Insulin, Glucose, and Cortisol Levels in Bulimia: Effect of

Treatment

janice Russell, F.R.A.N.Z.C.P., F.R.A.C.P. Michael Hooper, F.R.A.C.P.

Leonard Storlien, Ph.D. G.A. Smythe, Ph.D.

(Accepted 20 August 1988)

A study is described in which a modified glucose tolerance test was performed in each of five bulimic female patients on two separate occasions. Two of the patients were poorly controlled outpatients and three were inpatients in a strict hospital pro- gram of nutritional rehabilitation and psychotherapy. Plasma glucose, insulin, and cortisol levels, in response to a glucose load and following 3 days of normal nutri- tion, were compared with those documented following engagement in various bu- limic behaviors during the preceding 24 hours (i.e., fasting, binging, and vomiting.). In all five patients, following bulimic behaviors, peak insulin levels in response to a glucose load and the area under the curve of insulin secretion was increased whereas cortisol levels were lower, even in the one patient who was hypercorti- solemic. However, the insulin peaks were less in evidence in the treated patients than in those who continued to engage in bulimic behavior, and there was also less evidence of cortisol suppression in the treated patients. Furthermore, insulin secre- tion as measured by T,,, occurred more rapidly after engagement in bulimic be- havior and was delayed in treated patients following normal nutrition. lt is postulated that insulin potentiation and suppression of stress hormones as reflected by serum cortisol are important self-perpetuating mechanisms in bulimia and that these are related to the occurrence of intermittent starvation and its relief through binge eating. Treatment reduces this effect by reestablishing regular nutrition.

Self-induced starvation is an important component of both anorexia nervosa and bulimia (Pirke et al., 1985) where binge eating has been said to represent

Janice Russell, F.R.A.N.C.Z.P., F.R.A.C.P., is Senior Lecturer, Department of Psychiatry, University of Sydney and Repatriation General Hospital, where Michael Hooper, F.R.A.C.P., is Senior Staff Specialist, Department of Endocrinology. Leonard Storlien, Ph.D., is Senior Research Officer, Garvan Institute, St. Vincent’s Hospital, where C. A. Smythe, Ph.D., is Head, C. E. Heath Neuroscience Laboratory. Address reprint requests to Dr. 1. Russell, Room 6, Clinical Sciences Bldg., Repatriation Hospital, Hospital Rd., Concord NSW 2 139, Australia.

International lournal of Eatfng Disorders, Vol 8, No 6, 635-646 (1 989) 0 1989 by John Wiley & Sons, Inc CCC 0L76-~478/89/0606j5-11$04 00

636 Russell et al.

the physiological response (Russell, 1979; Mitchell et al., 1985). Constitutional, psychological, and maturational factors may determine the extent of this, which may then be countered by the bulimic patient engaging in various forms of purgation and intermittent abstinence from food. One mechanism whereby binge eating might be facilitated is the potentiation of insulin secretion in re- sponse to carbohydrate ingestion following starvation as demonstrated in a single case study of a bulimic patient by Russell et al. (1987). Schweiger et al. (1987) showed increased insulin secretion in bulimic patients following a test meal which lends further support to this hypothesis. In animal models corti- costerone levels are directly related to central noradrenergic activity where both are suppressed by glucose administration and increased plasma glucose (Smythe et al., 1983, Smythe et al., 1984). Thus corticosterone levels might be expected to reflect central noradrenergic activity, and if these reflect physiolog- ical stress, carbohydrate intake and binge eating may alleviate this (Storlein et al., 1985). Mood changes recognized in bulimia might be triggered by this mechanism.

In an effort to demonstrate these phenomena and the effects of treatment, five chronic bulimic patients were studied before and after engagement in bu- limic behavior in order to compare the responses of insulin, glucose, and corti- sol to a glucose load using the model of bulimic behavior proposed by Russell et al. (1987). Two patients were untreated outpatients, whereas three were par- ticipating in a hospital residential program composed primarily of nutritional rehabilitation and psychotherapy.

PATIENTS A N D METHODS

Five female patients who met DSM-III-R diagnostic criteria for bulimia ner- vosa were studied on two separate occasions at least 7 days apart (American Psychiatric Association, 1987). Patients 1 and 2 were untreated, whereas pa- tients 3, 4, and 5 were treated, receiving 7, 4, and 2 weeks of treatment, respec- tively, immediately prior to testing. Their ages ranged from 20 to 26 years and their body mass indices were between 18 and 24. All subjects gave informed consent to the procedure. Two modified glucose tolerance tests were per- formed in each subject using a 100-g glucose load. Blood was sampled at base- line and at 30-minute intervals for 3 hours via an indwelling cannula which was inserted in a forearm vein 60 minutes prior to administration of the glu- cose load at 9 a.m. Patients remained supine throughout the period of testing and were given lunch at the conclusion of testing. Blood samples were imme- diately spun down and frozen prior to transport to the laboratory. Analyses for glucose were performed using a standard enzymatic method. Insulin was de- termined by standard radioimmunoassay and cortisol by gas chromatography/ mass spectrometry according to the methods described by Smythe et al. (1983, 1984).

Preparation for the glucose tolerance test varied in the two test situations. Patients were tested on one occasion after eating normally for 3 days; they doc- umented types and quantities of all foods and beverages ingested and the times at which this occurred. They were tested on another occasion after en- gaging in their usual combination of bulimic behaviors over a period of at least

Bulimia: Effect of Treatment 637

24 hours prior to testing. Again they were asked to document, in a detailed manner, all foods and beverages ingested during this period, along with the occurrence of vomiting and abstinence from food. All patients fasted from 9 p.m. on the evening preceding testing and were asked to drink only water from that time until they came to the laboratory. Testing in the postbinge situation preceded testing in the control situation in patients 1 (untreated) and 3 (treated). Reverse order was observed in the other three patients. A period of 1-4 weeks elapsed between testing. One patient (patient 1) was maintained on thyroxin, 100 pg daily: she was clinically euthyroid. Another (patient 5) was taking a low dose oral contraceptive pill. All patients were asked specifically to avoid using laxatives or any other medications in the month prior to testing.

The area under the curve of insulin secretion was calculated using the trape- zoid rule.

RESULTS

All five patients engaged in definite binge eating, ingesting on average 5200 calories in the 24 hours before testing. In all but one (patient 2) this repre- sented a mean increase of 3,400 calories above documented "normal" intake [although both untreated patients (patients 1 and 2) frequently starved for long periods (up to 48 hours) or ate abstemiously between binges). In patient 2, whose usual calorie intake was higher, this increase in energy after binging was documented as being 2000 calories. Patients 1, 3, and 5 admitted to vom- iting repeatedly in the course of bulimic behavior, usually following ingestion of a large quantity of energy-rich food items (see Tables 1-3).

Insulin Levels

Insulin levels are shown in Figure 1. Insulin levels in response to a glucose load demonstrated a potentiation in all patients following engagement in bu- limic behavior (mean 128 mU/L following bulimic behavior compared with a mean 86 mU/L following normal nutrition). Peaks of 166 and 196 mU/L, repre- senting an increase of more than 100% and 60% (respectively) in C,,, insulin over that occurring in the control situation, were seen 60 minutes after glucose load in patients 1 and 2 with second peaks occurring at 150 and 180 minutes, respectively. Similarly, insulin peaks were observed in the treated patients, but C,,, for insulin was lower in all 3 than in the first 2 subjects (ranging from 101 to 77 mU/L). Insulin peaks after binging represented an increase of less than 40%, lo%, and 30% over C,,, for insulin in the control situation. The mean of the area under the curve for insulin secretion was greater overall after bulimic behavior (418 mU/L/30 min) than after normal nutrition (333.6 mU/L/30 min. Ratios of the areas under the curve for insulin secretion following bulimic be- havior compared with that after normal nutrition were 1.7 and 1.4 for patients 1 and 2 (mean 1.6), respectively, and 1.0, 0.9, and 1.5 (mean 1.3) in the treated patients. Time to maximal insulin level (Tmax) was substantially longer in treated patients following normal nutrition than after bulimic behavior, in-

638 Russell et al

Table 1. to OGTT and following bulimic behavior in preceding 24 hours.

Levels of glucose, insulin, and cortisol in response

Glucose Cortisol Patient Time (min) (mmoliL) Insulin (mUIL) (nmollL)

1 -15 0

30 60 90

120 150 180

2 - 15 0

30 60 90

120 150 180

3 -15 0

30 60 90

120 150 180

4 - 15 0

30 60 90

120 150 180

5 - 15 0

30 60 90

120 150 180

4.6 4.5 7.3 8.2 7.5 6.2 6.3 4.6 4.2 4.2 5.5 5.2 4.7 4.8 4.2 4.8

4.5 4.3 6.9 9.3 6.8 5.1 5.8 5.9

4.3 4.0 6.3 7.4 6.1 5.3 4.4 4.7

4.8 4.7 5.6 7.3 6.2 6.0 5.0 4.8

6.01<3.2 <3.212.1

84 166 96 38 73 26

3.2 3.2 96

196 131 89 64 90

4.3 7.9 42 64 99 44 49 32

5.0 4.4 101 40 56 68 57 88

3.5 3.8 48 77 56 69 47 33

199 152 119 81

176 182 229 176 300 431 480 367 313 243 347 361

45 1 448 487 418 370 331 279 372

440 388 368 356 463 473 377 310

1343 1156 1013 838 829 851 733 639

creasing by a factor of 2.8 (range 90-120 min). T,,, was little changed in un- treated patients (range 30-60 min) whether they engaged in bulimic behavior or normal eating over the preceding 3 days.

Cortisol levels

Cortisol levels are presented in Figure 2. In patients 1 and 2 cortisol levels were lower after engagement in bulimic behavior, being below the normal range in patient 1. It should be noted that these levels were early morning cor-

Bulimia: Effect of Treatment 639

Table 2 . to OGTT and following 3 days of normal nutrition.

Levels of glucose, insulin, and cortisol in response

Glucose Cortisol Patient Time (min) (mmol/L) Insulin (mU/L) (nMoliL)

1 - 15 0

30 60 90

120 150 180

2 - 15 0

30 60 90

120 150 180

3 - 15 0

30 60 90

120 150 180

4 -15 0

30 60 90

120 150 180

5 -15 0

30 60 90

120 150 180

4.0 4.7 6.1 7.0 5.7 6.3 6.2 5.8 4.5 4.1 5.5 5.0 5.1 5.1 4.5 4.1

4.7 4.5 6.8 7.2 6.1 4.9 4.6 4.4

4.1 4.2 5.9 7.3 6.3 6.4 5.1 4.3

4.9 5.0 5.3 6.6 6.3 5.1 4.4 4.3

3.2 3.2 33 80 66 58 32 24

21 12

126 59 85

106 55 34

4.5 7.4 62 51 65 73 49 37

3.1 58 58 75 94 87 63 57

7.3 4.1 3.9 30 40 58 54 28

25 1 217 253 282 257 35 1 236 228 229 503 559 505 450 395 266 243

465 450 439 377 356 336 298 245

470 444 416 433 409 371 357 374

1157 2039 1034 1144 981 956 910 780

tisols which would be expected to be near or in the upper part of the normal range at 9 a.m., which is the case in patient 2 in the control situation. In this pa- tient, though, cortisols fell, reaching the lower part of the normal range by ll a.m. In all three of the treated patients, cortisols were lower after engagement in bulimic behavior. In patients 3 and 4 after 4 weeks of treatment little difference was observed following ingestion of the glucose load. Patient 5 demonstrated hy- percortisolemia in both test situations, but following bulimic behaviour (and 2 weeks of treatment) her cortisols had almost reached the normal range by the end of the period of testing, being lower than in the control situation.

640 Russell et ill.

Table 3. occasions using a modified glucose tolerance test.

Summarizing the data concerning five bulimic patients tested on two

AUC T (rnin) C (mUIL) Energy (cal) (mUILI30 min) Max. Ins. Max. Ins.

Pt. Rx Status & No. BMI Age Duration Normal Bulimic N B N B N B

~-

1 22 26 OiP only 1500 5000 283.6 471.2 60 60 80 166 2 24 19 OiP only 2500 4500 456.3 622.6 30 60 126 196 3 19.5 19 8 weeks 1500 5000 318.5 314.5 120 60 73 99

4 18-19 20 7 weeks 1500 5500 406.9 368.4 90 60 94 101 IIP only

OIP & IIP 1 week IIP 2 weeks OIP 4 weeks IIP

OIP & IiP 5 23 26 2 weeks 2000 6000 202.8 313.4 120 60 58 77

Mean 1800 5200 333.6 418.0 85 60 86 128

Glucose Levels

Glucose levels are presented in Figure 3. Following bulimic behavior and glucose load, glucose levels in one untreated patient and one of the treated pa- tients exceeded 8 mmoliL. This would be considered to be in the doubtful area of glucose tolerance, but in all patients there was a rapid return to baseline lev- els by the end of the period of testing.

DISCUSSION

The limitations of the study are acknowledged. These include the small size of the sample, patients’ differing interpretation of bulimic behavior, the lack of spontaneity of their bulimic behavior, their variable compliance with instruc- tions and possibly faulty documentation of their eating behaviors. Neverthe- less, the patients’ reported consumption of calories during binging is comparable with that documented by Johnson et al. (1984). Although it is un- wise to make inferences concerning central events from peripheral levels of metabolites, it may be that peripheral levels of insulin and glucose (Morley & Levine, 1985; Blundell 1988) and possibly cortisol are more relevant to the ex- perience of hunger and satiety, particularly in bulimic patients.

The shortcomings of this limited study notwithstanding, insulin potentiation was again demonstrated following bulimic behaviors as indicated by an almost twofold increase in C,,, for insulin in patients 1 and 2 a similar although less striking finding to that obtained in an earlier study (Russell et al., 1987). Simi- larly, the ratio of areas under the curves of insulin secretion following bulimic behavior compared with normal nutrition was increased in all patients, but less so in the two patients (3 and 4) treated for more than 4 weeks. In all treated patients insulin secretion occurred at a substantially slower rate following nor- mal eating behavior. After bulimic behavior in treated patients and in un- treated patients, regardless of preceding eating behavior, peak insulin levels were reached early (i.e., after 60 min), suggesting that the rapidity of insulin

Bulimia. Effert of Trpatrnent

UNTREATED PATIENTS

64 1

Figure 1. The effect of an oral glucose load on plasma insulin in 5 patients following bulimic behavior (8) and following normal eating behavior (C). Untreated patients (n = 2) are shown at the top and treated patients (n = 3) in the lower part of the figure. Ar- row indicates time of administration of glucose load.

642

3000

0 .

p 2m-

v 2 w 5 I O O O -

8

Russell et al.

:L

UNTREATED PATIENTS

PATIENT3 500

d

8 Y

m- -100 100 2

G.L.7

P A T E " 4

OPEN SQUARE CONTROL CLOSED DIAMOND BULIMIA

Figure 2. The effect of an oral glucose load on plasma cortisol in 5 patients following bulimic behavior (B) and following normal eating behavior (C). Untreated patients (n = 2) are shown at the top and treated patients (n = 3) in the lower part of the figure. Ar- row indicates time of administration of glucose load.

Bulimia: Effect of Treatment

- -

a;

h

2 7 E w 6 - g 5

3 0 4 -

643

- s f i 6;- & u

UNTREATED PATIENTS

3 + 4 , 1

TREATED PATIENTS

10 - 8 ,

8 I : v w ? ; 1 ; : cJ 4 -

3 6 - 0 .

5 -

3-7 . I I i 4 ,100 0 100 200

G.L.7 -(Inin)

100 0 100 200

PATIENT 5 1

OPEN SQUARE CONTROL CLOSED DIAMOND BULIMIA

- 1

100 0 100 200

G . L . 7 =(Inin)

Figure 3. The effect of an oral glucose load on plasma glucose in 5 patients following bulimic behavior (B) and normal eating behavior (C). Untreated patients ( n = 2) are shown at the top and treated patients (n = 3) in the lower part of the figure. Arrow indicates time of administration of glucose load.

644 Russell et al.

secretion may play a part in the instigation of binge eating. However, tempo- rary impairment of glucose tolerance, as mentioned earlier and resulting from starvation, may be the mechanism. As in the clinical situation insulin exerts ef- fects on weight and appetite; this phenomenon could be important in the per- petuation of bulimic behavior so as to result in eventual weight gain. Resultant dissatisfaction with body weight and perceived lack of control leads to contin- ued engagement in weight-losing behaviors, precipitating further binge eating and ongoing preoccupation with weight and diet. Demoralization results along with frank eating disorder and the progressive increase in weight experienced by many bulimics. The high blood sugars observed in two of the patients (and also demonstrated in the single patient studied) most likely result from a tem- porary impairment in carbohydrate tolerance due to starvation (Unger et al., 1963).

Cortisol levels were shown to be lower at baseline in all patients and throughout the period of testing in four of the five patients who had engaged in bulimic behavior in the previous 24 hours, diurnal variation notwithstand- ing. The latter phenomenon renders the fall in cortisol, following a glucose load, of doubtful significance, although this finding is in accordance with the animal model [described by Smythe et al. (1983), Smythe et al. (1984), and Stor- lien et al. (1985)l where a stress-reducing effect of carbohydrate ingestion has been postulated. Follenius et al. (1982) cites animal work in which a fall in plasma corticosterone occurs upon food presentation following deprivation, again suggesting a reduction in perceived stress. This could represent a self- perpetuating mechanism in binge eating, where this follows dietary restraint or fasting. An alternative explanation is that cortisol is simply lowered in re- sponse to the high blood glucose levels following binging and described in two of the patients here and in the single patient reported earlier by our group. The frankly elevated levels of cortisol in patient 5 have been documented by our group in one other bulimic patient, hypercortisolemia and abnormalities of DST suppression being noted in bulimic patients by other authors (Krieg et al., 1987; Hudson et al., 1983). The patient reported in this study had been se- verely and impulsively depressed on admission to hospital and had been sus- pected of suffering from a concomitant depressive illness. However, her mood improved promptly with a 2-week period of hospitalization and control of her eating disorder; she remains well more than 1 year later and no longer fulfills the DSM-111-R diagnostic criteria for bulimia. Cortisol levels have not been re- peated. This observation also suggests a need for caution in the interpretation of the dexamethasone suppression test without reference to prior eating behav- ior and particularly carbohydrate ingestion. Carbohydrate tolerance is another potentially confounding factor with respect to the DST test which has been re- ported to be abnormal in patients with frank diabetes (Hudson et al., 1984; Cameron et al., 1984).

Menstrual status might have been expected to influence the results (Reid & Yen 1981). Patients 1, 2, and 4 were menstruating regularly (patient 4 at the time of her control test), patient 3 was amenorrheic, and patient 5 was taking a low dose sequential oral contraceptive (TriquilarTM). The patient reported ear- lier had been amenorrheic for some years. Despite disparate menstrual status, similar trends were demonstrated in the effects of bulimic behavior and its treatment on insulin and cortisol. Furthermore, some variation within the

Bulimia: Effect of Treatment 645

treated group can be explained by the fact that patient 5 (whose bulimickontrol ratio of insulin secretion was higher) had been in treatment for only 2 weeks, whereas patients 3 and 4 had been treated for 7 weeks and 4 weeks, respectively.

In summary then, it was possible to demonstrate, using the modified glu- cose tolerance test, insulin potentiation and cortisol suppression in five bulimic patients in response to a glucose load following engagement in bulimic activ- ity. This is in accorance with the findings reported earlier in a single patient (Russell et al., 1987). Treatment in a program which focussed on nutritional re- habilitation and stress management through behavioral and psychotherapeutic techniques appeared to be associated with modification of this response in the three treated patients.

Whatever combination of behaviors is used by an individual suffering from bulimia nervosa, starvation is an important component. It is postulated that in- termittent starvation and its relief through binge eating instigates a self-perpet- uating hyperinsulinemic reponse as a metabolic defense. Support for this hypothesis is provided by the findings in bulimic patients of Schweiger et al. (1987) and the early work of Unger et al. (1963) in experimental starvation and Crisp et al. (1967) and Kalucy et al. (1976) in patients with anorexia nervosa. Furthermore, stress reduction through carbohydrate ingestion in the chroni- cally intermittently starved individual might be reflected in a greater reduction in cortisol than a situation of normal nutrition. This might tend to render car- bohydrate ingestion so rewarding as to ensure its continuation to the point where an episode of binge eating eventuates. A suitable period of treatment of 4 weeks or more aimed at helping the patient avoid prolonged starvation by reestablishing a regular eating pattern would be expected to reduce the meta- bolic effects of carbohydrate ingestion even following a short period of bulimic behavior. Abolition of starvation would then both reduce the hyperinsulinemic response to carbohydrate ingestion and lessen the cortisol suppression. Since these mechanisms most likely play an important role in precipitating and per- petuating binge eating and possibly in triggering associated mood changes, their extinction would be expected to reduce bulimic behaviors and symptom- atology .

The results of this study may explain the short-term efficacy of treatment programs for bulimia where nutritional rehabilitation is a fundamental compo- nent. Other aspects such as anxiety reduction and stress management may as- sume more importance in the longer term.

The authors thank and acknowledge the valued assistance of the technical staff of the Garvan Institute and the staff of Ward 6 and the Endocrine Laboratory of Concord Hos- pital, in particular Sister Lily Low, and Ms Helen Storey, Nutritionist at the Mt. St. Mar- garet Private Hospital. Part of this work was supported by a Limited Research Grant from the N.S.W. Institute of Psychiatry.

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