CDL (co-management of diabetes-liver diseases strategy,) Literature Monthly Review – November 2023, Issue 10

Introduction:Diabetes and liver diseases are common chronic conditions in China, and they interact in terms of pathogenesis, clinical manifestations, and therapeutic targets, often posing mutual risk factors. Co-management of these conditions is beneficial for reducing the burden of disease. To support the development of diabetes and liver disease co-management in China, this publication Hepatology Digest, in collaboration with the co-management of diabetes-liver diseases strategy, (CDL), presents the CDL Literature Monthly Review column. Each month, we share research literature related to the mechanisms and therapeutic advances in diabetes combined with liver diseases. We invite experts in the field to comment on the literature, hoping to provide insights and assistance for professionals, researchers, and frontline medical workers engaged in scientific research and clinical diagnosis and treatment.

In this issue of the CDL Literature Monthly Review, we will share six pieces of basic or clinical research literature related to diabetes and liver diseases, including fatty liver and cirrhosis. Our invited expert commentators for this issue are: Dr. Jiajie Lu from West China Hospital, Sichuan University; Dr. Haifang Cao from Qinghai Province Fourth People’s Hospital; and Dr. Zuxiong Huang from Mengchao Hepatobiliary Hospital, Fujian Medical University.

Expert Commentators:

01

“IL-6 Trans-Signaling is Increased in Diabetes, Impacted by Glucolipotoxicity, and Associated with Liver Stiffness and Fibrosis in Fatty Liver Disease”

Gunes A, Schmitt C, Bilodeau L, et al. Diabetes. 2023 Sep 27.

 Many patients with diabetes also suffer from non-alcoholic fatty liver disease (NAFLD). Interleukin-6 (IL-6) is involved in both diseases, interacting with membrane-bound (classical) and circulating soluble receptors (trans-signaling). This study investigates whether the secretion of IL-6 trans-signaling co-receptor is altered in diabetic patients with NAFLD and whether this is associated with the severity of fatty liver disease. The results indicate that high blood glucose and hyperlipidemia can directly affect IL-6 trans-signaling, potentially relating to the increased severity of NAFLD in diabetic patients.

The secretion patterns were studied using human liver cells, stellate cells, and monocyte cell lines, and the association of IL-6 with liver pathology was investigated in cohorts of patients with biopsy-confirmed NASH and grade 3 obesity. The study found that stellate cells exposed to high glucose and palmitate increase the secretion of IL-6 and sgp130. Correspondingly, plasma sgp130 in both patient cohorts positively correlated with HbA1c, and higher levels of IL-6 and trans-signaling co-receptor were found in the circulation of diabetic subjects. Plasma sgp130 was closely related to liver stiffness and significantly increased in subjects with F4 fibrosis, while monocyte activation was associated with reduced secretion of sIL-6R.

Commentary (by Dr. Jiajie Lu)

Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are both metabolic diseases that causally influence and mutually exacerbate each other’s progression. Interleukin-6 (IL-6) is an inflammatory cytokine closely associated with metabolic diseases. In IL-6’s classical signaling and trans-signaling pathways, IL-6 forms a complex by binding with either the IL-6 receptor (IL-6R) or soluble IL-6 receptor (sIL-6R), which then binds to glycoprotein 130 (gp130), initiating intracellular signaling. The classical IL-6 signaling pathway is believed to be closely related to NAFLD/NASH (non-alcoholic steatohepatitis) and metabolism, while research on the relationship between IL-6 trans-signaling and NAFLD/NASH has been relatively limited.

Gunes A and others conducted research on the association between T2D and NAFLD and levels of IL-6, sIL-6R, and soluble glycoprotein 130 (sgp130)  all involved in IL-6 signaling in cohorts of NASH and grade 3 obesity patients using human liver cells, stellate cells, and monocyte cell lines. The results suggest that cytokines related to the IL-6 trans-signaling pathway are associated with the pathogenesis of NAFLD and that the liver may be a source of these inflammatory mediators in metabolic diseases. Additionally, liver IL-6 trans-signaling is also related to diabetes/high blood glucose.

However, this study has certain limitations. Firstly, it’s a retrospective analysis, inevitably subject to bias and confounding factors. Secondly, the limited sample size necessitates further validation with larger studies. Finally, the limitations of in vitro cell experiments and mouse models require further validation through in vivo experiments and clinical studies.

02

Liraglutide attenuates type 2 diabetes mellitus-associated non-alcoholic fatty liver disease by activating AMPK/ACC signaling and inhibiting ferroptosis

Guo T, Yan W, Cui X, et al. Mol Med. 2023 Sep 28.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of type 2 diabetes mellitus (T2DM). The pathogenesis of NAFLD involves various biological changes including insulin resistance, oxidative stress, inflammation, and genetic and environmental factors. Liraglutide has been used to control blood glucose, but its effects on T2DM-associated NAFLD are not well understood. Chinese scientists studied the effect of inhibiting ferroptosis on liraglutide in improving T2DM-associated NAFLD  and its potential molecular mechanisms. The results indicate that liraglutide may improve T2DM-associated NAFLD by activating the AMPK/ACC pathway and inhibiting ferroptosis.

The study modeled T2DM-associated NAFLD in mice by feeding them a high-fat diet and injecting them with streptozotocin, and analyzed gene expression in the liver through RNA-seq. Fasting blood glucose was measured during liraglutide and ferrostatin-1 administration, liver pathology was evaluated with hematoxylin and eosin staining, liver ferroptosis was measured by in vivo lipid peroxidation, and the mechanism of liraglutide’s inhibition of ferroptosis was studied through in vitro cell culture. The results showed that liraglutide improved not only glucose metabolism but also liver tissue damage. Transcriptome analysis indicated that liraglutide regulates lipid metabolism-related signaling including AMPK and ACC. Moreover, ferroptosis inhibitors, but not other cell death inhibitors, rescued liver cell viability in the presence of high glucose. Mechanistically, liraglutide induced the activation of AMPK phosphorylating ACC, and the AMPK inhibitor compound C blocked the ferroptosis inhibition mediated by liraglutide. Furthermore, ferroptosis inhibitors restored liver function in T2DM mice.

Commentary (by Dr. Jiajie Lu)

Non-alcoholic fatty liver disease (NAFLD) is a multisystem disease related to metabolic disorder, with type 2 diabetes mellitus (T2DM) being a major risk factor for its onset and progression. Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) receptor agonist primarily used to treat type 2 diabetes, but its impact on T2DM-related NAFLD and its mechanisms of action are relatively under-researched.

A recent basic research study by Tingli Guo and others used a liraglutide intervention in NAFLD mouse models and in vitro cell cultures to assess the therapeutic effects of liraglutide on NAFLD mouse models and explore its possible mechanisms of action. The results found that liraglutide could reduce liver lipid deposition and liver damage in NAFLD mouse models by activating the AMP-activated protein kinase/acetyl-CoA carboxylase (AMPK/ACC) signaling pathway and inhibiting ferroptosis, thereby improving NAFLD.

However, due to the limitations of the animal models and in vitro cell cultures used in this study, and considering that liraglutide can affect the development of NAFLD through multiple signaling pathways, the mechanisms of action of liraglutide in the treatment of NAFLD still need further clarification. Future research, including more clinical and basic studies, is required to verify the role of liraglutide in the treatment of NAFLD. This includes incorporating intra- and extracellular environmental factors into observation indicators, building a dynamic observation system, and deeply studying its mechanisms of action, with the aim of providing new ideas and strategies for the pharmacological treatment of NAFLD.

03

Hepatic FASN Deficiency Differentially Affects Nonalcoholic Fatty Liver Disease and Diabetes in Mouse Obesity Models

Toshiya Matsukawa, Takashi Yagi, et al. JCI Insight. 2023 Sep 8.

Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes are complications of obesity, and they influence each other. Increased de novo lipogenesis (DNL) in the liver, triggered by hyperinsulinemia and carbohydrate overload, is one of the mechanisms in their pathogenesis. Fatty acid synthase (FASN) is a key enzyme in hepatic DNL, and its upregulation is associated with insulin resistance. However, the therapeutic potential of targeting FASN in hepatocytes for obesity-related metabolic diseases remains unclear.

Toshiya and others found that hepatic FASN deficiency affects NAFLD and diabetes differently, depending on the cause of obesity. Hepatocyte-specific FASN deletion improved NAFLD and diabetes in mice with a melanocortin 4 receptor deficiency but not in diet-induced obese mice. In leptin-deficient mice, FASN deletion alleviated hepatic steatosis and improved glucose tolerance, but worsened hyperglycemia and liver dysfunction. The beneficial effects of hepatic FASN deficiency on NAFLD and glucose metabolism were associated with DNL inhibition, and weakened gluconeogenesis and fatty acid oxidation, respectively. In leptin-deficient mice, postoperative feeding-induced hyperglycemia seemed to promote glycogen accumulation and citrate-mediated glycolysis inhibition, leading to impaired hepatic glucose uptake. Therefore, the cause of obesity should be considered when further researching the therapeutic potential of hepatic FASN inhibition for human NAFLD and diabetes.

Commentary (by Dr. Haifang Cao)

NAFLD and type 2 diabetes are both complications of obesity, often coexisting and influencing each other. Increased hepatic DNL is one of their pathogenic mechanisms , and FASN is a key enzyme, and its up-regulation is related to insulin resistance. The research team used hepatocyte-specific FASN-deficient mice and found that hepatic FASN deficiency’s impact on NAFLD and diabetes varies depending on the cause of obesity. In this animal model, FASN deficiency mitigated hepatic steatosis and improved glucose tolerance, but exacerbated hyperglycemia and liver dysfunction. This suggests that hepatic FASN has further research significance and potential application value in the diagnosis and treatment of NAFLD and diabetes.

This study also has limitations, such as the significant differences in physiological and metabolic processes between animals and humans, which may prevent the experimental results from accurately reflecting human conditions. Similar studies need to be conducted in a broader human population.

04

Hepatic T-cell Senescence and Exhaustion are implicated in the Progression of Fatty Liver Disease in Patients with Type 2 Diabetes and Mouse Models with Nonalcoholic Steatohepatitis

Sim BC, Kang YE, et al. Cell Death Dis. 2023 Sep 21.

Immunosenescence and exhaustion play a role in the development and progression of type 2 diabetes (T2D) and metabolic liver diseases, including fatty liver, fibrosis, and cirrhosis. However, the relationship between T-cell aging, exhaustion, and insulin resistance-related liver diseases remains unclear. To better define the relationship between T2D and non-alcoholic fatty liver, South Korean scientists studied 59 T2D patients (average age 58.7±11.0 years; 47.5% male), finding that T-cell senescence is associated with insulin resistance and metabolic liver disease in T2D patients.

The study used flow cytometry to analyze peripheral blood mononuclear cells to characterize the patients’ systemic immune phenotype. Magnetic Resonance Imaging (MRI)-based proton density fat fraction and elastography analyses quantified liver fat and fibrosis markers, respectively. Compared to participants with lower Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) values, those with insulin resistance had a significant increase in CD28 – CD57+ senescent T-cells in both CD4+ and CD8+ cells. Using MRI-based elastography assessments, the abundance of senescent CD4+ and CD8+ T-cells, as well as HOMA-IR, correlated positively with the severity of liver fibrosis. The study revealed that interleukin IL-15 from hepatic mononuclear cells is an inducer of T-cell paracrine activation, associated with liver disease progression in T2D participants. Additionally, high expression of genes related to aging and exhaustion was found in CD4+ and CD8+ T-cells of participants with non-alcoholic steatohepatitis or cirrhosis. Finally, the study demonstrated that diet or chemically induced non-alcoholic steatohepatitis in mouse models induces hepatic T-cell senescence and exhaustion.

Commentary (by Dr. Haifang Cao)

Previous research has shown that T-cell exhaustion impacts the development and progression of chronic liver diseases, but the relationship between T-cell aging, exhaustion, and insulin resistance, as well as metabolic liver diseases, is still unclear. The research team studied this from both cellular and imaging perspectives, finding that the abundance of senescent CD4+ and CD8+ T-cells and HOMA-IR correlated positively with the severity of liver fibrosis. Interleukin IL-15 is an inducer of T-cell paracrine activation, related to liver disease progression in type 2 diabetes participants. These findings lay a theoretical foundation for further exploration of the role of T-cell activation, apoptosis, and exhaustion in the progression of metabolic liver diseases.

This study has limitations, such as significant physiological and metabolic differences between animals and humans, which may prevent the experimental results from accurately reflecting human conditions. Additionally, human immune senescence, beyond CD4+ and CD8+ cells, requires more valuable indicators for evaluation.

05

Association of Thyroid Function with Non-Alcoholic Fatty Liver Disease in Recent-Onset Diabetes

Saatmann N, Schön M, Zaharia OP, et al. Liver Int. 2023 Sep 12.

Non-alcoholic fatty liver disease (NAFLD) is associated with type 2 diabetes (T2D) and hypothyroidism. However, the relationship between thyroid function and NAFLD in diabetic patients is not clear. This study investigated the association between free thyroxine (fT4) or thyroid-stimulating hormone (TSH) and NAFLD in patients with recent-onset diabetes. The results indicate that the risk of steatosis in type 2 diabetes patients is related to decreased thyroid function, which is mediated by insulin resistance and body weight, particularly in males, while no such relationship exists in type 1 diabetes patients.

The German Diabetes Study (GDS) is a prospective longitudinal cohort study where patients with newly diagnosed type 1 diabetes (T1D, n=358), T2D (n=596), or no diabetes (CON, n=175) underwent Botnia clamp tests, and assessments of fT4, TSH, and Fatty Liver Index (FLI), with 1H-magnetic resonance spectroscopy analyses in a representative sub-cohort. Firstly, fT4 levels were similar between T1D and T2D (P=0.55) but higher than in the CON group (T1D: P<0.01; T2D: P<0.001), while TSH concentrations were not different across all groups. Secondly, only in T2D, fT4 was negatively correlated with FLI and positively correlated with insulin sensitivity (ß=-0.110, P<0.01; ß=0.126, P<0.05), especially in men adjusted for age, sex, and BMI (ß=-0.117, P<0.05; ß=0.162; P<0.01). However, the correlation between fT4 and FLI lost statistical significance after adjusting for insulin sensitivity (T2D: ß=-0.021, P=0.67; men with T2D: ß=-0.033; P=0.56). TSH was positively correlated with FLI only in male T2D patients (ß=0.116, P<0.05), but the correlation disappeared after adjusting for age and BMI (ß=0.052; P=0.30).

Commentary (by Dr. Zuxiong Huang)

Non-alcoholic fatty liver disease (NAFLD) is closely related to diabetes, with 60% – 80% of patients with type 2 diabetes and obesity also suffering from NAFLD. Diabetic patients often have concurrent hypothyroidism, and hypothyroidism increases the risk of NAFLD. However, the relationship between thyroid function and NAFLD in newly diagnosed diabetic patients is not clear.

This prospective longitudinal cohort study from the German Diabetes Study investigated the association between free thyroxine (fT4), thyroid-stimulating hormone (TSH), and NAFLD in newly diagnosed diabetic patients. It found that lower fT4 and higher TSH are related to a higher risk of steatosis in male patients with type 2 diabetes.

The study has some limitations: firstly, it used the Fatty Liver Index (FLI) as a surrogate marker for hepatic steatosis and fibrosis, instead of more sensitive and specific methods like MPDF or 1 H-MRS. Secondly, it did not measure fT3 and sex hormone levels, failing to explain gender differences in the results. Additionally, the correlation of low fT4 with increased steatosis risk applies only to type 2 diabetes, not type 1, and the discussion on insulin resistance and body weight mediation lacks in-depth mechanism exploration. The study highlights the need for thyroid function screening in patients with type 2 diabetes but requires further validation in other cohorts and clinical studies.

06

Diabetes Mellitus and the Progression of Non-Alcoholic Fatty Liver Disease to Decompensated Cirrhosis: A Retrospective Cohort Study

O’Beirne J, Skoien R, Leggett BA, et al. Med J Aust. 2023 Sep 25.

To determine the incidence and risk factors for decompensated cirrhosis in hospitalized patients with or without cirrhosis suffering from non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), a retrospective cohort study included patients aged 20 or above admitted to Queensland hospitals for NAFLD/NASH between July 1, 2009, and December 31, 2018, analyzing data with decompensated cirrhosis (ascites, hepatic encephalopathy, or esophageal variceal bleeding) as the primary endpoint. The results indicate that identifying advanced fibrosis and providing appropriate treatment to prevent disease progression is crucial, given the higher risk of cirrhosis decompensation in diabetic patients.

The analysis included data from 8006 patients (10,082 admissions), of whom 4632 were female (58%) and 2514 had diabetes (31%). The median follow-up was 4.6 years (interquartile range: 2.7–7.2 years), and 351 patients (4.4%) developed decompensated cirrhosis during follow-up. Among the 6900 patients without cirrhosis, 4.5% (95% CI: 3.6–5.7%) experienced decompensated cirrhosis over ten years (average annual rate: 0.5%; 95% CI: 0.4-0.6%); higher risk was seen in those aged 70 or older (aHR: 4.7; 95% CI: 2.0–11.0), with extrahepatic cancer (aHR: 5.0; 95% CI: 3.0–8.2), cardiovascular events (aHR: 1.9; 95% CI: 1.2–3.1), or a history of diabetes (aHR: 2.8; 95% CI: 2.0–3.9). Among 1106 patients with cirrhosis, 32.4% (95% CI: 27.2–38.3%) developed decompensated cirrhosis within ten years (average annual rate: 5.5%; 95% CI: 4.8–6.3%); higher progression risk was seen in patients with portal hypertension (aHR: 1.8; 95% CI: 1.3–2.7), extrahepatic cancer (aHR: 1.8; 95% CI: 1.1–2.9), or diabetes (aHR: 1.5; 95% CI: 1.1–2.0). Compared to those without cirrhosis or diabetes, individuals with cirrhosis (aHR: 10.7; 95% CI: 7.6–15.0) or both cirrhosis and diabetes (aHR: 14.4; 95% CI: 10.1–20.6) had a higher risk of decompensation.

Commentary (by Dr. Zuxiong Huang)

Nonalcoholic fatty liver disease (NAFLD) can develop major adverse cardiovascular events and extrahepatic complications such as cancer, as well as decompensated cirrhosis and hepatocellular carcinoma. Identifying patients with high-risk factors is important to prevent patients with NAFLD from progressing to decompensated cirrhosis.

This large retrospective cohort study from Australia investigated the incidence of decompensated cirrhosis and associated risk factors in hospitalized patients with NAFLD or nonalcoholic steatohepatitis (NASH) with or without cirrhosis. The study found that 37.1% of patients with NAFLD-associated cirrhosis and diabetes progressed to decompensated cirrhosis within 10 years (an average of 7.1% per year). The risk of progression to decompensated cirrhosis was higher in patients with NAFLD/NASH who had diabetes but no cirrhosis at admission (8.9% within 10 years) than in those without cirrhosis and diabetes (2.8% at 10 years). In addition, age, hypertension, extrahepatic tumors, and a history of major adverse cardiovascular events also affect progression, with a 13-fold increased risk of decompensated cirrhosis in people aged 50 years and older with diabetes, a history of major adverse cardiovascular events, and hypertension. Therefore, early identification of progressive liver fibrosis and appropriate treatment in patients with NAFLD/NASH with diabetes mellitus are essential to avoid disease progression.

There are still some limitations to the study: firstly, hospital-based cohort studies are not fully representative of the NAFLD/NASH population; Secondly, there may be biases in the retrospective cohort, such as insufficient assessment of liver fibrosis, inability to accurately include alcohol intake, and loss to follow-up, which requires further validation of prospective cohorts such as population-based.

TAG: review; commentary; fatty liver diease; NAFLD; diabetes