Новые возможности коррекции неалкогольной жировой болезни печени у мужчин с сахарным диабетом 2 типа и гипогонадизмом

Background: The common pathogenetic relations of type 2 diabetes mellitus (T2DM), testosterone (T) deficiency and non-alcoholic fatty liver disease (NAFLD) have indicated a new direction in the study of their mutual influence. It was found that NAFLD is more pronounced in men with T2DM and hypogonadism than in eugonadal patients and associated with hyperinsulinemia, insulin resistance, impaired lipid metabolism and adipose tissue dysfunction. However, the effects of testosterone replacement therapy (TRT) on the severity of NAFLD in men with hypogonadism have not been studied.Aims: To study the effect of TRT on the severity of NAFLD in men with T2DM and hypogonadism.MATERIALS AND METHODS: Anthropometric data, biochemical parameters (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltranspeptidase (GGTP), glucose, immunoreactive insulin, HOMA index, glycosylated hemoglobin, lipidogram), ELISA analysis (total T, LH, sex hormone binding globulin, resistin, adiponectin, leptin), as well as magnetic resonance imaging with determination of the liver fat fraction were examined.Results: The study included 60 men with T2DM and hypogonadism (mean age 54 [49; 57] years), who were randomized into 2 groups: 1 (n=30) - patients who received 1% transdermal T gel (50 mg/day) in addition to standard hypoglycemictherapy; 2 (n=30) - patients who received standard hypoglycemic therapy. The follow-up period was 6 months. T therapy was associated with a decrease in liver enzyme levels: AST by 31%, ALT by 21%, and GGTP by 15.9% (p<0.05) and the hepatic fat fraction by 1.7 times, which reflect the regress of liver inflammation, and, consequently, a decrease in the severity of NAFLD. Moreover, TRT has improved the function of adipose tissue - reduced the concentration of leptin by 1.4 times and resistin by 1.5 times, which was accompanied by an increase in adiponectin level by 1.3 times (p<0.01). The use of TRT was associated with decrease in the severity of visceral obesity, hyperinsulinemia by 1.5 times, an insulin resistance index HOMA by 2.2 times, fasting glycaemia and HbA1c levels, despite constant hypoglycemic therapy. Statistically significant decrease in the levels of total cholesterol and triglycerides was observed in men receiving TRT. Thus, a decrease in adipose tissue dysfunction and insulin resistance in men receiving TRT can be considered as a pathogenetic mechanism responsible for improving liver function and reducing the severity of NAFLD.Conclusions: TRT in men with T2DM and hypogonadism is accompanied by regress of inflammatory activity in liver and intensity of hepatocytes steatosis, reflected by decrease in liver enzymes levels and liver fat fraction.

PurposeLittle is known about the association between plasma adiponectin levels and nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). We examined whether there is an association between lower plasma adiponectin levels and the presence/severity of NAFLD in people with T2DM.MethodsWe cross-sectionally recruited 79 men with non-insulin-treated T2DM and no known liver diseases, who had consecutively attended our diabetes outpatient service over a 6-month period and who underwent both ultrasonography and Fibroscan-measured liver stiffness (LSM). Nine single nucleotide polymorphisms (PNPLA3 rs738409 and other genetic variants) associated with NAFLD were investigated.ResultsAmong the 79 participants included (mean age 67 ± 10 years, BMI 27.7 ± 4 kg/m2), 28 did not have NAFLD, 32 had steatosis alone, and 19 had NAFLD with coexisting significant fibrosis (LSM ≥ 7.0 kPa by Fibroscan®). Compared to those without NAFLD, patients with hepatic steatosis alone and those with hepatic steatosis and coexisting significant fibrosis had lower high-molecular-weight adiponectin levels (5.5 [IQR 2.3–7.6] vs. 2.4 [1.8–3.7] vs. 1.6 [1.0–2.9] µg/mL; p < 0.001). After adjustment for age, body mass index, insulin resistance, and the PNPLA3 rs738409 variant, lower plasma adiponectin levels were found to be associated with increased odds of both steatosis alone (adjusted-odds ratio [OR] 2.44, 95% CI 1.04–5.56, p = 0.042) and NAFLD with coexisting significant fibrosis (adjusted-OR 3.84, 95% CI 1.23–10.0, p = 0.020). Similar findings were observed after adjustment for the other eight genotyped NAFLD-related polymorphisms.ConclusionLower plasma adiponectin levels are closely associated with the presence and severity of NAFLD in men with T2DM, pointing to a role of adiponectin in NAFLD development and progression.

Comments on ‘Low serum sex hormone binding globulin is associated with nonalcoholic fatty liver disease in type 2 diabetic patients’

Defining severe NAFLD based on ICD codes in large cohorts: Balancing feasibility and limitations

Background: Diabetes mellitus is a chronic disease which has been increasing both in incidence and global impact. In the Philippines, cases of diabetes mellitus increase at an alarming rate. Previous study in Nigeria among Type 2 Diabetic patients with non-alcoholic fatty liver disease (NAFLD) has observed an increased prevalence of 69%. However, there is no definite association between severity of NAFLD and glycemic control (HbA1c). Objectives: To investigate the prevalence of NAFLD and its association with glycemic control of Type 2 Diabetes Mellitus (T2DM) patients at Batangas Medical Center (BatMC) – Out Patient Department (OPD). Methods: A single center, cross sectional study was performed on 80 T2DM patients, who underwent OPD consultation between November 2020 to October 2021. Clinicodemographic profile, duration of T2DM, diagnostic tests including HbA1c and ultrasound of the liver were taken. Chi-Square test of homogeneity and Fisher’s Exact test/Fisher-Freeman-Halton test were utilized for comparison of categorical variables from a single population to determine whether there is a significant association between the severity of NAFLD and patients characteristics and glycemic control. Results: 80 T2DM patients were included in the analysis, there was an equal number of male (50%) and female (50%). Majority of the patients were in the age of 50 – 59 years old (33%), with a BMI of 25 and above (81%), had been diagnosed with T2DM for &gt; 5 years (72%) and maintained with oral hypoglycemic agents (68%). The prevalence of NAFLD by ultrasonography among T2DM patients was 81%. 80% of these patients had mild NAFLD and 20% had moderate NAFLD; but none had severe NAFLD. The average HbA1c level of 8.9% had a mild NAFLD compared to patients with moderate NAFLD with an average HbA1c level of 10.1%. With a p=0.053, NAFLD severity and glycemic control do not show any statistically significant association. Subgroup analysis was not performed in the study due to limited sample size. In addition, results of association are not sufficient evidence for any conclusion; hence, there appear to be no group of interest. Conclusion: The result of this study confirmed that the prevalence of NAFLD in T2DM was high at 81% but there is no sufficient evidence to conclude a statistically significant association between the level of glycemic control and the severity of NAFLD. Keywords: Type 2 Diabetes Mellitus, Non-Alcoholic Fatty Liver Disease, NAFLD, Glycemic control, HbA1c, Dyslipidemia, Obesity, Metabolic Syndrome

Sarcopenia is associated with non-alcoholic fatty liver disease in men with type 2 diabetes

Non-alcoholic fatty liver disease (NAFLD) is considered as both a vital risk factor and a consequence of type 2 diabetes mellitus (T2DM). Low total testosterone (TT) is common in men with T2DM, contributing to increased risks of metabolic diseases. This study aimed to investigate the association between TT levels and the prevalence of NAFLD in men with T2DM. In this cross-sectional study, 1005 men with T2DM were enrolled in National Metabolic Management Center (MMC) of First Affiliated Hospital of Wenzhou Medical University between January 2017 and August 2021. NAFLD was diagnosed using ultrasound as described by the Chinese Liver Disease Association. Overweight/obesity was defined as body mass index (BMI) ≥ 25kg/m2 according to WHO BMI classifications. Individuals without NAFLD had higher serum TT levels than those with NAFLD. After adjustments for potential confounding factors, the top tertile was significantly associated with lower prevalence of NAFLD compared with the bottom tertile of TT level [odds ratio (OR) 0.303, 95% confidence interval (CI) 0.281-0.713; P < 0.001]. The association between TT with NAFLD in individuals with normal weight (OR 0.175, 95% CI 0.098-0.315; P < 0.001) was stronger than in individuals with overweight/obesity (OR 0.509, 95% CI 0.267-0.971; P = 0.040). There was a significant interaction of TT with overweight/obesity (P for interaction = 0.018 for NAFLD). Higher serum TT was significantly associated with a lower prevalence of NAFLD in men with T2DM. We found that the relationship of TT and NAFLD was stronger in individuals with non-overweight/obesity.

Associations of muscle mass and grip strength with severe NAFLD: A prospective study of 333,295 UK Biobank participants.

Background and AimsThioredoxin-interacting protein (TXNIP), a crucial modulator of the redox system, plays a crucial role in modulating lipid/glucose metabolism. Hence, this study aimed to explore whether circulating TXNIP is associated with non-alcoholic fatty liver disease (NAFLD) among patients with type 2 diabetes mellitus (T2DM).MethodsWe enrolled 110 new patients with T2DM. In this study, we determined hepatic fat fraction (HFF), which represents a hepatic fat level, by Dixon magnetic resonance imaging. TXNIP and the other biochemical profiles of the patients were measured using fasting plasma.ResultsAmong the 110 patients with T2DM, 41 were classified as without fatty liver, whereas 34 and 35 were with mild and moderate-to-severe fatty liver, respectively. The patients with diabetes and advanced fatty liver had significantly higher TXNIP levels (P <0.001) than other patients. The prevalence of severe NAFLD showed an increasing trend with the increase in TXNIP quartiles (for all trends, P <0.05). HFF showed a positive correlation with TXNIP (r = 0.516, P <0.001). Even main risk factors were adjusted, TXNIP level was associated with NAFLD as analyzed by logistic regression.ConclusionTXNIP level remarkably increases among diabetics, which shows its positive relationship with the severity of NAFLD. TXNIP is a promising NAFLD biomarker that offers an efficient way to evaluate and monitor fatty liver progression among patients with T2DM.

Obese animals and non-alcoholic fatty liver disease (NAFLD) patients exhibit elevated blood alcohol, suggesting potential contributions of alcohol metabolism to the development of NAFLD. Liver gene expression in patients with biopsy-proven mild (N = 40) and severe (N = 32) NAFLD were compared to that in healthy liver donors (N = 7) and alcoholic hepatitis (AH; N = 15) using microarrays. Principal components analyses (PCA) revealed similar gene expression patterns between mild and severe NAFLD which clustered with those of AH but were distinct from those of healthy livers. Differential gene expression between NAFLD and healthy livers was consistent with established NAFLD-associated genes and NAFLD pathophysiology. Alcohol-metabolizing enzymes including ADH, ALDH, CYP2E1, and CAT were up-regulated in NAFLD livers. The expression level of alcohol-metabolizing genes in severe NAFLD was similar to that in AH. The NAFLD gene expression profiles provide new directions for future investigations to identify disease markers and targets for prevention and treatment, as well as to foster our understanding of NAFLD pathogenesis and pathophysiology. Particularly, increased expression of alcohol-metabolizing genes in NAFLD livers supports a role for endogenous alcohol metabolism in NAFLD pathology and provides further support for gut microbiome therapy in NAFLD management. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley © Sons, Ltd.

Nonalcoholic Fatty Liver Disease in Children: Where Are We?

Non-alcoholic fatty liver disease (NAFLD) has become one of the most common forms of chronic liver disease worldwide and its prevalence is expected to continue rising. NAFLD has traditionally been considered a consequence of metabolic syndrome (MetS). However, the link between NAFLD and MetS components, especially type 2 diabetes mellitus (T2DM), hypertension (HTN), and cardiovascular disease (CVD) is more complex than previously thought. Indeed, the adverse effects of NAFLD extend far beyond the liver, with a large body of clinical evidence now suggesting that NAFLD may precede and/or promote the development of T2DM, HTN and atherosclerosis/CVD. The risk of developing these cardiometabolic diseases parallels the underlying severity of NAFLD. Accumulating evidence suggests that the presence and severity of NAFLD is associated with an increased risk of incident T2DM and HTN. Moreover, long-term prospective studies indicate that the presence and severity of NAFLD independently predicts fatal and nonfatal CVD events. In this review, we critically discuss the rapidly expanding body of clinical evidence that supports the existence of a bi-directional relationship between NAFLD and various components of MetS, particularly T2DM and HTN, as well as the current knowledge regarding a strong association between NAFLD and CVD morbidity and mortality. Finally, we discuss the most updated putative biological mechanisms through which NAFLD may contribute to the development of HTN, T2DM and CVD.

The pathophysiological mechanisms underlying the close relationship between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are multiple, complex and only partially known. The purpose of this paper was to review the current knowledge of these mechanisms in a unified manner. Subjects with NAFLD and T2DM have established insulin resistance (IR), which exacerbates the two comorbidities. IR worsens NAFLD by increasing the accumulation of free fatty acids (FFAs) in the liver. This occurs due to an increase in the influx of FFAs from peripheral adipose tissue by the activation of hormone-sensitive lipase. In addition, there is de novo increased lipogenesis, a transcription factor, the sterols regulatory element-binding transcription factor 1c (SREBP-1c), which activates the expression of several genes strongly promotes lipogenesis by the liver and facilitate storage of triglycerides. Lipids accumulation in the liver induces a chronic stress in the endoplasmic reticulum of the hepatocytes. Genome-wide association studies have identified genetic variants associated with NAFLD severity, but unrelated to IR. In particular, the alteration of patatin-like phospholipase domain-containing protein 3 contributes to the susceptibility to NAFLD. Furthermore, the lipotoxicity of ceramides and diacylglycerol, well known in T2DM, triggers a chronic inflammatory process favoring the progression from hepatic steatosis to steatohepatitis. Reactive oxygen species produced by mitochondrial dysfunction trigger both liver inflammation and beta-cells damage, promoting the progression of both NAFLD and T2DM. The close association between NAFLD and T2DM is bidirectional, as T2DM may trigger both NAFLD onset and its progression, but NAFLD itself may contribute to the development of IR and T2DM. Future studies on the mechanisms will have to deepen the knowledge of the interaction between the two pathologies and should allow the identification of new therapeutic targets for the treatment of NAFLD, currently substantially absent.

Non-alcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide.1–3 NAFLD exists on a spectrum from steatosis to non-alcoholic steatohepatitis, fibrosis and cirrhosis. Fibrosis in NAFLD...

Background: Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease worldwide and can progress to fibrosis and cirrhosis. NAFLD is increasingly prevalent, particularly in individuals with central obesity, type 2 diabetes mellitus (T2DM), dyslipidemia, and metabolic syndrome. Objective: To assess biochemical parameters in patients with T2DM and NAFLD at a tertiary care hospital in Bhopal. Methods: This study was conducted in the Department of Biochemistry at L.N. Medical College and J.K. Hospital, involving 70 subjects diagnosed with T2DM and NAFLD. NAFLD severity was classified into three grades (1–3) based on abdominal ultrasonography findings. Biochemical parameters analyzed included HbA1c, serum cholesterol, triglycerides, low-density lipoprotein (LDL), and high-density lipoprotein (HDL). Results: Among 70 participants, those with NAFLD Grade 3 had the highest total cholesterol levels (Mean TC = 266 mg/dL). Grade 3 participants (n=17) exhibited elevated triglyceride levels (Mean TG = 246 mg/dL), while Grade 2 participants (n=25) had increased LDL levels. Grade 1 participants had the lowest HDL levels (Mean HDL = 35 mg/dL). Dyslipidemia, characterized by elevated triglycerides or LDL with reduced HDL, was the most common abnormality. Total cholesterol, LDL, and HDL levels were significantly associated with NAFLD severity, whereas triglyceride variations across NAFLD grades were not statistically significant. Conclusion: This study highlights the importance of recognizing fatty liver as a component of metabolic syndrome in individuals with diabetes mellitus. Regular monitoring of lipid profiles in T2DM patients with NAFLD is essential for early intervention and management.