Gastrointestinal mechanisms underlying glucose lowering by metformin in type 2 diabetes

INTERVENTION: 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. CONDITION: Type 2 diabetes mellitus PRIMARY OUTCOME: differences in the gastric half‐emptying time (T50) derived from 13CO2 concentrations in the breath samples between the 3 treatments. differences in the incremental area under the curve (iAUC) for plasma GLP‐1 between the 3 treatments. differences in the incremental area under the curve (iAUC) for plasma glucose between the 3 treatments. SECONDARY OUTCOME: differences in the incremental area under the curve (iAUC) for blood pressure between the 3 treatments differences in the incremental area under the curve (iAUC) for heart rate between the 3 treatments. differences in the incremental area under the curve (iAUC) for plasma 3OMG between the 3 treatments. differences in the incremental area under the curve (iAUC) for plasma glucagon between the 3 treatments differences in the incremental area under the curve (iAUC) for plasma insulin differences in the incremental area under the curve (iAUC) for plasma lactate between the 3 treatments. differences in the incremental area under the curve (iAUC) for plasma metformin between the 3 treatments. 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)