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

Diabetes Obes Metab. 2019 Mar;21(3):640-647. doi: 10.1111/dom.13567. Epub 2018 Nov 21.


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 13 C-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.

Keywords: gastric emptying; glucagon-like peptide-1; metformin; post-prandial blood glucose; small intestinal infusion; type 2 diabetes.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Blood Glucose / drug effects*
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2* / blood
  • Diabetes Mellitus, Type 2* / drug therapy
  • Diabetes Mellitus, Type 2* / physiopathology
  • Drug Administration Routes
  • Female
  • Gastric Emptying / drug effects*
  • Glucagon-Like Peptide 1 / blood*
  • Glucose / administration & dosage*
  • Glucose / pharmacokinetics
  • Glucose Tolerance Test
  • Humans
  • Intestine, Small / drug effects*
  • Intestine, Small / metabolism
  • Male
  • Metformin / administration & dosage*
  • Middle Aged


  • Blood Glucose
  • Glucagon-Like Peptide 1
  • Metformin
  • Glucose