Where is metformin absorbed

Indeed, when lactic acidosis occurs in metformin-treated patients, early determination of the metformin plasma concentration appears to be the best criterion for assessing the involvement of the drug in this acute condition.

After confirmation of the diagnosis, treatment should rapidly involve forced diuresis or haemodialysis, both of which favour rapid elimination of the drug. Although serious, lactic acidosis due to metformin is rare and may be minimised by strict adherence to prescribing guidelines and contraindications, particularly the presence of renal failure. Finally, only very few drug interactions have been described with metformin in healthy volunteers.

Plasma levels may be reduced by guar gum and alpha-glucosidase inhibitors and increased by cimetidine, but no data are yet available in the diabetic population. Abstract The biguanide metformin dimethylbiguanide is an oral antihyperglycaemic agent widely used in the management of non-insulin-dependent diabetes mellitus NIDDM.

Role of metformin accumulation in metformin-associated lactic acidosis. Presse Med ; Lalau JD, Lacroix C. Lessons from in vivo and in vitro studies of metformin concentrations in plasma and in erythrocytes [abstract].

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Vet Hum Toxicol ; 21 Suppl. McLelland J. Recovery from metformin overdose. Diabetic Med ; 2: —1. Antihyperglycaemic agents: drug interactions of clinical importance. Drug Safety ; 32— Reduction of the acute bioavailability of metformin by the alpha-glucosidase inhibitor acarbose in normal man. Eur J Clin Invest ; 24 Suppl. The efficacy of acarbose in the treatment of patients with non-insulin-dependent diabetes mellitus. A multicenter controlled clinical trial.

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You can also search for this author in PubMed Google Scholar. Reprints and Permissions. Scheen, A. Clinical Pharmacokinetics of Metformin. Clin-Pharmacokinet 30, — Download citation. Published : 20 October Issue Date : May Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search SpringerLink Search. Summary The biguanide metformin dimethylbiguanide is an oral antihyperglycaemic agent widely used in the management of non-insulin-dependent diabetes mellitus NIDDM. References 1. Chichester: Wiley, —95 Google Scholar 3. Berlin: Springer Verlag, 7—42 Google Scholar 6. Clin Pharmacol Ther ; Google Scholar Adv Ther ; 21—33 Google Scholar Diabetic Med ; 4: A Google Scholar Pract Diabetes ; 9: 51—3 Article Google Scholar Scheen View author publications.

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Metformin is currently the most prescribed drug for treatment of type 2 diabetes mellitus in humans. It has been well established that long-term treatment with metformin improves glucose tolerance in mice by inhibiting hepatic gluconeogenesis.

Interestingly, a single dose of orally administered metformin acutely lowers blood glucose levels, however, little is known about the mechanism involved in this effect. Glucose tolerance, as assessed by the glucose tolerance test, was improved in response to prior oral metformin administration when compared to vehicle-treated mice, irrespective of whether the animals were fed either the standard or high-fat diet.

Blood glucose-lowering effects of acutely administered metformin were also observed in mice lacking functional AMP-activated protein kinase, and were independent of glucagon-like-peptide-1 or N-methyl-D-aspartate receptors signaling. Finally, metformin in a dose-dependent but indirect manner decreased glucose transport from the intestinal lumen into the blood, which was observed ex vivo as well as in vivo. Our results support the view that the inhibition of transepithelial glucose transport in the intestine is responsible for lowering blood glucose levels during an early response to oral administration of metformin.

Metformin, the most potent of the biguanide analogs, was synthetized at the beginning of 20 th century and introduced to human medicine in 1. Due to its excellent abilities to manage blood glucose levels accompanied by a superior safety profile, metformin became the most widely prescribed drug for type 2 diabetes T2DM 2. The main advantage of metformin is its ability to reduce blood glucose concentrations in the long term, which is accompanied by improvements in insulin sensitivity of peripheral tissues without increasing the risk of hypoglycaemia 3 or body weight gain 4.

Moreover, metformin has also shown benefits in reducing cancer risk and improving cancer prognosis 5 , which could be associated with the ability of metformin to negatively regulate aerobic glycolysis i. However, despite 60 years of its extensive use the precise mechanism of metformin action is not sufficiently clarified. It is widely accepted that the blood glucose-lowering effect of metformin is mediated mainly through the suppression of hepatic glucose production.

Metformin could reduce hyperglycaemia also by improving peripheral insulin sensitivity and increasing glucose uptake in skeletal muscle 10 , Several studies suggest that the intestine also participates in blood glucose-lowering effect of metformin, mainly via changes in glucose uptake and anaerobic metabolism of enterocytes 12 , while increased production of an incretin hormone glucagon-like peptide-1 GLP-1 could be involved as well Furthermore, there is convincing evidence that metformin changes intestinal microbiota in humans and the gut metabolome 14 , but the significance of this finding for whole-body glucose metabolism remains unclear.

On the other hand, the activation of the glucose-lactate-glucose futile cycle during long-term treatment with metformin, which includes both the intestine and the liver, results in increased energy consumption Long-term effects of metformin have been the main focus of the majority of studies so far, and only few studies focused on the mechanism associated with blood glucose lowering in response to acute administration of metformin 9 , 16 , Moreover, the expression of GLP-1 receptor GLP1R is widely distributed throughout the brain including neurons producing N-methyl-D-aspartate 19 , and vagal afferent activation enhances N-methyl-D-aspartate receptor NMDAR -mediated neuronal transmission in the nucleus of the solitary tract to lower glucose production via the hepatic vagal branch Further in this context, a rapid blood glucose-lowering effect during an oral glucose tolerance test OGTT has been demonstrated in mice and rats after oral administration of metformin 16 , 21 , however no clear explanation for this effect was provided.

Our results strongly implicate changes in glucose uptake and transport in the small intestine in the blood glucose-lowering effect of orally administered metformin and suggest that these effects are independent of functional AMPK, as well as of GLP1R and NMDAR signaling. Administration of a single dose of metformin resulted in the dose-dependent improvement of glucose tolerance as evidenced by decreased blood glucose concentrations during OGTT Fig. The level of glucose intolerance expressed as the total area under the glucose curve AUC was reduced in all metformin-treated groups as compared to vehicle-treated controls Fig.

Moreover, the reduction in AUC caused by the highest dose of metformin i. M was significantly greater than that caused by the lowest metformin dose i. M60; Fig. Metformin improves glucose tolerance independently of changes in plasma insulin levels. Dose-dependent improvement of glucose tolerance induced by metformin in the presence of similar plasma insulin levels suggest some alternative mechanism to lowering blood glucose levels in response to metformin.

Thus, in order to understand the blood glucose-lowering effect of a single dose of metformin we performed 2-[1,2—3H N ]-deoxy-D-glucose [ 3 H]DG uptake assay and examined the uptake of radioactively-labelled glucose from the blood into various tissues Fig.

Acute administration of metformin did not significantly affect [ 3 H]DG uptake in other major insulin-sensitive tissues such as adipose tissue and skeletal muscle when compared to vehicle-treated mice Fig. Next, we examined whether the response to orally given metformin is also associated with glucose tolerance of STD fed animals. OGTT in a standard diet STD fed mice see Table S1 in Supplementary appendix for basic characteristics revealed that orally given metformin is able to lower blood glucose levels independently of the diet Fig.

In the following experiments, we tested whether any of the previously published mechanisms regarding the involvement of AMPK or GLP1R and NMDAR signaling could be involved also in the glucose-lowering effect of acutely administered oral metformin. S2 , Exendin 9—39 Fig. Changes in tissue glucose uptake Fig. Thus, we focused on the effect of metformin on whole-body energy metabolism.

Indirect calorimetry measurements performed in overnight fasted animals treated orally with M or vehicle revealed no differences in the mean values of respiratory quotient RQ between the groups before glucose gavage Supplementary appendix Fig.

In response to glucose administration, RQ values increased more in the vehicle-treated group, suggesting a higher glucose oxidation in mice without metformin. However, the RQ curves observed after glucose loading did not differ significantly between the metformin- and vehicle-treated groups Supplementary appendix Fig. The maximal achieved glucose oxidation rates were significantly higher in the vehicle 1. Conversely, in the metformin-treated mice, a greater portion of exogenous glucose was not oxidized as compared to vehicle-treated mice Fig.

This could suggest that after metformin treatment there was an incomplete glucose oxidation to CO 2 or glucose was not transported from gastrointestinal tract to plasma. Whole-body glucose oxidation is reduced in response to oral administration of metformin.

Thirty min later i. Based on our observation that anaerobic glycolytic activity in the small intestine is not altered by oral gavage with metformin Supplementary appendix Fig. S4 , we investigated the effect of metformin on the intestinal transport of orally administered glucose Fig.

First, we performed PET imaging using radiopharmaceutical [ 18 F]-FDG to visualize the accumulation of the tracer in the small intestine of mice pretreated with either M or vehicle Fig. In order to further analyze the transport capacity of the intestine for glucose, we performed ex vivo analysis of glucose transepithelial transport in the direction from the intestinal lumen to the blood using the technique of everted sacs prepared from different intestinal segments of mice pretreated either with metformin or vehicle Fig.

However, under these conditions, glucose concentrations in the serosal fluid were similar in both groups Fig. To confirm the relationship between the reduced transepithelial glucose transport in the small intestine and blood glucose-lowering effect of acutely administered metformin, we tested whether the inhibition of intestinal glucose transport by metformin is also dose-dependent.

Metformin slows down the intestinal transit and stimulates glucose uptake from intestinal lumen into proximal intestinal segments while inhibiting glucose transport from intestinal lumen to circulation. The intestinal content was carefully removed before the measurement. These data demonstrate that metformin stimulates glucose uptake from the intestinal lumen to the tissue primarily in the proximal jejunum, but at the same time reduces the transport of glucose to the blood across intestinal epithelia in the proximal jejunum as well as in proximal ileum in a dose-dependent manner.

These metformin-driven changes in the intestinal glucose transport are apparent when metformin is administered by oral gavage in vivo but not when it is directly applied to intestinal tissue ex vivo. We present evidence that the small intestine plays a key role in the early response to oral administration of metformin in mice. Metformin was more effective in lowering blood glucose levels when it was administrated orally as compared to its intravenous administration. Long-term effects of metformin with regard to regulation of glucose homeostasis are based on several distinct activities in various organs and tissues, which include increased glucose disposal, particularly in the skeletal muscle 22 , as well as reduced hepatic glucose production 9 , However, in our current study, peripheral uptake of intraperitoneally injected [ 3 H]DG, a non-metabolizable analogue of glucose, increased significantly only in the brain and small intestine during the early phase of acute response to oral metformin in fasted HFD mice.

In this respect, an intense and diffuse accumulation of intravenously injected [ 18 F]-FDG has been previously observed in the small intestine and colon in humans, which was interpreted as a physiological response to both short- and long-term treatment with metformin 24 , This suggests that intestinal glucose uptake both from the intestinal lumen and from the circulation is an important determinant of the early-phase of metformin action.

Increased glucose utilization in the intestine may contribute to metformin-induced lactic acidosis. Our current data suggest that reduced transport of intragastrically administered glucose across intestinal epithelia might be responsible for blood glucose lowering in response to oral metformin administration.

This conclusion is based on the calculation of whole-body glucose oxidation, which was derived from the data obtained by indirect calorimetry, as well as on the fact that lactate production was not changed after oral metformin. An important role of the intestine is also supported by the fact that the strongest glucose-lowering effect of metformin is observed after its oral administration as compared to intraportal or intravenous infusions Non-metabolized metformin is also excreted in urine, since no metabolites have been reported We found that the acute response to oral administration of metformin followed by orally given glucose includes a profound inhibition of glucose transport from the intestinal lumen to circulation in the proximal segment of both jejunum and ileum.

The difference between the uptake of [ 18 F]-FDG into tissue in vivo and glucose transport in everted gut sacs of proximal ileum is presumably caused by different glucose availability. Thus, in postprandial state, glucose passing through the intestine reached low concentrations in the ileum, whereas all the gut segments that were analyzed as the everted sacs ex vivo were incubated in the solution of equally concentrated glucose.

Studies on Fanconi-Bickel patients with a mutation in GLUT2 suggest that there is another exit pathway for glucose that may involve exocytosis Little is known about how metformin regulates GLUT transporters, although some evidence shows that metformin promotes their translocation to the apical membrane Recently, a polymorphism in the Slc2a2 gene, associated with altered GLUT2 expression in the small intestine, liver and other tissues, was identified as a genetic component of the glycemic response to metformin using genome-wide association studies We showed that metformin-induced inhibition of the intestinal glucose transport to circulation, together with the observed increase of intestinal glucose uptake into enterocytes, lead to accumulation of glucose in the intestine.

This accumulation could be either a result of inhibited glucose transport to circulation or an impairment of glucose metabolism in enterocytes. Lack of an inhibitory effect of metformin on the intestinal transepithelial glucose transport observed when metformin was applied directly to everted sacs obtained from different intestinal segments of previously untreated mice suggests that this process is regulated indirectly and is dependent on the oral route of metformin administration.

However, our results do not rule out other possible mechanisms involved in the blood glucose-lowering effect of oral metformin, such as the inhibition of hepatic glucose production HGP driven by the gut-brain-liver axis The rate of gastric emptying is now recognized to be a major determinant of the early as well as the overall postprandial glucose excursions in both healthy individuals and T2DM subjects 39 , while the acute oral metformin administration was shown to slow down gastric emptying in both the diabetic and control mice 40 , The fact that intraduodenal administration of glucose did not diminish the blood glucose-lowering effect of metformin does not support the role of gastric emptying as the major mechanism involved.

In this regard, a study in healthy humans using intraluminal impedance monitoring indicated that pharmacological reduction of intraduodenal flow with an anticholinergic agent is associated with delayed absorption of luminal glucose Reversely, a previous study has documented that stimulation of intestinal motility is associated with a rise in nutrient absorption in rats In both mice and humans, intestinal smooth muscle cells contractility in response to acetylcholine is mediated by M2 and M3 muscarinic receptors Previous study implicated the M3 muscarinic pathway in the mediation of the effect of metformin On the other hand, acute changes in the blood glucose concentration are now recognised to have a major, reversible impact on the motor function of the gastrointestinal tract The upper gut function appears to be modified by inputs from the central nervous system.

Therefore, our finding that metformin increased glucose uptake also in the brain may suggest the role of CNS in the acute effect of metformin, probably at the level of glucose sensing and regulation of intestinal motility. It has been shown that acute metformin administration activated neurons in the paraventricular nucleus PVN , area postrema, and central amygdala GLUT2, the more suitable candidate for brain glucose-sensing, is expressed in the PVN 48 , and glucose-excited as well as glucose-inhibited neurons are also located there.