sialadenosis in patients with eating disorders. Int J Eat Disord 1993;13:117–24. 15. Arden MR, Budow L, Bunnell DW, Nussbaum MP, Shenker IR, Jacobson MS. Alkaline urine is associated with eating disorders. Am J Dis Child 1991;145:28–30.

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16. Marcos A, Varela P, Toro O, Nova E, Lopez-Vidriero I, Morande G. Evaluation of nutritional status by immunologic assessment in bulimia nervosa: influence of body mass index and vomiting episodes. Am J Clin Nutr 1997;66(2): 491S–7S. 17. Caregaro L, Favaro A, Santonastaso P, et al. Insulin-like growth factor 1 (IGF-1), a nutritional marker in patients with eating disorders. Clin Nutr 2001;20(3):251–7. 18. Monteleone P, Bortolotti F, Fabrazzo M, La Rocca A, Fuschino A, Maj M. Plasma leptin response to acute fasting and refeeding in untreated women with bulimia nervosa. J Clin Endocrinol Metab 2000;85(7):2499–503. 19. Casper RC, Pandy GN, Jaspan JB, Rubenstein AH. Hormone and metabolite plasma levels after oral glucose in bulimia and healthy controls. Biol Psychiatry 1988;24(6): 663–74. 20. Johnson WG, Jarrell MP, Chupurdia KM, Williamson DA. Repeated binge/purge cycles in bulimia nervosa: role of glucose and insulin. Int J Eat Disord 1994;15(4): 331–41. 21. Russell J, Hooper M, Hunt G. Insulin response in bulimia nervosa as a marker of nutritional depletion. Int J Eat Disord 1996;20:307–13. 22. Yasuhara D, Naruo T, Nagai N, Tanaka M, Muranaga T, Nozoe S. Insulinogenic index at 15 min as a marker of nutritional rehabilitation in anorexia nervosa. Am J Clin Nutr 2003;77(2):292–9. 23. Yasuhara D, Deguchi D, Tsutsui J, Nagai N, Nozoe S, Naruo T. A characteristic reactive hypoglycemia induced by rapid change of eating behavior in anorexia nervosa. Int J Eat Disord 2003;34(2):273–7. 24. Sheehan DV, Lecrubier Y, Sheehan KH, et al. The MiniInternational Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Pychiatry 1998;59(suppl 20):22–33. 25. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Association; 1994. 26. Tatebe Y, Nagai N, Munemoto T, Homan N, Naruo T, Nozoe S. Follow-up study of the patients with eating disorders after the inpatient treatment. Jpn J Psychosom Med 2002;42:661–8. 27. Kosaka K, Kuzuya T, Hagura R. Insulin response to oral glucose load is consistently decreased in established noninsulin-dependent diabetes mellitus: the usefulness of decreased early insulin response as a predictor of noninsulin-dependent diabetes mellitus. Diabetic Med 1996;13:109–19. 28. Curry DL, Bennett LL, Grodsky GM. Dynamics of insulin secretion by the perfused rat pancreas. Endocrinology 1968;83:572–84. 29. Porte Jr. D, Pupo AA. Insulin responses to glucose: evidence for a two pool system in man. J Clin Invest 1969;48:2309–19. 30. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and -cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–9. 31. Kal N, Chami T, Andersen A, Rosell FA, Schuster MM, Whitehead WE. Delayed gastrointestinal transit times in anorexia nervosa and bulimia nervosa. Gastroenterology 1991;101(5):1320–4. 32. Kobayashi N, Tamai H, Uehata S, et al. Pancreatic abnormalities in patients with eating disorders. Psychosom Med 1988;50(6):607–14.

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33. Tanaka M, Naruo T, Muranaga T, et al. Increased fasting plasma ghrelin levels in patients with bulimia nervosa. Eur J Endocrinol 2002;146:R1–3. 34. Tanaka M, Naruo T, Nagai N, et al. Habitual binge/purge behavior influences circulating ghrelin levels in eating disorders. J Psychiat Res 2003;37:17–22.

D. Yasuhara et al.

35. Saad MF, Bernaba B, Hwu CM, et al. Insulin regulates plasma ghrelin concentration. J Clin Endocrinol Metab 2002;87(8):3997–4000. 36. Date Y, Nakazato M, Hashiguchi S, et al. Ghrelin is present in pancreatic alpha-cells of rats and stimulates insulin secretion. Diabetes 2002;51(1):124–9.