Non-alcoholic Fatty Liver Disease In Type Research Articles

Hyperglucagonaemia and amino acid alterations in individuals with type 2 diabetes and non-alcoholic fatty liver disease.

Hyperglucagonaemia contributes to the pathophysiology in type 2 diabetes (T2D), but the mechanisms behind the inappropriate glucagon secretion are not fully understood. Glucagon and amino acids are regulated in a feedback loop referred to as the liver-α cell axis. Individuals with non-alcoholic fatty liver disease (NAFLD) appear to be glucagon resistant, disrupting the liver-α cell axis resulting in hyperglucagonaemia and hyperaminoacidaemia. We investigated the associations between circulating glucagon, amino acids, and liver fat content in a cohort of individuals with T2D. We included 110 individuals with T2D in this cross-sectional study. Liver fat content was quantified using 1H magnetic resonance spectroscopy (MRS). Associations between liver fat content and plasma glucagon and amino acids, respectively, were estimated in multivariate linear regression analyses. Individuals with NAFLD (n = 52) had higher plasma glucagon concentrations than individuals without NAFLD (n = 58). The positive association between plasma glucagon concentrations and liver fat content was confirmed in the multivariable regression analyses. Plasma concentrations of isoleucine and glutamate were increased, and glycine and serine concentrations were decreased in individuals with NAFLD. Concentrations of other amino acids were similar between individuals with and without NAFLD, and no clear association was seen between liver fat content and amino acids in the regression analyses. MRS-diagnosed NAFLD in T2D is associated with hyperglucagonaemia and elevated plasma concentrations of isoleucine and glutamate and low plasma concentrations of glycine and serine. Whether NAFLD and glucagon resistance per se induce these changes remains to be elucidated.

Plasma ceramides are associated with MRI-based liver fat content but not with noninvasive scores of liver fibrosis in patients with type 2 diabetes

BackgroundThere is growing evidence that ceramides play a significant role in the onset and progression of non-alcoholic fatty liver disease (NAFLD), a highly prevalent condition in patients with type 2 diabetes associated with hepatic and cardiovascular events. However, the relationship between plasma ceramide levels and NAFLD severity in type 2 diabetes remains unclear. The main purpose of the present study was to investigate whether circulating levels of ceramides in patients with type 2 diabetes are associated with liver steatosis assessed by the highly accurate magnetic resonance imaging proton density fat fraction (MRI-PDFF). The secondary objective was to assess the relationship between plasma ceramides and noninvasive scores of liver fibrosis.MethodsIn this cross-sectional single-center study, plasma concentrations of 7 ceramides were measured by liquid chromatography-mass spectrometry in 255 patients with type 2 diabetes (GEPSAD cohort). Liver fat content was assessed by MRI-PDFF, and noninvasive scores of liver fibrosis (i.e. Fibrosis-4 index, NAFLD Fibrosis Score, FibroTest® and Fibrotic NASH Index) were calculated. A validation cohort of 80 patients with type 2 diabetes was also studied (LIRA-NAFLD cohort).ResultsLiver steatosis, defined as a liver fat content > 5.56%, was found in 62.4 and 82.5% of individuals with type 2 diabetes in the GEPSAD and LIRA-NAFLD cohorts, respectively. In GEPSAD, MRI-PDFF-measured liver fat content was positively associated with plasma levels of total ceramides (r = 0.232, p = 0.0002), and 18:0, 20:0, 22:0 and 24:0 ceramides in univariate analysis (p ≤ 0.0003 for all). In multivariate analysis, liver fat content remained significantly associated with total ceramides (p = 0.001), 18:0 (p = 0.006), 22:0 (p = 0.0009) and 24:0 ceramides (p = 0.0001) in GEPSAD, independently of age, diabetes duration, body mass index and dyslipidemia. Overall, similar relationship between plasma ceramides and liver fat content was observed in the LIRA-NAFLD validation cohort. No significant association was found between plasma ceramides and noninvasive scores of fibrosis after adjustment for age in both cohorts.ConclusionsPlasma ceramide levels are associated with liver steatosis in patients with type 2 diabetes, independently of traditional risk factors for NAFLD. The independent association between plasma ceramides and liver steatosis adds new insights regarding the relationship between ceramides and NAFLD in type 2 diabetes.

THU585 Non-alcoholic Fatty Liver Disease (NAFLD), A Silent But Emerging Problem In Type 1 Diabetes

Abstract Disclosure: A. Taiwo: None. R. Merill: None. L. Wendt: None. D. Pape: None. H. Thakker: None. N. Pothireddy: None. B. Carlson: None. A. Sanchez: None. P. Ten Eyck: None. D. Jalal: None. A. Dokun: None. E. Taylor: None. W. Sivitz: None. Background: Non-alcoholic liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Risk factors include type 2 diabetes, insulin resistance and obesity. Although NAFLD has been widely studied in persons with type 2 diabetes, far less in known about the pathogenesis and severity of NAFLD in type 1 diabetes. Objective: The goal of this study was to understand the metabolic perturbations that contribute to the pathogenesis of NAFLD in type 1 diabetes. Study Design: We conducted a cross-sectional study of 30 participants with type1 diabetes recruited from our institutional diabetes clinic. To assess liver fat content and stiffness, a FibroScan was done. Based on the results, participants were stratified into a case group (evidence of NAFLD) or control group (no evidence of NAFLD). All participants had fasting plasma drawn to determine metabolites. Gas-Chromatography Mass Spectrometry was used for metabolomic analyses and Liquid Chromatography Mass Spectrometry for lipidomic and acylcarnitines analyses. Results: Sixteen of 30 participants were classified as cases and 14 as controls. Cases had higher BMI (P=0.001) and were taking higher daily insulin doses than controls (P=0.008). Metabolomic analyses revealed that cases had elevated levels of glutamate (P=0.001), alanine (P=<0.001), pyruvate (P=<0.001), phenylalanine (P = 0.005), lactate (P=0.019) and anthranilic acid (P=0.029). Lipidomics revealed that, cases had elevated ceramides (P= 0.02), diacylglycerol (P=0.0003) and triacylglycerol (P=0.0003). The acylcarnitine, isovalerylcarnitine (CAR.5.0) a metabolite of isoleucine catabolism, was elevated in the cases (P = 0.010). Pathway enrichment analysis revealed, phenylalanine and tyrosine metabolism, tryptophan metabolism, glucose-alanine cycle, glutamate metabolism and glutathione metabolism were significantly enriched in the cases. Conclusion: We observed evidence of elevated metabolite levels involved in gluconeogenesis, glucose-alanine metabolism, energy metabolism, insulin resistance, and dysfunctional fat synthesis in the cases compared to controls. Our cases had some features similar to Type 2 diabetes with NAFLD, with evidence of elevated levels of aromatic amino acids, ceramides, diacylglycerol and triacylglycerol. However unlike Type 2 diabetes, there was no elevation of branched-chain amino acids levels. Presentation: Thursday, June 15, 2023

An Assessment of Atherosclerotic Cardiovascular Disease in Non-alcoholic Fatty Liver Disease Patients with Type 2 Diabetes Mellitus

Background: Non-alcoholic fatty liver disease (NAFLD) is most frequently related to type 2 diabetes (T2DM), which can advance to fibrosis and cirrhosis. Prior research has shown that patients with T2DM with NAFLD have a synergistic increase in the atherosclerosis of the cardiac vasculature. Our study aimed to assess and correlate atherosclerotic heart disease in patients with NAFLD and T2DM. Materials and methods: An observational cross-sectional study to know cardiovascular atherosclerotic disease in NAFLD patients with T2DM was conducted between December 2019 and October 2021. Subjects included fifty-five T2DM patients screened as prospects for the study, including patients receiving treatment inside the outpatient department (OPD), an affiliated diabetes clinic, and affected individuals admitted to a hospital. Results: Results showed a moderately positive correlation between an ASCVD risk score and Fibro Scan E results, with the findings being statistically significant. However, there was no significant difference in A.S.C.V.D. Risk score in both fatty and non-fatty liver groups as well as steatosis and non-steatosis groups. Conclusion: Identifying NAFLD in type II DM patients may facilitate better cardiovascular disease risk estimation with practical management implications. Moreover, identifying people with NAFLD would highlight a subgroup of diabetic patients who may benefit from more intensive preventative treatment and cardio-protective measures to decrease their risk of future CVD.

Retinal Vascular Lesions in Patients with Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

Background: This systematic review and meta-analysis aimed to summarize and compare data on retinal vascular lesions between patients with nonalcoholic fatty liver disease (NAFLD) and individuals without the disease. Methods: Search was performed in PubMed, Scopus and Cochrane Library, complemented by handsearching (PROSPERO ID: CRD42022345558). Thirty-six studies comprising 24,985 individuals (12,387 NAFLD patients and 12,598 controls) were selected for the meta-analysis. Results: Apart from retinopathy, no study with a different type of retinal vascular lesion was retrieved. Overall, there was no significant difference in the presence of retinopathy in NAFLD patients compared to controls (Odds Ratio (OR) = 1.20; 95% Confidence Interval (CI): 0.91-1.59). Heterogeneity among studies was high (I2 = 93%; p < 0.00001), while Egger's test revealed no publication bias (p = 0.60). However, subgroup analysis showed positive association between retinopathy and NAFLD in type 1 diabetes mellitus (T1DM) (OR = 2.35; 95% CI: 1.53-3.60), but not in type 2 diabetes mellitus patients. Meta-regression analysis exploring potential confounders revealed no significant association. Conclusions: The presence of retinopathy was not overall different between individuals with and without NAFLD; however, T1DM patients with NAFLD had higher rates of retinopathy compared to T1DM patients without NAFLD, a finding warranting further research to show whether NAFLD may predict retinopathy in T1DM patients.

Is There any Need for the Early Detection of Non-alcoholic Fatty Liver Disease in Children with Type 1 Diabetes Mellitus?

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disorders worldwide. Regarding the shortage of evidence on NAFLD in type 1 diabetes mellitus (T1DM) and the importance of a thorough assessment of complications due to childhood diseases, this study aimed to assess the need for the early detection of NAFLD in children with T1DM. Methods: This cross-sectional study was conducted on 234 children with T1DM referred to 17 Shahrivar Hospital, Rasht, Iran. This study also assessed demographic characteristics, medical history, physical examination, laboratory tests, and hepatic ultrasound. The Mann-Whitney U and chi-square tests were used to compare the children with and without NAFLD. Additionally, univariate and multivariate logistic regressions were used to determine the predictors of NAFLD. Results: This study was conducted on 235 children with T1DM with a median age of 11.0 years (interquartile range (IQR): 8.0 - 14.0) and diabetes duration of 2.0 years (IQR: 1.0 - 4.0). The prevalence of NAFLD was estimated to be 10.2%. The children with NAFLD were significantly older (P = 0.016) and had a larger waist circumference (WC) z-score (P = 0.008) than those without NAFLD. Multiple logistic regression analyses showed that the odds of NAFLD increased with rising age (odds ratio (OR) = 1.29, 95% confidence interval (CI): 1.09 - 1.52) and WC z-score (OR = 2.39, 95% CI: 1.49 - 3.84). The cut-off point for the WC z-score was -0.025 (sensitivity = 58.3%, specificity = 72.0%). Conclusions: The NAFLD frequency in T1DM is relatively low (10.2%) and mainly consists of grade I fatty liver. The NAFLD screening should be further noticed in T1DM children with increasing age and WC as the predictors of NAFLD.

1573-P: Association of Thyroid Hormone Levels with NAFLD in Recent-Onset Diabetes

Nonalcoholic fatty liver disease (NAFLD) is a growing health concern associated with obesity and type 2 diabetes (T2D). Thyroid hormones are important regulators of lipid homeostasis. Indeed, people with hypothyroidism are at greater risk for NAFLD and it has been suggested that humans with T2D are more likely to develop hypothyroidism. However, little is known about the relationship of thyroid function with NAFLD in type 1 diabetes (T1D) and T2D. We hypothesized that (i) low free thyroxin (fT4) and high thyroid-stimulating hormone (TSH) levels are associated with increased hepatocellular lipid content (HCL) and (ii) that fT4 and TSH can identify persons at high-risk for hepatic steatosis in people with recent-onset diabetes. We examined people with T1D (n=358) or T2D (n=596) and 175 healthy participants of the German Diabetes Study (GDS). First, validation of the fatty liver index (FLI) against quantification of HCL by 1H-magnetic resonance spectroscopy revealed a close correlation (ß=0.715, p&amp;lt;0.001; n=446). Second, FLI negatively correlated with fT4 in males (ß=−0.139, p&amp;lt;0.01), but not in females with T2D (ß=−0.086, p=0.26). Likewise, TSH associated positively with FLI in males (ß=0.116, p&amp;lt;0.05), but not in females with T2D (ß=−0.057, p=0.45). TSH and FLI were differently associated between males and females before (p&amp;lt;0.05), but not after (p=0.82) adjustment for BMI. Finally, fT4 had a low diagnostic precision for steatosis (by FLI) as derived from the respective area under the receiver operating curve (0.57, 95% CI [0.53;0.62]; p&amp;lt;0.001) in T2D and was not significant in other groups. TSH had no diagnostic precision for steatosis in any groups. In conclusion, FLI can be used as a surrogate measure of HCL in recent-onset diabetes. The correlation of FLI with lower thyroid function in male T2D suggests a sex-specific interaction between thyroid and liver lipid metabolism, which is mainly driven by body mass. Both, fT4 and TSH offer no relevant efficacy to detect steatosis at least in recent-onset diabetes. Disclosure N. Saatmann: None. M. Schön: None. O.P. Zaharia: None. M. Huttasch: None. K. Strassburger: None. S. Trenkamp: None. Y. Kupriyanova: None. V. Schrauwen-Hinderling: None. S. Kahl: None. V. Burkart: None. R. Wagner: Speaker's Bureau; Novo Nordisk, Sanofi. Advisory Panel; Daiichi Sankyo. M. Roden: Advisory Panel; Eli Lilly and Company. Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis. Consultant; TARGET PharmaSolutions, Inc. Research Support; Sanofi.

Prevalence and Risk Factors of Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus: A Cross-Sectional Study at a Tertiary Care Center

Background: Non-Alcoholic Fatty Liver Disease (NAFLD) is an emerging concern among patients with Type 2 Diabetes Mellitus (DM). This study was designed to evaluate the prevalence of NAFLD in Type 2 DM patients and to identify associated factors that may contribute to its occurrence. Methodology: Conducted in a tertiary care center's general medicine department from May 2020 to June 2021, this cross-sectional study enrolled 400 type-II diabetic patients, aged 35 years and above. Comprehensive interviews were performed to determine disease duration and medication usage and to exclude alternative causes of NAFLD. Physical examinations, including measurements of BMI and waist-hip circumference, along with abdominal ultrasonography, were utilized to detect and grade fatty liver. Results: The sample consisted of 217 females (59.8%) and 146 males (40.2%), with 67.2% having a diabetes diagnosis for over 10 years. NAFLD was identified in 69.1% of patients, more frequently in females (69%). A significant relationship was established between NAFLD occurrence and the duration of DM, BMI, and waist-hip ratio (p &lt; 0.05). Conclusion: NAFLD was found in a striking majority of the diabetic population studied, approximately 70%, with a higher prevalence in females. Factors significantly linked to NAFLD incidence included the duration of diabetes and elevated measures of obesity and waist circumference. These findings underscore the need for heightened awareness and targeted interventions for this patient population. Keywords: Non-Alcoholic Fatty Liver Disease (NAFLD), Type-II Diabetes Mellitus (DM), prevalence, risk factors.

Non-Alcoholic Fatty Liver Disease: Current Concepts of a Silent, but Potentially Reversible Disorder

Non-alcoholic fatty liver disease (NAFLD) is a chronic condition characterized by the accumulation of triglycerides in the liver of individuals who consume little to no alcohol. NAFLD is akin to metabolic syndrome, obesity, type 2 diabetes mellitus, insulin resistance, and dyslipidemia, which contribute as crucial risk factors for the appearance and further progression of the disease. NAFLD is also the most common etiology of chronic liver disease worldwide. The high prevalence of this liver complication is estimated to be driven by obesity and diabetes. A recent meta-analysis found the global prevalence of NAFLD in type 2 diabetes as high as 55.5%. NAFLD is a complex disorder with multifactorial etiology and pathophysiology. The progression of NAFLD can lead to non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis or liver cancer. The exact cause of NAFLD is not fully understood, but it is believed to result from the interaction between genetic, environmental, and metabolic factors. The clinical presentation, including symptoms and signs associated with NAFLD, varies depending on the stage or progression of liver damage. In non-alcoholic fatty liver, the clinical presentation is often asymptomatic in its early stages. They may also present with nonspecific symptoms such as fatigue, malaise, or mild right upper abdominal discomfort. The diagnosis is made with a combination of clinical history, laboratory tests, and imaging studies tailored to the liver. The cornerstone of treatment involves implementing lifestyle changes. These include adopting a healthy diet, engaging in regular physical activity, losing weight, and quitting smoking. A small percentage of patients with NAFLD will develop Non-alcoholic steatohepatitis (NASH), associated with faster liver disease progression. Fibrosis development seems to occur more often in patients with NASH and is an essential histological feature associated with its mortality. Mortality rates vary among different subgroups of patients, with variables such as age, comorbidities, and severity of liver disease playing an important role. This narrative review comprehensively overviews this silent but potentially harmful condition.

Prevalence, risk factors and diagnostic accuracy of non-invasive tests for NAFLD in people with type 1 diabetes

Background & AimsThe epidemiology of non-alcoholic fatty liver disease (NAFLD) in people with type 1 diabetes (T1D) is not yet elucidated. This study aimed to assess the diagnostic accuracy of non-invasive tests for NAFLD, to investigate the prevalence and severity of NAFLD, and to search for factors contributing to NAFLD in people with T1D. MethodsIn this prospective cohort study, we consecutively screened 530 adults with T1D from a tertiary care hospital, using ultrasound (US), vibration-controlled transient elastography equipped with liver stiffness measurement (LSM) and controlled attenuation parameter, and the fatty liver index. Magnetic resonance spectroscopy (MRS) was performed in a representative subgroup of 132 individuals to validate the diagnostic accuracy of the non-invasive tests. ResultsBased on MRS as reference standard, US identified individuals with NAFLD with an AUROC of 0.98 (95% CI 0.95–1.00, sensitivity: 1.00, specificity: 0.96). The controlled attenuation parameter was also accurate with an AUROC of 0.85 (95% CI 0.77–0.93). Youden cut-off was ≥270 dB/m (sensitivity: 0.90, specificity: 0.74). The fatty liver index yielded a similar AUROC of 0.83 (95% CI 0.74–0.91), but the conventional cut-off used to rule in (≥60) had low sensitivity and specificity (0.62, 0.78). The prevalence of NAFLD in the overall cohort was 16.2% based on US. Metabolic syndrome was associated with NAFLD (OR: 2.35 [1.08–5.12], p = 0.031). The overall prevalence of LSM ≥8.0 kPa indicating significant fibrosis was 3.8%, but reached 13.2% in people with NAFLD. ConclusionsNAFLD prevalence in individuals with T1D is 16.2%, with approximately one in 10 featuring elevated LSM. US-based screening could be considered in people with T1D and metabolic syndrome. Impact and ImplicationsWe aimed to report on the prevalence, disease severity, and risk factors of NAFLD in type 1 diabetes (T1D), while also tackling which non-invasive test for NAFLD is the most accurate. We found that ultrasound is the best test to diagnose NAFLD. NAFLD prevalence is 16.2%, and is associated with metabolic syndrome and BMI. Elevated liver stiffness indicating fibrosis is overall not prevalent in people with T1D (3.8%), but it reaches 13.2% in those with T1D and NAFLD.

Factors related to the presence of nonalcoholic fatty liver disease in patients with type 2 diabetes: a single center study.

There is a close relationship between the development of diabetes and nonalcoholic fatty liver disease (NAFLD). The aim of the study was to determine the frequency and associated factors of NAFLD in type 2 diabetes mellitus (T2DM) patients according to the ultrasound examination and noninvasive hepatic fibrosis indices. 316 patients who were followed up in the Internal Medicine Diabetes clinic, over the age of 18, diagnosed with T2DM were included retrospectively. NAFLD was noted using ultrasound. NAFLD fibrosis score (NFS), fibrosis-4 index (FIB-4) and AST to platelet ratio index (APRI) were used as non-invasive hepatic fibrosis indices. The prevalence of NAFLD with hepatic ultrasound was 89.7% in T2DM patients. Among non-invasive fibrosis indices, NFS and FIB-4 were similar, but APRI was significantly higher in moderate-severe hepatosteatosis group (p values = 0.355, 0.246 and 0.003 respectively). In logistic regression analysis, while mild hepatosteatosis was associated with BMI and NFS (p = 0.004, p = 0.008), moderate to severe hepatosteatosis as associated with BMI and serum triglycerides (p < 0.001, p = 0.019). The prevalence of NAFLD is high in patients with T2DM. The frequency and degree of NAFLD is associated with the NFS, BMI and hypertriglyceridemia. While NFS is associated with mild hepatosteatosis; moderate to severe hepatosteatosis is associated with BMI and serum triglycerides.

Non-alcoholic fatty liver disease in type 1 diabetes: Prevalence and pathophysiology.

Non-alcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in the general population with a global prevalence of 25%. It is often associated with metabolic syndrome and type 2 diabetes, as insulin resistance and hyperinsulinemia are known to be favoring factors. Recent studies have described growing incidence of NAFLD in type 1 diabetes (T1D) as well. Although increasing prevalence of metabolic syndrome in these patients seems to explain part of this increase in NAFLD, other underlying mechanisms may participate in the emergence of NAFLD. Notably, some genetic factors are more associated with fatty liver disease, but their prevalence in T1D has not been evaluated. Moreover, oxidative stress, poor glucose control and long-lasting hyperglycemia, as well as exogenous insulin administration play an important role in intrahepatic fat homeostasis. The main differential diagnosis of NAFLD in T1D is glycogenic hepatopathy, which needs to be considered mostly in T1D patients with poor glycemic control. This article aims to review the prevalence and pathophysiology of NAFLD in T1D and open perspectives for clinicians taking care of T1D patients with potential hepatopathy.

Sodium-glucose cotransporter 2 inhibitors for non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus: A nationwide propensity-score matched cohort study

AimsThis study was to determine the association between sodium-glucose cotransporter 2 inhibitors (SGLT2i) and nonalcoholic fatty liver disease (NAFLD) in type 2 diabetes. MethodsWe used data from the Korean National Health Insurance Service from 2014 to 2017. New drug users were screened, dipeptidyl peptidase 4 inhibitors (DPP4i) were set as the active comparator, and the differences between the two groups were corrected through propensity score matching. NAFLD was evaluated by the fatty liver index (FLI), which was calculated using body mass index, waist circumference, triglycerides, and gamma glutamyl peptidase. ResultsAfter 1:1 matching, 25,371 patients in each group who received medication for an average of 299 days were analyzed. Despite similar baseline FLI of each group, the FLI of the SGLT2i users was 44.4 ± 26.7 and the FLI of the DPP4i users was 48.9 ± 27.3 (P value < 0.001) after treatment. SGLT2i showed more significant decrements than DPP4i in all components of FLI. The more the adherence to the SGLT2i increased, the greater the decrease in FLI. ConclusionsSGLT2i showed a significant reduction in FLI and its components. We suggest that SGLT2i may have beneficial effects in reducing the prevalence of NAFLD in type 2 diabetes.

Non-obese NAFLD had no better cardio-metabolic risk profile than obese NAFLD in type 2 diabetic patients

BackgroundNon-obese non-alcoholic fatty liver disease (NAFLD) has been reported to share clinical outcomes with its obese counterpart in the general population. However, conflicting results have been observed regarding the cardio-metabolic risk profile of non-obese NAFLD as compared to obese NAFLD. Moreover, in the context of type 2 diabetes mellitus (T2DM), this issue has been even less addressed. We hence aimed to examine the association of NAFLD with the cardio-metabolic risk profile in patients with T2DM according to their obesity status.MethodsA total of 2,708 patients with T2DM who were hospitalized between June 2018 and May 2021 were cross-sectionally assessed.ResultsThe prevalence of NAFLD was 49.3%. NAFLD was found in 34.1% of non-obese patients and 66.0% of obese patients. Non-obese NAFLD patients had more and worse metabolic disorders than obese patients without NAFLD in both men and women. Comparable cardio-metabolic risk profiles were noted between non-obese and obese NAFLD subjects. The associations of worse cardio-metabolic risk profiles with NAFLD were overall stronger in non-obese than in obese subjects among women with T2DM, while more pronounced in obese than in non-obese subjects among men with T2DM.ConclusionIn patients with T2DM, non-obese NAFLD had no better cardio-metabolic risk profile than obese NAFLD. The associations of metabolic disorders with NAFLD were stronger in non-obese than in obese patients in women patients with T2DM.

475-P: Plasma Fatty Acid Composition Is Associated with Nonalcoholic Fatty Liver Disease in Type 2 Diabetes Patients

Type 2 diabetes is frequently complicated by nonalcoholic fatty liver disease (NAFLD) , which is mainly caused by high-fat and high-calorie diets, and obesity. In this regard, both the quantity and quality of fat accumulating in the liver are important, and in particular, the proportion of each fatty acid may be an important biomarker for NAFLD. We investigated whether serum fatty acid composition, especially n-6 polyunsaturated fatty acid (PUFA) and, saturated fatty acid (MUFA) and desaturase activity are associated with NAFLD in type 2 diabetes patients. Eighty-five type 2 diabetes patients (age: 60.3±13.9 years, BMI 27.5±5.8 kg/m2) who had no history of alcohol drinking, and had a negative result for hepatitis viruses were included as study subjects. Fatty liver (FL) was diagnosed based on liver ultrasonographic findings. Patients with FL were included in the FL group (n=51) , whereas those without FL included in the non-FL group (n=34) . Serum fatty acid levels were measured using gas chromatography. Desaturase activity for n-6 PUFAs was calculated as the ratio of arachidonic acid to dihomo-gamma-linolenic acid (DGLA) for Δ5 desaturase (D5D) . Waist circumference, BMI, serum triglyceride (TG) concentration, and ALT level were significantly higher in the FL group than in the non-FL group. The FL group also demonstrated higher levels of palmitic acid (PAL) and stearic acid (STA) , PAL/STA ratio, and DGLA than the non-FL group. In the FL group D5D activity was significantly lower than that in the non-FL group. PAL level, DGLA, and PAL/STA ratio showed a significant positive correlation with TG and ALT levels. Multiple regression analysis showed that DGLA was independently associated with FL development. These results suggest that type 2 diabetes patients with NAFLD have changes in their blood fatty acid profile, especially increased DGLA and PAL levels. The high levels of blood DGLA indicate downregulation of n-6 PUFA metabolism, probably caused by the decreased activity of D5D. Disclosure M.Higa: None. T.Ichijo: None.

Efficacy of Sitagliptin on Nonalcoholic Fatty Liver Disease in High-fat-diet-fed Diabetic Mice

Nonalcoholic fatty liver disease (NAFLD) is a common cause of clinical liver dysfunction and an important prepathological change of liver cirrhosis. Central obesity, type 2 diabetes mellitus, dyslipidemia, and metabolic syndrome are the major risk factors for NAFLD. Sitagliptin (Sig) is a novel hypoglycemic agent that improves blood glucose levels by increasing the level of active incretin. Sig has been shown to prevent the development of fatty livers in mice on a fructose-rich diet. The purpose of this study was to observe the efficacy of Sig on NAFLD in type 2 diabetic mice. The diet-induced obesity mouse model was established, and the diabetic mice were screened by an intraperitoneal glucose tolerance trial. The mice were randomly divided into four groups for 8 weeks of intervention: high-fat diet (HFD) group, Sig group, metformin (Met) group, and Sig+Met group. After the intervention, the liver function indexes as well as the blood glucose and blood lipid levels of the mice were measured. In addition, the wet weight of the liver was measured; the pathological sections of the liver tissues were stained to observe the hepatocyte fatty degeneration, inflammation, necrosis, and fibrosis; and the hepatic histological injury was recorded as the NAFLD activity score (NAS). Compared with the normal control group, the body weight, liver weight, blood glucose level, insulin resistance (IR), blood lipid level, and transaminase level of the mice in the HFD group were significantly increased, showing typical metabolic syndrome. After treatment with Sig and/or Met, the mice gained less weight, had lower levels of blood glucose, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and transaminase, and had improved IR compared with the HFD group. The liver pathological NASs in the Sig group (P=0.01), Met group (P=0.028), and Sig+Met group (P<0.001) were lower than those in the HFD group (P<0.05), suggesting that the use of the two drugs alone or in combination can improve the state of liver inflammation. In terms of fibrosis, there was no fibrosis in the control group but there was significant fibrosis in the HFD group (P<0.001). There was no significant difference between the drug intervention groups and the HFD group, indicating that the drug therapy (Sig and/or Met) did not significantly improve the pre-existing fibrosis. Our experiment proved that Sig can improve NAFLD, including improvement of the serum transaminase level, hepatic pathological inflammation level, and hepatocyte adiposis, suggesting that Sig may play a role by improving glucose and lipid metabolism, reducing the body weight and liver weight, improving insulin sensitivity, and inhibiting fatty liver inflammation. Sig may be a new direction for the treatment of patients with a nonalcoholic fatty liver and diabetes, delaying the progression of NAFLD.

Therapeutic Effects of Milk Thistle (Silybum marianum L.) and Artichoke (Cynara scolymus L.) on Nonalcoholic Fatty Liver Disease in Type 2 Diabetic Rats.

Background At present, nonalcoholic fatty liver disease (NAFLD) does not have an approved pharmacologic therapy. The present study investigated the protective effects and possible mechanisms of milk thistle (Silybum marianum L.) and artichoke (Cynara scolymus L.) in treating NAFLD in type 2 diabetic rats. Methods The NAFLD was established in rats after four weeks of type 2 diabetes induction. The animals were treated with pharmaceutical preparations of milk thistle (Livergol®) and artichoke (Atheromod-B®) extracts for eight weeks. After the end of the intervention, oral glucose tolerance, the serum parameters of oxidative stress, liver functional tests, and lipid profiles were evaluated. Histopathological changes were assessed by hematoxylin and eosin staining. Results Treatment with preparations of milk thistle and artichoke nonsignificantly improved glucose tolerance in diabetic rats. Both preparations significantly improved serum superoxide dismutase activity and the level of malondialdehyde. Although treatment with milk thistle reduced serum activity of aspartate aminotransferase and serum levels of triglyceride (TG), total cholesterol, and low-density lipoprotein-cholesterol, artichoke extracts only attenuated the serum level of TG. Milk thistle also effectively protected the liver from histological changes. Conclusions Milk thistle could be a promising pharmacological option for the treatment of NAFLD. Nonetheless, long-term randomized clinical trials are necessary to confirm the observed results.

Correlational study on the levels of 25-hydroxyvitamin D and non-alcoholic fatty liver disease in type 2 diabetic patients

BackgroundIt is widely acknowledged that nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus(T2DM) are all chronic metabolic diseases. The objective of this study is to retrospectively probe the association between the 25-hydroxyvitamin D (25-(OH)D) and NAFLD in type 2 diabetic patients.MethodsThree hundred thirty-nine T2DM patients participated in this research and from November 2018 to September 2019 and were divided into simple T2DM group (108 cases) and T2DM with NAFLD group (231 cases) in conformity with abdominal ultrasound diagnosis. The NAFLD fibrosis score (NFS) ≥0.676 was defined as progressive liver fibrosis.231 T2DM with NAFLD patients were categorized into two subgroups: progressive liver fibrosis subgroup (48 cases) and without progressive liver fibrosis subgroup (183 cases).ResultsThe prevalence of NAFLD by Abdominal ultrasonography was 68%.The results indicated that the levels of 25-(OH) D were significantly lower in T2DM with NAFLD group than that in simple T2DM group(P < 0.01). The levels of 25-(OH) D were significantly lower in progressive liver fibrosis subgroup than that in patients without progressive liver fibrosis and simple T2DM,and 25-(OH) D levels were lower in without progressive liver fibrosis subgroup than that in simple T2DM group(p < 0.01 or p < 0.05). Multivariate logistic regression analysis showed that levels of 25-(OH) D were negative correlation with risk of NAFLD and progressive liver fibrosis(p = 0.011、p = 0.044,respectively).Conclusionswe could come to a conclusion that low levels of 25-(OH) D was a risk factor for NAFLD and progressive liver fibrosis in T2DM patients.

Effect of vitamin D3 supplementation on hepatic lipid dysregulation associated with autophagy regulatory AMPK/Akt-mTOR signaling in type 2 diabetic mice.

Vitamin D3 has been reported to protect liver against non-alcoholic fatty liver disease (NAFLD) by attenuating hepatic lipid dysregulation in type 2 diabetes mellitus (T2DM). However, the mechanism of vitamin D3 on hepatic lipid metabolism-associated autophagy in hyperglycemia-induced NAFLD remains yet to be exactly elucidated. C57BL/6J mice were intraperitoneally injected with 30 mg/kg of streptozotocin and fed a high-fat diet for induction of diabetes. All mice were administered with vehicle or vitamin D3 (300 ng/kg or 600 ng/kg) by oral gavage for 12 weeks. Histological demonstrations of the hepatic tissues were obtained by H&E staining and the protein levels related to lipid metabolism and autophagy signaling were analyzed by Western blot. Treatment with vitamin D3 improved insulin resistance, liver damage, and plasma lipid profiles, and decreased hepatic lipid content in the diabetic mice. Moreover, vitamin D3 administration ameliorated hepatic lipid dysregulation by downregulating lipogenesis and upregulating lipid oxidation under diabetic condition. Importantly, vitamin D3 treatment induced autophagy by activating AMP-activated protein kinase (AMPK), inactivating Akt and ultimately blocking mammalian target of rapamycin (mTOR) activation in the T2DM mice. Additionally, vitamin D3 was found to be effective in anti-apoptosis and anti-fibrosis in the liver of diabetic mice. The results suggested that vitamin D3 may ameliorate hepatic lipid dysregulation by activating autophagy regulatory AMPK/Akt-mTOR signaling in T2DM, providing insights into its beneficial effects on NAFLD in type 2 diabetic patients.

NAFLD in type 1 diabetes: overrated or underappreciated?

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in western countries, affecting 25–30% of the general population and up to 65% in those with obesity and/or type 2 diabetes. Accumulation of visceral adipose tissue and insulin resistance (IR) contributes to NAFLD. NAFLD is not an innocent entity as it not only may cause nonalcoholic steatohepatitis and cirrhosis but also contribute to cardiovascular morbidity and mortality. More and more people with type 1 diabetes (T1D) are becoming overweight and present with features of IR, but the prevalence and impact of NAFLD in this population are still unclear. The utility of noninvasive screening tools for NAFLD in T1D is being explored. Recent data indicate that based upon ultrasonographic criteria NAFLD is present in 27% (ranging between 19% and 31%) of adults with T1D. Magnetic resonance imaging data indicate a prevalence rate of 8.6% (ranging between 2.1% and 18.6%). There are, however, multiple factors affecting these data, ranging from study design and referral bias to discrepancies in between diagnostic modalities. Individuals with T1D have a 7-fold higher risk of cardiovascular disease (CVD) and cardiovascular mortality is the most prominent cause of death in T1D. Patients with T1D and NALFD are also more prone to develop CVD, but the independent contribution of NAFLD to cardiovascular events has to be determined in this population. Furthermore, limited data in T1D also point towards a 2 to 3 times higher risk for microvascular complications in those with NAFLD. In this article, we will discuss epidemiological and diagnostic challenges of NAFLD in T1D, explore the link between IR and NAFLD and chronic complications, and examine the independent contribution of NAFLD to the presence of macro-, and microvascular complications.