Metformin: An Old Drug with New Applications Zhou, Joseph; Massey, Scott; Story, Darren ...
International journal of molecular sciences,
09/2018, Volume:
19, Issue:
10
Journal Article
Peer reviewed
Open access
Metformin is a biguanide drug that has been used to treat type 2 diabetes mellitus for more than 60 years. The United Kingdom Prospective Diabetic Study (UKPDS) has shown metformin to improve ...mortality rates in diabetes patients, and recent studies suggest metformin has additional effects in treating cancer, obesity, nonalcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and metabolic syndrome. Metformin has also been shown to alleviate weight gain associated with antipsychotic medication. Metformin has recently been extensively studied and emerging evidence suggests metformin decreases hepatocyte triglyceride accumulation in NAFLD and prevents liver tumorigenesis. Interestingly, studies have also shown metformin reduces visceral fat, suppresses white-adipose-tissue (WAT) extracellular matrix remodeling, and inhibits obesity-induced inflammation. However, clinical evidence for using metformin to treat NAFLD, cancer, metabolic syndrome, or to prevent hepatocellular carcinoma in NAFLD patients is lacking. This review therefore addresses the potential beneficial effects of metformin on NAFLD, its role in protecting against cardiac ischemia⁻reperfusion (I/R) injury, atherosclerosis, glucotoxicity, and lipotoxicity induced oxidative and ER stress in pancreatic β-cell dysfunction, as well as its underlying molecular mechanisms of action.
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•NAFLD is associated with a nearly 2-fold increase in the overall risk of incident cancers.•The highest risk was noted in liver, uterine, stomach, pancreas and colon cancers.•Obesity ...in the absence of NAFLD had minimal impact on malignancy risk.
Cancer is a major cause of death in patients with non-alcoholic fatty liver disease (NAFLD). Obesity is a risk factor for cancers; however, the role of NAFLD in this association is unknown. We investigated the effect of NAFLD versus obesity on incident cancers.
We identified all incident cases of NAFLD in a US population between 1997-2016. Individuals with NAFLD were matched by age and sex to referent individuals from the same population (1:3) on the index diagnosis date. We ascertained the incidence of cancer after index date until death, loss to follow-up or study end. NAFLD and cancer were defined using a code-based algorithm with high validity and tested by medical record review. The association between NAFLD or obesity and cancer risk was examined using Poisson regression.
A total of 4,722 individuals with NAFLD (median age 54, 46% male) and 14,441 age- and sex-matched referent individuals were followed for a median of 8 (range 1–21) years, during which 2,224 incident cancers occurred. NAFLD was associated with 90% higher risk of malignancy: incidence rate ratio (IRR) = 1.9 (95% CI 1.3–2.7). The highest risk increase was noted in liver cancer, IRR = 2.8 (95% CI 1.6–5.1), followed by uterine IRR = 2.3 (95% CI 1.4–4.1), stomach IRR = 2.3 (95% CI 1.3–4.1), pancreas IRR = 2.0 (95% CI 1.2–3.3) and colon cancer IRR = 1.8 (95% CI 1.1–2.8). In reference to non-obese controls, NAFLD was associated with a higher risk of incident cancers (IRR = 2.0, 95% CI 1.5–2.9), while obesity alone was not (IRR = 1.0, 95% CI 0.8–1.4).
NAFLD was associated with increased cancer risk, particularity of gastrointestinal types. In the absence of NAFLD, the association between obesity and cancer risk is small, suggesting that NAFLD may be a mediator of the obesity-cancer association.
We studied the incidence of malignancies in a community cohort of adults with non-alcoholic fatty liver disease (NAFLD) in reference to age- and sex-matched adults without NAFLD. After 21 years of longitudinal follow-up, NAFLD was associated with a nearly 2-fold increase in the risk of developing cancers, predominantly of the liver, gastrointestinal tract and uterus. The association with increased cancer risk was stronger in NAFLD than obesity.
CD163, a surface hemoglobin-haptoglobin scavenger receptor, is expressed on macrophages and monocytes and up-regulated during macrophage activation. This study aimed to evaluate CD163 in nonalcoholic ...steatohepatitis patients as a diagnostic and prognostic marker in such patients. Methods: Serum samples were collected from 41 NAFLD patients and 14 healthy controls. All cases were subjected to clinical assessment, abdominal ultrasound examination, laboratory assessment including liver function and enzymes, kidney function, and lipid profile. Fib-4 and NAFLD fibrosis score were calculated for all patients. Also, serum levels of CD163 were detected by ELISA technique. Results: The present study showed that BMI, NAFLD fibrosis score (NFS), uric acid, cholesterol, and triglyceride levels were significantly elevated in the NAFLD cases compared with healthy controls (P < 0.05). The serum level of sCD163 was considerably higher in NAFLD cases (9.97 ± 9.97 ng/ml) vs. healthy controls (1.87 ± 0.83 ng/ml) (p < 0.001). Circulating level of sCD163 was significantly higher in the obese-diabetic subjects and diabetic non-obese patients as compared with the lean healthy subjects (11.15 ± 7.69 ng/ml) and 11.46 ± 13.83 ng/ml vs. 1.87 ± 0.83 ng/ml, P < 0.05; respectively. The sensitivity and specificity of this marker was 85.4%, and 92.9 for distinguishing patients with NAFLD in obese and/or diabetic subjects from healthy controls. Conclusion: serum level of CD163 can be used as a diagnostic marker for individuals with NAFLD. However, it didn’t correlate with NAFLD fibrosis score of those patients and thus couldn’t predict the severity of disease.
•NAFLD nowadays is ranked as the commonest chronic liver disease and its prevalence appears to be rising.•It is necessary to identify an effective and inexpensive biomarker for the early diagnosis, prognosis and staging of NAFLD.•CD163 could be used as a marker of diabetes since its level is higher in diabetic patients compared to healthy controls.•There was no correlation between sCD163 and NFS in NAFLD patients and thus it couldn’t predict the severity of the disease.
Non-alcoholic fatty liver disease (NAFLD) affects one-third of the world's adult population and is linked to metabolic syndrome. It can progress to steatohepatitis, cirrhosis and hepatocellular ...carcinoma. During the last four decades, it has been the subject of exhaustive research in multiple aspects to define its epidemiology, pathophysiological mechanisms and therapy.
In 2020, a group of international experts proposed the change of name to metabolic-associated fatty liver disease (MAFLD) with the main objective of making it an inclusive diagnosis prioritizing metabolic abnormalities. However, the change in terminology included the modification of the diagnostic criteria allowing the non-exclusion of other concomitant liver diseases such as alcohol liver disease, and chronic hepatitis B or C.
The proposal precipitated a wave of debates among experts based on theoretical opinions on the desirability of the rapid adoption of the new terminology. But it also precipitated a wave of epidemiological and clinical studies which, two years later, have provided clinical evidence on the differences and similarities of the two entities, specially, those that could be considered for future refinements of the diagnostic criteria of MAFLD. Likewise, this evidence may contribute to deciding the time of adoption of this terminology.
In this text, we discuss, in general terms, important aspects of the clinical evidence that has been generated to date in cross-sectional and longitudinal studies focusing on clinical characteristics and outcomes, mainly on all-cause and specific mortality of MAFLD.
Nonalcoholic fatty liver disease (NAFLD) has become a serious public health issue not only in Western countries but also in Japan. Within the wide spectrum of NAFLD, nonalcoholic steatohepatitis ...(NASH) is a progressive form of disease that often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma (HCC). While a definite diagnosis of NASH requires liver biopsy to confirm the presence of hepatocyte ballooning, hepatic fibrosis is the most important prognostic factor in NAFLD. With so many NAFLD patients, it is essential to have an effective screening method for NAFLD with hepatic fibrosis. As HCC with non-viral liver disease has increased markedly in Japan, effective screening and surveillance of HCC are also urgently needed. The most common death etiology in NAFLD patients is cardiovascular disease (CVD) event. Gastroenterologists must, therefore, pay close attention to CVD when examining NAFLD patients. In the updated guidelines, we propose screening and follow-up methods for hepatic fibrosis, HCC, and CVD in NAFLD patients. Several drug trials are ongoing for NAFLD/NASH therapy, however, there is currently no specific drug therapy for NAFLD/NASH. In addition to vitamin E and thiazolidinedione derivatives, recent trials have focused on sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) analogues, and effective therapies are expected to be developed. These practical guidelines for NAFLD/NASH were established by the Japanese Society of Gastroenterology in conjunction with the Japan Society of Hepatology. Clinical evidence reported internationally between 1983 and October 2018 was collected, and each clinical and background question was evaluated using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system. This English summary provides the core essentials of these clinical practice guidelines, which include the definition and concept, screening systems for hepatic fibrosis, HCC and CVD, and current therapies for NAFLD/NASH in Japan.
To assess the possible association between a validated Dietary Inflammatory Index (DII) and specific dietary components with suitable non-invasive markers of liver status in overweight and obese ...subjects within the PREDIMED study.
A cross-sectional study encompassing 794 randomized overweight and obese participants (mean ± SD age: 67.0 ± 5.0 y, 55% females) from the PREDIMED (PREvención con DIeta MEDiterránea) trial was conducted. DII is a validated tool evaluating the effect of diet on six inflammatory biomarkers (IL-1b, IL-4, IL-6, IL-10, TNF-α and C-reactive protein). Furthermore, a validated 137-item food-frequency-questionnaire was used to obtain the information about the food intake. In addition, anthropometric measurements and several non-invasive markers of liver status were assessed and the Fatty Liver Index (FLI) score was calculated.
A higher DII and lower adherence to Mediterranean diet (MeDiet) were associated with a higher degree of liver damage (FLI > 60) in obese as compared to overweight participants. Furthermore, the DII score was positively associated with relevant non-invasive liver markers (ALT, AST, GGT and FLI) and directly affected FLI values. Interestingly, a positive correlation was observed between liver damage (>50th percentile FLI) and nutrients and foods linked to a pro-inflammatory dietary pattern.
This study reinforced the concept that obesity is associated with liver damage and revealed that the consumption of a pro-inflammatory dietary pattern might contribute to obesity and fatty liver disease features. These data suggest that a well-designed precision diet including putative anti-inflammatory components could specifically prevent and ameliorate non-alcoholic fatty liver manifestations in addition to obesity.
Cytosolic lipid droplets (LDs) are present in most cell types, and consist of a core comprising neutral lipids, mainly triglycerides and sterol esters, surrounded by a monolayer of phospholipids. LDs ...are heterogeneous in their structure, chemical composition, and tissue distribution. LDs are coated by several proteins, including perilipins and other structural proteins, lipogenic enzymes, lipases and membrane-trafficking proteins. Five proteins of the perilipin (PLIN) family (PLIN1 (perilipin), PLIN2 (adipose differentiation-related protein), PLIN3 (tail-interacting protein of 47kDa), PLIN4 (S3-12), and PLIN5 (myocardial lipid droplet protein)), are associated with LD formation. More recently, the CIDE family of proteins, hypoxia-inducible protein 2 (HIG2), and patanin-like phospholipase domain-containing 3 (PNPLA3) have also gained attention in hepatic LD biology. Evidence suggests that LD proteins are involved in the pathophysiology of fatty liver diseases characterized by excessive lipid accumulation in hepatocytes. This review article will focus on how hepatic LDs and their associated proteins are involved in the pathogenesis of three chronic liver conditions: hepatitis C virus infection, non-alcoholic fatty liver disease, and alcoholic liver disease.
•We review the major perilipin and non-perilipin hepatic lipid droplet proteins.•We review theoretical models of hepatic lipid droplet formation.•We discuss the role of lipid droplet proteins in HCV, NAFLD, and ALD.
Abstract
Non-alcoholic fatty liver disease (NAFLD) is among the most frequently encountered chronic liver diseases in everyday clinical practice. It is considered the hepatic manifestation of ...metabolic syndrome. Today, liver biopsy is still the gold standard for NAFLD confirmation and assessing NAFLD's possible progression to non-alcoholic steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Because of the high prevalence of NAFLD and potential associated risks of invasive diagnostic procedures, it is of great interest to recruit the patients for liver biopsy. However, as the presence of liver fibrosis determines the further clinical course, liver biopsy is expectedly reserved for those with increased fibrosis risk. The quality of liver biopsy recruitment and patient monitoring could be significantly improved by using non-invasive tools to assess liver fibrosis presence and interactive collaboration between general practitioners, gastroenterologists, and endocrinologists. As a result, the quality of liver biopsy recruitment and patients monitoring could be significantly improved. Here, we proposed clinical practice guidelines that could be implemented for everyday clinical practice in NAFLD patients.
The gut microbiota plays critical roles in development of obese-related metabolic diseases such as nonalcoholic fatty liver disease (NAFLD), type 2 diabetes(T2D), and insulin resistance(IR), ...highlighting the potential of gut microbiota-targeted therapies in these diseases. There are various ways that gut microbiota can be manipulated, including through use of probiotics, prebiotics, synbiotics, antibiotics, and some active components from herbal medicines. In this review, we review the main roles of gut microbiota in mediating the development of NAFLD, and the advances in gut microbiota-targeted therapies for NAFLD in both the experimental and clinical studies, as well as the conclusions on the prospect of gut microbiota-targeted therapies in the future.
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