Effects of Weight Loss on Insulin Resistance and Liver Health in T2DM and NAFLD Patients

Introduction

METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE (MASLD):

MASLD, defined by hepatic fat accumulation exceeding 5% (MRI-PDFF >5.6%) without secondary causes [1], affects 25–30% of the world population, with higher prevalence in Asian populations [2–4]. Its spectrum ranges from benign steatosis (NAFL) to progressive non-alcoholic steato-hepatitis (NASH), ultimately leading to cirrhosis [5]. While imaging techniques (ultrasound, MRI) enable non-invasive diagnosis, liver biopsy remains the criterion standard for fibrosis staging [6]. The incidence of MASLD in children is also increasing [7], closely related to high-fat diets, sedentary behavior, and obesity [8,9]. MASLD encompasses a range of histological features, from non-alcoholic fatty liver (NAFL) (a non-progressive form of MASLD) to non-alcoholic steatohepatitis (NASH) (a progressive form of MASLD), leading to cirrhosis and eventual liver failure [5]. Imaging techniques such as liver ultrasound or MRI provide non-invasive insights into the extent of liver involvement in MASLD patients. However, liver biopsy remains the criterion standard for classifying the degree of hepatitis and fibrosis.

ASSOCIATION BETWEEN MASLD AND DIABETES MELLITUS (DM):

The liver is one of the primary organs controlling metabolic homeostasis. Hepatic steatosis and steatohepatitis can be associated with various liver-affecting diseases, including autoimmune hepatitis and hypothyroidism. When there is an imbalance between energy intake and expenditure, lipids accumulate in areas other than adipose tissue [10], such as the liver, omentum, muscles, perivascular regions, and visceral fat deposition [11], known as “ectopic fat accumulation”. In T2DM, MASLD often coexists as a comorbidity, primarily due to increased hepatic factor secretion associated with ectopic fat accumulation in MASLD [12], leading to increased gluconeogenesis, reduced glycogen synthesis, and inhibited insulin signaling. Excessive lipid accumulation in the liver often causes insulin resistance (IR) and chronic inflammation. T2DM is defined by high blood glucose levels, IR, and impaired pancreatic beta-cell function, making MASLD patients more at risk for DM [13]. Studies show that the prevalence of MASLD in obese adults with T2DM exceeds 70% [14]. Research indicates that T2DM is an independent risk factor for MASLD [15]. MASLD significantly increases the risk of T2DM, with higher chances of moderate to severe liver injury and hepatocellular carcinoma (HCC) in T2DM patients [16].

Insulin is a synthetic hormone that promotes the esterification and storage of fatty acids in lipid droplets and inhibits lipolysis. It regulates glucose metabolism by promoting glucose uptake in adipose and liver tissues and inhibiting hepatic glucose production [17]. In T2DM patients, the liver’s insulin clearance capacity is reduced [18]. IR refers to a decreased sensitivity and/or responsiveness to insulin. Given insulin’s dual anti-inflammatory and pro-inflammatory properties, IR and inflammation form a vicious cycle, accelerating the development of MASLD and other metabolic disorders [19].

DIET AND LIFESTYLE CONNECTIONS WITH MASLD:

Research indicates that genetic factors are key contributors to the susceptibility of T2DM, IR, MASLD, obesity, and other metabolic syndromes [20]. High intake of sugary beverages and meats increases the risk of cardiovascular, endocrine, and other diseases [21]. Although genetic factors are difficult to change, modifiable factors such as circadian rhythms [22] and lifestyle adjustments, including increased exercise, weight loss, and dietary changes, can effectively improve metabolic disorders and long-term clinical outcomes in MASLD and T2DM patients [23]. Maintaining an appropriate body weight is crucial for preventing MASLD. For overweight or obese patients, the best approach to reversing MASLD is weight loss. Lifestyle changes to lose weight are safe and effective [24], with patients achieving sustained weight loss of 7–10% through balanced, low-calorie diets and increased physical activity. A weight loss rate of 1 kg/week is considered safe for MASLD patients, with rapid weight loss potentially worsening liver disease [25]. Weight loss can improve serum insulin levels [26], liver function, and quality of life in MASLD patients. Studies also suggest [27] that even weight rebound after weight loss seems to have long-term beneficial effects on liver fat and insulin resistance.

APPLICATION OF MAGNETIC RESONANCE PROTON DENSITY FAT FRACTION (MRI-PDFF) IN LIVER FAT CONTENT ASSESSMENT:

Magnetic resonance imaging proton density fat fraction (MRI-PDFF) is a method using magnetic resonance chemical shift water-fat separation technology to quantify hepatic steatosis [28]. MRI is known for its high sensitivity to MASLD changes, quantifying lipid fat content. Among non-invasive assessment techniques, it provides more accurate quantification of liver steatosis compared to ultrasound or CT [29]. This technique calculates the ratio of the proton density of free triglycerides (TG) in the tissue to the total proton density of free TG and water, presented as a percentage, to precisely reflect the concentration level of free TG in tissue [6]. Since liver fat distribution is not uniform, PDFF values and their variability differ across different regions. Therefore, in practice, ROI selection should avoid large blood vessels, bile ducts, liver lesion areas, and potential artifacts in the image to ensure measurement accuracy and reliability. Studies show that a 4-ROI sampling strategy still provides high accuracy [30,31]. MRI-PDFF technology typically classifies liver steatosis into mild, moderate, and severe grades. Based on the measured PDFF values, steatosis is categorized as mild (5–10%), moderate (10.1–25%), and severe (≥25%).

Material and Methods

ETHICS APPROVAL:

This study was approved by the Ethics Committee of Jiashan Second People’s Hospital (Approval No. KY2022-001) and was conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from all participants.

STUDY DESIGN AND POPULATION:

The sample size was calculated using G*Power 3.1 based on an expected effect size of 0.5 (Cohen’s d) for HOMA-IR improvement, with 80% power and α=0.05, yielding a minimum requirement of 34 participants. Considering a 20% dropout rate, 45 participants were initially recruited.

This prospective observational study recruited MASLD patients with T2DM attending the Second People’s Hospital of Jiashan County, who had not experienced significant weight changes in the last 3 months. Comprehensive laboratory and imaging examinations were conducted. At the end of the follow-up, patients were divided into a non-compliant treatment group (Group A) and a compliant group (Group B) based on whether they lost more or less than 5% of their initial body weight (Figure 1).

EXCLUSION CRITERIA:

Patients were excluded if they had not maintained low alcohol intake (males <30 g/d, females <20 g/d[16]) in the last year; had type 1 diabetes; had a history of weight-loss surgery; were pregnant or milking; lacked informed consent; or if they had decompensated liver disease, major systemic diseases, were taking medications known to cause hepatic steatosis, or tested positive for hepatitis B surface antigen, hepatitis C virus RNA, or other liver diseases.

WEIGHT INTERVENTION:

Participants participated in a structured program. Daily caloric intake was restricted to 25 kcal/kg of ideal body weight, with macronutrient distribution at 40% carbohydrates, 30% protein, and 30% fat. A registered dietitian provided biweekly consultations via a mobile app (eg, photo-based food logging and AI nutrient analysis). Supervised aerobic sessions (60 mins/session) included brisk walking (40–60% VO2max) and resistance training (2 sets×12 reps), tracked via smartwatches (eg, daily step count ≥10 000). Compliance thresholds were ≥80% diet adherence and ≥3 sessions/week for classification into Group B.

CLINICAL EVALUATION:

Patients included in the study were not taking medications known or suspected to induce fatty degeneration or steatohepatitis. Routine medical history and physical examination were conducted before the experiment. Age, sex, height, weight, and BMI were recorded before and after weight loss. Laboratory indicators included TBIL (total bilirubin), TG (triglycerides), TC (total cholesterol), LDL-c (low-density lipoprotein), HDL-c (high-density lipoprotein), ALP (alkaline phosphatase), LDH (lactate dehydrogenase), ALT (alanine aminotransferase), AST (aspartate aminotransferase), GGT (gamma-glutamyl transferase), HOMA-IR (homeostatic model assessment for insulin resistance), and MRI-PDFF. HOMA-IR was calculated using the formula: HOMA-IR=(fasting blood glucose level (mmol/L)×fasting insulin level [mU/L])/22.5.

STATISTICAL METHODS:

Statistical analysis was performed using SPSS version 25.0. Non-parametric tests were done. The Mann-Whitney U test was used to compare the means between the study groups. The Wilcoxon test was used to compare variables obtained at the beginning and end of the study, with a P value of < 0.05 considered statistically significant.

Results

CHANGES IN WEIGHT AND BIOLOGICAL PARAMETERS:

The sample included 37 patients – 6 females and 31 males. After 3 months of diet and exercise management, all participants lost weight. Participants were stratified into a non-compliant group (Group A, n=11) and a compliant group (Group B, n=26) based on their weight loss (less than 5% or ≥5% of the initial weight). At the beginning of the study, there were no differences in clinical or demographic characteristics of compliant and non-compliant patients (Table 1). After 3 months of dietary and exercise intervention, there were some changes in the anthropometric parameters of the participants (Table 2) as well as in the laboratory parameters (Table 3). All participants showed significant changes compared to their starting values in TG, TC, LDL-c, blood glucose, HOMA-IR, and liver fat content. The HOMA-IR index in the compliant group decreased from 5.67±3.65 to 3.90±2.07. Significant changes were observed in TBIL, AST, ALT, and HDL-c in the compliant group, but not in the non-compliant group. (Table 3)

Linear regression analysis was performed with liver fat percentage (MRI) as the dependent variable. A linear regression model was constructed using MRI to assess changes in liver fat content and insulin resistance, cholesterol, total bilirubin, alanine aminotransferase, high-density lipoprotein, low-density lipoprotein, triglycerides, and aspartate aminotransferase. When considering these variables together, the model’s predictors explained 42.5% of the changes in liver fat content (%) assessed by MRI (Table 4).

DIET AND EXERCISE:

During the study, all patients engaged in aerobic exercise at least 3 times per week for more than 60 minutes each. Participants in the compliant group received at least 3 nutrition consultations and showed a significant reduction in calorie intake (decrease in total caloric value) and sugar intake, mainly due to a reduction in fat and cholesterol content intake, and an increase in unsaturated fatty acids and vitamin intake. In the compliant group, 20 participants adhered to aerobic exercise at least 5 times per week, covering a distance of more than 5 km, and 4 participants performed a daily morning run of 5 km and an evening brisk walk of 5 km. Throughout the exercise and diet intervention period, no participants reported physical discomfort.

Discussion

CLINICAL IMPLICATIONS AND LIMITATION:

While our findings support the 5% weight loss threshold, 3 limitations should be considered. (1) The lack of ALT normalization in 36.4% of Group B (4/11 with ALT >40 U/L post-intervention) suggests residual hepatocellular injury, possibly requiring adjunct pharmacotherapy in high-risk subgroups. (2) The study’s single-center design and short duration (3 months) limit generalizability, and future multi-center trials should validate these results over a period of at least 12 months [4]. (3) MRI-PDFF’s cost and accessibility barriers in rural areas necessitate development of simplified protocols (eg, 2-ROI sampling [30]).

FUTURE DIRECTIONS:

Building on these results, we propose use of precision monitoring, integration of continuous glucose monitoring (CGM) with MRI-PDFF to capture real-time metabolic fluctuations, nutrient timing to explore circadian-aligned interventions (eg, time-restricted eating [35]) to enhance hepatic lipid metabolism, and digital therapeutics involving development of AI-powered mobile platforms for personalized feedback, potentially boosting adherence to 85–90%, as shown in recent pilot studies [33].

Conclusions

Overall, this study provides new insights into the management of MASLD patients and confirms the central role of lifestyle adjustments in the management of T2DM and MASLD. The current challenge is effectively promoting and implementing this therapy in daily clinical practice.

Data Availability Statement

The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding author.