Vitalin Clinical Trials
Clinical Trials in Netherlands
The Effect of Vitalin® on the GH-IGF-1 Axis and Cognitive Functioning in Healthy Adults
Jan Berend Deijena & Lucia I. Arwertb
- Department of Clinical Neuropsychology, Free University, van der Boechorststraat 1, 1081 BT Amsterdam, the Netherlands
- Department of Endocrinology, VU University Medical Center, de Boelelaan 1117, 1081 HV Amsterdam, the Netherlands
Aging is associated with declining activity of the growth hormone (GH) - insulin-like growth factor 1(IGF-I) axis and with a decrease in cognitive function. The stimulatory effect of an orally administered preparation mainly consisting of glycine, glutamine and niacin (Vitalin®) on the GH-IGF-I axis and on mood and cognition was investigated. Forty-one healthy subjects (14 men and 27 women, aged 40-76 years) were enrolled in a randomized, double blind, placebo-controlled trial. They received five gram powder of Vitalin® or placebo, twice daily orally for a period of 3 weeks. At baseline and after 3 weeks, blood was collected to measure GH and IGF-I levels and mood and cognitive function were tested. Vitalin® ingestion for 3 weeks was found to increase serum GH levels with 70%, compared to placebo, whereas circulating IGF-I levels did not change. Mean GH (± SD) increased in this group from 3.23 mU/l (± 4.78) to 4,67 mU/l (± 5.27).
Aging is associated with declining activity of the growth hormone- insulin-like growth factor I (GH-IGF-1) axis and with a decrease in cognitive function. Growth hormone and IGF-I levels decrease with age in all mammals. From age 40 to 80 the amount of growth hormone in men progressively decreases. It is also known that cognitive function declines with aging. Several studies have showed associations between GH, IGF-I and cognitive function. Besides having somatic effects, growth hormone (GH) also affects (neuro)psychological functioning. Adults with growth hormone deficiency (GHD) , in a state characterized by low GH and low IGF-I levels, feel less energetic, are emotionally more labile, and experience disturbances in sex life and feelings of social isolation at a significantly higher frequency than controls. They are also found to have significant cognitive deficits. Adult men, with childhood-onset GH deficiency had lower memory function compared to controls, which improved to normal scores within one year of GH replacement therapy (Deijen, 1996; Deijen, 1998). Moreover, the changes in memory performance are positively correlated to the GH-induced changes in serum IGF-I concentration. Effects on memory can be explained by the presence of a high concentration of GH receptors in the hippocampus, which plays a major role in memory processes (Nyberg, 2000).
It has also been observed that GH treatment affects quality of life (QoL) in patients with GHD (Burman, 1995). A further support for a relationship between GHD and impaired cognitive functioning is given by studies on IGF-I plasma level and intellectual functioning. For instance, serum IGF-I concentration in GH-deficient males correlated positively with IQ score and education level. In healthy subjects, IGF-I plasma levels of elderly men and women were found positively associated with Mini Mental State Examination (MMSE) scores (Rollero, 1998). Similarly, IGF-I levels in elderly healthy men were found to be associated with better performance in tests sensitive to the effects of aging, especially speed of information processing (Aleman, 1999). In addition, higher serum total IGF-I levels in healthy elderly subjects (above 55 years) have been found to be associated with less cognitive decline over the following two years (Kalmijn, 2000). Thus, the GH-IGF-I axis may play a role in the level of, in particular, cognitive functioning in GHD patients and healthy persons. As the activity of the growth hormone-IGF-I axis and cognitive function both decline with age, it may well be possible to maintain or improve cognitive function by increasing the activity of this axis.
A number of studies have been performed concerning the interactions between nutrients and the GH-IGF-I axis. Proteins appear to control GH-stimulated IGF-I expression. The level of protein and calorie intake regulate plasma IGF-I and insulin-like growth factor binding proteins (IGFBPs) levels. Glycine may play an important role in the control of hypothalamic-pituitary function. In normal subjects there is a dose-dependent GH release to intravenous glycine ( Kasai, 1980). When glycine (250 ml 0.3 M) was administered into the duodenum in non-obese subjects there was an even more pronounced and significant increase in serum hGH value (Kasai, 1978). This demonstrated that glycine is one of the stimulatory agents inducing the pituitary to secrete GH. Arginine is also known to stimulate the GH release. However, the results in studies about amino-acids and GH secretion are not conclusive and the mechanism by with amino acids stimulate GH release are not known. There are no studies available on the association between nutrition, GH-IGF-I and cognition.
In the current study, the effect of the administration of Vitalin®, mainly consisting of glycine, glutamine and niacin on GH and IGF-I levels, mood and cognitive function in 41 healthy adults is studied.
The effects of Vitalin® on GH and IGF-I plasma levels and cognitive function were examined in 42 healthy non-obese volunteers, which were recruited by advertisements in daily papers. One female in the Vitalin® group was excluded from evaluation because of very extreme and variable values of growth hormone concentration (GH measurement 1: 67 mU/l, GH measurement 2 : 2.1 mU/l). The remaining number of males was 14 and of females 27, they were aged between 40 and 76 years (Table 1). None of the subjects had any history of serious psychiatric disease or were taking any medication at the time of the experiment. Exclusion criteria were professional sports participants, alcohol consumption > 3 units/day, vegetarians, dieting, use of drugs, hypnotics, antidepressants, the presence of sensory or motor handicaps.
Table 1. Subject characteristics (means ± SD)
|Number of Patients||Male||Female||Mean Age||Education (Yrs.)|
|Vitalin||22||9||13||60.2 ± 9.3||12.2 ± 3.9|
|Placebo||19||5||14||61.9 ± 6.0||12.8 ± 3.9|
Subjects were randomly assigned to the treatment groups matched for age, sex and education. Education was defined as the total number of years of having attended a school. The study was conducted to the principles of the Declaration of Helsinki and was approved by the Ethics Committee of the VU University Medical Center. All subjects gave their written informed consent before inclusion in the study.
We performed a double blind, placebo controlled study. Subjects participated in a 3-week trial and were randomly assigned to receive a powder of Vitalin® for three weeks or placebo treatment, which was also administrated as a powder. All the volunteers were asked to ingest 5 grams of powder with water twice a day on an empty stomach. Intake was in the morning and before bedtime, with the last meal or calorie containing food or drink consumption at least three hours before. No food was allowed to be consumed for at least 45 minutes after taking the powder. This regime was maintained for six days followed by one day of rest. This day off was included to make is easier for the subjects to comply with the protocol. The ingredients (in grams) of Vitalin® are a proprietary mixture of glycine and glutamine of 4.92 grams, niacin (0.02) with added vitamin A and Beta Carotene (1000iu), vitamin C (0.01), vitamin E (5 iu), selenium (15 mcg), green tea leaf powder (0.007), bilberry fruit powder (0.007), quercitin (0.005), alpha-lipoic acid (0.005) and coQ 10 (0.01) (Vitalin® , Revita Health Corp., USA). The placebo powder preparation was composed as (per 5 gram) 3.23 gr. maltodextrine. 0.1 gr. aspartame, 0.83 gr. cane sugar and 0.83 gr. soft brown sugar.
Subjects were examined individually in a quit room. The sequence of the tests was the same for all subjects and the test procedure as a whole took about 45 minutes. The tests were administered by two testing assistants, who were not aware which treatment the subjects had. On the day before starting the consumption of the food supplement a 5 cc venous blood sample was drawn after an overnight fast for determination of serum GH and IGF-I levels. Second blood samples and cognitive tests were performed after three weeks of ingestion the powder, 1 - 1.5 hour after taking the last powder on an empty stomach. The blood samples were centrifuged (10 minutes, 3500 r.p.m. at 4 C) and serum was stored at -20 C until analysis.
The following tests were selected from the Neurobehavioral Education System (NES) ( Letz, 1993) and were administered by means of a PC.
Mood. The Profile of Mood States (POMS) is a self-administered questionnaire in which the subjects rate themselves with respect to their feelings over the previous three days. The shorted Dutch version of 32 items was used, which consists of five sub-scales: Depression, Anger, Fatigue, Vigor and Tension. Responses are made by choosing from five response alternatives. Score: The rating (1-5) on each item and the scale to which each item contributes is recorded.
Memory. Short-term memory (STM): Associate learning task. Nine word pairs consisting of a name and an occupation are displayed on a computer screen at a constant rate of one pair per 3 seconds. After these pairs are presented, the subject is asked to choose one of the nine occupation alternatives. After each answer the results are given in the following manner: "Yes, John is a grocer", or "No, Susan is a teacher". Three trials are given in which the subject has to learn as many paired names and occupations as possible. By means of this recognition procedure short-term verbal learning is measured. Score: The number of correct associations on each trial (maximum score: 9). Visual digit span task. This test for the assessment of short term memory, concentration and attention has two parts. A sequence of digits is presented, one at the time to the subject. After the hole sequence is presented, the subject is required to enter the sequence on the computer keyboard. Increasingly longer spans of digits are presented, until the subject makes two errors at a span length. In the second testing condition, the subject is asked to respond with the order of digits reversed (backward). Score: The lengths of the longest span answered correctly forward and backward are recorded.
Symbol-digit substitution. This test is to measure the coding-speed. Nine symbols and nine digits are paired (in a "key") at the top of the screen. The subject is required to press the digits on the keyboard corresponding to a test set of the nine symbols presented in scrambled order. Six sets of nine symbol-digits pairs were presented. Score: the response latency for each of the 9 items in each trial and the number of digits incorrectly matched with the test symbols were recorded.
Intermediate memory: Associated learning delayed recognition task. To assess intermediate recall a single recognition trial of the nine names to be matched with one of the nine occupations used in the associate learning test is administered at the end of the testing session. The approximate 30 minutes delay between this final testing and the associate learning task comprises a retention task for intermediate memory. Score: The number of correct responses ( maximum score: 9).
Plasma GH and IGF-I levels were measured with commercially available assays ( GH, immunometric assay, Sorin Biomedica, Saluggia Italy; IGF-I, Chemoluminiscentic, Nichols Institute Diagnostics, San Juan Capristrano USA). The detection limits for GH and IGF-I are 1.0 mU/l (0.5 µg/l) and 6.0 nmol/l, respectively. The intra-assay coefficient of variation (CV) for GH is 4 % at serum GH of 4 mU/l. The interassay coefficient of variation (CV) for GH is 9 % at serum GH of 2.5 mU/l and 8% at serum GH of 8.6 mU/l. For IGF-I the intra-assay coefficient of variation is 3 % at serum IGF-I of 20 nmol/l and the inter assay coefficient of variation is 6 % at serum IGF-I of 33 nmol/l and 8 % at serum IGF-I of 7 nmol/l. In our laboratory the normal range for IGF-I for adults, aged > 61 years is 10.3 - 19.0 nmol/l (P5-P95). Normal values differ with age and sex.
All calculations were performed with the Statistical Package for the Social Sciences (SPSS). Data were analyzed by Analyses of variance (ANOVA) with group as independent factor and session as repeated measurement factor and t-tests. Differences were considered significant if p < 0.05. The Pearson correlation coefficient was calculated to assess possible relationships between serum hormone levels and scores on cognitive and mood scales. Statistical tests were one-tailed. Data are presented as mean ± standard deviation (SD), unless specified otherwise.
Characteristics of the volunteers are shown in table 1. Mean age and years of education were similar for people who had the Vitalin powder and placebo. There were no drop-outs during the study. One female in the food supplement group was excluded from evaluation because of very extreme and variable values of growth hormone concentration (GH measurement 1 : 67 mU/l, GH measurement 2 : 2.1 mU/l). All other subjects had serum values of GH and IGF-I within the normal limits or slightly above the normal range for age and sex.
GH and IGF-I Concentration
Regarding GH concentration, analysis of variance (ANOVA) with group as independent factor and session as repeated measures factor showed a significant interaction between group and session (F (1,39) = 2.75, p = 0.05. Paired t-tests indicated that the post-treatment GH concentration in the amino-acid group tended to be higher than the pre-treatment values (t (21) = -1.6, p = 0.06). Mean GH increased in this group from 3.23 (± 4.75) to 4.67 (± 5.27) mU/l. In the placebo group mean GH decreased from 3.92 (± 7.24) to 2.91 (± 2.96) mU/l (p = 0.4) (Fig. 1). The mean percentage of GH increase in the amino-acid group relatively to the placebo group is 70%.
Fig. 1. Mean GH concentration (mU/l) at sessions 1 and 2 for the Vitalin and the placebo group.
The ranges of GH change for all the individual subjects in the Vitalin® group are between -90 and 2100 %. The ranges for males are between -90 and 1200 %, for females between -65 and 2100 %. In the placebo group this range was between -80 % and 600 %.
With respect to the IGF-I concentration, no significant main effect for session and no interaction between group and session was found. This indicates that the IGF-I concentration does not change across sessions and no difference is seen between the amino-acid and placebo group. Also paired t-tests, separately performed for the food supplement and placebo group, do not reveal a significant difference between sessions in IGF-I for one of the two groups. IGF-1 in the amino-acid group increased from 17.47 (± 4.88) to 17.65 (± 4.66) nmol/l (p = 0.78). In the placebo group IGF-1 decreased from 18.11 (± 6.28) to 17.68 (± 4.64) nmol/l (p = 0.56) (Fig. 2).
Fig. 2. Mean IGF-I concentration (nmol/l) at sessions 1 and 2 for the Vitalin and the placebo group.
The intra-subject correlation of pre- and post treatment IGF-I concentration is high (r = 0.84, p < 0.0005). There was an association between pre-treatment GH and IGF-I found (r = 0.39, p = 0.006). Also post-treatment GH and IGF-I concentrations were significantly related (r = 0.31, p = 0.02). Pre-treatment GH did correlate significantly with post-treatment IGF-I (r = 0.44, p = 0.002).
Clinical Trials in Israel
Summary of tests done on 12 volunteers to define the blood GH Levels changes within 3 weeks of consumption of Vitalin.
Center No. 3650
|ng = Nanogram||ml = Milliliter|
|Patient Name||Patient Number||Patient Age||Patient Gender||GH Initials||3 Weeks||3 Months||% Change|
|M.K.||H2051||49||F||1.30 ng/ml||4.10 ng/ml||N/A||(+)215%|
|H.F.||H2056||52||F||1.10 ng/ml||2.30 ng/ml||N/A||(+)109%|
|R.W.||H2052||64||M||0.42 ng/ml||0.83 ng/ml||3.20 ng/ml||(+)662%|
|Z.O.||H2050||54||F||0.34 ng/ml||6.90 ng/ml||N/A||(+)1930%|
|E.S.||H1113||49||M||0.87 ng/ml||1.10 ng/ml||N/A||(+)26%|
|A.Y.||H1115||44||F||0.19 ng/ml||0.95 ng/ml||N/A||(+)400%|
|D.A.||H1120||62||M||0.10 ng/ml||0.37 ng/ml||(+)270%|
|D.S.||H1112||40||F||0.96 ng/ml||2.80 ng/ml||N/A||(+)192%|
|M.B.||H1119||56||M||0.09 ng/ml||0.44 ng/ml||N/A||(+)389%|
|H.K.||H2055||44||F||1.00 ng/ml||2.30 ng/ml||N/A||(+)130%|
|I.B.||H1114||71||M||0.27 ng/ml||0.65 ng/ml||N/A||(+)141%|
|R.G.||H1121||66||F||2.90 ng/ml||5.60 ng/ml||(+)93%|
|D.B.||H1118||57||F||0.51 ng/ml||3.70 ng/ml||N/A||(+)625%|
|M.R.||H1117||46||M||0.31 ng/ml||0.79 ng/ml||N/A||(+)155%|
|GROUP AVERAGE INCREASE IN GH LEVEL:||(+)381%|
- Average age is 54 years old
- 8 Females - average age is 51 years old
- 6 Men - average age is 58 years old
Tests performed during March thru June 2001, by:
American Medical Laboratories
Herzlia Medical Center