Not Yet RecruitingPhase 4ACTRN12613000843752

Molecular determinants of glucose sensing in human gastrointestinal tract of patients with type 2 diabetes and healthy volunteers.

In patients with type 2 diabetes as opposed to healthy volunteers, what will the GLP-1 release and expression of glucose sensing molecules be in functionally identified colonic cells, activated by glucose or glibenclamide

Sponsor

Dr. Nam Q Nguyen

Enrollment

40 participants

Start Date

Sep 2, 2013

Study Type

Interventional

Conditions

Type II Diabetes

Summary

It has been recently revealed that distinct mechanisms trigger the release of the incretin hormone glucagon-like peptide-1 (GLP-1) in the proximal and distal intestine in rodents. Stimuli for incretin release vary considerably between species, and whether such distinct proximal and distal mechanisms exist in humans has not been assessed. Specific aims of the proposal are to: 1 - Determine the release of GLP-1 during acute colonic perfusion with glucose or the potassium ATP ion channel (KATP) inhibitor, glibenclamide, in healthy subjects and patients with type 2 diabetes; 2 - Determine the expression of glucose sensing molecules in functionally identified colonic cells, activated by glucose or glibenclamide, in healthy subjects and patients with type 2 diabetes. We hypothesise that L-cells in the human colon can release endogenous GLP-1 following local inhibition of KATP channels. This signalling pathway may provide an avenue to augment endogenous GLP-1 release in patients with type 2 diabetes, which could potentially be used to optimise blood glucose control.

Eligibility

Sex: Both males and femalesMin Age: 18 YearssMax Age: 75 Yearss

Inclusion Criteria2

Patients with type 2 diabetes (World Health Organisation (WHO) criteria) managed by diet alone or metformin, with a HbA1c =/< 7.5%.
Healthy volunteers, matched as closely as possible to the diabetic subjects for age, sex, and body mass index.

Exclusion Criteria17

Significant illness other than diabetes, including impairment to cardiovascular or respiratory function that limits a subject’s activity and therefore would represent a risk to undertaking endoscopy safely (American Society of Anesthesiologists Grade 3 or more)
History of gastrointestinal disease, including significant upper or lower gastrointestinal symptoms (as assessed by a validated upper gastrointestinal symptom questionnaire, pancreatitis, or previous gastrointestinal surgery (other than uncomplicated appendicectomy or cholecystectomy)
Haemoglobin below the lower limit of the normal range (ie. <135g/L for men and 115g/L for women), and ferritin below the lower limit of normal (ie. <10mcg/L)
Impaired renal or liver function (as assessed by calculated creatinine clearance < 90 mL/min or abnormal liver function tests (> 2 times upper limit of normal))
History of severe respiratory, cardiovascular, hepatic and/or renal disease, chronic alcohol abuse or epilepsy (excluded by history)
Subjects requiring medication that may influence gastrointestinal function
Any patient with coagulopathy.
Allergy to glibencamide and/or sulphonamide derivatives
Patients with Thrombocytopenia
Patients requiring treatment with anticoagulants, anti-platelet agents and NSAIDS
Presence of mucosal abnormalities at sigmoidoscopy such as inflammatory bowel disease and colorectal cancer.
Body mass index greater than 32 kg/m2
Evidence of drug abuse, consumption of more than 20 g alcohol or 10 cigarettes per day
Female patients not using appropriate contraceptive method (ie oral contraceptive pill, diaphragm, Depo-Provera hormonal contraceptive injection, intrauterine device (IUD), Norplant method)
Vegetarian, lactation, or pregnancy (verified by urine testing in women of reproductive age; in these subjects, the study will be completed during the follicular phase of the menstrual cycle)
Donation of blood within the previous 3 months
Participation in any other research studies within the previous 3 months

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Interventions

ARM 1: Patients with Type II Diabetes After an overnight fast, a 1000 mL normal saline enema will be given by a registered nurse to cleanse the distal bowel. An intravenous cannula will be inserted i

ARM 1: Patients with Type II Diabetes After an overnight fast, a 1000 mL normal saline enema will be given by a registered nurse to cleanse the distal bowel. An intravenous cannula will be inserted into a forearm vein on each arm, one for blood sampling and the other for infusion of 25% glucose at a variable rate to maintain the blood glucose concentration = 5 mmol/L. The participant will then have the unsedated flexible sigmoidoscopy performed in the left lateral position using a flexible video colonoscope inserted first to the rectum, where four mucosal biopsies will be collected using biopsy forceps. The scope will then be advanced to the descending colon, where four additional biopsies will be collected. The colon will be perfused with a solution containing 3mg glibenclamide made up to 120 mL with normal saline (a 50 micromolar solution) At T=30 min, four additional biopsies will be collected from each site (total 16 biopsies per subject) and then the colonoscope will be withdrawn. A high carbohydrate meal with approx 45g of carbohydrates will be provided at T=120min, at which time the variable IV glucose infusion will cease and the subject will be observed for a further 6 hours with meals of sandwiches provided at 3 hourly intervals. ARM 2 - Healthy Control These people will undergo the same intervention and comparator treatment as those with diabetes.