NAFLD and NASH and Diabetes
2021; Mary Ann Liebert, Inc.; Volume: 23; Issue: S2 Linguagem: Inglês
10.1089/dia.2021.2515
ISSN1557-8593
AutoresKavita Garg, Trenton Reinicke, Satish K. Garg,
Tópico(s)Alcohol Consumption and Health Effects
ResumoDiabetes Technology & TherapeuticsVol. 23, No. S2 Original ArticlesFree AccessNAFLD and NASH and DiabetesKavita Garg, Trenton Reinicke, and Satish K. GargKavita GargBarbara Davis Center for Diabetes, University of Colorado, Denver, COSearch for more papers by this author, Trenton ReinickeBarbara Davis Center for Diabetes, University of Colorado, Denver, COSearch for more papers by this author, and Satish K. GargBarbara Davis Center for Diabetes, University of Colorado, Denver, COSearch for more papers by this authorPublished Online:31 May 2021https://doi.org/10.1089/dia.2021.2515AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail IntroductionThe exact incidence of nonalcoholic fatty liver disease (NAFLD) globally is unknown, and only a limited number of studies are available in the literature. Research suggests that the prevalence of NAFLD in Asia is higher than in Western countries. Several meta-analyses report NAFLD incidence in Asia to be 52.3 per 1000 person-years. While among the Western countries, NAFLD incidence is around 28 per 1000 person-years. It appears that African Americans, Hispanics, and South Asians are at a much higher risk of developing NAFLD and nonalcoholic steatohepatitis (NASH). NAFLD is also becoming the leading cause of chronic liver disease and cirrhosis. In addition, NAFLD is often associated with metabolic syndrome, cardiovascular disease, type 2 diabetes, and increased all-cause mortality.NAFLD is commonly defined by the presence of liver fat greater than 5% in the absence of excessive alcohol use, concurrent liver disease, or steatosis-inducing medications. The histopathological finding of fatty liver disease at different stages includes: (1) simple liver steatosis (fat), (2) NAFLD, and (3) NASH.The presence of NAFLD in the United States is about 24%–26%, which corresponds to roughly 85 million Americans. Approximately 20%–30% of these cases (17–25 million Americans) are thought to have NASH. Unfortunately, future projections estimate an 18% increase in NAFLD by 2025, thus affecting nearly 100 million Americans. Furthermore, NAFLD has a substantial economic impact that accounts for nearly $103 billion in direct medical care costs and another $188 billion in societal costs. In biopsy-diagnosed patients with NAFLD, roughly 58% develop type 2 diabetes and another 20% establish impaired glucose tolerance.Above and beyond the increasing prevalence of NAFLD and NASH and their sizeable economic burden, there is an increased mortality among patients with NAFLD who contract severe acute respiratory syndrome from coronavirus 2 (SARS-CoV-2), commonly referred to as COVID-19. In this article, we plan to highlight the emerging trends among the latest diagnostic methods, including imaging patients with NAFLD and NASH, as well as discussing the upcoming therapeutic options for patients with fatty liver disease.Key Articles Reviewed for the ArticleConcurrent nonalcoholic fatty liver disease and type 2 diabetes: diagnostic and therapeutic considerationsArrese M, Barrera F, Triantafilo N, Arab JPExpert Rev Gastroenterol Hepatol 2019;13: 849–866Evaluation of progression of hepatic fibrosis in a group of patients with non-alcoholic fatty liver disease accompanied for 10 yearsCastro PCS, Alberton HCP, Pedroso MLA, Morsoletto DBG, Pissaia Junior A, Ivantes CAPArq Gastroenterol 2019;56: 256–260Screening for non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus using transient elastographyLai LL, Wan Yusoff WNI, Vethakkan SR, Nik Mustapha NR, Mahadeva S, Chan WKJ Gastroenterol Hepatol 2019;34: 1396–1403Plasma fibroblast growth factor 21 is associated with severity of nonalcoholic steatohepatitis in patients with obesity and type 2 diabetesBarb D, Bril F, Kalavalapalli S, Cusi KJ Clin Endocrinol Metab. 2019;104: 3327–3336Modulation of insulin resistance in nonalcoholic fatty liver diseaseKhan RS, Bril F, Cusi K, Newsome PNHepatology 2019;70: 711–724Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trialBril F, Biernacki DM, Kalavalapalli S, Lomonaco R, Subbarayan SK, Lai J, Tio F, Suman A, Orsak BK, Hecht J, Cusi KDiabetes Care 2019;42: 1481–1488The SGLT2 inhibitor canagliflozin prevents carcinogenesis in a mouse model of diabetes and non-alcoholic steatohepatitis-related hepatocarcinogenesis: association with SGLT2 expression in hepatocellular carcinomaJojima T, Wakamatsu S, Kase M, Iijima T, Maejima Y, Shimomura K, Kogai T, Tomaru T, Usui I, Aso YInt J Mol Sci 2019;20: 5237Role of sodium-glucose co-transporter-2 inhibitors in the management of nonalcoholic fatty liver diseaseKontana A, Tziomalos KWorld J Gastroenterol 2019;25: 3664–3668Liraglutide improves non-alcoholic fatty liver disease in diabetic mice by modulating inflammatory signaling pathwaysLuo Y, Yang P, Li Z, Luo Y, Shen J, Li R, Zheng H, Liang Y, Xia NDrug Des Devel Ther 2019;13: 4065–4074Adiponectin is required for pioglitazone-induced improvements in hepatic steatosis in mice fed a high-fat diet.de Mendonça M, Dos Santos BAC, de Sousa É, Rodrigues ACMol Cell Endocrinol 2019;493: 110480Effects of different exercise modalities on novel hepatic steatosis indices in overweight women with type 2 diabetesBanitalebi E, Faramarzi M, Nasiri S, Mardaniyan M, Rabiee VClin Mol Hepatol 2019;25: 294–304Role of probiotics in non-alcoholic fatty liver disease: does gut microbiota matter?Xie C, Halegoua-DeMarzio DNutrients 2019;11: 2837Concurrent nonalcoholic fatty liver disease and type 2 diabetes: diagnostic and therapeutic considerationsArrese M1,2, Barrera F1, Triantafilo N3, Arab JP11Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; 2Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas Pontificia Universidad Católica de Chile, Centro de Envejecimiento y Regeneración (CARE), Santiago, Chile; 3Departamento de Hematologia y oncología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, ChileExpert Rev Gastroenterol Hepatol 2019;13: 849–866BackgroundThe correlation between NAFLD and type 2 diabetes mellitus (T2DM) is complicated and bidirectional. NAFLD increases the risk of incident diabetes and is common in T2DM patients. T2DM is, in turn, an aggravating factor for NAFLD. Diagnosis and treatment in T2DM patients with NAFLD and diagnosis, staging, and treatment of NAFLD in those with T2DM are significant concerns.MethodsPubMed/MEDLINE was explored for articles published between January 2013 and May 2019 related to associated occurrences of NAFLD and T2DM. Areas covered included epidemiological, diagnostic, and therapeutic aspects.ConclusionIncreased awareness of NAFLD adding liver disease as an end-organ complication of T2DM is crucial. Specialists should be highlighting the use of simple noninvasive tools to triage patients with potentially severe liver disease. To achieve significant weight loss in patients with NAFLD and T2DM, professionals rely on lifestyle optimization. There is no drug currently approved for treating NAFLD in patients with T2DM, although vitamin E and pioglitazone can be used in certain patients. Approved diabetic medications appear promising for NAFLD treatment, and various liver-specific drugs are being evaluated in clinical trials. In the future, a combination approach to NAFLD therapeutics will likely be pursued.Evaluation of progression of hepatic fibrosis in a group of patients with non-alcoholic fatty liver disease accompanied for 10 yearsCastro PCS1, Alberton HCP1, Pedroso MLA2, Morsoletto DBG1, Pissaia Junior A1, Ivantes CAP11Hospital Nossa Senhora das Graças, Departamento de Gastroenterologia, Hepatologia e Transplante de Fígado, Curitiba, PR, Brasil; 2Universidade Federal do Paraná, Hospital de Clínicas, Seção de Hepatologia, Serviço de Gastroenterologia, Curitiba, PR, BrasilArq Gastroenterol 2019;56: 256–260BackgroundNonalcoholic fatty liver disease has been increasingly diagnosed as a result of the surge in obesity and type 2 diabetes mellitus, which are its main risk factors. It is characterized by the buildup of fat in the hepatocytes correlated with lobular inflammation and balonization, which can lead to cirrhosis and hepatocarcinoma. Therefore follow-up pertaining to the fibrosis levels of these patients becomes important, being that the transient hepatic elastography is a reliable method for this evaluation with a measure of the kapa index.ObjectiveThe aim of this study was to determine the progression of hepatic fibrosis through elastography in patients with nonalcoholic fatty liver disease.MethodsThis study included patients who previously had hepatic biopsy and noninvasive scores for nonalcoholic steatohepatitis (NASH) and fibrosis. About 10 years after the first evaluation, these same subjects then submitted to clinical evaluation, including laboratory and liver elastography tests, defining the level of liver fibrosis.ResultsData from 66 patients who previously submitted to liver biopsy were analyzed. Of these 66, 16 were not found, 4 could not join because they were debilitated due to hepatic cirrhosis, 2 had died from car accidents, and 5 had died from complications of cirrhosis of the liver. Therefore, of the 50 patients with a known history, 9 (18%) had died of cirrhosis or were incapable of attending the examination because of their liver disease. The remaining population was mostly female (61.5%), mean age of 63 years, and overweight, with dyslipidemia (76.9%) disorders of the glycemic profile (76.9%), and metabolic syndrome (82.1%). Of the 39 cases assessed, 35% had the same degree of fibrosis at the initial evaluation (biopsy) and at the current evaluation (elastography), 33% had an increase in the degree of fibrosis, and another 30% had a decrease in the degree of fibrosis. In all, 28 patients had NASH at baseline. It was noted in the current evaluation of these patients that 25% remained stable in the degree of fibrosis, 39% progressed, and 35% regressed.ConclusionsSome limitations of this study were the small number of patients and the use of two different methods of evaluation (biopsy and elastography). Even so, the authors concluded that of the 39 evaluated cases, 33% (13) presented progression of fibrosis, and in the total group of 50 patients, 42% had cirrhosis or died due to liver disease. In this study, the presence of NASH on hepatic biopsy did not prove to be predictive of the evolution of hepatic fibrosis in patients.Screening for non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus using transient elastographyLai LL1, Wan Yusoff WNI1, Vethakkan SR2, Nik Mustapha NR3, Mahadeva S1, Chan WK11Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 2Endocrinology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 3Department of Pathology, Hospital Sultanah Bahiyah, Alor Setar, Malaysia.J Gastroenterol Hepatol 2019;34: 1396–1403ObjectiveScreening requirements for NAFLD among T2DM patients can differ among various guidelines. This paper aimed to study the prevalence of NALFD and advanced fibrosis among patients with T2DM.MethodsThis cross-sectional study included consecutive adult T2DM patients at the diabetes clinic of a university hospital. Based on transient elastography, if the controlled attenuation parameter was ≥263 dB/m and the liver stiffness measurement was ≥9.6 kPa using the M probe or ≥9.3 kPa using the XL probe, respectively, significant hepatic steatosis and advanced fibrosis was diagnosed. Patients with liver stiffness ≥8 kPa were referred to the gastroenterology and hepatology clinic for additional assessment, including liver biopsy.ResultsThe data of 557 patients were evaluated (mean age 61.4±10.8 years, male 40.6%). The prevalence of NAFLD and advanced fibrosis based on transient elastography was 72.4% and 21.0%, respectively. On multivariate analysis, independent factors related to NAFLD were central obesity (OR 4.856, 95% confidence interval [CI] 2.749–8.577, P=0.006), serum triglyceride (OR 1.585, 95% CI 1.056–2.381, P=0.026), and alanine aminotransferase levels (OR 1.047, 95% CI 1.025–1.070, P 25 (n=187) underwent: (1) euglycemic hyperinsulinemic clamp to assess tissue-specific IR; (2) liver magnetic resonance spectroscopy for intrahepatic triglyceride quantification; (3) liver biopsy (if NAFLD present; n=146); and (4) fasting plasma FGF21 levels.Participants were separated into three groups: (1) no NAFLD (n=41); (2) no NASH (patients with isolated steatosis or borderline NASH; n=52); and (3) NASH (patients with definite NASH; n=94). Groups were well matched for age/sex, prevalence of type 2 diabetes mellitus, and hemoglobin A1c. During euglycemic hyperinsulinemic insulin clamp, insulin sensitivity in skeletal muscle and adipose tissue worsened from no NAFLD to NASH (both P<0.001).ResultsPlasma FGF21 levels correlated inversely with insulin sensitivity in adipose tissue (r=−0.17, P=0.006) and skeletal muscle (r=−0.23, P=0.007), but not with liver insulin sensitivity. Plasma FGF21 was higher in patients with NASH (453±262 pg/mL) when compared with the no NASH (341±198 pg/mL, P=0.03) or no NAFLD (325±289 pg/mL, P=0.02) groups. Plasma FGF21 improved with the severity of necroinflammation (P=0.02) and most notably with worse fibrosis (P<0.001), but not with worsening steatosis (P=0.60).ConclusionsIn patients with NASH, plasma FGF21 correlates with severity of steatohepatitis, in particular of fibrosis. Measurement of FGF21 may help recognize patients who are at highest risk of disease progression.Modulation of insulin resistance in nonalcoholic fatty liver diseaseKhan RS1–3, Bril F4,5, Cusi K4,5, Newsome PN1–31National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, UK; 2Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; 3Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; 4Division of Endocrinology, Diabetes and Metabolism, The University of Florida, Gainesville, FL; 5Malcom Randall Veterans Administration Medical Center, Gainesville, FLHepatology 2019;70: 711–724ObjectiveNAFLD is approximately 25% prevalent in the general population, and cirrhosis secondary to NASH is expected to become the main cause of liver transplantation, but there is a lack of effective therapy for these ailments. There is a close link between IR and NAFLD, with prevalence of NAFLD being fivefold higher in patients with diabetes compared to those without. IR is implicated both in pathogenesis of NAFLD and in disease progression from steatosis to NASH. Therefore modulation of IR is a possible strategy for treating NAFLD. This review presents major proposed mechanisms linking IR and NAFLD, such as changes in rates of adipose tissue lipolysis and de novo lipogenesis, impairment of mitochondrial fatty acid β-oxidation (FAO), shifts in fat distribution, variations in the gut microbiome, and changes in levels of adipokines and cytokines. Additionally, the authors review the main pharmacological strategies used to treat IR in patients with NAFLD and their efficacy according to current experimental and clinical data. These include biguanides, glucagon-like peptide 1 receptor (GLP-1) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, peroxisome proliferator-activated receptor (PPAR-γ/α/δ) agonists, sodium glucose cotransporter 2 (SGLT2) inhibitors, and farnesoid X receptor (FXR) agonists, with novel treatments on the horizon. Ultimately, a combinatorial approach could achieve improved IR and reduced cardiovascular risk, and generate demonstrable improvements in NASH histology.CommentThe first abstract highlights the relationship between NAFLD and T2D, which appears to be bidirectional. Many approved oral and injectable diabetes medications hold promise as an effective treatment for fatty liver disease.In the two abstracts following, the importance of diagnosing hepatic fibrosis through elastography and/or transient elastography in patients with NAFLD is discussed. The data confirm the accuracy and prediction of NAFLD and NASH by elastography as compared to liver biopsy.The last two abstracts of this diagnostic methods section confirm the relationship between plasma fibroblast growth factor 21 (FGF21), insulin resistance, and steatohepatitis. Measuring FGF21 may help correlate the severity of NASH and may help identify patients at a higher risk of disease progression and therefore become an important biomarker.Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trialBril F1, Biernacki DM1, Kalavalapalli S1, Lomonaco R1, Subbarayan SK1, Lai J2, Tio F3, Suman A4, Orsak BK5, Hecht J6, Cusi K1,71Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL; 2Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL; 3Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX; 4Division of Gastroenterology, Hepatology, and Nutrition, Malcom Randall VA Medical Center, Gainesville, FL; 5Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX; 6Division of Diabetes, Audie L. Murphy Memorial VA Hospital, San Antonio, TX; 7Division of Endocrinology, Diabetes and Metabolism, Malcom Randall VA Medical Center, Gainesville, FLDiabetes Care 2019;42: 1481–1488ObjectiveVitamin E has proven to improve NASH in patients without diabetes, but research on patients with T2DM is insufficient. This study aimed to show whether vitamin E, alone or combined with pioglitazone, improves histology in patients with T2DM and NASH.MethodsPatients with T2DM and biopsy-proven NASH (n=105) participated in this proof-of-concept, randomized, double-blind, placebo-controlled trial that was conducted from 2010 to 2016. Participants were randomized to vitamin E 400 IU b.i.d., vitamin E 400 IU b.i.d. plus pioglitazone 45 mg/day, or placebo. A total of 86 patients finished the study, which lasted 18 months. The primary endpoint was a two-point reduction in the nonalcoholic fatty liver disease activity score from two different parameters, without worsening of fibrosis. Secondary outcomes were resolution of NASH without worsening of fibrosis, individual histological scores, and metabolic parameters.ResultsParticipants on combination therapy achieved the primary outcome more often than participants on the placebo (54% vs 19%, P=0.003), but not with vitamin E alone (31% vs 19%, P=0.26). Both groups showed improvements in resolution of NASH compared with placebo (combination group: 43% vs 12%, P=0.005; vitamin E alone: 33% vs 12%, P=0.04). While steatosis evaluated by histology improved with combination therapy (P<0.001) and vitamin E alone (P=0.018), inflammation (P=0.018) and ballooning (P=0.022) improved only with combination therapy. No improvement in fibrosis was seen in any group.ConclusionsIn patients with NASH and T2DM, combination therapy was better than placebo at improving liver histology. Vitamin E alone did not significantly change the primary histological outcome.The SGLT2 inhibitor canagliflozin prevents carcinogenesis in a mouse model of diabetes and non-alcoholic steatohepatitis-related hepatocarcinogenesis: association with SGLT2 expression in hepatocellular carcinomaJojima T1, Wakamatsu S1, Kase M1, Iijima T1, Maejima Y2, Shimomura K2, Kogai T3, Tomaru T1, Usui I1, Aso Y11Department of Endocrinology and Metabolism, Dokkyo Medical University, Tochigi, Japan; 2Department of Pharmacology, Fukushima Medical University School of Medicine, Fukushima, Japan; 3Department of Infection Control and Clinical Laboratory Medicine, Dokkyo Medical University, Tochigi, JapanInt J Mol Sci 2019;20: 5237BackgroundThis study aimed to determine the effects of canagliflozin, a selective SGLT2 inhibitor, on NASH and NASH-related hepatocellular carcinoma (HCC) in a mouse model of diabetes and NASH-HCC.MethodsFive-week-old mice were divided into either vehicle group or canagliflozin group and then treated for 3 weeks. Afterward, 5-week-old mice were split into three groups of nine animals each: the vehicle group, early canagliflozin group (treated from 5 to 9 weeks), and continuous canagliflozin group (treated from 5 to 16 weeks). Canagliflozin was given at a dose of 30 mg/kg. Additionally, the in vitro effects of canagliflozin were evaluated using HepG2 cells, a human HCC cell line.ResultsAt the ages of 8 or 16 weeks, the histological nonalcoholic fatty liver disease activity score was lower in the canagliflozin-treated mice than in vehicle-treated mice. Notably fewer hepatic tumors in the continuous canagliflozin group occurred than in the vehicle group. Immunohistochemistry showed significantly fewer glutamine synthetase-positive nodules in the continuous canagliflozin group than in the vehicle group. Expression of α-fetoprotein mRNA, a marker of HCC, was downregulated in the continuous canagliflozin group compared with the vehicle group. At 16 weeks, there was diffuse SGLT1 expression in the hepatic lobules and strong expression by hepatocytes in the vehicle group, and SGLT2 expression was stronger in liver tumors than in the lobules. For the in vitro study, canagliflozin (10 μM) suppressed the proliferation of HepG2 cells. Flow cytometry indicated that canagliflozin decreased the percentage of HepG2 cells in the G2/M phase due to arrest in the G1 phase along with decreased expression of cyclin D and Cdk4 proteins, whereas it increased the percentage of cells in the G0/1 phase. Canagliflozin also induced apoptosis of HepG2 cells via activation of caspase 3.ConclusionsIn this mouse model of diabetes and NASH/HCC, canagliflozin showed antisteatotic and anti-inflammatory effects that lessened the advancement of NASH and stopped the progression of NASH to HCC, partly due to the induction of cell cycle arrest and/or apoptosis as well as the reduction of tumor growth through the direct inhibition of SGLT2 in tumor cells.Role of sodium-glucose co-transporter-2 inhibitors in the management of nonalcoholic fatty liver diseaseKontana A, Tziomalos KFirst Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, GreeceWorld J Gastroenterol 2019;25: 3664–3668AbstractNAFLD is the most prevalent cause of chronic liver disease worldwide and is substantially more frequent in T2DM patients as well as more severe histologically in this group. SGLT2 inhibitors are the newest class of antidiabetic agents and seem to be a promising therapy for of NAFLD patients with T2DM. In multiple studies, treatment with SGLT2 inhibitors caused a reduction in hepatic steatosis and in transaminase levels. Yet current studies are minimal, their follow-up period short, and none evaluated the effects of SGLT2 inhibitors on liver histology. Larger studies are needed to confirm these preliminary results and define the role of SGLT2 inhibitors in the treatment of NAFLD in patients with T2DM.Liraglutide improves non-alcoholic fatty liver disease in diabetic mice by modulating inflammatory signaling pathwaysLuo Y1, Yang P1, Li Z2, Luo Y2, Shen J1, Li R1, Zheng H3, Liang Y2, Xia N11Department of Endocrinology and Metabolism, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China; 2Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China; 3Life Sciences Institute, Guangxi Medical University, Nanning, People's Republic of ChinaDrug Des Devel Ther 2019;13: 4065–4074BackgroundMetabolic diseases such as obesity and T2DM are closely associated with a chronic low-grade inflammatory state in tissues. The prevalence of NAFLD in T2DM patients is related to the role of inflammation in the disease. The authors of this study examined the role of liraglutide in improving lipid metabolism disorders and preventing their progression to NAFLD by modulating inflammatory signaling pathways, thereby presenting new treatment possibilities for NAFLD.MethodsThe authors created a 2×2 factorial analysis experiment. A mouse model of NAFLD with T2DM was produced by feeding mice a high-fat diet (HFD). The NAFLD mice with HFD-induced diabetes were administered liraglutide for 10 weeks. To observe the accumulation of triglycerides in the liver, hematoxylin and eosin staining, Oil Red O staining, and electron microscopy were used. RT-PCR and Western blotting were used to study the expression of α-SMA, IL-1β, TNF-α, NF-κB, and the NF-κB inhibitory protein IκB in the liver at the gene and protein levels, respectively.ResultsLiraglutide decreased the body weight and fasting blood glucose levels of HFD mice. The expression of α-SMA, IL-1β, TNF-α, and NF-κB in the liver of HFD mice was improved at the mRNA and protein levels, but liraglutide treatment diminished the expression of these molecules. The expression of IκB in the liver decreased at the mRNA and protein levels but was upregulated after liraglutide treatment.ConclusionLiraglutide can substantially improve hepatic steatosis, primarily by downregulating the expression of inflammatory signaling mediators in the TNF-α pathway.Adiponectin is required for pioglitazone-induced improvements in hepatic steatosis in mice fed a high-fat dietde Mendonça M, Dos Santos BAC, de Sousa É, Rodrigues ACInstitute of Biomedical Sciences, Department of Pharmacology, University of Sao Paulo, Sao Paulo, SP, BrazilMol Cell Endocrinol 2019;493: 110480BackgroundPioglitazone has been used to treat NAFLD-related to diabetes. The role of adiponectin in pioglitazone-induced advancements in NAFLD was evaluated by using wild-type (adipoWT) and adiponectin knockout (adipoKO) mice.MethodsHFD mice were insulin resistant, glucose intolerant, and had increased hepatic lipid accumulation, as shown by increased NAFLD activity score. Despite that pioglitazone improved insulin resistance in both genotypes, hepatic steatosis was only improved in adipoWT obese mice.ResultsImprovement of NAFLD in adipoWT mice promoted by pioglitazone was correlated with upregulation of Pparg and Fgf21, and downregulation of Pepck liver expression. In addition, resistance to pioglitazone treatment in adipoKO mice was correlated with increased expression of miR-192 and Hsl, which were not followed by increased fatty acid oxidation.ConclusionsThe authors' data shows that increased adiponectin production by pioglitazone is required for beneficial action on NAFLD.Effects of different exercise modalities on novel hepatic steatosis indices in overweight women with type 2 diabetesBanitalebi E1, Faramarzi M1, Nasiri S1, Mardaniyan M1, Rabiee V21Department of Sport Sciences, Faculty of Humanities, Shahrekord University, Shahrekord, Iran; 2Department of Exercise Physiology, Faculty of Sport Sciences, Shahid Chamran University of Ahvaz, Ahvaz, IranClin Mol Hepatol 2019;25: 294–304BackgroundFatty liver is a common condition in T2D patients. The authors of this study assessed the effects of various exercise modalities on nonalcoholic fatty liver indices (fatty liver index [FLI], lipid accumulation product [LAP], hepatic steatosis index [HSI], and Framingham Steatosis Index [FSI]) in women with T2D.MethodsA total of 52 females with T2D (mean age of 55.07±5.92 years, BMI 28.94±4.09 kg/m2, and hemoglobin A1c [HbA1c] 9.41±0.82%) were randomized to either a sprint interval training (SIT) (n=17), combined aerobic and resistance (A+R) training (n=17), or control group (n=18) for 10 weeks. Two-way repeated analysis of variance (ANOVA) was employed to determine differences between groups and the effects of time and Time×Group interactions after 10 weeks on nonalcoholic fatty liver indices. Ultimately, ANOVA models were created to establish the effects of group allocation and change in nonalcoholic fatty liver indices.ResultsSignificant time interactions for FLI (P<0.001), HSI (P<0.001), and LAP (P<0.001) existed. There were also significant Time×Group interactions for fasting blood glucose (P=0.034) and HbA1c (P=0.006).ConclusionThe results of this study show that exercise training, regardless of mode of training, is effective in improving some indices related to hepatic steatosis and blood glucose profiles in women with T2D.Role of probiotics in non-alcoholic fatty liver disease: does gut microbiota matter?Xie C, Halegoua-DeMarzio DDepartment of Medicine, Division of Gastroenterology and Hepatology, Thomas Jefferson University, Philadelphia, PANutrients 2019;11: 2837BackgroundThe link between gut microbiota (GM) and NAFLD has gained substantial attention in recent years. Studies have shown that GM affects hepatic lipid metabolism and impacts the balance between pro- and anti-inflammatory effectors in the liver.MethodsAlthough studies show the correlation between GM dysbiosis and NAFLD, decoding the mechanisms of gut dysbiosis resulting in NAFLD continues to be a challenge. The possible pathophysiology that links GM dysbiosis to NAFLD can be described as: (1) disrupting the balance between energy harvest and expenditure, (2) promoting hepatic inflammation (impairing intestinal integrity, facilitating endotoxemia, and initiating inflammatory cascades with cytokines releasing), and (3) altered biochemistry metabolism and GM-related metabolites (i.e., bile acid, short-chain fatty acids, aromatic amino acid derivatives, branched-chain amino acids, choline, ethanol).ResultsBecause of the theory that probiotics/synbiotics could normalize GM and reverse dysbiosis, scientists have explored the therapeutic effect of probiotics/synbiotics in patients with NAFLD. Current randomized clinical trials suggest that probiotics/synbiotics could improve transaminases, hepatic steatosis, and decrease hepatic inflammation. These results are promising, but future studies are required to appreciate the full role GM plays in NAFLD development and progression.ConclusionsFurther data are also needed to unravel probiotics/synbiotics efficacy, safety, and sustainability as novel pharmacologic approaches to NAFLD.CommentMany therapeutic agents have been evaluated for treating the early stages of NAFLD, primarily when associated with type 2 diabetes. The abstracts listed above illustrate the importance of vitamin E, GLP analogs, SGLT2 inhibitors, exercise, and the need for adiponectin when used in combination with pioglitazone in reducing NAFLD progression. Most of these drugs help by facilitating weight loss. Many investigators have emphasized that lifestyle modifications play an essential role in weight loss and in the progression of NAFLD.Changes in gut microbiota have been evaluated in many studies, and necessary treatment options have been offered. The two drugs that have consistently been shown to improve insulin resistance in patients with NAFLD include thiazolidinediones (TZDs) and vitamin E. Phase 3 clinical trials on tirzepatide are ongoing for their effective use in patients with NAFLD. Most of the effect is associated with weight loss, improved glucose control in type 2 diabetes, and associated liver fat reduction.ConclusionUnfortunately, NAFLD and NASH are increasing in prevalence globally and quickly becoming the leading cause of end-stage liver failure. Current imaging methods like elastography are becoming more popular in screening and managing patients with NAFLD and NASH. Percutaneous liver biopsy is no longer considered the gold standard for diagnosing NAFLD and NASH because of the small sample size, sampling error, and complications related to the invasive nature of the procedure. Other biochemical markers like FGF21 and measurement of liver enzymes are noninvasive and reasonably accurate in diagnosing NAFLD.Many studies in the literature have shown a direct correlation between alterations in the gut microbiota and the development of NAFLD. Research has also looked into using probiotics and other means to change gut microbiota as an alternative method to treat NAFLD's early stages. Genetic predisposition also seems to play an essential role in the development of NAFLD and NASH.Therapies like resveratrol, vitamin D, and probiotics are currently being evaluated as an effective treatment for patients with early stages of NAFLD. Many type 2 diabetes medications like GLP analogs or SGLT2 inhibitors, alone or in combination, have been shown to significantly reduce liver fat and further progression of NAFLD and NASH. Metabolic surgery, like bariatric surgery, as discussed in the 2019 ATTD "NAFLD/NASH and Diabetes" article, continues to be used in few cases as a useful tool to ameliorate fatty liver disease and type 2 diabetes.Author Disclosure StatementNo competing financial interests exist.FiguresReferencesRelatedDetailsCited byEarly Cost-Effectiveness and Price Threshold Analyses of Resmetirom: An Investigational Treatment for Management of Nonalcoholic Steatohepatitis14 September 2022 | PharmacoEconomics - Open, Vol. 7, No. 1 Volume 23Issue S2Jun 2021 InformationCopyright 2021, Mary Ann Liebert, Inc., publishersTo cite this article:Kavita Garg, Trenton Reinicke, and Satish K. Garg.NAFLD and NASH and Diabetes.Diabetes Technology & Therapeutics.Jun 2021.S-198-S-205.http://doi.org/10.1089/dia.2021.2515Published in Volume: 23 Issue S2: May 31, 2021PDF download
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