Clinical Studies | Hormone Disorders


CLINICAL STUDY 1 — The Effects of Tyrosine on Cognitive Performance during Extended Wakefulness

—Neri DF, Wiegmann D, Stanny RR, Shappell SA, McCardie A, McKay DL. – Naval Aerospace Medical Research Laboratory, Pensacola, FL, USA

Tyrosine, a large neutral amino acid found in dietary proteins, has received recent attention as a potential treatment for stress. The behavioral effects of tyrosine were examined during an episode of continuous nighttime work involving one night’s sleep loss. Subjects performed nine iterations of a battery of performance tasks and mood scales for approximately 13 h, beginning at 1930 and ending at 0820. They remained awake throughout the day on which the experiment began and were awake for more than 24 h by the end of testing. Six hours after the experiment began, one-half of the subjects received 150 tyrosine in a split dose while the other half received cornstarch placebo in a double-blind procedure. Tyrosine administration was associated with a significant amelioration of the usual performance decline on a psychomotor task and a significant reduction in lapse probability on a high-event-rate vigilance task. The improvements lasted on the order of 3 h. The results of this study also suggest that tyrosine is a relatively benign treatment at this dose. After further testing with other doses and timing of administration, tyrosine may prove useful in counteracting performance decrements during episodes of sustained work coupled with sleep loss. PMID: 7794222

(phenylalanine is the precursor to tyrosine)

CLINICAL STUDY 2 — GABA, Gamma-Hydroxybutyric Acid, and Neurological Disease

—Wong CG, Bottiglieri T, Snead OC 3rd. – Institute of Medical Sciences, University of Toronto, Faculty of Medicine and Brain and Behavior Research Program, Hospital for Sick Children, Ontario, Canada

Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABA is converted from glutamic acid by the action of glutamic acid decarboxylase (GAD) of which two isoforms exist GAD65 and GAD67. GABA then is broken down, both within the cell and in the synaptic cleft by GABA transaminase to form succinic semialdehyde. In turn, succinic semialdehyde is converted either to succinic acid by succinic semialdehyde dehydrogenase or into gamma-hydroxybutyric acid (GHB) by succinic semialdehyde reductase. Because GABA modulates the majority of inhibition that is ongoing in the brain, perturbations in GABAergic inhibition have the potential to result in seizures. Therefore, the most common disorder in which GABA is targeted as a treatment is epilepsy. However, other disorders such as psychiatric disease, spasticity, and stiff-person syndrome all have been related to disorders of GABAergic function in the brain. This review covers the roles of GABAergic neurotransmission in epilepsy, anxiety disorders, schizophrenia, stiff-person syndrome, and premenstrual dysphoric disorder. In the final section of this review, the GABA metabolite GHB is discussed in terms of its physiological significance and its role in epilepsy, sleep disorders, drug and alcohol addiction, and an inborn error of GABA metabolism, succinic semialdehyde dehydrogenase deficiency. PMID: 12891648

(l-glutamine is the precursor to gamma-aminobutyric acid GABA)

CLINICAL STUDY 3 — Tyrosine Improves Cognitive Performance and Reduces Blood Pressure in Cadets After One Week of a Combat Training Course

—Deijen JB, Wientjes CJ, Vullinghs HF, Cloin PA, Langefeld JJ. – Department of Clinical Neuropsychology, Vrije Universiteit, Amsterdam, The Netherlands

The effects of the amino acid tyrosine on cognitive task performance were studied on a group of 21 cadets during a demanding military combat training course. In addition, the effects on mood, blood pressure and the norepinephrine metabolite MHPG were determined. Ten subjects received five daily doses of a protein-rich drink containing 2 g tyrosine, and 11 subjects received a carbohydrate rich drink with the same amount of calories (255 kcal). Assessments were made both immediately prior to the combat course and on the 6th day of the course. The group supplied with the tyrosine-rich drink performed better on a memory and a tracking task than the group supplied with the carbohydrate-rich drink. In addition, the supplementation of tyrosine decreased systolic blood pressure. No effects on mood were found. These findings suggest that supplementation with tyrosine may, under operational circumstances characterized by psychosocial and physical stress, reduce the effects of stress and fatigue on cognitive task performance. PMID: 10230711

(phenylalanine is the precursor to tyrosine)

CLINICAL STUDY 4 — Chromium (D-Phenylalanine) Improves Obesity-Induced Cardiac Contractile Defect in Ob/ob Mice

—Dong F, Yang X, Sreejayan N, Ren J. – Center for Cardiovascular Research and Alternative Medicine and Division of Pharmaceutical Sciences, University of Wyoming, Laramie, Wyoming

OBJECTIVE: Low-molecular weight chromium compounds, such as chromium picolinate, improve insulin sensitivity, although toxicity is a concern. We synthesized a novel chromium complex, chromium (d-phenylalanine) (d-phe), in an attempt to improve insulin sensitivity

with reduced toxicity. The aim of this study was to compare the two chromium compounds on cardiac contractile function in ob/ob obese mice. RESEARCH METHODS AND PROCEDURES: C57BL lean and ob/ob obese mice were randomly divided into three groups: H (2) O, Cr (3), or Cr (3) (45 mug/kg per day orally for 6 months). RESULTS: The glucose tolerance test displayed improved glucose clearance by Cr (d-phe) (3) but not Cr (3). Myocytes from ob/ob mice exhibited depressed peak shortening (PS) and maximal velocity of shortening/relengthening (+/-dL/dt), prolonged time-to-PS and time-to-90% relengthening (TR90), reduced electrically stimulated rise in intracellular Ca (2+) (Deltafura-2 fluorescence intensity), and slowed intracellular Ca (2+) decay. Although a 3-month Cr (d-phe) (3) treatment for a separate group of ob/ob and lean 2-month-old mice only rectified reduced +/-dL/dt in ob/ob mice, all mechanical and intracellular Ca (2+) abnormalities were significantly attenuated or ablated by 6 months of Cr (d-phe) (3) but not Cr (3) treatment (except TR90). Sarco (endo) plasmic reticulum Ca (2+) ATPase activity and Na (+) –Ca (2+) exchanger expression were depressed in ob/ob mice, which were reversed by both Cr (d-phe) (3) and Cr (3), with a more pronounced effect from Cr (d-phe) (3). Cr (d-phe) (3) corrected reduced insulin-stimulated glucose uptake and improved basal phosphorylation of Akt and insulin receptor, as well as insulin-stimulated phosphorylation of Akt and insulin receptor in ob/ob myocytes. Heart homogenates from ob/ob mice had enhanced oxidative stress and protein carbonyl formation compared with the lean group, which were attenuated by both Cr (d-phe) (3) and Cr (3). DISCUSSION: Our data suggest that the new Cr (d-phe) (3) compound possesses better cardio-protective and insulin-sensitizing properties against obesity. PMID: 18070761

(phenylalanine is the precursor to tyrosine, which in turn is the precursor to l-dopa)

CLINICAL STUDY 5 — Insulin-Sensitizing and Cholesterol-Lowering Effects of Chromium (D-Phenylalanine)

—Yang X, Li SY, Dong F, Ren J, Sreejayan N. – University of Wyoming, School of Pharmacy, Division of Pharmaceutical Sciences and Center for Cardiovascular Research and Alternative Medicine, 1000 E. University Avenue, Laramie, WY, USA

Low-molecular weight organic chromium complexes are thought to play a key role in carbohydrate and lipid metabolism and therefore have been gaining popularity as nutritional supplement for patients with diabetes and concomitant lipid disorders. The aim of the present study was to evaluate the effects of a novel synthetic chromium (d-phenylalanine) (3) complex on insulin-sensitivity, plasma lipid-profile and oxidant stress in a mouse model of type II diabetes. Plasma glucose levels following intraperitoneal insulin-challenge (1U/kg) to obese ob/ob(+/+) mice treated with Cr (d-phe) (3) (150 microg/kg/day for 6 weeks) were significantly lower compared to vehicle-control (control: 175.8+/-43.2mg/dL versus Cr (d-phe) (3) 115.3+/-18.0mg/dL, p<0.01, n=12). Total serum cholesterol to high-density lipoprotein ratio was significantly reduced following Cr (d-phe) (3)-treatment (control: 2.19+/-0.08 versus Cr (d-phe) (3) 1.63+/-0.05; p<0.05). Hepatic oxidant stress, assessed as malondialdehyde equivalents and protein-carbonyl content were significantly attenuated following Cr (d-phe) (3) treatment. The complex also inhibited lipid-peroxidation in vitro, in a concentration dependent manner. Taken together, these data suggest that Cr (d-phe) (3) may be of potential value in the therapy or prophylaxis of insulin-resistance and dyslipidemia associated with obesity. PMID: 16545457

CLINICAL STUDY 6 — L-Glutamine Supplementation Induces Insulin Resistance in Adipose Tissue and Improves Insulin Signalling in Liver and Muscle of Rats with Diet-Induced Obesity

—Prada PO, Hirabara SM, de Souza CT, Schenka AA, Zecchin HG, Vassallo J, Velloso LA, Carneiro E, Carvalheira JB, Curi R, Saad MJ. – Departamento de Clínica Médica da Universidade Estadual de Campinas, Rua Tessália Viera de Camargo 126, Campinas, San Paulo, Brazil

AIMS/HYPOTHESIS: Diet-induced obesity (DIO) is associated with insulin resistance in liver and muscle, but not in adipose tissue. Mice with fat-specific disruption of the gene encoding the insulin receptor are protected against DIO and glucose intolerance. In cell culture, glutamine induces insulin resistance in adipocytes, but has no effect in muscle cells. We investigated whether supplementation of a high-fat diet with glutamine induces insulin resistance in adipose tissue in the rat, improving insulin sensitivity in the whole animal. MATERIALS AND METHODS: Male Wistar rats received standard rodent chow or a high-fat diet (HF) or an HF supplemented with alanine or glutamine (HFGln) for 2 months. Light microscopy and morphometry, oxygen consumption, hyperinsulinaemic-euglycaemic clamp and immunoprecipitation/immunoblotting were performed. RESULTS: HFGln rats showed reductions in adipose mass and adipocyte size, a decrease in the activity of the insulin-induced IRS-phosphatidylinositol 3-kinase (PI3-K)-protein kinase B-forkhead transcription factor box 01 pathway in adipose tissue, and an increase in adiponectin levels. These results were associated with increases in insulin-stimulated glucose uptake in skeletal muscle and insulin-induced suppression of hepatic glucose output, and were accompanied by an increase in the activity of the insulin-induced IRS-PI3-K-Akt pathway in these tissues. In parallel, there were decreases in TNFalpha and IL-6 levels and reductions in c-jun N-terminal kinase (JNK), IkappaB kinase subunit beta (IKKbeta) and mammalian target of rapamycin (mTOR) activity in the liver, muscle and adipose tissue. There was also an increase in oxygen consumption and a decrease in the respiratory exchange rate in HFGln rats. CONCLUSIONS/INTERPRETATION: Glutamine supplementation induces insulin resistance in adipose tissue, and this is accompanied by an increase in the activity of the hexosamine pathway. It also reduces adipose mass, consequently attenuating insulin resistance and activation of JNK and IKKbeta, while improving insulin signalling in liver and muscle. PMID: 17604977

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