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3A) Glutaminase activity inhibition in cells assay (%), according to metformin concentration; 3B) Ammonia concentration in cells assay, according to metformin concentration. Each bar represents the mean ± SD (all experiments were conducted by triplicate). *p≤0.05 vs. the corresponding control sample. #p≤0.05 vs. the same group collected at the previous time point.
Source publication
AIM: To investigate the influence of metformin use on liver dysfunction and hepatic encephalopathy in a retrospective cohort of diabetic cirrhotic patients. To analyze the impact of metformin on glutaminase activity and ammonia production in vitro. METHODS: Eighty-two cirrhotic patients with type 2 diabetes were included. Forty-one patients were cl...
Citations
... This deterioration of brain function is due to the liver's incapacity to remove blood toxins, such as ammonia and lipopolysaccharides, which causes systemic inflammation and activation of the circulatory neutrophils [146]. Then, ammonia and other toxic agents move to the brain, generating pathological changes such as neuroinflammation and neuropathy [147]. Because metformin contributes to intestinal barrier integrity and prevents bacteria translocation from the gut to the bloodstream, it may have a role in preventing hepatic encephalopathy [148]. ...
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.
... It has also been shown that metformin decreases the risk of hepatic encephalopathy in cirrhotic patients with diabetes, partially inhibiting glutaminase activity and improving insulin sensitivity. In more detail, in a study of 82 patients with T2D and cirrhosis, Ampuero et al. [27] provided evidence that encephalopathy occurred in 23.2 % with metformin compared to 41.5 % without metformin, while they also found that metformin decreased glutaminase activity by up to 24 % at 72 h after treatment. Along the same line, a more recent in-vivo study demonstrated that metformin regulates ammonia homeostasis by modulating glutamine metabolism in the enterocyte, exerting indirect control of glutamine uptake and degradation, reducing the production of metabolites and energy and indirectly decreasing ammonia production, lowering the risk of hepatic encephalopathy [28]. ...
... Metformin is the first-line therapy for patients with diabetes and cirrhosis, but assumed to increase the risk of lactic acidosis [27]. However, in [36], and hepatic encephalopathy [37]. American Diabetes Association (ADA) has declared acarbose safe and well-tolerated in patients with CLD, but it increases the risk of hyperammonemia in patients with advanced hepatic impairment [9]. ...
... Second, DM is associated with alterations in the gut microbiome itself (Qin et al. 2012). Third, DM could increase ammonia production by inducing small intestine glutaminase type K and accelerating muscle breakdown (Ampuero et al. 2012). Fourth, T2DM-associated insulin resistance (IR) may promote an increased protein catabolism, which may result in higher blood ammonia levels. ...
... in glycemic control on HE-risk. A study by Ampuero et al. demonstrated in a preclinical model that metformin inhibits glutaminase activity and may therefore have the potential to prevent HE (Ampuero et al. 2012). This hypothesis was validated in a retrospective analysis of 82 patients with cirrhosis. ...
Hepatic encephalopathy (HE) is one of the major complications of cirrhosis, and its presence is associated with poor survival. Several risk factors for HE are well established, including age, history of HE, portosystemic shunts, or poorer liver function. In recent years, diabetes mellitus (DM) has emerged as another potential risk factor for the development of HE. This may be important for many patients, as the incidence of type 2 DM (T2DM) is increasing worldwide and, consequently, the incidence of NAFLD-related cirrhosis is rising simultaneously. In addition, DM is a critical factor in the progression of other liver diseases, such as alcohol-related liver disease. Thus, the number of patients with cirrhosis and comorbid T2DM will also increase. To date, the prevalence of DM already ranges between 22 - 40% in patients with cirrhosis. DM-associated factors that may influence the risk of HE include systemic inflammation, insulin resistance with increased muscle protein breakdown as well as autonomic dysfunction with prolonged intestinal transit time and small intestinal bacterial overgrowth. Currently, the evidence for an association between DM and both minimal and overt HE is weak and it seems likely that only poor glycemic control has an impact on HE risk. In addition, there are some early signs indicating that DM may impair the response of patients with HE to pharmacological therapies such as rifaximin. Thus, improvements in the management of glycemic control may be a candidate future target to reduce the risk of HE. In this concise review, we summarize the current evidence on the association between DM and HE and its potential future implications.
... 54 A previous study has reported partial inhibition of glutaminase activity (about 20%), both in chemical and cell assays compared with controls. 55 On the other hand, pioglitazone, a peroxisome proliferator-activated receptor (PPAR)-γ agonist, is another antidiabetic drug that could interferes with the glutaminolysis-ammonia-urea cycle axis by restricting the conversion of glutamine to glutamate by reducing the expression of GLS1, the rate-limiting enzyme. 56 Thus, in a personalized medicine scenario, some antidiabetic drugs are effective for NAFLD patients in whom the glutaminolysis-ammonia-urea cycle axis is the predominant pathogenic insult of liver disease. ...
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide, reflecting the current epidemics of obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome. NAFLD is characterized by the accumulation of fat in the liver, and is known to be a cause of cirrhosis. Although many pathways have been proposed, the cause of NAFLD-linked fibrosis progression is still unclear, which posed challenges for the development of new therapies to prevent NASH-related cirrhosis and hepatocellular carcinoma. Cirrhosis is associated with activation of hepatic stellate cells (HSC) and accumulation of excess extracellular matrix proteins, and inhibiting the activation of HSCs would be expected to slow the progression of NAFLD-cirrhosis. Multiple molecular signals and pathways such as oxidative stress and glutaminolysis have been reported to promote HSC activation. Both mechanisms are plausible antifibrotic targets in NASH, as the activation of HSCs the proliferation of myofibroblasts depend on those processes. This review summarizes the role of the glutaminolysis-ammonia-urea cycle axis in the context of NAFLD progression, and shows how the axis could be a novel therapeutic target.
... 64 It has been shown that metformin reduces the risk of hepatic encephalopathy in cirrhotic patients with diabetes, possibly by partial inhibition of glutaminase activity and improving insulin sensitivity. In a study of 82 cirrhotic patients with type 2 diabetes, Ampeuro et al. 65 found that hepatic encephalopathy occurred in 23.2% However, a recent population-based study from the Taiwan National Health Insurance Research Database by Yen et al. 66 found that metformin use was associated with higher risks of mortality and decompensation in patients with compensated cirrhosis. ...
The management of diabetes in cirrhosis and liver transplantation can be challenging. There is difficulty in diagnosis and monitoring of diabetes as fasting blood sugar values are low and glycosylated hemoglobin may not be a reliable marker. The challenges in the management of diabetes in cirrhosis include the likelihood of cognitive impairment, risk of hypoglycemia, altered drug metabolism, frequent renal dysfunction, risk of lactic acidosis, and associated malnutrition and sarcopenia. Moreover, calorie restriction and an attempt to lose weight in obese diabetics may be associated with a worsening of sarcopenia. Many commonly used antidiabetic drugs may be unsafe or be associated with a high risk of hypoglycemia in cirrhotics. Post-transplant diabetes is common and may be contributed by immunosuppressive medication. There is inadequate clinical data on the use of antidiabetic drugs in cirrhosis, and the management of diabetes in cirrhosis is hampered by the lack of guidelines focusing on this issue. The current review aims at addressing the practical management of diabetes by a hepatologist.
... Ampuero et al. reported that metformin could inhibit glutaminase activity and protect patients from hepatic encephalopathy,24 but our study found that using metformin in compensated liver cirrhosis could significantly increase the risks of variceal bleeding and cirrhotic decompensation, except hepatic encephalopathy. The difference might be due to different study methods, patient numbers and some of our participants having chronic viral infection, different from Ampuero's patients, most of whom had nonalcoholic fatty liver disease. ...
Aims
To compare the risks of all‐cause mortality, hepatic outcomes, major adverse cardiovascular events between metformin users and nonusers for patients with diabetes and cirrhosis.
Methods
From the Taiwan's National Health Insurance Research Database, we selected propensity‐score matched metformin users and nonusers from the cohorts of type 2 diabetes mellitus with compensated (n = 26 164) or decompensated liver cirrhosis (n = 15 056) between 1 January 2000 and 31 December 2009, and followed them until 31 December 2010. Cox proportional hazards models with robust sandwich standard error estimates were used to assess risk of investigated outcomes for metformin users.
Results
The incidence rates of mortality during follow‐up were 3.8 and 3.3 per 100 patient‐years (adjusted hazard ratio [aHR] 1.13, 95% confidence interval 1.01–1.25) for metformin users and nonusers, respectively. The incidence rates of cirrhotic decompensation during follow‐up were 5.9 and 4.9 per 100 patient‐years (aHR 1.15, 95% confidence interval 1.04–1.27) for metformin users and nonusers. The risk of death (P for trend <.01) and cirrhotic decompensation (P for trend <.0001) associated with metformin use was significant for those taking metformin for >40 defined daily doses in 90 days or >1000 mg/d. The outcomes of metformin use vs nonuse for type 2 diabetes mellitus with decompensated liver cirrhosis were not statistically different, except that metformin users had higher risk of mortality (aHR 1.15).
Conclusion
Metformin use was associated with higher risks of mortality and cirrhotic decompensation in patients with compensated liver cirrhosis. Prospective studies are required to confirm our results.
... 40 Metformin was also reported to reduce the incidence of hepatic encephalopathy in a cohort of 82 patients with cirrhosis and T2D, possibly via inhibition of glutaminase activity. 41 Finally, metformin has an anticarcinogenic effect, confirmed in several cohort studies and on several cancer sites, 42 including the liver. In a meta-analysis including 105 495 patients with T2D, metformin significantly reduced the risk of liver cancer (odds ratio [OR], 0.38; 95% CI, 0.24-0.59) ...
Diabetes is common in patients waitlisted for liver transplantation because of end-stage liver disease or hepatocellular cancer as well as in posttransplant phase (posttransplantation diabetes mellitus). In both conditions, the presence of diabetes severely affects disease burden and long-term clinical outcomes; careful monitoring and appropriate treatment are pivotal to reduce cardiovascular events and graft and recipients' death. We thoroughly reviewed the epidemiology of diabetes in the transplant setting and the different therapeutic options, from lifestyle intervention to antidiabetic drug use-including the most recent drug classes available-and to the inclusion of bariatric surgery in the treatment cascade. In waitlisted patients, the old paradigm that insulin should be the treatment of choice in the presence of severe liver dysfunction is no longer valid; novel antidiabetic agents may provide adequate glucose control without the risk of hypoglycemia, also offering cardiovascular protection. The same evidence applies to the posttransplant phase, where oral or injectable noninsulin agents should be considered to treat patients to target, limiting the impact of disease on daily living, without interaction with immunosuppressive regimens. The increasing prevalence of liver disease of metabolic origin (nonalcoholic fatty liver) among liver transplant candidates, also having a higher risk of noncirrhotic hepatocellular cancer, is likely to accelerate the acceptance of new drugs and invasive procedures, as suggested by international guidelines. Intensive lifestyle intervention programs remain however mandatory, both before and after transplantation. Achievement of adequate control is mandatory to increase candidacy, to prevent delisting, and to improve long-term outcomes.
... 111,[113][114][115] In addition, studies have also revealed a lower risk of occurrence hepatic encephalopathy associated with metformin. 116 However, this drug should be used with caution, especially in patients with advanced liver dysfunction (Child Class C) and those with renal dysfunction. The dose of metformin should be reduced/ avoided in patients with moderate liver disease (Child B), whereas it should be avoided in severe hepatic dysfunction (Child C). 117 Patients with active infection with sepsis and renal failure should promptly be switched to insulin therapy till resolution of sepsis and organ failures because of increased risk of lactic acidosis. ...
As liver is one of the primary organs involved in glucose homeostasis, it is not surprising that patients with liver dysfunction in chronic liver disease usually develop impaired glucose tolerance and subsequently overt diabetes later in their natural course. The diabetes which develops after the onset of cirrhosis of liver is usually referred to as hepatogenous diabetes(HD). It is an underrecognized and a hallmark endocrinological event in chronic liver disease. Hepatogenous diabetes is associated with a higher risk of developing hepatic decompensations such as ascites, variceal bleeding, hepatic encephalopathy, renal dysfunction, refractory ascites and hepatocellular carcinoma along with reduced survival rates than normoglycemic patients with cirrhosis of liver. It is quite different than type 2 diabetes mellitus with the absence of classical risk factors, dissimilar laboratory profiles and decreased incidence of microvascular complications. Further, the management of patients with hepatogenous diabetes is challenging due to altered pharmacokinetics of most antidiabetic drugs and increased risk of hypoglycemia and other adverse effects. Hence, a clear understanding of the epidemiology, pathophysiology, clinical implications, laboratory diagnosis and management of hepatogenous diabetes is essential for both hepatologists as well as endocrinologists, which is narrated briefly in this review.
... Frontiers in Pharmacology | www.frontiersin.org February 2021 | Volume 11 | Article 616157 have shown that metformin has an inhibitory effect on glutaminase (GLS) activity in tumor cells (Ampuero et al., 2012;Saladini et al., 2019). Glutaminase enzyme mediates glutamine deamination and subsequent glutamate production, converted to α-ketoglutarate, an intermediate of the TCA cycle, and thus provides an alternative energy source to glucose in cells (Roberts et al., 2014). ...
Metformin is widely used in the treatment of Type 2 Diabetes Mellitus (T2DM). However, it is known to have beneficial effects in many other conditions, including obesity and cancer. In this study, we aimed to investigate the metabolic effect of metformin in T2DM and its impact on obesity. A mass spectrometry (MS)-based metabolomics approach was used to analyze samples from two cohorts, including healthy lean and obese control, and lean as well as obese T2DM patients on metformin regimen in the last 6 months. The results show a clear group separation and sample clustering between the study groups due to both T2DM and metformin administration. Seventy-one metabolites were dysregulated in diabetic obese patients (30 up-regulated and 41 down-regulated), and their levels were unchanged with metformin administration. However, 30 metabolites were dysregulated (21 were up-regulated and 9 were down-regulated) and then restored to obese control levels by metformin administration in obese diabetic patients. Furthermore, in obese diabetic patients, the level of 10 metabolites was dysregulated only after metformin administration. Most of these dysregulated metabolites were dipeptides, aliphatic amino acids, nucleic acid derivatives, and urea cycle components. The metabolic pattern of 62 metabolites was persistent, and their levels were affected by neither T2DM nor metformin in obesity. Interestingly, 9 metabolites were significantly dysregulated between lean and obese cohorts due to T2DM and metformin regardless of the obesity status. These include arginine, citrulline, guanidoacetic acid, proline, alanine, taurine, 5-hydroxyindoleacetic acid, and 5-hydroxymethyluracil. Understanding the metabolic alterations taking place upon metformin treatment would shed light on possible molecular targets of metformin, especially in conditions like T2DM and obesity.
