Metabolic-Associated Steatotic Liver Disease (MASLD) and Type 2 Diabetes: Mechanisms, Diagnostic Approaches, and Therapeutic Interventions

Abstract

Metabolic-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus (T2DM) are interrelated metabolic disorders with significant global health impacts. MASLD, the hepatic manifestation of metabolic dysfunction, is driven by insulin resistance, ectopic lipid accumulation, and systematic inflammation. T2DM exacerbates the progression of MASLD, increasing the risk of advanced fibrosis, cardiovascular complications, and hepatocellular carcinoma (HCC). This bidirectional relationship highlights the need for integrated management strategies. The pathology of these conditions involves disrupted lipid and glucose metabolism, leading to a cycle of metabolic dysfunction which worsens both hepatic and systemic outcomes. Non-invasive diagnostic tools have improved early detection but lack precision in staging liver disease, emphasizing the need for more accurate biomarkers. Routine screening for MASLD in diabetic populations is critical for early intervention. Management focuses on weight reduction through lifestyle changes, although long-term adherence remains a challenge. Pharmacological advancements, including glucagon-like peptide-1 receptor agonists (GLP-1Ras) and sodium–glucose cotransporter-2 (SGLT2) inhibitors, show promise in reducing liver fat, improving glycemic control, and slowing fibrosis progression. However, these therapies are less effective in advanced stages of fibrosis and cirrhosis, underscoring the need for novel treatment options. In conclusion, the intertwined nature of MASLD and T2DM necessitates a multidisciplinary approach integrating early diagnosis, lifestyle interventions, and targeted therapies. Future research should prioritize refining diagnostic accuracy and developing innovative treatments for delivering personalized care strategies to mitigate the growing burden of these conditions. These efforts are crucial for improving outcomes in this vulnerable population.

1. Introduction

Metabolic dysfunction-associated steatotic liver disease (MASLD) impacts roughly 30% of the adult population globally, with its prevalence notably increasing from 22% in 1991 to 37% in 2019 [1]. This rise is closely linked to the growing rates of obesity and other associated metabolic disorders [2]. The more severe form of MASLD, referred to as metabolic dysfunction-associated steatohepatitis (MASH), is marked by significant histological characteristics such as hepatocyte ballooning and lobular inflammation, which considerably heighten the risk of fibrosis progression [3]. A multicenter cohort study conducted in Asia found that 63% of patients with MASLD who underwent liver biopsies were diagnosed with MASH, in contrast to merely 7% of those with MASLD who did not have biopsies performed [4].

Cardiovascular disease (CVD) continues to be the primary cause of mortality among patients with MASLD [5]. The impact of CVD in individuals suffering from MASH remains inadequately defined, especially when compared with other hepatic disorders such as MASLD [5]. A cohort study indicated that the rate of cardiovascular events was 2.03 per 100 person-years, whereas liver-related events were recorded to be 0.43 per 100 person-years among patients with MASLD who underwent liver biopsies [6]. Notably, liver-related events were restricted to individuals with advanced fibrosis, demonstrating a cumulative incident of 9.1%, with no occurrences in patients without advanced fibrosis. For patients classified as having F3 and F4 fibrosis, the rates of liver-related events were 1.47 and 3.85 per 100 person-years, respectively [7]. Typically, liver fibrosis is scored in stages and necroinflammation is evaluated by grade. Liver fibrosis is histologically staged by assessing the amount of fibrosis and the level of architectural disorganization. The fibrosis score is a grading system used to assess the level of inflammation and tissue breakdown in the liver. It ranges from F0 to F4, with F0 indicating no fibrosis, while F1 represents portal fibrosis without septa. As the severity increases, F2 denotes portal fibrosis with a few septa, and F3 indicates numerous septa without cirrhosis. The most advanced stage, F4, corresponds to cirrhosis, signifying significant liver damage and scarring [8].

At present, MASLD is acknowledged as the most prevalent chronic liver condition worldwide, with projections indicating a continued increase in its occurrence. This condition is intricately linked to T2DM and various cardiometabolic risk factors, thereby heightening the likelihood of developing cardiovascular disease, chronic kidney disease, and malignancies including hepatocellular carcinoma (HCC). Additionally, complications related to the liver, such as liver failure, are commonly encountered. The escalating socioeconomic impact of MASLD underscores the critical necessity for proactive measures from healthcare systems and policymakers [9].

MASLD is characterized by an excessive buildup of triglycerides in the liver, which is usually linked to at least one cardiometabolic risk factor. This condition encompasses a range of disorders, including isolated liver cirrhosis, metabolic dysfunction-associated steatotic liver (MASL), MASH, and complications such as fibrosis and cirrhosis. The term MASLD has superseded the term non-alcoholic fatty liver disease (NAFLD) and now forms part of an expanded classification of steatotic liver diseases (SLDs). This revised framework additionally incorporates moderate alcohol-related MASLD (MetALD), alcohol-related liver disease (ALD), drug-induced SLD, monogenic disorders, and cryptogenic SLD [9].

Recent modifications in terminology highlight the essential importance of metabolic risk factors, with particular emphasis on T2DM, in the context of MASLD. T2DM interferes with glucose and lipid metabolism, resulting in systemic complications which adversely affect various organs [9]. The reciprocal relationship between T2DM and MASLD indicates that T2DM not only accelerates the progression of MASLD but also heightens the risk of both hepatic and extrahepatic complications. In turn, MASLD increases the likelihood of developing T2DM and deteriorates glycemic control in individuals who have already been diagnosed [9]. It is crucial to conduct early screening for liver disease in patients with T2DM and regular diabetes screening for those who have been diagnosed with MASLD in clinical practice. Although weight loss continues to be a fundamental aspect of treatment, additional options such as hypoglycemic medications, advanced therapies, and bariatric surgery are available when lifestyle modifications prove to be inadequate [9].

A meta-analysis encompassing more than 1.8 million individuals diagnosed with T2DM revealed that 65.04% presented with MASLD, with prevalence rates of 58.84% in eastern regions and 72.65% in western regions, respectively [10]. Among these individuals, 46.88% were diagnosed with MASH. Data derived from the National Health and Nutrition Examination Surveys (2017–2018) revealed that the prevalence of high-risk MASH varied from 8.7% to 22.5% in the demographic population with T2DM, indicating that at least 2 million adults in the United States are impacted by this condition [11]. It is clear that T2DM plays a significant role in the advancement of MASLD. Given that MASLD is recognized as a hepatic manifestation of a dysmetabolic condition, it is intricately linked to the onset of T2DM. A longitudinal study involving 220 patients found liver fibrosis as an independent predictor of incident diabetes and cirrhosis complications, while CVE was linked to baseline diabetes and the AST/ALT ratio [12].

2. Pathophysiological Processes Linking MASLD and T2DM

The intricate interplay between T2DM and MASLD is predominantly influenced by insulin resistance (IR), which is crucial in the advancement of both disorders. The epidemiological association between MASLD and T2DM is well established. Clinical evidence, along with murine models, indicates that MASLD may either precede or elevate the risk of developing T2DM. Indeed, the presence of hepatocellular steatosis, particularly the buildup of hepatic diacylglycerol (DAG) within cytoplasmic lipid droplets, serves as a strong predictor of hepatic insulin resistance. This occurs through the downregulation of insulin receptor expression on the membrane and the activation of hepatic protein kinase C, which disrupts cellular insulin signaling [13]. Within the liver, the accumulation of hepatic diacylglycerol promotes the activation of protein kinase Cε, which then translocates to the cell membrane, leading to the disruption in insulin signaling. This disruption in insulin signaling diminishes glycogen synthesis while promoting gluconeogenesis, causing substantial variations in glucose and insulin levels [13]. Likewise, the accumulation of ectopic lipids in skeletal muscle exacerbates IR, as the tissue transitions towards the de novo lipogenesis rather than glycogen storage [13].

An elevated rate of lipolysis in dysfunctional adipose tissue, marked by decreased levels of adiponectin, a heightened influx of long-chain fatty acids, and increased proinflammatory cytokines, intensifies systemic insulin resistance [14]. Additional factors that contribute to this condition encompass dysregulated bile acid metabolism, imbalances in the gut microbiota, and changes in hepatokine activity, all of which are implicated in the progression of MASLD and T2DM [15]. The interplay among these interrelated mechanisms highlights the necessity for further investigation to elucidate the relationships between these conditions. The rising lipolysis within adipose tissues results in an increased influx of free fatty acids (FFAs) into ectopic tissues, which intensifies insulin resistance and induces apoptosis in liver and muscle cells. This series of reactions culminates in a “lipotoxic state”, which is a hallmark of metabolic dysfunction-associated steatohepatitis (MASH), alternately leading to hepatocyte necroinflammation [16].

The liver’s accumulation of triacylglycerol (TAG) arises from three primary sources: 59% is sourced from circulating FFAs, 26% is attributed to de novo lipogenesis (DNL)—the conversion of carbohydrates into lipids—and 14% is derived from dietary intake [17]. Upon entering the portal circulation, FFAs can either undergo β-oxidation, be re-esterified into TAG for secretion as very low-density lipoprotein (VLDL), or be retained within the liver following re-esterification. The presence of insulin resistance worsens de novo lipogenesis, thereby increasing TAG accumulation [18]. In MASLD, impaired glycogen synthesis coupled with heightened gluconeogenesis results in an elevated production of pyruvate, a crucial substrate for DNL. This metabolic pathway produces acetyl-CoA, which is then transformed into malonyl-CoA, promoting DNL instead of entering the citric acid cycle [19].

Hepatic insulin resistance is additionally marked by the movement of protein kinase C from the cytosol to the membrane, which disrupts the activation of insulin receptor substrate-phosphoinositol-3 kinase [20]. The presence of elevated ceramide levels also leads to the repression of protein kinase B activity, thereby weakening insulin signaling. Recent findings have bolstered the understanding of ceramides’ role in hepatic insulin resistance. One investigation revealed that haploinsufficiency of CerS2 in mice resulted in a reduction in very-long-chain ceramides (C22/C24/C24:1), while simultaneously causing an increase in C16-ceramide, which heightened susceptibility to HFD-induced insulin resistance [21]. Comparable findings were observed in CerS2-null mice, which displayed glucose intolerance and where phosphorylation of both the insulin receptor and Akt was impaired in the liver, although this was not the case in adipose tissue or skeletal muscle [22]. In contrast, the overexpression of CerS2 in primary mouse hepatocytes led to a targeted accumulation of long-chain ceramides and enhanced insulin signaling [23]. The transition from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), and its advancement to fibrosis, is influenced by oxidative stress, mitochondrial dysfunction, and circulating cytokines. Furthermore, the impaired regeneration of hepatocytes contributes to the advancement of fibrosis [23].

3. Screening for MASLD in T2DM

The significant correlation between T2DM and the advancement of hepatic fibrosis underscores the importance of early screening, given its link to heightened mortality rates and liver-related complications [24]. A variety of non-invasive techniques, such as serum biomarkers and imaging modalities, are commonly employed to evaluate the risk of fibrosis in individuals with T2DM. Among these methods, vibration control transient elastography (VCTE) stands out as one of the most precise instruments [24].

An effective method for identifying individuals at low risk for advanced fibrosis involves a sequential approach that initiates with the Fibrosis-4 index (FIB-4 test), followed by VCTE for patients whose FIB-4 scores exceed 2.67 [25]. However, the efficiency of standalone non-invasive tests (NITs) such as FIB-4, the MASLD fibrosis score (NFS), and the aspartate transaminase-to-platelet ratio index (APRI) in populations with type 2 diabetes mellitus is still limited [26]. In a longitudinal study which included 96 patients with biopsy-proven MASLD, 50 of them underwent a 12-month follow-up to assess clinical–biochemical parameters, liver stiffness (LS) by transient elastography, PRO-C3, and multiple NITs such as ADAPT, FIB-4, NFS, and APRI. Among these, LS showed the highest accuracy for detecting advanced fibrosis (AUROC 0.82, cut-off 9.4 kPa), while the ADAPT score performed best among NITs (AUROC 0.80, cut-off 5.02, Se 62%, Sp 89%). Comparing LS vs. ADAPT, no statistical difference was found (DeLong test, p = 0.348). Over 12 months, LS slightly decreased, but PRO-C3 significantly increased (11.2 to 13.9 ng/mL, p = 0.017), and the ADAPT score rose (5.3 to 6.1, p = 0.019), suggesting worsening fibrosis progression. Other NITs (FIB-4, NFS, APRI) remained unchanged over the follow-up period [27]. A cross-sectional study involving 213 patients found that the AUC of FIB-4, APRI, and NFS for screening advanced fibrosis among the T2DM population was 0.85, 0.86, and 0.64, respectively, which were all inferior to the competency of N-terminal propeptide of type 3 collagen, a direct serum biomarker of fibrosis [20]. Another cohort study showed that the AUC of FIB-4 for screening advanced fibrosis in patients with T2DM was only 0.653, significantly lower than the AUC of 0.826 in patients without T2DM [28].

Newly developed diagnostic instruments have been designed to fill these gaps. For example, the Fibrotic MASH Index has attained an AUC of 0.89 in populations with T2DM, surpassing the FIB-4 AUC of 0.67. This diagnostic tool has shown reliable accuracy across different durations of disease and varying levels of HbA1c [24]. Likewise, innovative techniques such as the Enhanced Liver Fibrosis panel, FibroSpect, and the FIB-C3 model incorporate serum biomarkers that reflect hepatic fibrosis. However, despite their potential, these tools necessitate further validation, specifically within the T2DM population [24].

The most recent guidelines [29,30,31] recommend regular screening for hepatic fibrosis in patients with T2DM; however, there are ongoing uncertainties regarding the most effective combinations of non-invasive tests and their optimal cut-off values [24]. For the practical implementation of these strategies, it is crucial to validate them with clinical care pathways in both primary care and diabetes-centered environments. Additionally, a significant number of studies do not distinguish between fibrosis attributable to MASLD/MASH and that arising from other conditions, which may lead to bias in evaluations and treatment strategies.

4. Non-Pharmacological Treatment of MASLD

Weight loss and caloric restriction are recognized as effective non-pharmacological approaches for enhancing MASLD-related biomarkers, such as liver enzymes, steatosis, MASH, and fibrosis, even without an increase in physical activity [32,33,34,35]. There is a dose-dependent correlation between the degree of weight loss and the level of improvement in biomarkers of liver damage [36]. Nonetheless, the evidence concerning the effects of weight loss interventions on advanced fibrosis is still limited.

A study established that a weight loss of more than 5% is essential for reducing liver lipid levels, while a decrease of 7% to 10% is required to diminish inflammation, and a reduction exceeding 10% is necessary for improving fibrosis [37]. Nevertheless, for most individuals, maintaining a sustained weight loss beyond 5% continues to pose a significant challenge [32,33]. The long-term compliance with behavioral interventions often proves insufficient, as evidenced by research on dietary interventions that usually span 2 to 24 months [33,34,35,36]. Most weight loss is observed within the initial six months, but this is commonly succeeded by a gradual regain of weight. By the 12-to-24-month mark, the average net weight loss hovers around 5%, which is accompanied by the partial return of liver lipid content and stiffness [37,38,39,40,41,42,43]. These findings highlight the necessity for cost-effective, long-term lifestyle modification programs that integrate diet, physical activity, and behavioral therapy. Furthermore, there is an immediate requirement for randomized controlled trials extending beyond two years to enhance our understanding of the long-term impacts of lifestyle interventions.

Research indicates that physical activity alone, without any modifications to the diet, can lead to a decrease in liver steatosis among patients with MASLD [44]. For instance, 150–240 min per week of at least moderate-intensity aerobic exercise can reduce hepatic steatosis by ~2–4% (absolute reduction), but as little as 135 min/week has been shown to be effective [45]. Various forms of exercise, such as aerobic, resistance, and high-intensity interval training, have proven effective in diminishing liver fat. Nevertheless, the most effective exercise protocol for addressing fibrosis remains uncertain [46,47,48]. A meta-analysis encompassing 19 randomized controlled trials that compared traditional moderate-intensity continuous training with high-intensity interval training revealed that both methods were similarly effective in reducing liver fat [49].

5. Pharmacological Treatment of MASLD

A multitude of clinical trials is currently under way to assess the safety and effectiveness of pharmacological interventions for MASLD/MASH, focusing particularly on patients who also have T2DM [49,50,51]. Due to the significant correlation between T2DM and the advancement of MASLD, numerous randomized controlled trials have utilized T2DM as a stratification criterion during the randomization process. Among the hypoglycemic agents being studied, glucagon-like peptide-1 receptor agonists (GLP-1Ras), peroxisome proliferator-activated receptor (PPAR) agonists, PPARα agonists, and other dual-agonists have demonstrated substantial potential in enhancing liver histology and managing glycemic levels.

5.1. Thiazolidinediones

Glitazones facilitate the sensitization of adipose tissue to insulin via the activation of PPARγ, which subsequently leads to the uptake and storage of fatty acids [52]. Additionally, there is an elevation in adiponectin levels accompanied by a reduction in proinflammatory adipokines, thereby decreasing gluconeogenesis and the influx of fatty acids, which enhances insulin sensitivity [53]. Furthermore, these compounds contribute to the restoration of normal adipose tissue biology, resulting in an improvement in hepatic steatosis [54]. The effects of thiazolidinediones on liver steatosis have been well-documented (see Appendix A-

Table A1. ↓ means decrease, → means stable, ↑ means increase.

Study Authors and Year	Drug Family	Drug Name	Targeted Pathways	Metabolic Outcomes
Harrison et al., 2023 [55]	PPARγ Agonists	PXL065	PPARγ	↓ Liver Fat and ↑ Glycemia/Insulin Sensitivity
Yoneda et al., 2021 [56]	SGLT2 Inhibitors and Thiazolidinediones	Tofogliflozin and Pioglitazone	SGLT2 and PPARγ	↓ Hepatic Steatosis; Tofogliflozin → Weight Loss, and Pioglitazone → Weight Gain
Cusi et al., 2016 [54]	Thiazolidinediones	Pioglitazone	PPARγ	↓ Steatosis, ↓ Fibrosis, and ↑ Insulin Sensitivity
Francque et al., 2021 [57]	Pan-PPAR Agonists	Lanifibranor	PPARα, PPARγ, and PPARδ	↓ Fibrosis, ↓ Lipotoxicity, ↓lipid, inflammatory, and fibrosis biomarkers, and ↑ Metabolic Outcomes
Kinoshita et al., 2020 [58]	SGLT2 Inhibitors, Thiazolidinediones, and Sulfonylureas	Dapagliflozin, Pioglitazone, and Glimepiride	SGLT2, PPARγ, and Sulfonylurea Receptor	Pioglitazone → ↑ Adiponectin; Dapagliflozin → ↓ Body Weight and ↓ Visceral Fat
Harrison et al., 2025 [60]	GLP-1/GCG Dual-Agonists	Pemvidutide	GLP-1R and GCG	↓ Liver Fat (68.5%) and ↓ Body Weight
Newsome et al., 2021 [61], and Loomba et al., 2023 [62]	GLP-1R Agonists	Semaglutide	GLP-1R	↓ MASH progression
Armstrong et al., 2016 [63], and Guo et al., 2020 [64]	GLP-1R Agonists	Liraglutide	GLP-1R	↓ MASH progression
Kuchay et al., 2020 [65], and Gastaldelli et al., 2022 [66]	GLP-1R Agonists	Dulaglutide and Tirzepatide, respectively	GLP-1R and GIP, respectively	↓ Liver Fat, ↓ Weight, and ↑ Glycemic Control
Romero-Gómez et al., 2023 [67], and Xiang et al., 2024 [68]	GLP-1R Agonists	Efinopeglutide and HEC88473, respectively	GLP-1R	↓ Liver Fat and ↑ Glycemic Levels
Ito et al., 2024 [69]	SGLT2 Inhibitors	Ipragliflozin	SGLT2	↓ Fibrosis, ↑ Glycemic Control, and ↓ Body Weight
Bi et al., 2014 [70], and Liu et al., 2020 [71]	GLP-1R Agonists	Exenatide	GLP-1R	↓ Visceral Fat, ↓ Liver Fat, and ↑ Glycemic Control
Shen et al., 2024 [72]	SGLT2 and DPP4 Inhibitors	Various	SGLT2 and DPP4	Limited efficacy in advanced liver disease
Cusi et al., 2019 [76]	SGLT2 Inhibitors	Canagliflozin	SGLT2	↓ Liver Steatosis, ↓ Weight, ↓ Fasting Glucose, and ↑ Insulin Sensitivity
Eriksson et al., 2018 [77]	SGLT2 Inhibitors	Dapagliflozin	SGLT2	↓ Liver Fat, ↓ Enzymes, ↓ Fibrosis, ↓ Body Weight, and ↑ Glycose Control
Taheri et al., 2020 [78]	SGLT2 Inhibitors	Empagliflozin	SGLT2	↓ Steatosis, ↓ Fibrosis, and ↓ Body Weight
Chehrehgosha et al., 2021 [79]	SGLT2 Inhibitors	Empagliflozin	SGLT2	↓ Steatosis, ↓ Fibrosis, and ↓ Body Weight
Elhini et al., 2022 [80]	SGLT2 Inhibitors	Empagliflozin	SGLT2	↓ Steatosis, ↓ Fibrosis, ↓ Body Weight, and ↓ HbA1c
Takahashi et al., 2022 [81]	SGLT2 Inhibitors	Ipragliflozin	SGLT2	↓ Liver Fat, ↓ Visceral Fat, ↓ Fibrosis, ↓ HbA1c, and ↓ BMI
Shibuya et al., 2018 [82]	SGLT2 Inhibitors	Luseogliflozin	SGLT2	↓ Steatosis, ↓ Visceral Fat, ↓ BMI, and ↓ HbA1c (greater than metformin)
Yoneda et al., 2021 [56]	SGLT2 Inhibitors	Tofogliflozin	SGLT2	↓ Liver Fat, ↓ Body Weight (vs. Pioglitazone), ↑ ALT, and ↓ Fibrosis

).

Harrison et al. [55] evaluated PXL065 (deuterium-stabilized (R)-449 pioglitazone), demonstrating significant reductions in liver fat content and improvements in metabolic and histological parameters over 36 weeks. This highlighted PXL065’s potential as a well-tolerated therapy for MASH. Yoneda et al. [56] investigated the effects of tofogliflozin, a sodium–glucose contrasporter-2 (SGLT2) inhibitor, and pioglitazone, a thiazolidinedione, over 24 weeks. Both medical substances significantly reduced hepatic steatosis. Tofogliflozin induced weight loss, while pioglitazone led to weight gain, highlighting their mechanisms of action and the importance of personalized medical approaches. Cusi et al. [54] confirmed the long-term benefits of pioglitazone in patients with T2DM and biopsy-confirmed MASH. Pioglitazone improved histological features, enhanced insulin sensitivity, and reduced hepatic triglycerides. Franque et al. [57] investigated lanifibranor, a pan-PPAR agonist in fibrosis reduction and MASH resolution. In this Phase IIb trial, lanifibranor significantly improved histological and metabolic outcomes. Kinoshita et al. [58] compared dapagliflozin, pioglitazone, and glimepiride use in patients with T2DM. The results showed that pioglitazone increased adiponectin significantly while dapagliflozine notably reduced body weight and visceral fat.

5.2. Glucagon-like Peptide-1 (GLP-1) Receptor Agonists

Animal studies have demonstrated that analogs of glucagon-like peptide-1 (GLP-1) can alleviate hepatic steatosis and steatohepatitis through mechanisms related to weight reduction and the expression of the GLP-1 receptor [59]. Additionally, GLP-1 agonists exert a direct effect on the inhibition of lipogenesis within hepatocytes, leading to improved insulin action in both hepatocytes and adipose tissue. The effects of GLP-1 receptor agonists on liver steatosis have been well-documented (see Appendix A-Table A1).

The effectiveness of pemvidutide (peptide-based GLP-1/glucagon dual-receptor agonist) was demonstrated by Harrison et al. [60], achieving significant weight loss along with a 68.5% reduction in liver fat content. Newsome et al. [61] and Loomba et al. [62] found that semaglutide exhibited substantial effectiveness in addressing MASH in both studies, especially at elevated doses. In Armstrong et al. [63] and Guo et al. [64], it was shown that liraglutide slowed down the progression of MASH. Additionally, tirzepatide and dulaglutide revealed significant reductions in liver fat content and improvements in glycemic control and weight management, as shown in Kuchay et al. [65] and Gastaldelli et al. [66]. Efinopeglutide and HEC88473 demonstrated significant reductions in liver fat and improvements in glycemic levels, most of the times surpassing semaglutide in terms of liver fat reduction, as investigated by Romero-Gómez et al. [67] and Xiang et al. [68]. In the research conducted by Ito et al. [69], it was found that ipragliflozin indicated sustained long-term enhancements in fibrosis markers, glycemic management, and body weight. The findings of Bi et al. [70] and Liu et al. [71] highlighted exenatide’s greater effectiveness in decreasing visceral and liver fat compared to insulin glargine and pioglitazone. Shen et al. [72] noted the limited efficacy of SGLT2 and DPP4 inhibitors in preventing advanced liver diseases, indicating that their role may be more aligned with metabolic functions rather than being hepatic.

5.3. Metformin

Metformin is a foundational oral therapy for managing T2DM and is well known for its wide-ranging metabolic benefits and protective effects against numerous conditions. However, its impact on liver health appears limited, as clinical trials have shown minimal effects on hepatic fibrosis and only modest improvements in hepatic steatosis [69]. A retrospective analysis of patients with T2DM with bridging fibrosis caused by MASH or compensated cirrhosis reinforced these observations. Given the complexity of metformin’s pharmacological actions, further investigation is necessary to fully understand its potential role in protecting liver health [73].

5.4. SGLT2 Inhibitors

In recent years, there has been growing research interest in the potential effects of SGLT2 inhibitors in the treatment of MASLD [74]. These medications have demonstrated proven benefits in patients with cardiometabolic disorders, which often coexist and interact with MASLD [74,75]. The effects of SGLT2 inhibitors on liver steatosis have been well-documented (see Appendix A-Table A1).

Canagliflozin, as shown by Cusi et al. [76], demonstrated significant benefits for patients with T2DM and MASLD, including greater remission of livers steatosis compared to the placebo, along with weight loss, reduced fasting glucose, and improved insulin sensitivity. Dapagliflozin, highlighted in studies like EFFECT-II [77], effectively reduced liver fat, enzymes, and fibrosis, showing superior performance in combination therapies and reducing sDPP-4 levels, which may enhance liver function. Empagliflozin demonstrated notable efficacy in reducing severe steatosis, fibrosis, and body weight, outperforming pioglitazone and ursodeoxycholic acid in several studies [78,79,80] and showing strength in combination therapies. Ipragliflozin proved effective in reducing liver fat, visceral fat, fibrosis, and HbA1c, and it helped prevent the progression of simple steatosis to MASH, as shown in long-term studies [81]. Luseogliflozin, compared to metformin, exhibited greater reductions in steatosis, visceral fat, BMI, and HbA1c, establishing itself as a potent treatment option for MASLD in patients with T2DM [82]. Finally, tofogliflozin, as evidenced by the ToPiND study [56], significantly reduced liver fat and body weight compared to pioglitazone, and combination therapies with pioglitazone further improved ALT, steatosis, and fibrosis, suggesting its enhanced efficacy in MASLD management.

5.5. Bariatric Surgery

Bariatric surgery is not only effective in achieving significant and sustained weight loss but also plays a crucial role in improving obesity-related conditions such as type 2 diabetes mellitus, hypertension, dyslipidemia, and obstructive sleep apnea [83,84,85]. It further reduces the risk of cardiovascular events, including heart attacks and strokes, while contributing to lower overall mortality rates [84]. MASLD, which is strongly associated with obesity, T2DM, and metabolic syndrome, benefits significantly from the metabolic improvements induced by bariatric surgery. These benefits include reductions in liver fat and inflammation, as well as fibrosis resolution, which are linked to weight loss and enhanced insulin sensitivity [85]. The effects of bariatric surgery on liver steatosis have been well-documented (see Appendix A-

Table A2. Bariatric surgery studies (↓ means decrease, → means stable, ↑ means increase).

Study Authors and Year	Procedure	Targeted Pathways	Metabolic Outcomes
Klein et al., 2006 [86]	Gastric Bypass	Inflammation and Fibrosis Reduction	↓ MCP-1, ↓ IL-8, ↓ TGF-β1, ↓ TIMP-1, ↓ α-SMA, and ↓ Collagen-a1
Cazzo et al., 2015 [87]	Roux-en-Y Gastric Bypass (RYGB)	Fibrosis Reduction and Metabolic Improvement	↓ MASLD Fibrosis Score (55% resolution in 12 months), ↓ Steatosis, and ↓ Inflammation
Mummadi et al., 2008 [88]	Bariatric Surgery (Various)	Liver Disease Resolution	↓ Steatosis (91.6%), ↓ Steatohepatitis (81.3%), and ↓ Fibrosis (65.5%)

).

Research has demonstrated that weight reduction through bariatric surgery leads to favorable changes in hepatic inflammation. For example, Klein et al. [86] found that gastric bypass surgery decreased the hepatic expression of inflammatory markers, including macrophage chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8), as well as fibrosis-related factors such as transforming growth factor-β1 (TGF-β1), the issue inhibitor of metalloproteinase-1 (TIMP-1), α-smooth muscle actin (α-SMA), and collagen-a1 (I). Similarly, Cazzo et al. [87] observed that Roux-en-Y gastric bypass (RYGB) significantly reduced the mean MASLD fibrosis score, with 55% of patients showing resolution of severe fibrosis within 12 months post surgery. Additionally, RYGB has been associated with marked reductions in steatosis, liver inflammation, and ballooning, as measured by improvements in the MASLD activity score, over one year of follow-up. According to Mummadi et al. [88], bariatric surgery led to improvement or resolution in 91.6% of cases for steatosis, 81.3% for steatohepatitis, and 65.5% for fibrosis, as observed in an analysis of 15 studies with 766 paired liver biopsies.

6. Conclusions

The bidirectional relationship between MASLD and T2DM is well established. The subtle characteristics of both T2DM and MASLD complicate the identification of these diseases. Ideally, a clearly defined referral pathway should be established to recognize patients at an elevated risk of disease progression and associated complications, ensuring accurate referral to specialized clinics for further assessment, as well as determining suitable follow-up intervals and evaluation methods in a cost-efficient manner. Successfully navigating the complex management of T2DM and MASLD necessitates a multidisciplinary team that includes hepatologists, diabetologists, gastroenterologists, nutritionists, physical therapists, and cardiologists. Timely treatment and early intervention are critical for both conditions. Although traditional hypoglycemic medications have demonstrated potential, they do not fully satisfy the clinical requirements.

In summary, the interconnected relationship between MASLD and T2DM necessitates a comprehensive strategy that integrates early diagnosis, lifestyle modifications, and sophisticated pharmacological treatments. Future investigations ought to prioritize the enhancement of diagnostic instruments, the exploration of innovative therapeutic agents, and the development of personalized treatment approaches to effectively tackle the worldwide impact of these related conditions.