Comparative effects of proximal and distal small intestinal administration of metformin on plasma glucose and glucagon‐like peptide‐1, and gastric emptying after oral glucose, in type 2 diabetes

Abstract

Aims The gastrointestinal tract, particularly the lower gut, may be key to the anti‐diabetic action of metformin. We evaluated whether administration of metformin into the distal, vs the proximal, small intestine would be more effective in lowering plasma glucose by stimulating glucagon‐like pepetide‐1 (GLP‐1) and/or slowing gastric emptying (GE) in type 2 diabetes (T2DM). Materials and methods Ten diet‐controlled T2DM patients were studied on three occasions. A transnasal catheter was positioned with proximal and distal infusion ports located 13 and 190 cm beyond the pylorus, respectively. Participants received infusions of (a) proximal + distal saline (control), (b) proximal metformin (1000 mg) + distal saline or (c) proximal saline + distal metformin (1000 mg) over 5 minutes, followed 60 minutes later by a glucose drink containing 50 g glucose and 150 mg 13C‐acetate. “Arterialized” venous blood and breath samples were collected over 3 hours for measurements of plasma glucose, GLP‐1, insulin and glucagon, and GE, respectively. Results Compared with control, both proximal and distal metformin reduced plasma glucose and augmented GLP‐1 responses to oral glucose comparably (P < 0.05 each), without affecting plasma insulin or glucagon. GE was slower after proximal metformin than after control (P < 0.05) and tended to be slower after distal metformin, without any difference between proximal and distal metformin. Conclusions In diet‐controlled T2DM patients, glucose‐lowering via a single dose of metformin administered to the upper and lower gut was comparable and was associated with stimulation of GLP‐1 and slowing of GE. These observations suggest that the site of gastrointestinal administration is not critical to the glucose‐lowering capacity of metformin.

Metformin attenuates the postprandial fall in blood pressure in type 2 diabetes

“…As reported previously, metformin increased plasma total GLP‐1 concentrations (i.e. the incremental area under the curve) and prolonged the gastric half‐emptying time ( P < 0.05 for each), when compared with control.…”

“…However, HR did not differ between the 2 study days in the current study, perhaps because of the varying duration of metformin therapy or route of glucose exposure (oral vs. ID). Interestingly, we observed that ID metformin slowed gastric emptying and increased plasma GLP‐1 levels, both of which are known to mitigate the postprandial BP fall . Moreover, metformin has been reported to inhibit small intestinal glucose absorption and improve left ventricular function, which may also be of relevance to the effects of metformin on postprandial BP …”

“…BP and HR were evaluated in 10 diet‐controlled T2DM patients (five male/five female; mean age 65.6 ± 3.1 years; body mass index [BMI] 30.1 ± 1.7 kg/m 2 ; HbA1c 6.4 ± 0.2% [45.8 ± 1.6 mmol/mol]; duration of known diabetes 5.5 ± 1.0 years), in whom we recently reported comparative effects of ID and intraileal administration of metformin on plasma glucose and glucagon‐like peptide‐1 (GLP‐1), and gastric emptying after oral glucose . Two participants were receiving antihypertensive medications (an angiotensin receptor blocker in one and a thiazide‐like diuretic in the other), and were instructed to withhold these for 24 hours before each study day.…”

“…Two participants were receiving antihypertensive medications (an angiotensin receptor blocker in one and a thiazide‐like diuretic in the other), and were instructed to withhold these for 24 hours before each study day. The inclusion and exclusion criteria have been reported . The protocol was approved by the Human Research Ethics Committee of the Royal Adelaide Hospital, and prospectively registered on a clinical trials database (ACTRN12617000243314).…”

“…After a standardized evening meal (McCain beef lasagne, Victoria, Australia) and an overnight fast, participants attended the laboratory at ~0800 hours the following day. An ID catheter (Dentsleeve International, Ontario, Canada) was positioned with an infusion port opening 13 cm beyond the pylorus . Subsequently, a solution containing metformin 1 g (metformin hydrochloride USP, PCCA, Australia) dissolved in 40 mL 0.9% saline, or 0.9% saline alone (control) was administered through the ID catheter at t = −60 minutes over 5 minutes, followed by a 200 mL drink containing 50 g glucose (a test meal used widely to diagnose postprandial hypotension), and 150 mg 13 C‐acetate (as a marker of gastric emptying) during t = −2 to 0 minutes.…”