Sustained influence of metformin therapy on circulating glucagon‐like peptide‐1 levels in individuals with and without type 2 diabetes

Preiss, David; Dawed, Adem Y; Welsh, Paul; Heggie, Alison; Jones, Angus G.; Dekker, Joost; Koivula, Robert W.; Hansen, Tue H.; Stewart, C.; Holman, Rury R.; Franks, Paul W.; Walker, Mark; Pearson, Ewan R.; Sattar, Naveed

doi:10.1111/dom.12826

Cited by 50 publications

(41 citation statements)

References 30 publications

(55 reference statements)

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“…Studies have shown a metformin‐mediated increase in glucose use by enterocytes with consequent lowering of serum glucose levels. The drug is also known to increase the secretion of glucagon‐like peptide‐1, another agent to lower serum glucose levels . Metformin's alteration of gut microbiota is another mechanism thought to be responsible for its metabolic effects (see later).…”

Section: Links To Microbiotamentioning

confidence: 99%

Is metformin poised for a second career as an antimicrobial?

Malik

Mehdi

Ali

et al. 2018

Diabetes Metabolism Res

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Metformin, a widely used antihyperglycaemic, has a good safety profile, reasonably manageable side-effects, is inexpensive, and causes a desirable amount of weight loss. In 4 studies of patients with tuberculosis (1 prospective and 3 retrospective), metformin administration resulted in better outcomes. In mice with several models of endotoxemia, metformin diminished levels of proinflammatory cytokines and improved survival. Laboratory studies showed effectiveness of the drug on multiple pathogens, including Trichinella spiralis, Staphylococcus aureus, Pseudomonas aeruginosa, hepatitis B virus, hepatitis C virus, and human immunodeficiency virus. Metformin administration in humans and mice produced major changes in the composition of the gut microbiota. These recently discovered microbe-modulating properties of the drug have led investigators to predict wide therapeutic utility for metformin. The recent easing in United States Food and Drug Administration (FDA) guidelines regarding administration of metformin to patients with kidney disease, and reduced anxiety about patient safety in terms of lactic acidosis, increase the probability of broadening of metformin's usage as a treatment of infectious agents. In this text we review articles pertinent to metformin's effects on microorganisms, both pathogens and commensals. We highlight the possible role of metformin in a wide range of infectious diseases and a possible expansion of its therapeutic profile in this field. A systematic review was done of PubMed indexed articles that examined the effects of metformin on a wide range of pathogens. Metformin was found to have efficacy as an antimicrobial agent in patients with tuberculosis. Mice infected with Trypanosomiasis cruzi had higher survival when also treated with metformin. The drug in vitro was active against T. spiralis, S. aureus, P. aeruginosa, and hepatitis B virus. In addition there is emerging literature on its role in sepsis. We conclude that metformin may have a potential role in the therapy for multiple infectious diseases. Metformin, in addition to its traditional effects on glucose metabolism, provides anti-microbial benefits in patients with tuberculosis and in a very wide range of other infections encounters in vitro and in vivo.

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Section: Links To Microbiotamentioning

confidence: 99%

Is metformin poised for a second career as an antimicrobial?

Malik

Mehdi

Ali

et al. 2018

Diabetes Metabolism Res

View full text Add to dashboard Cite

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“…10 Several gastrointestinal effects of metformin have been reported in both preclinical and clinical studies, including inhibition of intestinal glucose absorption, 11 enhancement of anaerobic glucose metabolism, 12 suppression of bile acid resorption, 13 modulation of gut microbiota, 14,15 and stimulation of the incretin hormone glucagon-like peptide-1 (GLP-1). 16,17 The observation that blockade of GLP-1 signalling by the GLP-1 receptor antagonist exendin abolished the suppression of hepatic glucose production by metformin in a rodent model of insulin resistance suggests a major role for GLP-1 in mediating its glucose-lowering effect. 18 Given that GLP-1 is released from enteroendocrine L-cells located predominantly in the ileum and colon, 19 the lower gut, as compared with the proximal small intestine, may be of greater therapeutic relevance to glucose-lowering with metformin.…”

mentioning

confidence: 99%

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

Borg

Bound

Grivell

et al. 2018

Diabetes Obesity Metabolism

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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.

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“…There is research suggesting that there may be genetic variations that affect the pharmacodynamics, pharmacokinetics, and metabolism of metformin, which may be a contributing factor to the development of hypoglycemia [29]. Antagonism of glucagon activity may be the primary mechanism by which metformin causes hypoglycemia; however, increased glucose consumption during aerobic metabolism may be a concurrent factor [21,22,[30][31][32]. In both diabetic and nondiabetic patients, metformin has been shown to independently increase glucagon-like peptide 1 (GLP-1) [22,33].…”

Section: Discussionmentioning

confidence: 99%