None listed
Conditions
Brief summary
Emerging evidence suggests that the anti-diabetic action of metformin resides primarily in the gut. Metformin has been shown to increase plasma concentrations of GLP-1 which are released from enteroendocrine L-cells located in the ileum and colon. GLP-1 has the capacity to restore blood glucose homeostasis in type 2 diabetes via pleiotropic actions including stimulation of insulin secretion and suppression of glucagon in a glucose-dependent manner, slowing of gastric emptying, and inhibition of hepatic glucose production and energy intake. Hence, the region of the gut exposed to metformin may be an important determinant of the lowering of blood glucose in type 2 diabetes. In this trial, we wish to investigate whether administration of metformin into the 'distal small intestine' (190cm beyond the pylorus) results in a lower glycaemic response to oral glucose when compared with administration into the 'proximal small intestine' (10cm beyond the pylorus) and evaluate the associated changes in plasma GLP-1, insulin, glucagon, 3OMG, lactate and metformin and rate of gastric emptying in patients with type 2 diabetes. There is increasing evidence that the incretin system has important cardiovascular effects and hence, we also wish to assess the changes in blood pressure and heart rate, in response to oral glucose, in the presence and absence of "proximal" or "distal" metformin.
Interventions
Following a screening visit, each subject will be studied on 3 occasions, separated by at least 7 days, in a double-blinded randomised order. On each study day, a customised multilumen silicone catheter will be inserted nasally into the gastrointestinal (GI) tract. Passage to the desired small intestinal depth will be confirmed by continuous measurement of the transmucosal potential difference between proximal and distal channels along with the use of a reference electrode inserted subcutaneous
Following a screening visit, each subject will be studied on 3 occasions, separated by at least 7 days, in a double-blinded randomised order. On each study day, a customised multilumen silicone catheter will be inserted nasally into the gastrointestinal (GI) tract. Passage to the desired small intestinal depth will be confirmed by continuous measurement of the transmucosal potential difference between proximal and distal channels along with the use of a reference electrode inserted subcutaneously into the left forearm. Once correctly positioned, one of three treatments will be administered: 0.9% saline (control), ‘proximal metformin’ 1000 mg (10cm beyond pylorus), or ‘distal metformin’ 1000 mg (190cm beyond pylorus) over 5 min, followed 60 min later by an oral glucose drink (containing 50 g glucose). The catheter will be removed 10 minutes prior to an oral glucose load.
Sponsors
University of Adelaide
Study design
Allocation
Randomised controlled trial
Intervention model
Crossover
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver)
Eligibility
Sex/Gender
All
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Type 2 diabetes (World Health Organisation (WHO) criteria), managed by diet only Body mass index (BMI) 20 - 40 kg/m2 Males and post-menopausal females Glycated haemoglobin (HbA1c) less than 8.5% Haemoglobin above the lower limit of the normal range (ie. greater than 135g/L for men and 115g/L for women), and ferritin above the lower limit of normal (ie. greater than 30ng/mL for men and greater than 20mg/mL for women)
Exclusion criteria
Use of any medication that may influence gastrointestinal motor function within 48 hours or 5 half-lives of the study, specifically: opiates, anticholinergics, levodopa, clonidine, nitrates, phosphodiesterase type 5 inhibitors, sumatriptan, metoclopramide, domperidone, cisapride, tegaserod, or erythromycin Evidence of drug abuse, or consumption of more than 20 g alcohol or 10 cigarettes on a daily basis History of gastrointestinal disease, including significant upper or lower gastrointestinal symptoms, pancreatitis, or previous gastrointestinal surgery (other than uncomplicated appendicectomy or cholecystectomy) Other significant illness, including epilepsy, cardiovascular or respiratory disease Impaired renal or liver function (as assessed by calculated creatinine clearance less than 90 mL/min or abnormal liver function tests (greater than 2 times upper limit of normal range)) Donation of blood within the previous 3 months Participation in any other research studies within the previous 3 months Females who are pre-menopausal Inability to give informed consent Participants who do not eat beef Vegetarian diet
Outcome results
None listed