None listed
Conditions
Brief summary
Obesity has reached epidemic proportions globally and is associated with serious co-morbidities, including type 2 diabetes. Once adipose tissue has been accumulated, and food intake is limited by low calorie diets, counter-regulatory mechanisms induce an increase in appetite and a decrease in energy expenditure, which makes weight loss very difficult to maintain. To combat the global burden of obesity and its co-morbidities, a major challenge lies in the development of effective therapies that increase fullness and satiety, and result in good blood glucose control, while lacking adverse effects that are often associated with current therapies. There is increasing evidence that nutrient stimuli in the gastrointestinal tract play a central role in the control of energy intake and blood glucose. Proteins, and their building blocks, amino acids, are of interest, since high-protein diets are very effective for weight loss, particularly loss of fat, rather than muscle mass, and for improving postprandial glycaemic control, in obese individuals with and without type 2 diabetes. There is some evidence that a number of amino acids (including those to be studied) may also have effects on energy intake, blood glucose and gut function in humans. Thus, they are of special interest in terms of potential therapeutic approaches for obesity and type 2 diabetes. This study will investigate the dose-related effects of intragastric administration of specific L-amino acids on gastric emptying, gut hormone release, glycaemic control, appetite perceptions and energy intake in healthy, normal weight and overweight or obese type 2 diabetic patients.
Interventions
The study is comprised of nine sub-studies. Eight of the sub-studies will investigate one L-amino acid as follows: i) L-isoleucine; ii) L-valine; iii) L-tyrosine; iv) L-methionine; v) L-lysine; vi) L-arginine; vii) L-cysteine; viii) L-phenylalanine. The ninth sub-study (ix) will investigate a comparison between L-isoleucine and L-leuine. Separate recruitment will be conducted for each sub-study.
Gastric emptying (measured by 2D ultrasound and breath testing), blood glucose, gut hormones releas
The study is comprised of nine sub-studies. Eight of the sub-studies will investigate one L-amino acid as follows: i) L-isoleucine; ii) L-valine; iii) L-tyrosine; iv) L-methionine; v) L-lysine; vi) L-arginine; vii) L-cysteine; viii) L-phenylalanine. The ninth sub-study (ix) will investigate a comparison between L-isoleucine and L-leuine. Separate recruitment will be conducted for each sub-study. Gastric emptying (measured by 2D ultrasound and breath testing), blood glucose, gut hormones release, insulin concentrations, appetite perceptions (measured by Visual Analogue Scales, VAS) and energy intake during a buffet meal, will be measured in each sub-study. Subjects enrolled in each sub-study i) to viii) will receive, in randomized, double-blind fashion, an intragastric bolus infusion (200mls) of i) 5g L-amino acid; ii) 10g L-amino acid; iii) saline (control). Those enrolled in study ix) will receive in randomized, double-blind fashion, an intragastric bolus infusion (200mls) of i) 5g L-isoleucine; ii) 5g L-leucine; iii) saline (control). Subjects will receive one infusion per visit. Study visits will be separated by 3-7 days. For each study visit a baseline blood sample, VAS, ultrasound, and breath sample will be taken (t = -20). At t = -17 min the infusion will be administered over 2 minutes using a feeding tube. At t = -2 min a further VAS and ultrasound will be taken. At t = -1 min, subjects will consume, within 1 minute, a mixed-nutrient drink (Ensure, 400 kcal, 300 ml) labeled with 150 mg of 13C-acetate for measurement of gastric emptying by breath sampling. Blood samples, VAS and ultrasound measurements will be taken every 15 minutes over the next hour (t = 0 to 60 min). Breath samples will be taken every 5 minutes from t = 0 to 60 min. At t = 60 min, subjects will be presented with a cold, buffet-style meal. Subjects will be allowed 30 minutes to freely consume the buffet meal until comfortably full. At t = 90 min a final blood sample will be taken, and VAS administered.
Sponsors
Christine Feinle-Bisset
Study design
Allocation
Randomised controlled trial
Intervention model
Crossover
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
A total of 20 healthy, lean (BMI 19-25 kg/m2) and 20 obese T2DM (BMI 30-35 kg/m2) male and female Caucasian subjects, aged between 18 - 55 years, will be included in each sub-study i) - ix). T2DM diagnosis will be based on WHO criteria. HbA1c will be >=6.5 - <=7.9% at screening. Patients will be diet-controlled, with or without metformin (<2 g/d). All subjects will be required to be weight stable (ie <5% fluctuation) at study entry, which will be ascertained by a stable body weight in the preceeding 4 weeks. Subjects will be required to maintain their normal physical activity over the course of the study, which will be assessed using diaries.
Exclusion criteria
All subjects: Significant gastrointestinal symptoms, disease or surgery; use of prescribed or non-prescribed medications (including vitamins and herbal supplements) which may affect energy metabolism, gastrointestinal function, body weight or appetite (eg domperidone and cisapride, anticholinergic drugs (eg atropine), metoclopramide, erythromycin, hyoscine, orlistat, green tea extracts, Astragalus, St Johns Wort etc.); lactose intolerance/other food allergy(ies); current gallbladder or pancreatic disease; cardiovascular or respiratory diseases; individuals with low ferritin levels (females less than 15 ng/mL, males less than 30 ng/mL), or who have donated blood in the 12 weeks prior to taking part in the study; any other illnesses as assessed by the investigator (including chronic illnesses not explicitly listed above); high performance athletes; current intake of greater than 2 standard drinks on greater than 5 days per week; current smokers of cigarettes/cigars/marijuana; current intake of any illicit substance; vegetarians; inability to comprehend study protocol; unable to tolerate naso-gastric tube; in female subjects, pregnancy or lactation; phenylketonuria (only applies to the part involving L-phenylalanine). Healthy subjects only: fasting glucose >6.9 mmol/l or HbA1c >=6.5%; restrained eaters (score >12 on the three factor eating questionnaire). Obese T2DM subjects only: HbA1c <6.5% - >7.9%; metformin medication >2g/d; estimated glomerular filtration rate <45ml/min. The degree of eating restraint will be assessed, but not used as an exclusion criteria, as obese often have some degree of eating restraint.
Outcome results
None listed