Introduction
Metabolic Dysfunction-Associated Fatty Liver Disease (MASLD) and Type 2 Diabetes Mellitus (T2DM) are two prevalent metabolic disorders that often coexist and exacerbate each other’s progression. This article explores the complex interrelationship between these conditions, highlighting the pathophysiological pathways involved, the clinical implications, and potential therapeutic interventions.
The Intertwined MASLD and T2DM Relationship
MASLD is characterized by liver macrosteatosis in more than 5% of hepatocytes, often associated with insulin resistance conditions such as obesity, T2DM, and metabolic syndrome. While MASLD frequently presents as a mild disease, it can progress to metabolic dysfunction-associated steatohepatitis (MASH) in 20-25% of cases, leading to liver cirrhosis and increased liver-related mortality.
T2DM and MASLD are global health concerns with significant public health burdens. The prevalence of T2DM is expected to rise from 529 million individuals in 2021 to 1.23 billion by 2050. Similarly, MASLD is one of the most common causes of liver disease worldwide, with a prevalence increase from 25.5% before 2005 to 37.8% in recent years.
Pathogenic Pathways Involved in the Synergic Interaction
Insulin Resistance, Liver Lipotoxicity, and Adipocyte Dysfunction
Insulin resistance is a key driver for both MASLD and T2DM. In the liver, it disrupts glucose metabolic pathways, leading to hyperglycemia and increased insulin secretion. This metabolic derangement induces chronic hyperinsulinemia, contributing to T2DM development. In peripheral adipose tissue, insulin resistance increases lipolysis and free fatty acid production, which are captured by hepatocytes, leading to liver steatosis and lipotoxicity.
Microbiota Dysbiosis
Microbiota dysbiosis plays a significant role in metabolic dysfunction. Changes in intestinal flora promote MASLD progression by increasing intestinal permeability and interacting with liver cells. Dysbiosis is also present in T2DM, contributing to systemic inflammation and increased risk of MASLD and hepatocellular carcinoma (HCC).
Bile Acid Metabolic Pathways
Bile acid signaling, involving receptors like FXR and TGR5, regulates glucose and lipid metabolism. FXR activation reduces lipogenesis and increases fatty acid oxidation, while TGR5 activation promotes insulin secretion and increases energy expenditure. Modifications in bile acid metabolism are observed in MASH, independent of obesity and T2DM.
Genetic Factors for MASLD and T2DM
Genetic predisposition plays a role in both T2DM and MASLD. Variants influencing insulin production, insulin resistance, and adiposity are linked to T2DM. For MASLD, genetic variants involved in lipid processing and hepatocyte function contribute to disease progression and increased hepatic insulin resistance.
Clinical Implications of the MASLD and T2DM Association
Surveillance, Diagnosis, and Staging
Due to the high prevalence and multisystemic implications, managing MASLD and T2DM requires a multidisciplinary approach. Regular screening for T2DM in MASLD patients and vice versa is recommended. Liver function tests alone are insufficient for MASLD assessment; non-invasive tests (NITs) like FIB-4 and imaging-based elastography are essential for evaluating liver fibrosis.
Importance of T2DM Surveillance in MASLD Patients
MASLD patients have a 2-3 fold increased risk of developing T2DM. Regular screening with fasting glucose and HbA1c is recommended, especially in obese individuals or those with a family history of T2DM. T2DM diagnosis impacts liver fibrosis progression and the risk of HCC in MASLD patients.
MASLD and Microvascular Complications of T2DM
MASLD increases the risk of microvascular complications in T2DM, particularly chronic kidney disease (CKD) and diabetic neuropathy. The presence of MASLD is associated with a higher risk of CKD and neuropathy, necessitating vigilant monitoring and management.
Cardiovascular Disease in Subjects with T2DM and MASLD
Cardiovascular disease (CVD) is the leading cause of death in T2DM and MASLD. Both conditions independently increase the risk of coronary artery disease, cerebrovascular disease, and heart failure. Managing associated risk factors is crucial to prevent CVD in patients with combined T2DM and MASLD.
Surveillance of MASLD and Liver Complications in Patients with T2DM
MASLD assessment in T2DM patients is recommended in most guidelines. Diagnosis involves detecting liver steatosis, ruling out other causes, and assessing liver fibrosis severity using NITs. Regular monitoring and appropriate management of liver complications are essential for improving patient outcomes.
Therapeutic Interventions for T2DM and MASLD
Lifestyle Interventions
Weight loss through lifestyle modifications is the cornerstone of treatment for both T2DM and MASLD. A weight reduction of more than 7% is associated with significant improvements in MASH and liver fibrosis. The Mediterranean diet and regular exercise are recommended for their beneficial effects on metabolic control and cardiovascular health.
Cardiovascular Disease Prevention
Preventing cardiovascular events is a major goal in treating T2DM and MASLD. Aggressive management of hypertension, dyslipidemia, and other CVD risk factors is essential. Statins are recommended for cholesterol management, and antiplatelet therapy may be considered for primary prevention in high-risk patients.
Bariatric Surgery
Bariatric surgery is an effective intervention for patients with obesity and T2DM or high-risk MASLD. It induces significant weight loss, improves glycemic control, and resolves MASH in a substantial proportion of patients. Careful selection and multidisciplinary care are crucial for optimal outcomes.
Pharmacologic Treatment for MASLD
Currently, no specific medication is recommended for MASLD therapy, although several drugs are under investigation. Vitamin E and pioglitazone have shown some benefits in clinical trials, but further research is needed to establish their long-term efficacy and safety.
Pharmacologic Treatment for T2DM in Patients with MASLD
Medications like GLP-1 receptor agonists and pioglitazone have shown promise in treating T2DM and MASLD. These drugs improve glycemic control, promote weight loss, and have beneficial effects on liver histology. Recent guidelines recommend their use in T2DM patients with MASLD.
Conclusion
The intricate relationship between T2DM and MASLD necessitates integrated management approaches. Understanding the shared pathophysiological mechanisms and clinical implications is crucial for developing effective therapeutic strategies. Lifestyle modifications, pharmacologic interventions, and regular monitoring are essential for improving patient outcomes and reducing the global burden of these metabolic disorders.
Authors
Francisco Barrera, Javier Uribe, Nixa Olvares, Paula Huerta, Daniel Cabrera, Manuel Romero-Gomez
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