Metformin is an oral antidiabetic drug, first approved for use in the USA in 1994. It helps control blood sugar in several ways, including decreasing hepatic glucose production, decreasing intestinal absorption of glucose and improving insulin sensitivity.
In Medieval Europe, the Gallega officinalis plant was used as a folk medicine to treat diabetes. In the late 1800s, the plant was found to be rich in guanidine, and a subsequent animal study in 1918 showed that guanidine had a blood glucose-lowering effect.1 However, guanidine proved to be too toxic for clinical use. In 1929, dimethylbiguanide, which included phenformin and metformin, was synthesized. These compounds preserved the glucose-lowering effect of their parent compounds but with reduced toxicity. Phenformin is more potent than metformin in improving hyperglycaemia, but the high occurrence of lactic acidosis led to the withdrawal of phenformin from the market in the 1970s.2 This adverse event is extremely rare with metformin, allowing its use in an increasingly comprehensive way for the treatment of hyperglycaemia in patients with type 2 diabetes (T2D).
The biguanide metformin is currently the preferred first-line drug used, along with lifestyle modifications, in the treatment of T2D. Despite the extensive use of metformin, the mechanisms underlying its glucose-lowering effect are not totally clear.
Increased hepatic glucose production is the major cause of fasting hyperglycaemia in T2D patients.3 Metformin improves hyperglycaemia mainly through suppression of gluconeogenesis in the liver – in one study in patients with T2D, the suppression of gluconeogenesis was by 37%.4 In another study, patients with diabetes exhibited a twofold increase in the rate of gluconeogenesis, which was decreased by 33% by the administration of metformin.5
Interestingly, metformin has also been shown to increase intestinal glucose utilization and to reduce food intake, which may help to explain the weight reduction observed in some obese metformin-treated patients.6,7 Importantly, metformin is ineffective when administered intravenously.8 These findings suggest that the major glucose lowering mechanism(s) of metformin may lie hidden in the gastrointestinal tract. One such mechanism may be mediated by the gut-derived incretin hormone glucagon-like-peptide 1 (GLP-1). GLP-1 is secreted to the circulation after nutrient intake from intestinal enteroendocrine L cells located in the epithelium of the gastrointestinal tract and found in highest numbers in the distal part of the small intestine and in the colon.9 The glucose-lowering actions of GLP-1 include endocrine stimulation of insulin secretion from pancreatic β cells and inhibition of glucagon release from pancreatic α cells.10
In 1998, Lugari et al.11 found that treatment with metformin increased postprandial GLP-1 levels in patients with T2D. Since then, increased GLP-1 concentrations after metformin administration have been observed in several human studies.12,13
Studies describing metformin-induced release of GLP-1 increases understanding of metformin’s glucose-lowering action and contributes to explaining the multifaceted effects of metformin. A probable explanation for the GLP-1 secretory effects of metformin seems to be associated with its effect on bile acids, which have been shown to modulate GLP-1 release via TGR5 and FXR. Several human studies report that metformin leads to alteration of the bile acid pool.14,15 Importantly, metformin has shown inconsistent ability to stimulate GLP-1 secretion in vitro, in the absence of bile acids,16 indicating that the interplay between bile acids and enteroendocrine L cells plays an essential role in metformin’s mode of action. Currently, the bile acid-dependent hypothesis seems a compelling explanation behind metformin-induced GLP-1 secretion, but several other mechanisms may also contribute. For instance, recently published data suggest that metformin induces alterations in the composition of the human gut microbiota,16,17 favouring generation of specific bile acids with GLP-1-secreting properties. Further publications suggest short chain fatty acid-producing bacteria could be contributing to metformin-induced GLP-1 secretion,18,19 and that metformin increases β cell GLP-1 sensitivity by increasing the expression of GLP-1 receptors.20
Together, these findings constitute possible explanations for metformin-induced GLP-1 secretion and sensitivity, which warrant further investigation in human studies.21
The discovery of new possible mechanisms of action of metformin brings increased understanding regarding the effectiveness and safety of this drug. For this reason, despite a long trajectory of use, metformin remains a gold standard in the treatment of patients with T2D.
- Watanabe CK. Studies in the metabolic changes induced by administration of guanidine bases. I. Influence of injected guanidine hydrochloride upon blood sugar content. J Biol Chem 1918:33;253–265.
- An H, He L. Current understanding of metformin effect on the control of hyperglycemia in diabetes. J Endocrinol. 2016;228(3):R97-106.
- Wajngot A, Chandramouli V, Schumann WC, et al. Quantitative contributions of gluconeogenesis to glucose production during fasting in type 2 diabetes mellitus. Metabolism 2001:50:47–52.
- Stumvoll M, Nurjhan N, Perriello G, et al. Metabolic effects of metformin in non-insulin-dependent diabetes-mellitus. New Eng J Med 1995:333:550–554.
- Hundal RS, Krssak M, Dufour S, et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 2000:49;2063–2069.
- Pénicaud L, Hitier Y, Ferré P, Girard J. Hypoglycaemic effect of metformin in genetically obese (fa/fa) rats results from an increased utilization of blood glucose by intestine. Biochem J. 1989;262:881–885.
- Lee A, Morley JE. Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin dependent diabetes. Obes Res. 1998;6:47–53.
- Sum CF, Webster JM, Johnson AB, et al. The effect of intravenous metformin on glucose metabolism during hyperglycaemia in type 2 diabetes. Diabet Med. 1992;9:61–65.
- Jorsal T, Rhee NA, Pedersen J, et al. Characterizing the distribution of enteroendocrine cells in patients with type 2 diabetes and nondiabetic controls. ADA 2015 (Abstract 2054-P).
- Kreymann B, Williams G, Ghatei MA, Bloom SR. Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet. 1987;2:1300–1304.
- Lugari R, Dell’Anna C, Sarti L, Gnudi A. Effects of metformin on intestinal and pancreatic endocrine secretion in type 2 (non-insulin dependent) diabetes. In: Molecular and Cell Biology of Type 2 Diabetes and its Complications. Belfiore F, Lorenzi M, Molinatti GM, Porta M, eds. Basel, Switzerland: Karger; 1998; p.161–163.
- Mannucci E, Ognibene A, Cremasco F, et al. Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. Diabetes Care. 2001;24:489–494.
- Mulherin AJ, Oh AH, Kim H, et al. Mechanisms underlying metformin-induced secretion of glucagon-like peptide-1 from the intestinal L cell. Endocrinology. 2011;152:4610–4619.
- Carter D, Howlett HCS, Wiernsperger NF, Bailey CJ. Differential effects of metformin on bile salt absorption from the jejunum and ileum. Diabetes Obes Metab. 2003;5:120–125.
- Chen L, Yao X, Young A, et al. Inhibition of apical sodium-dependent bile acid transporter as a novel treatment for diabetes. Am J Physiol Endocrinol Metab. 2012;302:E68–76.
- Thomas C, Gioiello A, Noriega L, et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 2009;10:167–177.
- Wu T, Bound MJ, Standfield SD, et al. Effects of rectal administration of taurocholic acid on glucagon-like peptide-1 and peptide YY secretion in healthy humans. Diabetes Obes Metab. 2013;15:474–477.
- Lin HV, Frassetto A, Kowalik EJ, et al. Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS One. 2012;7:e35240.
- Cani PD, Lecourt E, Dewulf EM, et al. Gut microbiota fermentation of prebiotics increases satietogenic and incretin gut peptide production with consequences for appetite sensation and glucose response after a meal. Am J Clin Nutr. 2009;90:1236–1243.
- Pan QR, Li WH, Wang H, et al. Glucose, metformin, and AICAR regulate the expression of G protein-coupled receptor members in INS-1 beta cell. Horm Metab Res. 2009;41:799–804.
- Bahne E, Hansen M, Bronden A, et al. Involvement of glucagon-like peptide-1 in the glucose-lowering effect of metformin. Diabetes Obes Metab. 2016;18(10):955–61.