Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-α in mice.
OBJECTIVE
Metformin is widely used for the treatment of type 2 diabetes. Although it reduces hepatic glucose production, clinical studies show that metformin may reduce plasma dipeptidyl peptidase-4 activity and increase circulating levels of glucagon-like peptide 1 (GLP-1). We examined whether metformin exerts glucoregulatory actions via modulation of the incretin axis.


METHODS
Metformin action was assessed in Glp1r(-/-), Gipr(-/-), Glp1r:Gipr(-/-), Pparα (also known as Ppara)(-/-) and hyperglycaemic obese wild-type mice with or without the GLP-1 receptor (GLP1R) antagonist exendin(9-39). Experimental endpoints included glucose tolerance, plasma insulin levels, gastric emptying and food intake. Incretin receptor expression was assessed in isolated islets from metformin-treated wild-type and Pparα(-/-) mice, and in INS-1 832/3 beta cells with or without peroxisome proliferator-activated receptor (PPAR)-α or AMP-activated protein kinase (AMPK) antagonists.


RESULTS
In wild-type mice, metformin acutely increased plasma levels of GLP-1, but not those of gastric inhibitory polypeptide or peptide YY; it also improved oral glucose tolerance and reduced gastric emptying. Metformin significantly improved oral glucose tolerance despite loss of incretin action in Glp1r(-/-), Gipr(-/-) and Glp1r(-/-) :Gipr(-/-) mice, and in wild-type mice fed a high-fat diet and treated with exendin(9-39). Levels of mRNA transcripts for Glp1r, Gipr and Pparα were significantly increased in islets from metformin-treated mice. Metformin directly increased Glp1r expression in INS-1 beta cells via a PPAR-α-dependent, AMPK-independent mechanism. Metformin failed to induce incretin receptor gene expression in islets from Pparα(-/-) mice.


CONCLUSIONS
As metformin modulates multiple components of the incretin axis, and enhances expression of the Glp1r and related insulinotropic islet receptors through a mechanism requiring PPAR-α, metformin may be mechanistically well suited for combination with incretin-based therapies.
Maida
A
A
Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
Lamont
B J
BJ
Cao
X
X
Drucker
D J
DJ
D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000097:blood; D004435:Eating / Q000187:drug effects; D005749:Gastric Inhibitory Polypeptide / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000627:therapeutic use; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics / Q000378:metabolism*; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000097:blood; D015398:Signal Transduction / Q000187:drug effects
C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D047493:PPAR alpha; D010446:Peptide Fragments; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; C083773:exendin (9-39); D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D008687:Metformin; C041086:gastric inhibitory polypeptide receptor; D018819:Dipeptidyl Peptidase 4