Poster Presentation Australian & New Zealand Obesity Society 2016 Annual Scientific Meeting

Metformin directly triggers GLP-1 and PYY secretion in human colon and ileum (#216)

Emily WL Sun 1 , Alice P Liou 2 , Margaret L Jackson 2 , Dayan de Fontgalland 3 , Philippa Rabbitt 3 , Paul Hollington 3 , Luigi Sposato 3 , Steven Due 3 , David A Wattchow 3 , Richard L Young 4 5 , Damien J Keating 1 5
  1. Discipline of Human Physiology and Centre for Neuroscience, Flinders University of South Australia, Adelaide, Australia
  2. Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, USA
  3. Discipline of Surgery, Flinders University, Adelaide, South Australia, Australia
  4. Adelaide Medical School, University of Adelaide, South Australia
  5. Nutrition and Metabolism, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia

Background: Metformin is the first-line therapy for type 2 diabetes (T2D) for more than half a century. The exact mechanisms that mediate its blood glucose-lowering effect remain uncertain. Recent reports of superior efficacy of delayed-release oral formulations of metformin over the parenteral route suggest at least part of its anti-diabetic action is gut-mediated. There is evidence suggesting chronic metformin treatment increases plasma levels of GLP-1 and PYY, secretory products of the enteroendocrine L cells and are pivotal in glucose and energy homeostasis. We hypothesized metformin directly triggers release of these peptides from human ileal and colonic mucosae, where the highest density of L cells are found.

Method: An ex vivo preparation of human mucosa for secretion assay was developed from surgically resected human colon and ileum sections; mucosal tissue was obtained from 46 human colons (11 with T2D) and 10 ileums (3 with T2D) soon after surgical resection. 15-minute static incubations of the preparations with metformin were performed and the secretion supernatants were assayed for GLP-1 and PYY content.

Results: Acute exposure of human gut mucosal tissue to 10 μM metformin significantly induced GLP-1 and PYY release. This stimulatory effect was preserved across BMI and T2D subjects. GLP-1 and PYY co-release was tightly correlated. Metformin-induced GLP-1 and PYY release was blocked by AMPK inhibition and by inhibiting transporters associated with metformin internalization.

Conclusion: We demonstrated acute exposure of the human gut mucosa to metformin significantly triggers GLP-1 and PYY release, independent of any neural inputs. We also showed that AMPK activation and internalization of metformin were required for metformin-induced GLP-1 and PYY release from the mucosa. This mechanism may subserve weight loss and glycaemia benefits of metformin and are in-line with the growing acceptance that the gastrointestinal tract is the primary site of metformin’s action.