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• W2022182182 abstract "This review mainly focuses on metformin, and considers oral antidiabetic therapy in kidney transplant patients and the potential benefits and risks of antidiabetic agents other than metformin in patients with chronic kidney disease (CKD). In view of the debate concerning lactic acidosis associated with metformin, this review tries to solve a paradox: metformin should be prescribed more widely because of its beneficial effects, but also less widely because of the increasing prevalence of contraindications to metformin, such as reduced renal function. Lactic acidosis appears either as part of a number of clinical syndromes (i.e., unrelated to metformin), induced by metformin (involving an analysis of the drug’s pharmacokinetics and mechanisms of action), or associated with metformin (a more complex situation, as lactic acidosis in a metformin-treated patient is not necessarily accompanied by metformin accumulation, nor does metformin accumulation necessarily lead to lactic acidosis). A critical analysis of guidelines and literature data on metformin therapy in patients with CKD is presented. Following the present focus on metformin, new paradoxical issues can be drawn up, in particular: (i) metformin is rarely the sole cause of lactic acidosis; (ii) lactic acidosis in patients receiving metformin therapy is erroneously still considered a single medical entity, as several different scenarios can be defined, with contrasting prognoses. The prognosis for severe lactic acidosis seems even better in metformin-treated patients than in non-metformin users. This review mainly focuses on metformin, and considers oral antidiabetic therapy in kidney transplant patients and the potential benefits and risks of antidiabetic agents other than metformin in patients with chronic kidney disease (CKD). In view of the debate concerning lactic acidosis associated with metformin, this review tries to solve a paradox: metformin should be prescribed more widely because of its beneficial effects, but also less widely because of the increasing prevalence of contraindications to metformin, such as reduced renal function. Lactic acidosis appears either as part of a number of clinical syndromes (i.e., unrelated to metformin), induced by metformin (involving an analysis of the drug’s pharmacokinetics and mechanisms of action), or associated with metformin (a more complex situation, as lactic acidosis in a metformin-treated patient is not necessarily accompanied by metformin accumulation, nor does metformin accumulation necessarily lead to lactic acidosis). A critical analysis of guidelines and literature data on metformin therapy in patients with CKD is presented. Following the present focus on metformin, new paradoxical issues can be drawn up, in particular: (i) metformin is rarely the sole cause of lactic acidosis; (ii) lactic acidosis in patients receiving metformin therapy is erroneously still considered a single medical entity, as several different scenarios can be defined, with contrasting prognoses. The prognosis for severe lactic acidosis seems even better in metformin-treated patients than in non-metformin users. This review of antidiabetic therapy mainly focuses on metformin in view of its first-line position in the treatment of type 2 diabetes mellitus patients and the debate concerning the drug’s beneficial and potential harmful effects.1.Prikis M. Mesler E.L. Hood V.L. et al.When a friend can become an enemy! Recognition and management of metformin-associated lactic acidosis.Kidney Int. 2007; 72: 1157-1160Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar Although lactic acidosis associated with metformin is rare, it still influences today’s treatment strategies because of the high proportion of patients presenting an established or suspected risk of contraindication, particularly in the context of renal failure. Moreover, the relationship between metformin and lactic acidosis is not a simple one in which accumulation of the drug inevitably leads to this adverse event. This review mainly addresses solving a paradox: on one hand, metformin should be prescribed more widely because of its beneficial, pleiotropic effects2.Group UKPDS Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).Lancet. 1998; 352: 854-865Abstract Full Text Full Text PDF PubMed Scopus (4869) Google Scholar and on the other hand it should be prescribed less widely because of the high and increasing prevalence of contraindications to metformin. Indeed, there are more diabetic patients living longer with complications such as kidney disease. This review therefore consists of a critical examination of the fear of lactic acidosis in metformin therapy. As the use of metformin may coincide with, cause, or be co-responsible for lactic acidosis, (i) lactic acidosis in general (i.e., lactic acidosis that is unrelated to metformin), (ii) lactic acidosis induced by metformin, involving an analysis of the drug’s pharmacokinetics and mechanisms of action, and (iii) an intermediate, more complex situation, called ‘metformin-associated lactic acidosis’ will successively be discussed. A critical analysis of guidelines and literature data on metformin therapy in patients with chronic kidney disease (CKD), the particular case of oral antidiabetic therapy in kidney transplant patients, and the potential benefits and risks of antidiabetic agents other than metformin in patients with CKD are also examined. As described by Fitzgerald3.Fitzgerald M. The lactic acid myths.Competitor. 2012; (Accessed: 25 February 2014)running.competitor.com/2010/01/training/the-lactic-acid-myths_7938Google Scholar and Robergs4.Robergs R.A. Ghiasvand F. Parker D. Biochemistry of exercise-induced metabolic acidosis.Am J Physiol Regul Integr Comp Physiol. 2004; 287: R502-R516Crossref PubMed Scopus (422) Google Scholar recently, there are many myths about lactic acid. Perhaps the greatest of all is the notion that there is lactic acid in the human body. There is not. Lactic acid is a weak acid dissociating in water, resulting in anion lactate and H+. Under physiological circumstances the pH is much higher than the pKa (3.86) of that reaction, and hence almost all lactic acid in the body is dissociated and is present as lactate anion. The potential confusion between lactate and exercise could be traced to the 1920s, when researchers showed that the exposure of frog legs to high levels of lactic acid (not lactate) interfered with the ability of the muscles to contract in response to electrical stimulation. Later, other research discovered that lactate was released through anaerobic glycolysis, or through the breakdown of glucose or glycogen molecules in the process of energy production deprived of oxygen. Researchers then derived that fatigue occurred at high exercise intensities because the cardiovascular system could no longer supply the muscles with enough oxygen to keep pace with muscular energy demands, resulting in increasing reliance on anaerobic glycolysis, and hence lactate buildup.3.Fitzgerald M. The lactic acid myths.Competitor. 2012; (Accessed: 25 February 2014)running.competitor.com/2010/01/training/the-lactic-acid-myths_7938Google Scholar At the time, biochemists (incorrectly) believed that lactate must be formed in the body by the removal of a proton from lactic acid. When protons accumulate in living tissues, these tissues become more acidic, and when muscles become too acidic they lose their ability to contract. However, this past research used to support the lactic acidosis ‘problem’ is entirely based on derived associations and evidence, such as the results from the frog experiment. There had not been any experimental research demonstrating a cause–effect relationship between the production of lactate and acidosis of the muscle tissue.5.Kravitz L. Lactate not guilty as charged. 2013www.drlenkravitz.com/Articles/lactatearticle.htmlGoogle Scholar The evidence began to unravel in 1977,6.Gevers W. Generation of protons by metabolic processes in heart cells.J Mol Cell Cardiol. 1977; 9: 867-874Abstract Full Text PDF PubMed Scopus (149) Google Scholar when South African biochemist Wieland Gevers showed that the production of lactate actually goes together with the consumption of a pair of protons, suggesting that lactate delays rather than induces muscular acidosis. In the reaction from 1 glucose to 2 lactate molecules, two ATPs are formed from ADP+PO4+H+. Hence, 2H+ are cleared in the glycolytic pathway. Much more recently, scientists have observed that, although protons do accumulate in the muscles during high-intensity exercise, increasing muscle acidity, these protons are produced through a reaction that should be viewed as a completely separate process from that which produces lactate.6.Gevers W. Generation of protons by metabolic processes in heart cells.J Mol Cell Cardiol. 1977; 9: 867-874Abstract Full Text PDF PubMed Scopus (149) Google Scholar When oxygen supply is sufficiently available for the required muscular effort, cells in the body metabolize glucose to form water and carbon dioxide in a two-step process. First, glucose is broken down to pyruvate through glycolysis. Then, mitochondria oxidize the pyruvate into water and carbon dioxide by means of the Krebs cycle and oxidative phosphorylation. This second step requires oxygen. The net result is ATP, the energy carrier used by the cell to drive useful activity, such as muscle contraction. When the energy in ATP is used during cell work (ATP hydrolysis), protons are produced. The mitochondria normally incorporate these protons back into ATP, thus preventing buildup of protons and maintaining a neutral pH. However, when oxygen supply is inadequate (hypoxia), the mitochondria are unable to continue ATP synthesis at a rate sufficient to supply the cell with the required ATP. In this situation, glycolysis is increased to provide additional ATP, and the excess pyruvate produced is converted into lactate and released from the cell into the bloodstream, where it may accumulate over time. Despite the fact that increased glycolysis, although much less efficiently, helps compensate for less ATP from oxidative phosphorylation, it cannot bind the protons resulting from ATP hydrolysis. Therefore, proton concentration increases and causes acidosis. The process of lactate production by itself does not consume or produce protons but is chemically neutral and therefore cannot be the cause of acidosis. There is no cause link between lactate production and acidosis; instead, lactate production is a consequence of intracellular acidosis, slowing down the acidosis process with increasing levels of lactate. Lactate is a good marker for the metabolic condition of the cell; lactate does serve as a direct and indirect fuel for muscle contraction, and is one of the most important energy sources during intensive muscle activity. Recently, Overgaard and Nielsen7.Overgaard K. Nielsen O.B. Activity-induced recovery of excitability in K(+)-depressed rat soleus muscle.Am J Physiol Regul Integr Comp Physiol. 2001; 280: R48-R55PubMed Google Scholar have shown that high levels of lactate partially restore muscle cell function from a depolarized condition, a major cause of muscle fatigue at high exercise level. Until very recently, lactate was vilified in the literature as the cause of acidosis, whereas it plays a ‘mythical’/important role in the body’s defense mechanisms against acidosis. Metformin has a dissociation constant of ∼11.5. Consequently, >99.9% of the molecules exist as cations at physiological pH; hence, rapid, passive diffusion into cells is unlikely. The drug is stable and not metabolized. The fractional oral bioavailability is 50–60%. After intravenous administration, the majority of metformin (80–100%) is eliminated unchanged in the urine (for a review, see ref. 8.Graham G.G. Punt J. Arora M. et al.Clinical pharmacokinetics of metformin.Clin Pharmacokinet. 2011; 50: 81-98Crossref PubMed Scopus (198) Google Scholar). Metformin is eliminated both rapidly and actively by the kidney. The mean renal clearance in subjects with normal renal function was reported as 510ml±130ml/min,8.Graham G.G. Punt J. Arora M. et al.Clinical pharmacokinetics of metformin.Clin Pharmacokinet. 2011; 50: 81-98Crossref PubMed Scopus (198) Google Scholar suggesting tubular secretion following glomerular filtration. A study in obese and non-obese diabetic patients showed that the apparent clearance rate for metformin was influenced by the lean body weight.9.Bardin C. Nobecourt E. Larger E. et al.Population pharmacokinetics of metformin in obese and non-obese patients with type 2 diabetes mellitus.Eur J Clin Pharmacol. 2012; 68: 961-968Crossref PubMed Scopus (10) Google Scholar By pooling data from studies performed in patients with varying degrees of CKD, Graham et al.8.Graham G.G. Punt J. Arora M. et al.Clinical pharmacokinetics of metformin.Clin Pharmacokinet. 2011; 50: 81-98Crossref PubMed Scopus (198) Google Scholar found a significant inverse and close correlation between renal clearance of metformin and kidney function. Quoting a half-life (t1/2) for elimination is difficult, as the drug’s plasma concentration–time curves follow a bi-exponential or even tri-exponential model.8.Graham G.G. Punt J. Arora M. et al.Clinical pharmacokinetics of metformin.Clin Pharmacokinet. 2011; 50: 81-98Crossref PubMed Scopus (198) Google Scholar The terminal t1/2 is ∼20h. Such a high value indicates the existence of a deep compartment for metformin. After oral administration of a 1.5g dose of metformin, the peak plasma concentration is reached after ∼3h. Given that metformin is essentially present as a cation in vivo, its transfer across the cell membrane must be carrier-mediated. Organic cation transporters (OCTs) and the plasma membrane monoamine transporter (PMAT) are polyspecific transporters for small, hydrophilic organic cations and enable uptake of metformin by the gut (mostly via PMAT, but also via OCT1 and OCT3), the liver (via OCT1 and possibly OCT3), and the kidney (via OCT1, OCT2, and PMAT). OCT1 is abundantly expressed in the liver and, to a lesser degree, in the kidney, where it is localized in the basolateral membrane. Metformin, however, is a much better substrate for renal OCT2 than for hepatic OCT1.10.Kimura N. Masuda S. Tanihara Y. et al.Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1.Drug Metab Pharmacokinet. 2005; 20: 379-386Crossref PubMed Google Scholar The multidrug and toxin extrusion 1 and 2 (MATE1 and MATE2K) proteins are located in the luminal membrane of the kidney and liver and mediate the elimination of metformin into the bile and the urine. Genetic variations modulate metformin’s pharmacodynamics and pharmacokinetics (for a review, see refs 11.Gong L. Goswami S. Giacomini K.M. et al.Metformin pathways: pharmacokinetics and pharmacodynamics.Pharmacogenet Genomics. 2012; 22: 820-827Crossref PubMed Scopus (37) Google Scholar,12.Zolk O. Disposition of metformin: variability due to polymorphisms of organic cation transporters.Ann Med. 2012; 44: 119-129Crossref PubMed Scopus (29) Google Scholar). The impact of genetic variations on intestinal absorption appears to be low, whereas they have a significant effect on hepatic handling of metformin and on therapeutic response to metformin in glucose tolerance tests.13.Wang D.S. Jonker J.W. Kato Y. et al.Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin.J Pharmacol Exp Ther. 2002; 302: 510-515Crossref PubMed Scopus (222) Google Scholar,14.Shu Y. Sheardown S.A. Brown C. et al.Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action.J Clin Invest. 2007; 117: 1422-1431Crossref PubMed Scopus (417) Google Scholar The impact of these polymorphisms has been confirmed in patients taking 1g of metformin twice daily over a 24-month period.15.Christensen M.M. Brasch-Andersen C. Green H. et al.The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c.Pharmacogenet Genomics. 2011; 21: 837-850Crossref PubMed Scopus (61) Google Scholar Strikingly, an 80-fold interindividual variation in trough steady-state plasma concentrations of metformin was documented. Interestingly, metformin plasma concentrations and metformin’s impact on HbA1c were both correlated to the number of reduced function alleles in OCT. Genome-wide association studies reveal that other candidate genes may be involved in the therapeutic response to metformin.16.Zhou K. Bellenguez C. Spencer C.C. et al.Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes.Nat Genet. 2011; 43: 117-120Crossref PubMed Scopus (165) Google Scholar,17.van Leeuwen N. Nijpels G. Becker M.L. et al.A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts.Diabetologia. 2012; 55: 1971-1977Crossref PubMed Scopus (35) Google Scholar These genetic factors are also responsible for modulation of drug–drug interactions that affect metformin’s pharmacokinetics (implying, for instance, the inhibitory effect of the H2 blocker, proton pump inhibitors, and the antidiabetic compounds repaglinide and rosiglitazone)18.Wang Z.J. Yin O.Q. Tomlinson B. et al.OCT2 polymorphisms and in-vivo renal functional consequence: studies with metformin and cimetidine.Pharmacogenet Genomics. 2008; 18: 637-645Crossref PubMed Scopus (117) Google Scholar,19.Nies A.T. Hofmann U. Resch C. et al.Proton pump inhibitors inhibit metformin uptake by organic cation transporters (OCTs).PLoS One. 2011; 6: e22163Crossref PubMed Scopus (39) Google Scholar and also influence hepatic OCT1 and OCT3 expression.20.Nies A.T. Koepsell H. Winter S. et al.Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver.Hepatology. 2009; 50: 1227-1240Crossref PubMed Scopus (119) Google Scholar Knowledge of tissue metformin levels is needed to correctly interpret data from cell-based and animal experiments. Metformin is concentrated for some hours in particular tissues, such as the gut and, to a lesser extent, in the liver and kidney.21.Wilcock C. Bailey C.J. Accumulation of metformin by tissues of the normal and diabetic mouse.Xenobiotica. 1994; 24: 49-57Crossref PubMed Scopus (162) Google Scholar A relatively new approach is the measurement of levels in erythrocytes. After a single oral dose of metformin, due to a terminal t1/2 about sixfold higher in erythrocytes compared with plasma, concentrations in plasma and erythrocytes cross each other ∼13h after the plasma peak (Table 1). Metformin would have disappeared from plasma 24 hours after the oral intake, whereas it would remain detectable in erythrocytes for up to 48h.22.Robert F. Fendri S. Hary L. et al.Kinetics of plasma and erythrocyte metformin after acute administration in healthy subjects.Diabetes Metab. 2003; 29: 279-283Abstract Full Text PDF PubMed Google ScholarTable 1Kinetic parameters (mean±s.e.m.) for metformin in plasma and erythrocytes in six healthy subjects after a single oral dose of 0.85g (from Robert et al.22.Robert F. Fendri S. Hary L. et al.Kinetics of plasma and erythrocyte metformin after acute administration in healthy subjects.Diabetes Metab. 2003; 29: 279-283Abstract Full Text PDF PubMed Google Scholar)PlasmaErythrocytesP-valueTime of maximal concentration (h)3.0±0.34.7±0.5NS (0.068)Maximal concentration (mg/l)1.7±0.10.3±0.00.028Elimination half-life (h)2.7±0.223.4±1.9<0.001Area under the curve (mg·h/l)8.9±0.47.5±1.5NSDistribution volume (l)146±11—— Open table in a new tab Although metformin’s action on glucose metabolism is not fully understood, it is nevertheless accepted that metformin mainly acts as an insulin sensitizer and reduces hepatic glucose output from gluconeogenesis.23.Natali A. Ferrannini E. Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review.Diabetologia. 2006; 49: 434-441Crossref PubMed Scopus (132) Google Scholar Metformin also has a variety of other effects on different tissues (Table 2). In brief, metformin counteracts the determinants of the imbalance between glucose production and glucose utilization, with the noticeable exception of pancreatic β-cell failure.Table 2Anti-hyperglycemic effects of metformin and the corresponding mechanismsTissueEffectsMechanism(s)IntestineIncrease in glucose utilization.Activation of the incretin axis.Conversion of glucose into lactate in the splanchnic bed.Modulation of several components of the incretin axis.LiverInhibition of gluconeogenesis and (to a lower extent) glycogenolysis.Decrease in substrate availability.Decrease in hepatic energy state (through inhibition of fatty acid oxidation and direct inhibition of oxidative phosphorylation).Antagonism of glucagon.Insulin-dependent peripheral tissues (muscle, adipose tissue)Increased insulin-mediated glucose uptake.Decreased release of free fatty acids from adipose tissue.Enhanced insulin receptor expression and tyrosine kinase activity.Non insulin-dependent peripheral tissuesEnhanced glucose disposal.Stimulation of non-insulin-dependent glucose transport. Open table in a new tab Metformin’s pleiotropic actions have been associated with the activation of AMP-activated protein kinase (AMPK).24.Zhou G. Myers R. Li Y. et al.Role of AMP-activated protein kinase in mechanism of metformin action.J Clin Invest. 2001; 108: 1167-1174Crossref PubMed Google Scholar AMPK can be viewed indeed as a key ‘fuel gauge’ that protects cells under energy-restricted conditions. It is activated by an increase in the AMP/ATP ratio and thus by an imbalance between ATP production and consumption. This activation requires phosphorylation by upstream kinases (STK11/LKB1). Further studies have shown that metformin activates the LKB1/AMPK pathway secondarily to its effect on the mitochondria through time-dependent, self-limiting inhibition of the mitochondrial respiratory chain complex 1 in liver and other tissues. This complex is the sole entry point for NADH, which promotes the maintenance of the mitochondrial proton gradient required for ATP production (it should be borne in mind that gluconeogenesis is a costly process).25.Owen M.R. Doran E. Halestrap A.P. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain.Biochem J. 2000; 348: 607-614Crossref PubMed Scopus (676) Google Scholar Metformin’s maximum inhibitory effect on complex 1 activity is ∼30%.25.Owen M.R. Doran E. Halestrap A.P. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain.Biochem J. 2000; 348: 607-614Crossref PubMed Scopus (676) Google Scholar The partial, reversible inhibition of complex 1 activity leads to a reduction in the cell’s energy content and thus activation of AMPK. However, Foretz et al.26.Foretz M. Hébrard S. Leclerc J. et al.Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state.J Clin Invest. 2010; 120: 2355-2369Crossref PubMed Scopus (372) Google Scholar, 27.Miller R.A. Birnbaum M.J. An energetic tale of AMPK-independent effects of metformin.J Clin Invest. 2010; 120: 2267-2270Crossref PubMed Scopus (65) Google Scholar, 28.Viollet B. Guigas B. Sanz Garcia N. et al.Cellular and molecular mechanisms of metformin: an overview.Clin Sci (Lond). 2012; 122: 253-2570Crossref PubMed Scopus (288) Google Scholar recently reported that metformin inhibits hepatic gluconeogenesis through a decrease in the energy charge and that this occurs independently of the LKB1/AMPK pathway. Very recently, Miller29.Miller R.A. Chu Q. Xie J. et al.Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP.Nature. 2013; 494: 256-260Crossref PubMed Scopus (151) Google Scholar suggested a novel mechanism through which metformin reduces hepatic glucose output via antagonism of glucagon and decreased production of cyclic AMP. The relationship between molecular characteristics of this drug and its biological effects remains to be established. As a cationic compound, metformin binds to protein negative charges and may easily insert into the phospholipid bilayer. It may therefore be hypothesized that metformin behaves as a membrane fluidizer.30.Wiernsperger N.F. Membrane physiology as a basis for the cellular effects of metformin in insulin resistance and diabetes.Diabetes Metab. 1999; 25: 110-127PubMed Google Scholar Pleiotropic actions of metformin implicate membrane-related events, including, at the cell level, a stimulation of insulin receptor tyrosine kinase activity and an amelioration of the increased membrane stiffness and, at the mitochondrion level, a depression of the respiratory chain at complex I. Interestingly, (i) a reduction in membrane fluidity may contribute to the development of diabetic complications and (ii) metformin’s action on the respiratory chain, besides its antihyperglycemic effect, is associated with an inhibitory effect on reactive oxygen species production31.Batandier C. Guigas B. Detaille D. et al.The ROS production induced by a reverse-electron flux at respiratory complex 1 is hampered by metformin.J Bioenerg Biomembr. 2006; 38: 33-42Crossref PubMed Scopus (94) Google Scholar and a prevention of hyperglycemia- and ischemia/reperfusion-induced cell death through a mitochondrial permeability transition-dependent process.32.Detaille D. Guigas B. Chauvin C. et al.Metformin prevents high-glucose-induced endothelial cell death through a mitochondrial permeability transition-dependent process.Diabetes. 2005; 54: 2179-2187Crossref PubMed Scopus (120) Google Scholar Such effects may explain the association between preadmission metformin use with decreased 30-day mortality among intensive care patients with type 2 diabetes (the adjusted HRs were 0.80 (95% CI: 0.69, 0.94) for metformin monotherapy users and 0.83 (0.71, 0.95) for metformin combination therapy users, compared non-users).33.Christiansen C.F. Johansen M.B. Christensen S. et al.Preadmission metformin use and mortality among intensive care patients with diabetes: a cohort study.Crit Care. 2013; 17: R192Crossref PubMed Scopus (6) Google Scholar Noticeably, the pleiotropic effects of metformin (e.g., in cardiovascular disease, hepatic steatosis, cancer, inflammation, and polycystic ovary syndrome) also include a protective effect on diabetic nephropathy.34.Morales A.I. Detaille D. Prieto M. et al.Metformin prevents experimental gentamicin-induced nephropathy by a mitochondria-dependent pathway.Kidney Int. 2010; 77: 861-869Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar,35.Louro T.M. Matafome P.N. Nunes E.C. et al.Insulin and metformin may prevent renal injury in young type 2 diabetic Goto-Kakizaki rats.Eur J Pharmacol. 2011; 653: 89-94Crossref PubMed Scopus (8) Google Scholar It has also been shown that metformin is associated with a significant reduction in the incidence of diabetes itself.36.Knowler W.C. Barrett-Connor E. Fowler S.E. et al.Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.N Engl J Med. 2002; 346: 393-403Crossref PubMed Scopus (9158) Google Scholar Metformin is linked to lactate metabolism in different ways. In addition to inhibition of lactate conversion through gluconeogenesis and augmentation of lactate production in insulin-dependent tissues, it augments lactate production by accelerating glycolysis in response to mitochondrial impairment and by activating anaerobic metabolism of glucose in the intestine. This does not result in a significant increase in plasma lactate at usual therapeutic levels because of the conversion of lactate back to glucose in the liver (via the Cori cycle). In contrast, high therapeutic metformin levels provoked a reduction in lactate uptake by the liver.37.Radziuk J.D. Zhang Z. Wiernsperger N. et al.Effects of metformin on lactate uptake and gluconeogenesis in the perfused rat liver.Diabetes. 1997; 46: 1406-1413Crossref PubMed Google Scholar Metformin accumulation may therefore combine hyperproduction of lactate from the intestine and other organs and reduced lactate clearance by the liver. This may ultimately generate hyperlactatemia or even lactic acidosis, which has been referred to as ‘metformin-induced lactic acidosis’ (Figure 1). Metformin may accumulate because of defective elimination or excessive intake. In fact, overdose should be considered the only cause of ‘pure’ metformin-induced lactic acidosis. ‘Metformin-induced lactic acidosis’ is, however, exceptional, as isolated metformin overdoses are rare. In a review on metformin overdoses, Dell’Aglio et al.38.Dell’Aglio D.M. Perino L.J. Kazzi Z. et al.Acute metformin overdose: examining serum pH, lactate level, and metformin concentrations in survivors versus nonsurvivors: a systematic review of the literature.Ann Emerg Med. 2009; 54: 818-823Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar cited our reports but omitted available information on mutidrug intoxication in 11 of our 13 cases.39.Lalau J.D. Mourlhon C. Bergeret A. et al.Consequences of metformin intoxication.Diabetes Care. 1998; 21: 2036-2037Crossref PubMed Scopus (42) Google Scholar Nevertheless, overdose is a good model for understanding how metformin can generate hyperlactatemia. The liver has a key role in this phenomenon. Indeed, using OCT1−/− mice and metformin overdose, it was shown th" @default.
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• W2022182182 title "Metformin and other antidiabetic agents in renal failure patients" @default.
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