Effects of Oral 5-Hydroxy-Tryptophan on Energy Intake and Macronutrient Selection in Non-Insulin Dependent Diabetic Patients
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International Journal of Obesity (1998) 22, 648±654 ß 1998 Stockton Press All rights reserved 0307±0565/98 $12.00 http://www.stockton-press.co.uk/ijo Effects of oral 5-hydroxy-tryptophan on energy intake and macronutrient selection in non-insulin dependent diabetic patients C Cangiano,1 A Laviano,1 M Del Ben,2 I Preziosa,1 F Angelico,2 A Cascino1 and F Rossi-Fanelli1 1Laboratory of Clinical Nutrition, Department of Clinical Medicine; and 2Dietetics Service, Institute of Systematic Medical Therapy, University of Rome `La Sapienza', viale dell'Universita' 37, 00185 Rome, Italy OBJECTIVE: In obese patients, brain serotonergic stimulation via orally administered 5-hydroxy-tryptophan (5-HTP), the precursor of serotonin, causes decreased carbohydrate intake and weight loss. Since diabetes mellitus is associated with depressed brain serotonin, hyperphagia and carbohydrate craving, we hypothesized that in diabetic patients, orally administered 5-HTP stimulates brain serotonergic activity and thus normalizes eating behaviour. To test this hypothesis, we investigated whether in diabetic patients: 1) predicted brain serotonin concentrations are depressed as a result of decreased availability of the precursor, tryptophan; and 2) oral 5-HTP is effective in reducing energy and carbohydrate intake. SUBJECTS AND METHODS: 25 overweight non-insulin dependent diabetic outpatients were enrolled in a double- blind, placebo-controlled study, and randomized to receive either 5-HTP (750 mg=d) or placebo for two consecutive weeks, during which no dietary restriction was prescribed. Energy intake and eating behaviour, as expressed by macronutrient selection, were evaluated using a daily diet diary. Plasma amino acid concentrations and body weight, as well as serum glucose, insulin and glycosylated haemoglobin were assessed. RESULTS: 20 patients (nine from the 5-HTP group and 11 from the Placebo group) completed the study. Brain tryptophan availability in diabetic patients was signi®cantly reduced when compared to a group of healthy controls. Patients receiving 5-HTP signi®cantly decreased their daily energy intake, by reducing carbohydrate and fat intake, and reduced their body weight. CONCLUSIONS: These data con®rm the role of the serotonergic system in reducing energy intake, by predominantly inhibiting carbohydrate intake, and suggest that 5-HTP may be safely utilized to improve the compliance to dietary prescriptions in non-insulin dependent diabetes mellitus. Keywords: eating behaviour; diabetes mellitus; carbohydrate craving; tryptophan; serotonin; brain Introduction carbohydrate craving, which is characteristically observed in diabetic patients, deserves special con- sideration by both patients and physicians. Unfortu- Non-insulin dependent diabetes mellitus (NIDDM) is nately, compliance with a well-balanced diet is often a complex metabolic disorder, impingeing highly on an extremely dif®cult task to accomplish, despite the the health and quality of life of patients, as well as fact that patients are usually aware that this will result greatly contributing to the costs of the national health in a delay in both the need for exogenous insulin and care system worldwide.1 It is estimated that in the US the onset of major complications. alone, more than 10 million people are diabetic,2 and During the last two decades, evidence has accumu- that approximately $100 billion are spent each year lated suggesting that brain serotonin has an inhibitory for the care of diabetic patients.3 Thus, the possible in¯uence on eating behaviour both in animals and therapeutic and economic bene®ts deriving from an humans.6 Reported studies in favour of a role played improved metabolic control of diabetes become self- by the serotonergic system in the pathogenesis of evident. anorexia accompanying different diseases, further Both in animals and humans, NIDDM is character- support this thesis.7±10 Although the pathogenic ized by hyperphagia4,5 and hyperglycaemia. In the mechanism(s) responsible for disturbed eating beha- clinical setting, the control of hyperphagia is one viour and impaired carbohydrate metabolism in of the mainstays of NIDDM therapy. In particular, NIDDM need(s) to be more precisely de®ned, con- sistent evidence suggests that the hypothalamic sero-tonergic system plays a key role in mediating Correspondence: Prof Filippo Rossi-Fanelli, Department of hyperphagia. Experimental studies indicate that Clinical Medicine, University of Rome `La Sapienza', Viale depressed hypothalamic serotonergic activity is asso- dell'Universita' 37, 00185 Rome, Italy. ciated with hyperphagia and obesity,11 and that in Received 22 October 1997; revised 22 January 1998; accepted 2 March 1998 streptozotocin-induced diabetic rats, hypothalamic Oral 5-HTP in NIDDM C Cangiano et al 649 serotonin concentrations are reduced.12 Further evi- Twenty-®ve patients (14 male, 11 female) aged dence shows that in obese hyperphagic patients, the between 35 ± 70 y, were found eligible for the study. oral administration of 5-hydroxy-tryptophan (5-HTP), Among them, patients on treatment with oral hypo- the direct precursor of serotonin, is effective in redu- glycaemic drugs were invited not to withdraw or cing energy intake and in enhancing patients' com- reduce their therapy. pliance to a hypoenergetic diet.13,14 Beside its anorectic effect, brain serotonin appears to be also Study design involved in macronutrient selection. Although contro- The study design was approved by the Ethics Com- versy still exists on the role of sero-tonin in modulat- mittee at the University of Rome `La Sapienza', and ing selective macronutrient intake (for review, see was in accordance with the Helsinki Declaration of Ref. 15), a number of animal studies have shown that 1975, as revised in 1983. The three-week study period the serotonergic system may modulate carbohydrate was subdivided into a baseline observation period intake (for review, see Ref. 6). These ®ndings have (one week) followed by a two-week treatment recently been con®rmed in obese hyperphagic period. On day77, all patients meeting the inclusion patients.13,14 In these investigations, the oral adminis- criteria were enrolled after giving written, informed tration of 5-HTP reduced the patient's energy intake consent, and were asked to record daily, in a diet by signi®cantly inhibiting carbohydrate intake, while diary, their intake for the following three weeks (see protein and lipid consumption was minimally below). On day 0, overnight fasting blood samples affected. were collected for biochemical measurements (includ- Brain serotonin synthesis depends on the availability ing plasma amino acid determination) and patients to the brain of its amino acid precursor, tryptophan were examined to evaluate eating behaviour and body (TRP).16 In plasma, approximately 90% of this amino weight. On the same day, patients were randomly acid is bound to albumin, while less than 10% is free assigned to receive either 5-HTP (250 mg three time- (free TRP). Although controversial, the predictability of s=d, n 12) or placebo (n 13), composed of corn brain TRP concentrations seems to be more appropriate starch, mannitol and magnesium stearate; (both when the ratio between free TRP and the other large obtained from Sigma-Tau Industries, Pomezia, neutral amino acids (LNAA) is considered.8,17 ± 19 Italy). The drug, which was in the form of capsules Since plasma branched-chain amino acids (BCAA), not dissolving until pH 8.6, was taken three times per which compete with TRP for brain entry, have been day, 30 min before each meal. During the two-week found to be increased in NIDDM patients,20,21 we treatment period, no dietary restrictions were recom- hypothesize that brain tryptophan availability and mended. Subjects were then followed up every week serotonergic activity are depressed in NIDDM. This (day 7 and day 14) to evaluate eating behaviour, body might, in turn, be responsible for the hyperphagia and weight and blood biochemistry. Also, patients were disturbed eating behaviour.11,12 Consequently, the questioned for the presence of side effects, including pharmacologically-induced stimulation of the brain nausea and vomiting, using a previously validated serotonergic system might be bene®cial in reducing questionnaire.13,14 To test patients' compliance to hyperphagia, inhibiting carbohydrate intake and even- treatment 24 h urinary excretion of 5-hydroxy-indole- tually improving the metabolic control of diabetes. To acetic acid (5-HIAA) was also determined on day 0, test this hypothesis, we carried out the present double- day 7 and day 14, using the chromatographic-colori- blind, placebo controlled study, which aims at inves- metric method described by Udenfriend et al.22 tigating whether brain tryptophan availability is Data obtained in the study group were then com- reduced in patients with NIDDM, and whether in pared to those simultaneously obtained in a control the same patients the oral administration of 5-HTP group of 18 gender- and age-comparable healthy may decrease carbohydrate dietary intake. subjects. Blood samples were obtained and processed as described for diabetic patients. Methods Biochemistry Baseline plasma amino acid concentrations were determined using the ion-exchange technique pre- Patients viously described.23 Total TRP concentrations were Adult patients with NIDDM (diagnosis made 3y determined separately using the spectrophoto¯uori- earlier) with a body mass index (BMI) between 25 and metric method described by Denckla and Dewey24 30, and