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    Efficacy of exenatide and insulin glargine on nonalcoholic fatty liver disease in patients with type 2 diabetes. Liu Lin,Yan Hongmei,Xia MingFeng,Zhao Lin,Lv Minzhi,Zhao Naiqin,Rao Shengxiang,Yao Xiuzhong,Wu Weiyun,Pan Baishen,Bian Hua,Gao Xin Diabetes/metabolism research and reviews BACKGROUND:The aim of this study was to investigate the efficacy of exenatide and insulin glargine in patients with newly diagnosed type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). METHODS:We performed a 24-week randomized controlled multicentre clinical trial. Seventy-six patients were randomly assigned 1:1 to receive exenatide or insulin glargine treatment. The endpoints included changes in liver fat content (LFC), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) measured by magnetic resonance spectroscopy, blood glucose, liver enzymes, lipid profile, body weight, and Fibrosis-4 index (FIB-4). RESULTS:LFC, VAT, SAT, and FIB-4 were significantly reduced after exenatide treatment (ΔLFC, -17.55 ± 12.93%; ΔVAT, -43.57 ± 68.20 cm ; ΔSAT, -28.44 ± 51.48 cm ; ΔFIB-4, -0.10 ± 0.26; all P < .05). In comparison, only LFC (ΔLFC, -10.49 ± 11.38%; P < .05), and not VAT, SAT, or FIB-4 index (all P > .05), was reduced after insulin glargine treatment. Moreover, exenatide treatment resulted in greater reductions in alanine transaminase (ALT), aspartate transaminase (AST), and gamma glutamyl transpeptidase (GGT) than insulin glargine (P < 0.05). The body weight, waist circumference, postprandial plasma glucose, and low-density lipoprotein cholesterol (LDL-C) in the exenatide group also presented greater reductions than the insulin glargine group (P < .05). The proportion of adverse events were comparable between the two groups. CONCLUSION:Both exenatide and insulin glargine reduced LFC in patients with drug-naive T2DM and NAFLD; however, exenatide showed greater reductions in body weight, visceral fat area, liver enzymes, FIB-4, postprandial plasma glucose, and LDL-C. 10.1002/dmrr.3292
    Genetic susceptibility of increased intestinal permeability is associated with progressive liver disease and diabetes in patients with non-alcoholic fatty liver disease. Miele Luca,Giorgio Valentina,Liguori Antonio,Petta Salvatore,Pastorino Roberta,Arzani Dario,Alberelli Maria A,Cefalo Consuelo,Marrone Giuseppe,Biolato Marco,Rapaccini Gianludovico,Boccia Stefania,Gasbarrini Antonio,Craxì Antonio,Grieco Antonio Nutrition, metabolism, and cardiovascular diseases : NMCD BACKGROUND AND AIM:Increased intestinal permeability plays a key role in the pathogenesis of fat deposition in the liver. The aim of our study was to assess whether a single nucleotide polymorphism of protein tyrosine phosphatase non-receptor type 2 (PTPN2) (rs2542151 T→G), involved in intestinal permeability, may be associated with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). METHODS AND RESULTS:We recruited a prospective cohort of NAFLD subjects and matched controls. Clinical data, PTPN2 genotype and laboratory data were collected for each patient. Results were stratified according to liver histology and diabetes. We enrolled 566 cases and 377 controls. PTPN2 genotype distribution did not significantly differ between patients and controls. In the entire population, patients with PTPN2 rs2542151 T→G (dominant model) have a higher prevalence of diabetes; 345 patients (60.9%) underwent liver biopsy: 198 (57.4%) had steatohepatitis and 75 (21.7%) had advanced fibrosis. At multiple logistic regression analysis PTPN2 rs2542151 T→G was associated with T2DM (OR 2.14, 95% CI 1.04-4.40, P = 0.03). Patients who underwent liver biopsy, rs2542151 T→G of PTPN2 was independently associated with severe steatosis (OR 2.00, 95% CI 1.17-3.43, p = 0.01) and severe fibrosis (OR 2.23, 95% CI 1.06-4.72, P = 0.03). CONCLUSION:Our study shows that NAFLD patients with rs2542151 T→G of PTPN2 have a higher severity of fatty liver disease and a higher prevalence of T2DM. These results suggest that individual genetic susceptibility to intestinal permeability could play a role in liver disease progression. 10.1016/j.numecd.2020.06.013
    Prevalence of Nonalcoholic Fatty Liver Disease (NAFLD) in Patients With Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis. de Vries Marieke,Westerink Jan,Kaasjager Karin H A H,de Valk Harold W The Journal of clinical endocrinology and metabolism CONTEXT:Nonalcoholic fatty liver disease (NAFLD) prevalence is high, especially in patients with obesity and type 2 diabetes, and is expected to rise steeply in the coming decades. OBJECTIVE:We estimated NAFLD prevalence in patients with type 1 diabetes and explored associated characteristics and outcomes. DATA SOURCES:We reviewed PubMed and Embase for studies on NAFLD and type 1 diabetes to March 2020. We screened references of included articles. STUDY SELECTION:Two authors independently screened titles/abstracts. One author screened full text articles. NAFLD was defined as described in the individual studies: steatosis and/or fibrosis. Studies not reporting alternative causes of hepatic steatosis or defining NAFLD only as elevated liver enzymes, were excluded. Initially, 919 articles met the selection criteria. DATA EXTRACTION:One researcher performed data extraction and risk of bias assessment using standardized tables. DATA SYNTHESIS:We assessed pooled prevalence rates by meta-analysis using a random-effects model, subsequently exploring heterogeneity by subgroup-, meta-regression-, and sensitivity analysis. Twenty studies between 2009 and 2019 were included (n = 3901). Pooled NAFLD prevalence was 19.3% (95% CI, 12.3%-27.5%), increasing to 22.0% (95% CI, 13.9%-31.2%) in adults only. Pooled prevalence of ultrasound studies was high (27.1%, 95% CI, 18.7%-36.3%) compared to studies using magnetic resonance imaging (8.6%, 95% CI, 2.1%-18.6%), liver biopsy (19.3%, 95% CI, 10.0%-30.7%), or transient elastography (2.3%, 95% CI, 0.6%-4.8%). CONCLUSION:NAFLD prevalence in patients with type 1 diabetes is considerable and is highly dependent on the specific diagnostic modality and NAFLD definition used. These data are helpful in directing actions to standardize NAFLD diagnosis, which will help defining contributing mechanisms and outcomes. 10.1210/clinem/dgaa575
    Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: A Bidirectional Relationship. Muzica Cristina M,Sfarti Catalin,Trifan Anca,Zenovia Sebastian,Cuciureanu Tudor,Nastasa Robert,Huiban Laura,Cojocariu Camelia,Singeap Ana-Maria,Girleanu Irina,Chiriac Stefan,Stanciu Carol Canadian journal of gastroenterology & hepatology Worldwide, the leading cause of chronic liver disease is represented by nonalcoholic fatty liver disease (NAFLD) which has now become a global epidemic of the 21st century, affecting 1 in 4 adults, and which appears to be associated with the steadily increasing rates of metabolic syndrome and its components (obesity, type 2 diabetes mellitus (T2DM), and dyslipidemia). NAFLD has been reported to be associated with extrahepatic manifestations such as cardiovascular disease, T2DM, chronic kidney disease, extrahepatic malignancies (e.g., colorectal cancer), endocrine diseases (e.g., hypothyroidism, polycystic ovarian syndrome, psoriasis, and osteoporosis), obstructive sleep apnea, and iron overload. The prevalence of NAFLD is very high, affecting 25-30% of the world population and encloses two steps: (1) nonalcoholic fatty liver (NAFL), which includes steatosis only, and (2) nonalcoholic steatohepatitis (NASH) defined by the presence of steatosis and inflammation with hepatocyte ballooning, with or without fibrosis which can progress to liver fibrosis, hepatocellular carcinoma, and liver transplantation. Current data define a more complex relationship between NAFLD and T2DM than was previously believed, underlining a bidirectional and mutual association between the two entities. This review aims to summarize the current literature regarding the incidence of T2DM among patients with NAFLD and also the prevalence of NAFLD in T2DM patients, highlighting the recent key studies. Clinicians should screen, diagnose, and treat T2DM in patients with NAFLD in order to avoid short- and long-term complications. 10.1155/2020/6638306
    Association of glucagon-to-insulin ratio and nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. Moh Moh Myint Aung,Jung Chan-Hee,Lee Bora,Choi Dughyun,Kim Bo-Yeon,Kim Chul-Hee,Kang Sung-Koo,Mok Ji-Oh Diabetes & vascular disease research OBJECTIVE:The aim of this study is to investigate the association between glucagon-to-insulin ratio and the presence of nonalcoholic fatty liver disease on ultrasonography in participants with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS:This cross-sectional study was performed with data obtained from 172 participants with type 2 diabetes mellitus admitted to a University hospital of Korea. Participants were assessed for serum fasting and postprandial serum glucagon-to-insulin ratio and divided into tertiles. Nonalcoholic fatty liver disease was defined as ultrasonographically detected fatty liver. RESULTS:Prevalence of nonalcoholic fatty liver disease was significantly decreased across tertile of fasting and postprandial glucagon-to-insulin ratio ( p = 0.009 for trend, p = 0.001 for trend, respectively). Lower glucagon-to-insulin ratio was significantly associated with the presence of nonalcoholic fatty liver disease even after adjustment for potential confounding variables [fasting glucagon-to-insulin ratio: odds ratio (95% confidence interval), 2.68 (1.08-6.86)], postprandial glucagon-to-insulin ratio: [2.72 (1.03-7.35)]. The participants in the lowest tertile of fasting glucagon-to-insulin ratio had higher body mass index, visceral fat thickness, subcutaneous fat thickness, homeostasis model assessment-insulin resistance and shorter duration of diabetes mellitus. CONCLUSION:This study suggests that lower glucagon relative insulin may be independently associated with nonalcoholic fatty liver disease in participants with type 2 diabetes. 10.1177/1479164118810691
    The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD). Tanase Daniela Maria,Gosav Evelina Maria,Costea Claudia Florida,Ciocoiu Manuela,Lacatusu Cristina Mihaela,Maranduca Minela Aida,Ouatu Anca,Floria Mariana Journal of diabetes research Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) remain as one of the most global problematic metabolic diseases with rapidly increasing prevalence and incidence. Epidemiological studies noted that T2DM patients have by two-fold increase to develop NAFLD, and vice versa. This complex and intricate association is supported and mediated by insulin resistance (IR). In this review, we discuss the NAFLD immunopathogenesis, connection with IR and T2DM, the role of screening and noninvasive tools, and mostly the impact of the current antidiabetic drugs on steatosis liver and new potential therapeutic targets. 10.1155/2020/3920196
    Non-alcoholic Fatty Liver Disease and Diabetes Mellitus. Khneizer Gebran,Rizvi Syed,Gawrieh Samer Advances in experimental medicine and biology Nonalcoholic fatty liver disease (NAFLD) has emerged as the leading liver disease globally. NAFLD patients can have a progressive phenotype, non-alcoholic steatohepatitis (NASH) that could lead to cirrhosis, liver failure and cancer. There is a close bi-directional relationship between NAFLD and type 2 diabetes mellitus (T2DM); NAFLD increases the risk for T2DM and its complications whereas T2DM increases the severity of NAFLD and its complications. The large global impact of NAFLD and T2DM on healthcare systems requires a paradigm shift from specialty care to early identification and risk stratification of NAFLD in primary care and diabetes clinics. Approach to diagnosis, risk stratification and management of NAFLD is discussed. In addition to optimizing the control of coexisting cardiometabolic comorbidities, early referral of NAFLD patients at high risk of having NASH or significant fibrosis to hepatology specialist care may improve management and allow access for clinical trials. Lifestyle modifications, vitamin E, pioglitazone and metformin are currently available options that may benefit patients with T2DM and NAFLD. The burst of clinical trials investigating newer therapeutic agents for NAFLD and NASH offer hope for new, effective and safe therapies in the near future. 10.1007/5584_2020_532
    Albuminuria Is Associated with Steatosis Burden in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease. Han Eugene,Kim Mi Kyung,Jang Byoung Kuk,Kim Hye Soon Diabetes & metabolism journal BACKGROUND:This study aimed to investigate the association between hepatic steatosis burden and albuminuria in Korean patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). METHODS:We recruited 100 patients with both T2DM and NAFLD, but without chronic kidney disease. Albuminuria was defined as a spot urinary albumin-to-creatinine ratio (ACR) ≥30 mg/g. Transient elastography was performed, and the steatosis burden was quantified by controlled attenuation parameter (CAP) with significant steatosis defined as CAP >302 dB/m. RESULTS:The prevalence of significant steatosis and albuminuria was 56.0% and 21.0%, respectively. Subjects with significant steatosis were significantly younger and had a significantly shorter duration of T2DM, greater waist circumference, and higher body mass index, total cholesterol, triglyceride, and low density lipoprotein cholesterol levels, than subjects without severe NAFLD (all P<0.05). Albuminuria was higher in patients with significant steatosis than in patients without significant steatosis (32.1% vs. 6.8%, P=0.002). Urinary ACR showed a correlation with CAP (r=0.331, P=0.001), and multiple linear regression analysis revealed a significant association between a high degree of albuminuria and high CAP value (r=0.321, P=0.001). Additionally, multivariate logistic regression analysis demonstrated the independent association between urinary ACR and significant steatosis after adjustment for confounding factors including age, body mass index, duration of T2DM, low density lipoprotein level, and renin-angiotensin system blocker use (odds ratio, 1.88; 95% confidence interval, 1.31 to 2.71; P=0.001). CONCLUSION:T2DM patients with NAFLD had a higher prevalence of albuminuria, which correlated with their steatosis burden. 10.4093/dmj.2020.0118
    Sodium-Glucose Cotransporter-2 Inhibitors Ameliorate Liver Enzyme Abnormalities in Korean Patients With Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease. Euh Won,Lim Soo,Kim Jin-Wook Frontiers in endocrinology Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are reported to reduce body fat in patients with type 2 diabetes mellitus (T2DM), and SGLT2i-induced weight reduction may help improve comorbid nonalcoholic fatty liver disease (NAFLD). This study aimed to investigate the potential benefit of SGLT2is over other oral antidiabetic drugs (OADs) in patients with T2DM-associated NAFLD. We enrolled real-world Korean patients with T2DM-associated NAFLD in whom initial metformin therapy had been modified by stepwise addition of OAD(s) due to insufficient glucose control. Propensity score (PS) matching was used for the comparison of changes in clinical and biochemical parameters to balance potential covariates. Among the 765 enrolled patients, 663 patients received additional OADs other than SGLT2i and 102 patients received SGLT2i therapy. PS matching selected 150 and 100 patients from the control and the SGLT2i group, respectively. The SGLT2i group lost more weight than the control group at 6 months (mean -1.3 kg 0.0 kg; < 0.001). Alanine aminotransferase (ALT) levels also decreased more in the SGLT2i group at 3 (-11 U/L -1 U/L), 6 (-12 U/L -1 U/L), and 12 months (-14 U/L -2 U/L) (all < 0.05). Addition of SGLT2is was an independent predictor of ALT improvement in a multivariate logistic regression model (odds ratio 1.91; = 0.016). Compared with other OADs, addition of SGLT2is was more effective in weight reduction and ALT improvement in patients with T2DM and comorbid NAFLD. 10.3389/fendo.2021.613389
    Serum Retinol-Binding Protein Levels Are Associated with Nonalcoholic Fatty Liver Disease in Chinese Patients with Type 2 Diabetes Mellitus: A Real-World Study. Zhang Zhi-Hui,Ke Jiang-Feng,Lu Jun-Xi,Liu Yun,Wang Ai-Ping,Li Lian-Xi Diabetes & metabolism journal BACKGROUND:The association of serum retinol-binding protein (RBP) levels with nonalcoholic fatty liver disease (NAFLD) remains controversial. Furthermore, few studies have investigated their relationship in type 2 diabetes mellitus (T2DM) patients. Therefore, the aim of the present study was to explore the association between serum RBP levels and NAFLD in Chinese inpatients with T2DM. METHODS:This cross-sectional, real-world study included 2,263 Chinese T2DM inpatients. NAFLD was diagnosed by abdominal ultrasonography. The subjects were divided into four groups based on RBP quartiles, and clinical characteristics were compared among the four groups. The associations of both RBP levels and quartiles with the presence of NAFLD were also analyzed. RESULTS:After adjustment for sex, age, and diabetes duration, there was a significant increase in the prevalence of NAFLD from the lowest to the highest RBP quartiles (30.4%, 40.0%, 42.4%, and 44.7% for the first, second, third, and fourth quartiles, respectively, P<0.001 for trend). Fully adjusted multiple logistic regression analysis revealed that both increased RBP levels (odds ratio, 1.155; 95% confidence interval, 1.012 to 1.318; P=0.033) and quartiles (P=0.014 for trend) were independently associated with the presence of NAFLD in T2DM patients. CONCLUSION:Increased serum RBP levels were independently associated with the presence of NAFLD in Chinese T2DM inpatients. Serum RBP levels may be used as one of the indicators to assess the risk of NAFLD in T2DM patients. 10.4093/dmj.2020.0222
    Reenvisioning Traditional to Regenerative Therapeutic Advances in Managing Nonalcoholic Fatty Liver Disease in Diabetes Mellitus. Tsai Lung-Wen,Lu Yi-Hsiang,Dubey Rajni,Chiou Jeng-Fong Journal of diabetes research Reports indicate the increasing prevalence of liver disorders in diabetes mellitus (DM) patients. Clinically, it has also been revealed that the existence of nonalcoholic fatty liver disease (NAFLD) enhances the incidence of type 2 diabetes mellitus (T2DM), while T2DM exacerbates NAFLD to extremely severe forms of steatohepatitis, cirrhosis, and hepatocellular carcinoma. This implies the coexistence and bidirectional nature of NAFLD and T2DM, which function synergistically to drive adverse consequences in clinical practice. For treatment of such comorbid state, though the existing practices such as lifestyle management, traditional Chinese medicines (TCM), and pharmaceuticals have offered somewhat relief, the debate continues about the optimal therapeutic impacts. Recent developments in the field of tissue engineering have led to a renewed interest in novel biomaterial alternatives such as stem cells. This might be attributable to their differentiation potential towards hepatic and pancreatic lineage. These cellular therapies could be further complemented by platelet-derived biomaterials, TCM formulations, or any specific drug. Based on these abovementioned approaches, we aimed to comprehensively analyze various preclinical and clinical studies from traditional to regenerative therapeutic approaches in managing concomitant NAFLD and T2DM. 10.1155/2021/7692447