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Psychosomatic Medicine 67:669-676 (2005)
© 2005 American Psychosomatic Society

ORIGINAL ARTICLES

Glucose Tolerance Predicts Short-term Refeeding Outcome in Females With Anorexia Nervosa

Daisuke Yasuhara, MD, Tetsuro Naruo, MD, PhD, Nobuatsu Nagai, MD, Tetsuro Muranaga, MD, Toshihiro Nakahara, MD, Muneki Tanaka, MD, PhD, Shinya Kojima, MD, Ken-ichiroh Sagiyama, MD, PhD, Akinori Masuda, MD, PhD and Akio Inui, MD, PhD

From the Department of Behavioral Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima-City, Japan.

Address correspondence and reprint requests to Daisuke Yasuhara, MD, Department of Behavioral Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima-City 890-8520, Japan. E-mail: yasuhara{at}m3.kufm.kagoshima-u.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Objective: Little is known about biologic predictors of refeeding outcome in anorexia nervosa (AN). Because nutritional status mirrors glucose metabolism during an oral glucose tolerance test (OGTT) in AN, this study investigated whether pretreatment glucose response patterns during the OGTT might be associated with refeeding progress in patients with AN.

Methods: Sixty-four female patients with anorexia (33 restrictors and 31 binge/purgers) and 13 healthy control subjects underwent an OGTT before nutritional rehabilitation, including desensitization to fear of energy intake of 1000 to 1600 kcal/day. Patients were divided into flat-type responders, impaired glucose tolerance (IGT)-type responders, and normal-type glucose responders. Daily energy intake, weekly weight gain, and the duration of desensitization period were evaluated until the 12th week.

Results: The patients with anorexia consisted of 20 flat-type, 21 IGT-type, and 23 normal- type responders. Normal-type responders required a shorter time to complete the desensitization period than other responders (p = .003 for restrictors, p < .001 for binge/purgers). In terms of refeeding progress, significant group effects for daily energy intake and weekly weight gain were evident in restrictors (p = .006, p = .028, respectively) and binge/purgers (p < .001, p = .003, respectively); normal-type responders showed good refeeding progress compared with other responders in both AN subtypes.

Conclusions: The present study found a close relationship between pretreatment glucose responses, therapeutic progress of desensitization to fear of energy intake, and refeeding progress in both AN subtypes. Our findings suggest that glucose tolerance may be a useful predictor of short-term refeeding outcome in this disorder.

Key Words: anorexia nervosa • fear of energy intake • energy intake • weight gain • oral glucose tolerance test • oral refeeding

Abbreviations: AN = anorexia nervosa; ANOVA = analysis of variance; AUC = insulin area under the curve; BMI = body mass index; DM = diabetes mellitus; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, fourth edition; FBG = fasting blood glucose concentration; FIRI = fasting serum insulin concentration; HOMA-IR = homeostasis model assessment for insulin resistance; IGT = impaired glucose tolerance; II15min = insulinogenic index at 15 minutes; OGTT = oral glucose tolerance test.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Anorexia nervosa (AN) is characterized by severe emaciation, abnormal eating behavior, and various malnutritional complications (1). Recent studies of long-term prognosis in AN have revealed that this disorder diminishes quality of life among adolescents and young adults (2,3). Although weight gain during hospitalization is an important prognostic factor for disease outcome (2), patients with AN are ambivalent about treatment and often experience poor refeeding progress. Thus, the identification of factors associated with the success of weight restoration is clinically important for this disorder. Earlier studies have reported several psychobehavioral predictors for weight restoration (4–6), but little is known about biologic predictors of refeeding outcome in this disorder.

Previous studies on AN have shown changes in glucose/insulin metabolism such as glucose intolerance (7,8), altered insulin sensitivity (9–11), and insulin resistance (12,13); these abnormalities were reversible after weight restoration. Recent studies have revealed characteristic changes in neuroendocrine parameters relevant to glucose metabolism (e.g., leptin, insulin-like growth factor 1, adiponectin, and ghrelin) during refeeding in this disorder (14–20). Moreover, we recently found that patients with AN who underwent rapid refeeding showed a reactive hypoglycemia and corresponding increased fear of energy intake during an oral glucose tolerance test (OGTT) (21–23); these abnormalities were reversible after refeeding. These findings suggest that normalization of abnormalities in glucose metabolism may be associated with weight restoration in patients with AN.

In an attempt to define a more useful predictor of weight gain during nutritional rehabilitation, we examined glucose metabolism, particularly glucose responses during the OGTT. Previous studies have shown that patients with AN present a broad spectrum of glucose response patterns to the OGTT, and flat-type and impaired glucose tolerance (IGT)-type responders were particularly observed in patients with AN before weight restoration (7,12,13). We proposed that patients with AN with these abnormalities in glucose tolerance on the pretreatment OGTT might show poor refeeding progress compared with those with normal glucose tolerance. The aim of this study was to determine whether pretreatment glucose response patterns during the OGTT might be associated with refeeding progress in patients with AN.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Subjects
Participants included patients with AN who were admitted to our department at the Kagoshima University Hospital or similar departments of our affiliated hospitals between January 1999 and December 2002. Diagnoses, including AN subtype, were carried out by trained interviewers using the Mini-International Neuropsychiatric Interview (24) according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) (25). Inclusion criteria were female gender; no personal history of diabetes mellitus (DM) or other metabolic diseases; no personal history of alcohol abuse, depressive disorders, bipolar disorders, or other psychotic disorders (e.g., schizophrenia by DSM-IV criteria); and no severe physical complications (e.g., pneumonia, gastric ulcer, or heart failure) (1). A total of 67 patients met the criteria and participated in the study. Of the 67 patients, 33 presented with AN, restricting type and 34 presented with AN, binge eating/purging type. In addition, 13 healthy female volunteers were recruited for participation by advertisement in a local community. They were assessed by clinical interview, and all were found to be mentally and physically healthy and suitable for participating in the study as controls. They did not habitually use any medications, and had no personal or family history of DM or other metabolic disease. They did not experience severe energy restriction (e.g., daily carbohydrate intake less than 150 g/day) during 3 days before the OGTT, and they did not show any weight changes for at least 2 weeks before participation. The Institutional Committee of Kagoshima University approved the protocol, and written informed consent was obtained from all participants after a complete description of the study was provided.

Institutional Treatment Program
During the first week after admission (observation period), our staff observed the eating behavior of the patients directly, including watching patients for at least 2 hours after meals. Each patient was served meals totaling 2000 kcal per day, and our staff recorded total amounts of daily energy intake of served meals; patients were not required to eat 100% of their food during this period. Activity was restricted with patients 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.

Thereafter, all patients with AN started a treatment program consisting of nutritional rehabilitation (oral refeeding) and cognitive behavior therapy (22). Initially, all patients were confined to bedrest and all stimuli, including contact with their families and friends, were controlled. The total energy of the daily diet started at 1000 kcal, and energy intake was increased gradually by 200 kcal per week until the daily diet reached 1600 kcal per day (desensitization period). Patients were required to eat 100% of their food during this period. Patients who failed to eat their food because of fear of energy intake were encouraged to start at the same stage of energy intake again. Completely eating the served meals for 1 week was positively reinforced by allowing the patient, step by step, to listen to the radio, watch TV, read books, or have contact with their families and friends; patients were also allowed to start at the next stage of energy intake. The total length of this period was expected to be approximately 4 weeks.

After patients completed the desensitization period, at the patient’s request, energy intake was increased gradually by 200 kcal per week until the daily diet reached 2000 kcal per day (refeeding period). During this period, weight increases of more than 0.5 kg per week were positively reinforced, and patients who failed to gain weight were encouraged to start at the same stage of energy intake again. The total length of this period was expected to be approximately 8 weeks. After an initial treatment course of 12 weeks (i.e., desensitization and refeeding periods), patients continued a further refeeding program in similar departments of affiliated hospitals.

Oral Glucose Tolerance Test and Classification of Glucose Response Patterns
A corrected OGTT was done on the patients on the seventh hospital day, according to our earlier research (22). After an overnight fast, blood samples were collected through a butterfly needle inserted into a forearm vein at 7:00 am. The catheter was kept patent by a saline infusion with heparin as an anticoagulant. Subjects then drank a solution of 1.75 g glucose/kg body weight (up to the maximum of 75 g glucose by World Health Organization criteria) dissolved in 225 mL of water (Trelan G75; Shimizu Pharmaceutical Co., Ltd., Shizuoka, Japan) over 3 minutes (26). Blood samples were collected at 0, 15, 30, 60, and 120 minutes after glucose administration. During testing, all patients remained recumbent and no activity or eating was permitted. Blood samples were collected and mixed in tubes containing an antiglycolysis agent (NaF method) and then stored at 4°C. Glucose concentrations were determined using a glucose autoanalyzer (Hitachi 7170 Autoanalyzer; Hitachi Ltd., Tokyo, Japan). Plasma was separated by centrifugation (2000 g for 5 minutes at room temperature), and insulin concentrations were measured by radioimmunoassay.

Patients were divided into 3 groups according to OGTT results by World Health Organization criteria (26): normal-type responders (fasting glucose concentrations <6.1 mmol/ L and 2-hour postprandial glucose concentrations <7.75 mmol/ L), IGT-type responders (fasting glucose concentrations from 6.1 to <7.0 mmol/L or 2-hour postprandial glucose concentrations from 7.75 to 11.1 mmol/ L), and DM-type responders (fasting glucose concentrations ≥7.0 mmol/ L or 2-hour postprandial glucose concentrations ≥11.1 mmol/ L). In addition, we evaluated flat-type glucose responders, defined as peak glucose concentrations <5.56 mmol/L during the OGTT; this response is frequently seen in patients with AN before weight restoration (7,12,13). Control subjects also underwent the corrected OGTT (Trelan G75; Shimizu Pharmaceutical Co., Ltd.), and they were advised to undergo no energy restriction, no excessive exercise, and no alcohol consumption for at least 3 days before participation.

Evaluation of Carbohydrate Metabolism and Other Variables
Before treatment, we examined the following carbohydrate variables (22,27,28): fasting serum insulin (FIRI), fasting blood glucose (FBG) concentrations, the insulin area under the curve, the homeostasis model assessment for insulin resistance (HOMA-IR), and the insulinogenic index at 15 minutes (II15 min), which has been shown to correlate well with weight gain and frequency of vomiting in patients with eating disorders (22,28). Serum potassium and aminotransferase concentrations that might affect glucose metabolism were also examined.

Evaluations of Progress During Desensitization Period, Daily Energy Intake, and Weekly Weight Gain During Refeeding
Our treatment program involved a desensitization program early in the treatment course. This method was used because we considered it necessary that the patient be desensitized to the fear of energy intake, which is 1 of the core symptoms in AN (21–23). To assess the extent of resistance to desensitization to the fear of energy intake, we evaluated the duration between start of treatment and completion of this period.

To assess the weekly progress during the desensitization and refeeding periods, we evaluated daily energy intake and weekly weight gain for 12 weeks. Our staff observed the eating behavior of the patients directly, including watching patients for at least 2 hours after meals, and they recorded total amounts of daily energy intake. With regard to weekly weight gain, we weighed the patients at 7:00 am every Thursday. To accurately evaluate weekly weight gain if we considered results to be questionable, we additionally weighed the patients at 7:00 am on Friday; this was done because patients with AN often manipulate their weight gain during nutritional rehabilitation (22). We applied the lower values for measuring weekly changes in body weight.

Statistical Analysis
Data were analyzed with SPSS software, version 10.0 (SPSS Inc., Chicago, IL). Demographics and carbohydrate variables were analyzed by 1-factor analysis of variance (ANOVA). For insulin response curves, the main effects and interactions of the group (each AN glucose responder type and controls) and the time course (0, 15, 30, 60, and 120 minutes) for serum insulin concentrations were evaluated among each AN glucose responder group and controls by 2-factor repeated-measures ANOVA. When interaction (the group x the time course) was significant, 1-factor ANOVA was used to evaluate differences in serum insulin concentrations between group means at each time point on the OGTT. Kaplan-Meier survival analysis and the log rank t test were used to evaluate therapeutic progress during desensitization period among patients with AN; the clinical end point was the completion of the desensitization program, and patients with AN who did not complete the desensitization program in 12 weeks were censored. For refeeding progress, the main effects and interactions of the group (each type of AN glucose responder) and the treatment course (pretreatment and the first to 12th week during desensitization and refeeding periods) for daily energy intake and weekly weight gain were evaluated among AN glucose responders by 2-factor repeated-measures ANOVA. Subgroup analysis was done during each hospital week during treatment. With regard to 1-factor ANOVA, post hoc Bonferroni correction was done for glucose responders (alpha, p < .016) and all subjects (alpha, p < .012). All other results were considered significant at p < .05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
All but 3 patients completed the study; the 3 patients who dropped out (all binge/purgers) consisted of 1 flat-type responder and 2 IGT-type responders. There were no DM-type responders. All control subjects completed the study. The total study population consisted of 64 patients with AN, including 20 flat-type responders, 21 IGT-type responders, and 23 normal-type responders, as well as 13 controls.

Demographics and Carbohydrate Variables
Significant group effects in mean values of daily energy intake and daily carbohydrate intake during the first week after admission (observation period) were detected among the various types of AN restrictors (F[2, 30] = 4.15, p = .026; F[2, 30] = 3.94, p = .030). Significant group effects in body mass index (BMI) at admission, lowest ever BMI after the onset of AN, FBG, FIRI, HOMA-IR, and II15 min values were detected among the various types of AN restrictors and controls (F[3, 42] = 127.78, p < .0001; F[3, 42] = 173.66, p < .0001; F[3, 42] = 4.63, p = .007; F[3, 42] = 3.99, p = .014; F[3, 42] = 4.76, p = .006; F[3, 42] = 3.77, p = .018, respectively). Table 1 shows the differences between the individual groups. Daily energy intake and daily carbohydrate intake during the observation period were significantly lower in IGT-type responders than in normal-type responders. Values of BMI at admission and lowest ever BMI after the onset of anorexia nervosa were significantly higher in controls than in patients with AN. FBG values of flat- and IGT-type responders were significantly lower than those of controls. FIRI values of normal-type responders were significantly lower than those of controls. HOMA-IR values of normal- and IGT-type responders were significantly lower than those of controls. The II15 min values for flat-type responders were significantly higher than values in IGT-type responders and controls.


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  		TABLE 1. Demographic and Carbohydrate Variables in Patients With Anorexia Nervosa and Controls

 

As shown in Table 1, significant group effects in BMI at admission, lowest ever BMI after the onset of anorexia nervosa, FBG, and II15 min values were detected among binge/purgers and controls (F[3, 40] = 60.38, p < .0001; F[3, 40] = 60.55, p < .0001; F[3, 40] = 4.56, p = .008; F[3, 40] = 15.85, p < .0001, respectively). Values of BMI at admission and lowest ever BMI after the onset of AN were significantly higher in controls than in patients with AN. FBG values of flat- and IGT-type responders were significantly lower than those of controls. The II15 min values for flat-type responders were significantly higher than values in other groups.

Glucose and Insulin Response Curves
As shown in Figure 1, 2-factor repeated-measures ANOVA in restrictors and controls revealed significant main effects of time course for serum insulin concentrations (F[4, 168] = 25.64, p < .0001). We detected no significant main effects of the group for serum insulin concentrations (F[3, 42] = 1.45, p = .24). Significant interactions between the group and the time course for serum insulin concentrations were detected (F[12, 168] = 3.79, p < .0001). Figure 1 also shows that peak values of blood glucose concentrations (mean ± standard deviation [SD], 5.02 ± 0.46 mmol/L) occurred at 30 minutes in flat-type responders. With respect to IGT-type responders, peak values of blood glucose concentrations (mean ± SD, 9.34 ± 3.26 mmol/L) occurred at 120 minutes; corresponding insulin concentrations (120 minutes) were higher than those of other responders.



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  		Figure 1. Mean ± standard error blood glucose (top) and serum insulin (bottom) response curves during the oral glucose tolerance test in patients with anorexia nervosa (restricting type) and healthy controls. *p < .01 versus controls, {dagger}p < .01 versus impaired glucose tolerance-type responders.

 

As shown in Figure 2, 2-factor repeated-measures ANOVA in binge/purgers and controls revealed significant main effects of time course for serum insulin concentrations (F[4, 160] = 22.68, p < .0001). We detected no significant main effects of the group for serum insulin concentrations (F[3, 40] = 0.06, p = .98). Significant interactions between the group and the time course for serum insulin concentrations were detected (F[12, 160] = 2.08, p = .021). Figure 2 also shows that peak values of blood glucose concentrations in flat-type responders (mean ± SD, 4.73 ± 0.65 mmol/L) occurred 15 minutes after the glucose load. With respect to IGT-type responders, peak values of blood glucose concentrations (mean ± SD, 8.81 ± 2.34 mmol/L) occurred at 120 minutes.



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  		Figure 2. Mean ± standard error blood glucose (top) and serum insulin (bottom) response curves during the oral glucose tolerance test in patients with anorexia nervosa (binge/purging type) and healthy controls. *p < .01 versus controls.

 

Relationship Between Pretreatment Glucose Responses and Progress of the Desensitization Period
In terms of effects of pretreatment glucose response on progress of desensitization period in restrictors (Fig. 3), significant differences among glucose responders emerged ({chi}2 = 11.85, p = .003). The 7 censored patients consisted of 3 flat-type responders and 4 IGT-type responders. Flat-type responders (mean ± standard error [SE], 7.90 ± 1.05 weeks) and IGT-type responders (mean ± SE, 7.91 ± 0.97 weeks) required a longer time to complete the desensitization period than normal-type responders (mean ± SE, 4.58 ± 0.29 weeks).



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  		Figure 3. The Kaplan-Meier curves for therapeutic progress during desensitization period in restricting (left) and binge/purging (right) patients with anorexia nervosa. *p < .01 versus normal-type responders.

 

With regard to binge/purgers (Fig. 3), significant differences among glucose responders also emerged ({chi}2 = 14.28, p < .001). The 8 censored patients consisted of 2 flat-type responders and 6 IGT-type responders. Flat-type responders (mean ± SE, 8.40 ± 0.95 weeks) and IGT-type responders (mean ± SE, 9.70 ± 1.06 weeks) required a longer time to complete the desensitization period than normal-type responders (mean ± SE, 5.18 ± 0.44 weeks).

Relationship Between Pretreatment Glucose Responses and Daily Energy Intake During Refeeding
In terms of daily energy intake in restrictors (Fig. 4), 2-factor repeated-measured ANOVA revealed significant main effects of the group and the treatment course for daily energy intake (F[2, 30] = 6.01, p = .006; F[11, 330] = 126.74, p < .0001, respectively). Significant interactions between the group and the time course for daily energy intake were also detected (F[22, 330] = 2.50, p < .001). We detected significant group effects for weight gain between the first and 12th weeks during desensitization and refeeding periods: normal-type responders showed more daily energy intake than IGT-type responders.



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  		Figure 4. Mean ± standard error daily energy intake during desensitization and refeeding periods in restricting (left) and binge/purging (right) patients with anorexia nervosa. *p < .01 versus normal-type responders, {dagger}p < .001 versus normal-type responders.

 

With regard to binge/purgers (Fig. 4), 2-factor repeated-measures ANOVA revealed significant main effects of the group and the treatment course for daily energy intake (F[2.28] = 9.69, p < .001; F[11, 308] = 124.87, p < .0001, respectively). Significant interactions between the group and the time course for daily energy intake were detected (F[22, 308] = 4.95, p < .0001). We detected significant group effects for daily energy intake between the second and 12th weeks during desensitization and refeeding periods: normal-type responders showed more daily energy intake than other responders.

Relationship Between Pretreatment Glucose Responses and Weekly Weight Gain During Refeeding
In terms of weekly weight gain in restrictors (Fig. 5), 2-factor repeated-measures ANOVA revealed significant main effects of the group and the treatment course for weight gain (F[2, 30] = 4.02, p = .028; F[12, 360] = 77.75, p < .0001, respectively). Significant interactions between the group and the time course for weekly weight gain were also detected (F[24, 360] = 3.19, p < .0001). We detected significant group effects for weekly weight gain between the eighth and 12th weeks during desensitization and refeeding periods: normal-type responders gained more weight than other responders.



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  		Figure 5. Mean ± standard error weekly weight gain during desensitization and refeeding periods in restricting (left) and binge/purging (right) patients with anorexia nervosa. *p < .01 versus normal-type responders, {dagger}p < .001 versus normal-type responders.

 

With regard to binge/purgers (Fig. 5), 2-factor repeated-measures ANOVA revealed significant main effects of the group and the treatment course for weekly weight gain (F[2, 28] = 7.04, p = .003; F[12, 336] = 55.93, p < .0001, respectively). Significant interactions between the group and the time course for weekly weight gain were detected (F[24, 336] = 6.00, p < .0001). We detected significant group effects for weekly weight gain between the fourth and 12th weeks during desensitization and refeeding periods: normal-type responders gained more weight than other responders.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
The most important findings of this study were that, in both AN subtypes, both flat-type responders and IGT-type responders gained less weight during desensitization and refeeding periods compared with normal-type responders. We found significant differences in the duration of the desensitization period among patients with AN, suggesting that flat-type responders and IGT-type responders may have difficulties becoming desensitized to their fear of energy intake compared with normal-type responders. We deem that these difficulties lead to a slower rate of weekly weight gain through reduced daily energy intake in flat- and IGT-type responders. Moreover, we found low daily energy intake and low daily carbohydrate intake before the OGTT (observation period) in restricting IGT-type responders, suggesting that the OGTT response might be a proxy for nutritional status before therapeutic intervention. Patients with AN with abnormal responses at baseline might have been sicker in some way (e.g., severe energy restriction) compared with those with normal responses, which might also affect refeeding progress in these patients. The present findings support our hypotheses and extend previous findings by showing that abnormalities in pretreatment glucose tolerance correlates with not only undernutrition before weight restoration (7–13), but also to resistance to becoming desensitized to the fear of energy intake and reduced daily energy intake, which led to a slower rate of weekly weight gain in patients with AN.

In this study, the relationship between the resistance to becoming desensitized to the fear of energy intake and glucose responder types was noteworthy despite the fact that the mechanism for this finding was unclear. In addition to low daily energy intake and low daily carbohydrate intake during the observation period in restricting IGT-type responders, we detected lower FBG values in flat- and IGT-type responders than normal-type responders in both AN subtypes. We suggest that low FBG values may be associated with blunted glucose metabolism, because previous studies have shown that blunted glucose metabolism may be correlated with prolonged starvation (12,13,29) and represent a way to preserve calories by enhancing energy storage (i.e., lipogenesis) (30,31) in this disorder. Therefore, it is possible that flat- and IGT-type responders might experience severe undernutrition before therapeutic intervention, which might affect their resistance to becoming desensitized to the fear of energy intake. On the other hand, some research on carbohydrate metabolism has shown that the perception of hunger in response to insulin-induced hypoglycemia was disturbed in patients with AN (32). Moreover, our recent reports have shown that patients with AN with good response to oral refeeding showed increased early-phase insulin secretion during the OGTT (22), but patients with AN with excessive and rapid refeeding showed reactive hypoglycemia and corresponding increased fear of energy intake during the OGTT (23). These reports suggest that there are psychological effects of glucose metabolism on food intake in this disorder, and it is possible that these factors also play an important role in refeeding progress in treatment-resistant patients. Thus, future studies in terms of biopsychological aspects of refeeding progress among glucose responders may be an important step in understanding the core psychopathology in this disorder.

The mechanism of glucose response in patients with AN has not been well documented. Previous researchers have considered prolonged starvation and gastrointestinal dysfunction to be associated with flat-type responders; in addition, delayed gastric emptying, beta-cell dysfunction, insulin resistance, and impaired regulation of neuroendocrine parameters (e.g., ghrelin) are correlated with IGT-type responders (12,13,29,33,34). In addition to low daily carbohydrate intake during the observation period in IGT-type responders and low FBG values in flat- and IGT-type responders, which might represent blunted glucose metabolism relevant to prolonged starvation (12,13,29), we found significant high II15 min values in flat-type responders. In restrictors, we suggest that increased daily energy intake during the observation period might mirror II15 min values in flat-type responders (22,28). In binge/purgers, it is possible that effects of other factors (e.g., binge eating or vomiting) might exist in flat-type responders (22,28). We deem that the mechanism of these treatment-resistant patients might be associated with pretreatment undernutrition and rapid change in eating behavior early in the treatment course (21). Responder type appeared to be associated with refeeding progress in this study, and thus further investigations of the mechanism of the different response types could shed light on the treatment of AN.

In terms of other predictors of refeeding outcome in AN, some studies have revealed that the prevalent psychiatric disorder (e.g., depressive disorders, personality disorders, and psychotic disorders) seemed to predict clinical outcome in the short-term (6). Other studies also addressed no previous hospitalizations, no denial of illness, the presence of hunger, overactivity before treatment, high premorbid body weight, and binge/purging subtype as predictors of good outcome (4,5,35). These previous studies suggested that refeeding outcome was influenced by multiple factors relevant to the pathophysiology of this disorder. The present study clearly showed a close relationship between pretreatment glucose responses and refeeding progress in both AN subtypes; thus, it appears that further research examining the foregoing psychobehavioral/nutritional factors relevant to each glucose responder is needed.

There were several limitations to this research. First, we could not examine the impact of energy expenditure on refeeding outcome in each glucose responder. With respect to restrictors, there were no significant differences in daily energy intake between flat- and normal-type responders despite significant differences in weekly weight gain, suggesting that refeeding progress in flat-type responders might be influenced by increases in activity-induced or diet-induced thermogenesis (30,31). Second, the nutritional intervention in this study, which would be a common refeeding paradigm in Japan (22), was atypical for other countries; however, we considered it necessary for the patient to be desensitized to the fear of caloric intake, especially early in the treatment course (21). Our findings showed significant differences in refeeding progress among glucose responders, despite a less aggressive refeeding paradigm than some other programs; thus, further research with common nutritional interventions is required to confirm our findings. Finally, we could not examine the impact of pretreatment glucose tolerance on long-term refeeding outcome. Chronicity after weight restoration (2,3) and suicidality, which is appeared to be affected by metabolic factors (36), is a serious problem in patients with longstanding AN; thus, the relationship between glucose tolerance and long-term refeeding outcome will be the subject of further research.

In summary, we found a close relationship between pretreatment glucose responses, therapeutic progress of desensitization to fear of energy intake and refeeding progress during oral refeeding in both AN subtypes. Our findings imply that glucose tolerance might be a useful predictor of short-term refeeding outcome in patients with AN. Clinicians should consider careful monitoring and assessment of glucose metabolism in this disorder, which could provide useful data to predict responses to an oral refeeding program. Flat- and IGT-type responders may require other refeeding approaches that encourage increased energy intake and weight gain early in the treatment course in addition to an oral refeeding.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 

This work was supported by a research grant from the Japanese Ministry of Health, Labor and Welfare. We acknowledge Shin-ichi Nozoe and Ryuji Kubota for helpful discussions during the preparation of the manuscript.

DOI:10.1097/01.psy.0000170332.47378.a1


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 

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