Biguanides and lactic acidosis:unraveling the complex relationship

Biguanides,such as metformin,have long been established as frontline medications for the management of type 2 diabetes due to their glucose-lowering effects and favorable safety profiles.However,concerns regarding the risk of lactic acidosis associated with biguanide use have sparked considerable debate and scrutiny.This research article aims to provide a comprehensive analysis of the relationship between biguanides,particularly metformin,and lactic acidosis.We delve into the underlying mechanisms,epidemiological evidence,risk factors,clinical manifestations,diagnostic considerations,and management strategies related to biguanide-induced lactic acidosis.Additionally,we explore recent research developments,controversies,and future directions in this critical area of pharmacovigilance and clinical practice.

Diarrhea and Acute Renal Injury Culminating in Metformin-Induced Lactic Acidosis

Background: Metformin (M) is an effective first-line hypoglycemic agent in obese type 2 diabetes mellitus due to its low cost and safety profile. The Case: A 66-year-man presented with shock due to lactic acidosis induced by M-supersaturation subsequent to acute renal failure following infective diarrhea. The drug has been used, by this patient, for >10 years without complication. Physical examination, laboratory tests, radiological investigations and blood cultures did not show evidence of new cardiac, hepatic and septic insult. Despite discontinuation of M and 2-days of aggressive hydration, bicarbonate infusions and pressors;toxic levels of the drug persisted and shock-state culminated in severe and oliguric renal failure with serum urea and creatinine up to 50 mmol/L and 1270 umol/L, respectively. Hence, continuous venovenous hemodiafiltration (CVVHDF) was used, for 16-hours, to remove the drug, correct his acidosis and support his severe renal complications. Hours after the procedure;drug level, lactic acidosis and its associated shock improved followed by gradual renal recovery. The patient was discharged after 6 days and serum creatinine reached his base line (180 umol/L) 2 weeks later. The drug was not recommended for his future use. Conclusion: M-induced lactic acidosis, should be considered in assessment of shock in M-treated patients and management of unstable patients indicates early-use of CVVHDF.

糖尿病乳酸性酸中毒(Diaberic lactic acidosis DLA)的治疗

糖尿病患者可因体内乳酸累积而发生乳酸性酸中毒,如不及时诊断和治疗,可发生死亡。乳酸是葡萄糖的中间代谢产物。葡萄糖的分解代谢包括葡萄糖的有氧氧化和葡萄糖的无氧酵解。前者是葡萄糖在正常有氧条件下彻底氧化产生二氧化碳和水,它是体内糖分解产能的主要途径,大多数组织能获得足够的氧气以供有氧氧化之需而很少进行无氧糖酵解;而后者是葡萄糖在无氧条件下分解成为乳酸,它虽然已非主要代谢途径而且产能有限,但仍是重要的代谢方式并具有病理生理意义。

EVALUATION OF MITOCHONDRIAL ENCEPHALOMYOPATHY WITH LACTIC ACIDOSIS AND STROKE-LIKE EPISODES WITH MAGNETIC RESONANCE IMAGING AND PROTON MAGNETIC RESONANCE SPECTROSCOPY

Objective To study the characteristics of spectra on proton magnetic resonance spectroscopy （^1H-MRS） and its value in patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes （MELAS）. Methods Seven clinically diagnosed patients with MELAS underwent magnetic resonance imaging （MRI） and ^1H-MRS examinations. The ^1H-MRS techniques, characteristics of the spectra, and its correlation with the laboratory tests were analyzed. Reaults Cerebral abnormalities were revealed in all 7 patients on conventional MR images, and most abnormal signals were observed in bilateral occipital, parietal, and temporal lobes. We found 4 cases with basal ganglia involvement, 2 cases with mild frontal lobe lesions, and 1 case with involvement of lateral cerebral peduncles and thalami. Additionally, 1 patient was involved with left insular lobe. Spectra from prominent lesions in brain parenchyma showed lactate doublet peak in 6 patients, 3 of whom were also noted lactate peak in ventricular cerehrospinal fluid （CSF）. Conclusion ^1H-MRS may provide more direct information about the metabolism changes, which aids to affirm the diagnosis, and may replace the conventional invasive method of quantifying lactate in CSF.

Pyruvate is a prospective alkalizer to correct hypoxic lactic acidosis

Type A lactic acidosis resulted from hypoxic mitochondrial dysfunction is an independent predictor of mortality for critically ill patients. However, current therapeutic agents are still in shortage and can even be harmful. This paper reviewed data regarding lactic acidosis treatment and recommended that pyruvate might be a potential alkalizer to correct type A lactic acidosis in future clinical practice. Pyruvate is a key energy metabolic substrate and a pyruvate dehydrogenase(PDH) activator with several unique beneficial biological properties, including anti-oxidant and antiinflammatory effects and the ability to activate the hypoxia-inducible factor-1(HIF-1α)-erythropoietin(EPO) signal pathway. Pyruvate preserves glucose metabolism and cellular energetics better than bicarbonate, lactate, acetate and malate in the efficient correction of hypoxic lactic acidosis and shows few side effects. Therefore, application of pyruvate may be promising and safe as a novel therapeutic strategy in hypoxic lactic acidosis correction accompanied with multi-organ protection in critical care patients.

Metformin Intoxication: A Case of a Combination of Severe Hypoglycaemia and Severe Lactic Acidosis (LA)

Metformin is a worldwide used and effective antihyperglycemic agent. It is generally well tolerated but contraindicated in severe renal dysfunction. Metformin does not cause hypoglycaemia, however this case describes hypoglycaemia after an overdose. Another well-known, but rare and potentially life-threatening complication of metformin is the occurrence of LA, the so-called metformin-associated lactic acidosis (MALA). The severe consequences of an overdose of metformin, as well as the pathophysiologic mechanisms and the clinical consequences of LA in combination with severe hypoglycaemia are described in this report. Early recognition and swift clinical intervention is of paramount importance in case of auto-intoxication with metformin to prevent a lethal outcome.

Metformin Induced Lactic Acidosis What Is the Effective Treatment?

Metformin is known to be an effective treatment for patients with type 2 diabetes mellitus. Metformin induced lactic acidosis (MALA) is a serious illness which should identify and treat urgently. In this review article, we will present our own data and review the literature to highlight the importance of recognizing MALA;causes, presentations and the proper treatment, even though there are few published studies discussing MALA treatment modalities. The two cases that we presented here were patients admitted to the ICU and undergoing hemodynamic instability, which improved after removal of Metformin and clearance of associated lactic acidosis with SLED and CVVH. A case could be made for SLED and CVVH as modalities of choice for patients with MALA and hemodynamic instability, but further research is needed in this direction.

Metformin associated lactic acidosis in Auckland City Hospital 2005 to 2009

AIM： To determine the incidence, clinical characteristics and outcomes of patients with metformin associated lactic acidosis （MALA）.METHODS： Auckland City Hospital drains a population of just over 400000 people. All cases presenting with metabolic acidosis between July 2005 and July 2009 were identifed using clinical coding. A retrospective case notes review identifed patients with MALA. Prescribing data for metformin was obtained from the national pharmaceutical prescribing scheme.RESULTS： There were 42 cases of metabolic lactic acidosis over 1718000 patient years. There were 51000 patient years of metformin prescribed to patients over the study period. There were thirty two cases of lactic acidosis due to sepsis, seven in patients treated with metformin. Ten cases of MALA were identified. The incidence of MALA was estimated at 19.46 per 100000 patient year exposure to metformin. The relative risk of lactic acidosis in patients on metformin was 13.53 （95%CI： 7.88-21.66） compared to the general population. The mean age of patients with MALA was 63 years, range 40-83 years. A baseline estimated glomerular fltration rate was obtained in all patients and ranged from 23-130 mL/min per 1.73 m^2. Only two patients had chronic kidney disease G4.Three patients required treatment with haemodialysis. Two patients died.

Metformin and Lactic Acidosis in Diabetic Patients

Metfommin is the basic drug in the clinical treatment of Diabetes,often used in the treatment of Type 2 Diabetes Mellitus(T2DM).Its effect has been fully verificd in the clinical treatment of T2DM.However,in the treatment of T2DM with metformin,there is still a certain probability of related lactic acidosis,and the fatality rate is high.Therefore,is the use of metformin drug treatment a direct risk factor for lactic acidosis in diabetic patients?This paper will review the hypoglycemic mechanism of metformin and related studies on lactic acidosis,so as to further explore the relationship between metformin and lactic acidosis in diabetic patients,and provide help and reference for metformin drugs in the clinical treatment ofT2DM.

Mucosal necrosis of the small intestine in myopathy,encephalopathy,lactic acidosis,and stroke-like episodes syndrome

This report presents a case of massive mucosal necrosis of the small intestine in a patient with mitochondrial myopathy,encephalopathy,lactic acidosis,and stroke-like episodes(MELAS),which particularly affects the brain,nervous system and muscles.A 45-year-old Japanese female,with an established diagnosis of MELAS,presented with vomiting.Computed tomography showed portomesenteric venous gas and pneumatosis intestinalis.She underwent a resection of the small intestine.A microscopic study showed necrosis of the mucosa and vacuolar degeneration of smooth muscle cells in the arterial wall.Immunohistochemistry showed anti-mitochondrial antibody to be highly expressed in the crypts adjacent the necrotic mucosa.The microscopic and immunohistochemical findings suggested the presence of a large number of abnormal mitochondria in MELAS to be closely linked to mucosal necrosis of the small intestine.

Constructing a stable interface on Ni-rich LiNi_(0.8)Co_(0.1)Mn_(0.1)O_(2) cathode via lactic acid-assisted engineering strategy

Ni-rich layered oxides are potential cathode materials for next-generation high energy density Li-ion batteries due to their high capacity and low cost.However,the inherently unstable surface properties,including high levels of residual Li compounds,dissolution of transition metal cations,and parasitic side reactions,have not been effectively addressed,leading to significant degradation in their electrochemical performance.In this study,we propose a simple and effective lactic acid-assisted interface engineering strategy to regulate the surface chemistry and properties of Ni-rich LiNi_(0.8)Co_(0.1)Mr_(0.1)O_(2) cathode.This novel surface treatment method successfully eliminates surface residual Li compounds,inhibits structural collapse,and mitigates cathode-electrolyte interface film growth.As a result,the lactic acidtreated LiNi_(0.8)Co_(0.1)Mn_(0.1)O_(2) achieved a remarkable capacity retention of 91.7% after 100 cycles at 0.5 C(25℃) and outstanding rate capability of 149.5 mA h g^(-1) at 10 C,significantly outperforming the pristine material.Furthermore,a pouch-type full cell incorporating the modified LiNi_(0.8)Co_(0.1)Mn_(0.1)O_(2) cathode demonstrates impressive long-term cycle life,retaining 81.5% of its capacity after 500 cycles at 1 C.More importantly,the thermal stability of the modified cathode is also dramatically improved.This study offers a valuable surface modification strategy for enhancing the overall performance of Ni-rich cathode materials.

Application of Next Generation Sequencing for Rapid Identification of Lactic Acid Bacteria

The rapid identification of lactic acid bacteria,which are essential microorganisms in the food industry,is of great significance for industrial applications.The identification of lactic acid bacteria traditionally relies on the isolation and identification of pure colonies.While this method is well-established and widely used,it is not without limitations.The subjective judgment inherent in the isolation and purification process introduces potential for error,and the incomplete nature of the isolation process can result in the loss of valuable information.The advent of next generation sequencing has provided a novel approach to the rapid identification of lactic acid bacteria.This technology offers several advantages,including rapidity,accuracy,high throughput,and low cost.Next generation sequencing represents a significant advancement in the field of DNA sequencing.Its ability to rapidly and accurately identify lactic acid bacteria strains in samples with insufficient information or in the presence of multiple lactic acid bacteria sets it apart as a valuable tool.The application of this technology not only circumvents the potential errors inherent in the traditional method but also provides a robust foundation for the expeditious identification of lactic acid bacteria strains and the authentication of bacterial powder in industrial applications.This paper commences with an overview of traditional and molecular biology methods for the identification of lactic acid bacteria.While each method has its own advantages,they are not without limitations in practical application.Subsequently,the paper provides an introduction of the principle,process,advantages,and disadvantages of next generation sequencing,and also details its application in strain identification and rapid identification of lactic acid bacteria.The objective of this study is to provide a comprehensive and reliable basis for the rapid identification of industrial lactic acid bacteria strains and the authenticity identification of bacterial powder.

Screening of glucosinolates degrading lactic acid bacteria and their utilization in rapeseed meal fermentation

Rapeseed meal is a promising food ingredient, but its utilization is limited by the presence of some potentially harmful ingredients, such as glucosinolates. Fermentation is a cost-effective method of detoxication but a food-grade starter culture with glucosinolates degradation capacity is required. In this study, 46 strains of lactic acid bacteria from traditional paocai brines were screened for their ability to glucosinolate degradation. The results showed that more than 50% of the strains significantly degraded glucosinolates. Two strains of Lactiplantibacillus(p7 and s7) with high capacity of glucosinolates degradation through producing enzymes were identified. Then,an optimized condition for rapeseed meal fermentation by p7 was established to degrade glucosinolates, which can achieve about 80% degradation. UPLC/Q-TOF-MS analysis showed that the degradation rate of individual glucosinolates was different and the degradation rate of gluconapin and progoitrin in rapeseed meal can reach more than 90%. Meanwhile, fermentation with p7 can improve safety of rapeseed meal by inhibiting the growth of Enterobacteriaceae and improve its nutritional properties by degrading phytic acid. The in vitro digestion experiments showed that the content of glucosinolates in rapeseed meal decreased significantly during gastric digestion. Meanwhile, fermentation with p7 can greatly improve the release of soluble protein and increase the contents of free essential amino acids, such as lysine(increased by 12 folds) and methionine(increased by 10 folds).

Allergen degradation of bee pollen by lactic acid bacteria fermentation and its alleviatory effects on allergic reactions in BALB/c mice

Food allergy as a global health problem threatens food industry.Bee pollen(BP)is a typical food with allergenic potentials,although it performs various nutritional/pharmacological functions to humans.In this study,lactic acid bacteria(LAB)were used to ferment Brassica napus BP for alleviating its allergenicity.Four novel allergens(glutaredoxin,oleosin-B2,catalase and lipase)were identified with significant decreases in LAB-fermented BP(FBP)than natural BP by proteomics.Meanwhile,metabolomics analysis showed significant increases of 28 characteristic oligopeptides and amino acids in FBP versus BP,indicating the degradation of LAB on allergens.Moreover,FBP showed alleviatory effects in BALB/c mice,which relieved pathological symptoms and lowered production of allergic mediators.Microbial high-throughput sequencing analysis showed that FBP could regulate gut microbiota and metabolism to strengthen immunity,which were closely correlated with the alleviation of allergic reactivity.These findings could contribute to the development and utilization of hypoallergenic BP products.

Preparation of lactic acid bacteria compound starter cultures based on pasting properties and its improvement of glutinous rice flour and dough

The effects of 5 lactic acid bacteria(LAB)fermentation on the pasting properties of glutinous rice flour were compared,and suitable fermentation strains were selected based on the changes of viscosity,setback value,and breakdown value to prepare LAB compound starter cultures.The results revealed that Latilactobacillus sakei HSD004 and Lacticaseibacillus rhamnosus HSD005 had apparent advantages in increasing the viscosity and reducing the setback and breakdown values of glutinous rice flour.In particular,the compound starter created using the two abovementioned LAB in the ratio of 3:1 had better performance than that using a single LAB in improving the pasting properties and increasing the water and oil absorption capacity of glutinous rice flour.Moreover,the gelatinization enthalpy of the fermented samples increased significantly.For frozen glutinous rice dough stored for 28 days,the viscoelasticity of frozen dough prepared by compound starter was better than that of control dough,and the freezable water content was lower than that of control dough.These results indicate that compound LAB fermentation is a promising technology in the glutinous rice-based food processing industry,which has significance for its application.

Lactic acidosis during telbivudine treatment for HBV: A case report and literature review

All oral nucleoside analogues against hepatitis B virus,with an exception of telbivudine,have been reported causing lactic acidosis(LA).Here we report the first case of chronic hepatitis B developing severe refractory LA during telbivudine monotherapy.A 36-year-old man of Chinese origin received telbivudine antiviral treatment for chronic hepatitis B.After 11 mo of therapy,he developed anorexia,nausea,and vomiting with mild muscle weakness.The patient was found with elevated serum creatine phosphokinase up to 3683 U/L(upper limit of normal 170 U/L)and marked LA.LA did not resolve immediately following discontinuation of telbivudine.His condition began to improve after hemodialysis treatment for 16 times and usage of glucocorticosteroid.The patient fully recovered after 16 wk of treatment.This is the first documented case with severe LA caused by telbivudine monotherapy.Besides serum creatine phosphokinase,blood lactate level should also be closely monitored in patients receiving telbivudine.

Renal calcification in children with renal tubular acidosis:What a paediatrician should know

Renal tubular acidosis(RTA)can lead to renal calcification in children,which can cause various complications and impair renal function.This review provides pediatricians with a comprehensive understanding of the relationship between RTA and renal calcification,highlighting essential aspects for clinical manage-ment.The article analyzed relevant studies to explore the prevalence,risk factors,underlying mechanisms,and clinical implications of renal calcification in children with RTA.Results show that distal RTA(type 1)is particularly associated with nephrocalcinosis,which presents a higher risk of renal calcification.However,there are limitations to the existing literature,including a small number of studies,heterogeneity in methodologies,and potential publication bias.Longitudinal data and control groups are also lacking,which limits our understanding of longterm outcomes and optimal management strategies for children with RTA and renal calcification.Pediatricians play a crucial role in the early diagnosis and management of RTA to mitigate the risk of renal calcification and associated complications.In addition,alkaline therapy remains a cornerstone in the treatment of RTA,aimed at correcting the acid-base imbalance and reducing the formation of kidney stones.Therefore,early diagnosis and appropriate therapeutic interventions are paramount in preventing and managing renal calcification to preserve renal function and improve long-term outcomes for affected children.Further research with larger sample sizes and rigorous methodologies is needed to optimize the clinical approach to renal calcification in the context of RTA in the pediatric population.

Lactic Acidosis and Atrial Tachycardia: Unusual Presentations of Disseminated Burkitt-Like Lymphoma

Lactic acidosis is a rare complication of malignancies and is seen more frequently in high grade lymphoma and leukemia. Although, its pathogenesis is not well understood, it remains a surrogate of poor prognosis. Herein, we present a case of Burkitt-like lymphoma presenting with metabolic abnormalities including lactic acidosis and hypoglycemia along with atrial tachycardia. We will discuss the different mechanisms involved in these metabolic disturbances and we will provide insight on novel therapeutic strategies based on our understanding of the underlying pathophysiology.

Susceptibility of dairy cows to subacute ruminal acidosis is reflected in both prepartum and postpartum bacteria as well as odd-and branched-chain fatty acids in feces

Background:The transition period is a challenging period for high-producing dairy cattle.Cows in early lactation are considered as a group at risk of subacute ruminal acidosis(SARA).Variability in SARA susceptibility in early lactation is hypothesized to be reflected in fecal characteristics such as fecal pH,dry matter content,volatile and odd-and branched-chain fatty acids(VFA and OBCFA,respectively),as well as fecal microbiota.This was investigated with 38 periparturient dairy cows,which were classified into four groups differing in median and mean time of reticular pH below 6 as well as area under the curve of pH below 6.Furthermore,we investigated whether fecal differences were already obvious during a period prior to the SARA risk(prepartum).Results:Variation in reticular pH during a 3-week postpartum period was not associated with differences in fecal pH and VFA concentration.In the postpartum period,the copy number of fecal bacteria and methanogens of unsusceptible(UN)cows was higher than moderately susceptible(MS)or susceptible(SU)cows,while the genera Ruminococcus and Prevotellacea_UCG-001 were proportionally less abundant in UN compared with SU cows.Nevertheless,only a minor reduction was observed in iso-BCFA proportions in fecal fatty acids of SU cows,particularly iso-C15:0and iso-C16:0,compared with UN cows.Consistent with the bacterial changes postpartum,the lower abundance of Ruminococcus was already observed in the prepartum fecal bacterial communities of UN cows,whereas Lachnospiraceae_UCG-001 was increased.Nevertheless,no differences were observed in the prepartum fecal VFA or OBCFA profiles among the groups.Prepartum fecal bacterial communities of cows were clustered into two distinct clusters with 70%of the SU cows belonging to cluster 1,in which they represented 60%of the animals.Conclusions:Inter-animal variation in postpartum SARA susceptibility was reflected in post-and prepartum fecal bacterial communities.Differences in prepartum fecal bacterial communities could alert for susceptibility to develop SARA postpartum.Our results generated knowledge on the association between fecal bacteria and SARA development which could be further explored in a prevention strategy.

Coordinated response of milk bacterial and metabolic profiles to subacute ruminal acidosis in lactating dairy cows

Background Bovine milk is an important source of nutrition for human consumption,and its quality is closely associated with the microbiota and metabolites in it.But there is limited knowledge about the milk microbiome and metabolome in cows with subacute ruminal acidosis.Methods Eight ruminally cannulated Holstein cows in mid lactation were selected for a 3-week experiment.The cows were randomly allocated into 2 groups,fed either a conventional diet(CON;40%concentrate;dry matter basis)or a high-concentrate diet(HC;60%concentrate;dry matter basis).Results The results showed that there was a decreased milk fat percentage in the HC group compared to the CON group.The amplicon sequencing results indicated that the alpha diversity indices were not affected by the HC feeding.At the phylum level,the milk bacteria were dominated by Proteobacteria,Actinobacteria,Bacteroidetes,and Firmicutes both in the CON and HC groups.At the genus level,the HC cows displayed an improved proportion of Labrys(P=0.015)compared with the CON cows.Results of both the principal components analysis and partial least squares of discriminant analysis of milk metabolome revealed that samples of the CON and HC groups clustered separately.A total of 31 differential metabolites were identified between the two groups.Of these,the levels of 11 metabolites decreased(α-linolenic acid,prostaglandin E2,L-lactic acid,L-malic acid,3-hydroxysebacic acid,succinyladenosine,guanosine,pyridoxal,L-glutamic acid,hippuric acid,and trigonelline),whereas the levels of the other 20 metabolites increased in the HC group with respect to the CON group(P<0.05).Conclusion These results suggested that subacute ruminal acidosis less impacted the diversity and composition of milk microbiota,but altered the milk metabolic profiles,which led to the decline of the milk quality.