Figure 4 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Schematic representation of intracellular lactate synthesis. Metformin inhibits the mitochondrial transport chain, inducing the blocking of aerobic glycolysis (mitochondrial compartment) and an increase in anaerobic glycolysis (the cytosolic compartment) with an accumulation of lactic acid.
Source publication
Metformin, a molecule belonging to the biguanide family, represents one of the most commonly prescribed medications for the treatment of diabetes mellitus in the world. Over the sixty years during which it has been used, many benefits have been described, which are not limited to the treatment of diabetes mellitus. However, since metformin is simil...
Citations
... As such, it is the cut-off point for exercise intensity that cannot be sustained, the most reliable predictor for endurance performance [25]. A minority of people with T1D uses metformin as adjunctive therapy and should be aware of the potential danger of lactic acidosis with acute kidney injury [26]. ...
... In future automated insulin delivery systems, integration of CLM data might obviate the need of the user to announce exercise (~60 min before). Lactate monitoring could also be useful in people using metformin, as this may rarely cause lactic acidosis, mainly in conditions of acute kidney injury [26]. ...
Objective
To evaluate the safety and performance of an implantable near-infrared (NIR) spectroscopy sensor for multi-metabolite monitoring of glucose, ketones, lactate, and ethanol.
Research design and methods
This is an early feasibility study (GLOW, NCT04782934) including 7 participants (4 with type 1 diabetes (T1D), 3 healthy volunteers) in whom the YANG NIR spectroscopy sensor (Indigo) was implanted for 28 days. Metabolic challenges were used to vary glucose levels (40–400 mg/dL, 2.2–22.2 mmol/L) and/or induce increases in ketones (ketone drink, up to 3.5 mM), lactate (exercise bike, up to 13 mM) and ethanol (4–8 alcoholic beverages, 40-80g). NIR spectra for glucose, ketones, lactate, and ethanol levels analyzed with partial least squares regression were compared with blood values for glucose (Biosen EKF), ketones and lactate (GlucoMen LX Plus), and breath ethanol levels (ACE II Breathalyzer). The effect of potential confounders on glucose measurements (paracetamol, aspartame, acetylsalicylic acid, ibuprofen, sorbitol, caffeine, fructose, vitamin C) was investigated in T1D participants.
Results
The implanted YANG sensor was safe and well tolerated and did not cause any infectious or wound healing complications. Six out 7 sensors remained fully operational over the entire study period. Glucose measurements were sufficiently accurate (overall mean absolute (relative) difference MARD of 7.4%, MAD 8.8 mg/dl) without significant impact of confounders. MAD values were 0.12 mM for ketones, 0.16 mM for lactate, and 0.18 mM for ethanol.
Conclusions
The first implantable multi-biomarker sensor was shown to be well tolerated and produce accurate measurements of glucose, ketones, lactate, and ethanol.
Trial registration
Clinical trial identifier: NCT04782934 .
... Metformin operates mainly by affecting mitochondrial respiration, promoting catabolic pathways while inhibiting anabolic ones, primarily impacting liver gluconeogenesis and peripheral tissue glucose uptake [6,7]. Despite its benefits [7][8][9][10][11][12], metformin has notable side effects, including gastrointestinal disturbances and a rare risk of lactic acidosis, primarily in patients with renal impairment [13][14][15]. Furthermore, its bitter taste poses challenges in patient compliance [16], leading to efforts in pharmaceutical formulations to mask this taste [17,18], particularly with artificial sweeteners in diabetic patients [19]. ...
... The values of the hydration numbers for all three systems are calculated and are given in Table S5. From there the values of the hydration numbers at infinite dilution were received through equation (13). Received values of h n o are shown in Table 7. ...
Measurements of the density, sound velocity, and viscosity of metformin hydrochloride (MetHCl) solutions in water and 0.1 mol∙kg−1 aqueous solution of sodium saccharin (Na-Sah) and acesulfame potassium (Ace-K) were carried out over the concentration range up ∼ 0.16 mol∙kg−1 to MetHCl at nine temperatures T = (278.15, 283.15, 288.15, 293.15, 298.15, 303.15, 308.15, 313.15, 318.15) K. Several physicochemical properties of these systems were determined from the experimental data, including apparent molar volumes, apparent molar volumes at infinite dilution, finite apparent molar volumes of transfer, apparent specific volumes at infinite dilution, apparent molar isentropic compressibility at infinite dilution, hydration numbers, viscosity B coefficients, and thermodynamic parameters of viscous flow. The results were further discussed in terms of solute–solvent and solute–solute interactions to enlighten the interactions of metformin with artificial sweeteners in water and the possibility that artificial sweeteners mask the bitter taste of metformin.
... MALA is a rare condition resulting in altered lactate and hydrogen metabolism defined as pH < 7.35 and lactate > 5.0 mmol/L in the setting of metformin use or overdose [196]. A proposed mechanism suggests that metformin reduces mitochondrial complex activity, increasing enterocyte glycolysis and lactate production to maintain energy homeostasis [197]. ...
... A proposed mechanism suggests that metformin reduces mitochondrial complex activity, increasing enterocyte glycolysis and lactate production to maintain energy homeostasis [197]. In the incidental form of MALA, predisposing pathophysiological conditions determine supratherapeutic metformin levels in plasma; in particular, this situation occurs in the presence of chronic comorbidities such as kidney, liver, and heart failure, shock, and critical illness [196]. The risk is minimised when metformin is used appropriately, the dosage is adjusted according to kidney function, and contraindications are considered [198]. ...
Metformin is a highly effective medication for managing type 2 diabetes mellitus. Recent studies have shown that it has significant therapeutic benefits in various organ systems, particularly the liver. Although the effects of metformin on metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis are still being debated, it has positive effects on cirrhosis and anti-tumoral properties, which can help prevent the development of hepatocellular carcinoma. Furthermore, it has been proven to improve insulin resistance and dyslipidaemia, commonly associated with liver diseases. While more studies are needed to fully determine the safety and effectiveness of metformin use in liver diseases, the results are highly promising. Indeed, metformin has a terrific potential for extending its full therapeutic properties beyond its traditional use in managing diabetes.
... 경우 치명적일 수 있는 젖산산증이 발생할 수 있어서 만성 콩팥병 4기 이상의 환자나 급성 콩팥 손상이 발생할 수 있는 상황에서는 투약하지 않아야 한다[3].급성 폐색성 요관결석 에 의한 급성 콩팥 손상도 메트포민 복용 환자에서 젖산산증 발생의 촉발 인자가 될 수 있어 메트포민 처방 시 고려해야 할 사항이나 이와 관련된 보고는 매우 드물다. ...
A 35-year-old male with type-2 diabetes mellitus and a history of insulin and metformin (2,000 mg/day) use presented to the emergency department (ED) with generalized weakness. Abdominal computed tomography (CT) performed 3 months prior to presentation showed a severely atrophic right kidney and a few tiny stones in the left kidney, with a serum level of creatinine of 1.14 mg/dL. At the ED, the patient’s blood pressure was 153/89 mmHg. Workup revealed acute kidney injury (creatinine, 11.97 mg/dL), high-anion-gap metabolic acidosis (pH, 6.93), and a blood lactic acid level > 15 mmol/L. Based on the medication history, the patient was diagnosed with metformin-associated lactic acidosis. CT showed a left distal ureteral stone, measuring 6 mm in size, which resulted in hydroureteronephrosis. The patient was initially treated with continuous renal replacement therapy. Subsequently, left percutaneous nephrostomy was performed, which led to the return of the creatinine level to baseline, with complete resolution of lactic acidosis.
... Serum levels of total ketone bodies, acetoacetic acid, and 3-hydroxybutyric acid were elevated albeit lower levels as compared with typical cases with diabetic ketoacidosis (DKA) ( Table 1) [8]. These data support the diagnosis of lactic acidosis rather than DKA in type 2 DM [8][9][10]. ...
... Second, the impaction of GI bezoars into the small bowel causes SBO via decreased GI motility associated with hyperglycemia because hyperglycemia has been shown to decrease GI motility [12][13][14][15]. Finally, dehydration and hypoperfusion induced by both SBO and hyperglycemia lead to the development of lactic acidosis [9,10]. In line with this scenario, normalization of hyperglycemia and metabolic acidosis by fluid and insulin therapy led to the rapid resolution of SBO by expulsion of the impacted enterolith via the recovery of GI motility although the decompressing effects of a nasogastric tube on the GI tract also contributed to SBO resolution. ...
Although delayed gastric emptying promotes gastrointestinal bezoar formation in patients with diabetes mellitus (DM), the association between movement of gastrointestinal bezoars and glycemic status remains unclear. We report a case of small bowel obstruction (SBO) caused by impaction of the migrated gastric bezoar into the small bowel in a patient with DM. Correction of hyperglycemia and lactic acidosis led to normalization of gastrointestinal motility, followed by expulsion of the impacted bezoar and resolution of SBO. This case suggests a link between hyperglycemia, metabolic acidosis, and gastrointestinal motility based on visualization of gastrointestinal bezoar movement in the gastrointestinal tract using computed tomography.
... Um deles é a terapia com biguanida no diabetes tipo 2 com metformina ou, no passado, com fenformina pode causar acidose láctica tipo B. É mais provável que a metformina gere acidose láctica quando níveis elevados resultam de uma sobredosagem aguda acidental ou intencional. [11][12][13] A terapia com biguanida em pacientes com função renal reduzida pode gerar níveis tóxicos, uma vez que esses medicamentos são quase totalmente removidos pelos rins, resultando em acidose láctica. No entanto, isso é incomum, e os pacientes que desenvolvem acidose láctica grave no contexto de função renal reduzida quase sempre apresentam fatores de risco adicionais. ...
... Seu principal efeito é a inibição do metabolismo oxidativo periférico. 13 A metformina inibe a gliconeogênese, mas tem baixa afinidade pela membrana mitocondrial e não inibe significativamente o metabolismo oxidativo. A fenformina foi retirada do mercado dos EUA em 1977 devido à predisposição para precipitar acidose láctica grave em pacientes diabéticos. ...
Este estudo tem como objetivo ampliar nossa visão fisiológica da acidose láctica, ultrapassando as barreiras da hiperlactatemia tipo A e trazer para a prática diária da clínica os diagnósticos diferenciais. Foi realizada uma revisão narrativa acerca do tema, buscando artigos, ensaios clínicos e relatos de casos sobre o tema, através da qual concluímos que o lactato é acumulado quando o uso mitocondrial de piruvato para produzir energia está com defeito ou quando a via da gliconeogênese (via de armazenamento) está com defeito. O aumento do lactato sanguíneo serve como um marcador de desarranjo metabólico a partir de uma infinidade de etiologias clínicas. A abordagem do paciente com elevação inicial do lactato deve se concentrar na identificação precoce da fonte para adequar o tratamento.
... Metformin-associated LA usually requires both high plasma levels of metformin (often resulting from renal impairment) and a secondary condition that impairs lactate production or clearance, such as sepsis or cirrhosis [9]. Thus far, other studies have differed in their findings on the associations of LA incidence rate with any of these factors [22,25,30,32,[35][36][37][38][39]. ...
... Furthermore, as potential confounding factors on the relationship between age and risk of developing LA after biguanide use, obesity, heart, and renal and/or liver function should be considered, though data on these factors were not available in this study [16,22,25,26,32,33,[36][37][38][39]42]. NDB data available to researchers included neither anthropometric information (e.g., height and weight) nor patient laboratory test results, so we were unable to ascertain whether any of these factors affected the association between biguanide prescription and LA incidence rate. ...
Patient data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) are used to assess the effect of biguanide administration on rates of lactic acidosis (LA) in hospitalized diabetes mellitus (DM) patients. In this retrospective cohort study (from April 2013 to March 2016), we compare DM inpatients prescribed biguanides to DM inpatients who were not prescribed biguanides to quantify the association between biguanides and incidence of LA. In total, 8,111,848 DM patient records are retrieved from the NDB. Of the 528,768 inpatients prescribed biguanides, 782 develop LA. Of the 1,967,982 inpatients not prescribed biguanides, 1310 develop LA. The rate ratio of inpatients who develop LA and are administered biguanides to those who developed LA without receiving biguanides is 1.44 (95% CI, 1.32–1.58). Incidence rates and rate ratios for both sexes are elevated in the group prescribed biguanides for patients aged 70 years and older, markedly in those 80 years and older: 40.12 and 6.31 (95% CI, 4.75–8.39), respectively, for men and 34.96 and 5.40 (95% CI, 3.91–7.46), respectively, for women. Biguanides should be used conservatively in patients older than 70 years, particularly for those with comorbidities, and with caution in patients 80 years and older.
Background: Type 2 diabetes mellitus (T2DM) often accompanies by diabetic kidney disease (DKD). The occurrence and progression of T2DM and DKD are closely related to the inflammatory response and oxidative stress triggered by metabolic abnormalities including hyperglycemia and dyslipidemia. 12(S)-HETE, a metabolite of arachidonic acid, is considered as a critical lipid mediator in inflammation and oxidative stress and is believed to play a role in the occurrence and progression of DKD. Metformin is widely used as an initial drug for T2DM, but its effect on diabetic kidney disease still remains to be elucidated. Therefore, this study aimed to evaluate the impact of metformin treatment on serum 12(S)-HETE level in T2DM patients combined with DKD.
Methods: A total of 121 T2DM patients were enrolled, including 63 T2DM patients with DKD and 58 T2DM patients without DKD. Then the T2DM patients with DKD were divided into two groups based on the use of metformin. There were 33 patients in the metformin group and 30 patients in the non-metformin group. Renal function was assessed by measuring glomerular filtration rate and urinary albumin-to-creatinine ratio for all the patients. Serum 12(S)-HETE was extracted and quantified using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Spearman’s correlation analysis was utilized to assess the relationship between serum 12(S)-HETE level and relevant variables associated with T2DM combined with DKD.
Results: We reported a significant elevation of serum 12(S)-HETE level in T2DM patients with DKD compared to T2DM patients without DKD (P<0.05). Among T2DM patients combined with DKD, patients receiving metformin treatment showed significantly lower serum 12(S)-HETE level compared to patients receiving treatment without metformin (P<0.05). Spearman’s correlation analysis showed that serum 12(S)-HETE level had moderate positive correlations with ACR (R=0.3878, P<0.0001) and uAER (R=0.3198, P=0.0007) of renal function, and showed a moderate positive correlation with LDL-C/HDL-C levels of serum lipids (R=-0.3030, P=0.0014).
Conclusions: Metformin reduced serum 12(S)-HETE level in T2DM patients with DKD. The mechanism might be related to the improvement of the abnormal lipid metabolic state through metformin.
Recent research has revealed that aerobic glycolysis has a strong correlation with sepsis-associated pulmonary fibrosis. However, at present, the mechanism and pathogenesis remain unclear. We aimed to test the hypothesis that the adenosine monophosphate-activated protein kinase (AMPK) activation and suppression of hypoxia-inducible factor 1α (HIF-1α) induced aerobic glycolysis play a central role in septic pulmonary fibrogenesis. Cellular experiments demonstrated that lipopolysaccharide (LPS) increased fibroblast activation through AMPK inactivation, HIF-1α induction, alongside an augmentation of aerobic glycolysis. By contrast, the effects were reversed by AMPK activation or HIF-1α inhibition. Additionally, pretreatment with metformin, which is an AMPK activator, suppresses HIF-1α expression and alleviates pulmonary fibrosis associated with sepsis, which is caused by aerobic glycolysis, in mice. HIF-1α knockdown demonstrated similar protective effects in vivo . Our research implies that targeting AMPK activation and HIF-1α-induced aerobic glycolysis with metformin might be a practical and useful therapeutic alternative for sepsis-associated pulmonary fibrosis.
Metformin-associated lactic acidosis (MALA) and euglycaemic diabetic ketoacidosis (EKA) are both life-threatening endocrine emergencies. MALA is a well-documented complication of anti-glycaemic therapy in diabetics while EKA is an increasingly recognized disease entity with the advent of use of sodium-glucose co-transporter-2 (SGLT-2) inhibitors. However, the occurrence of concurrent metformin-associated lactic acidosis and euglycaemic ketoacidosis (MALKA) is uncommon and rarely reported in the literature. We report an unusual case of MALKA, in a 74-year-old gentleman with no previous history of chronic kidney disease and SGLT-2 inhibitor use, who presented with altered mental status, acute renal failure and profound high anion-gap metabolic acidosis (HAGMA) with lactaemia, ketonaemia and normoglycaemia (pH 6.965, bicarbonate 3.1, creatinine 522, glucose 6.6, lactate 17.5, ketones >8). The patient was initiated on intravenous insulin infusion with dextrose-containing drip and continuous renal replacement therapy (CRRT) in the intensive care unit (ICU). The patient had a prolonged hospital stay but was eventually discharged with a normalised renal function without need for long-term dialysis. The parallel occurrence of MALA and EKA suggest a metformin-associated inhibition of gluconeogenesis. This case highlights the importance of early recognition and investigation of concurrent diabetic ketoacidosis in the presence of MALA and vice versa as MALKA benefits from both prompt institution of parenteral glucose therapy and insulin infusion and consideration of initiation of haemodialysis.
