Abstract
Introduction
Blood asprosin levels have been found to be elevated in patients with type 2 diabetes and those with Metabolic Dysfunction-Associated Steatotic Liver Disease (MAFLD). MAFLD is common in individuals with diabetes. We investigated the relationship between pioglitazone treatment and asprosin levels in patients with diabetes and MAFLD.
Materials and Methods
Blood samples were collected from 25 patients diagnosed with diabetes and MAFLD at the time of diagnosis and 6 months after pioglitazone treatment. Additionally, blood samples were collected from 15 healthy volunteers as controls.
Results
Compared to the 6-month control after pioglitazone treatment, significant reductions were observed in glucose, HbA1c, AST, ALT, GGT, ALP, and Fib-4 scores. However, no significant difference was detected in asprosin levels.
Discussion
The significant decrease in glucose, HbA1c, AST, ALT, GGT, ALP, and Fib-4 scores after pioglitazone treatment indicates that pioglitazone is effective in the treatment of both diabetes and MAFLD. The fact that asprosin levels were not different in patients with diabetes and MAFLD compared to healthy controls suggests that diabetic fatty liver occurs through mechanisms independent of asprosin.
Conclusion
These results imply that while pioglitazone is effective in treating both diabetes and MAFLD, its action does not involve modulating asprosin levels.
Keywords: Asprosin, Diabetes mellitus, Pioglita-zone, MAFLD
INTRODUCTION
Asprosin is a protein hormone released from white adipose tissue during fasting, which stimulates glycogenolysis and gluconeogenesis in the liver (1). It crosses the blood-brain barrier and has an orexigenic (appetite-stimulating) effect. Studies have shown that food intake and weight gain are reduced in obese mice treated with anti-asprosin antibodies (2). Asprosin also increases inflammation in skeletal muscle, contributing to insulin resistance, and decreases cAMP-dependent insulin secretion in the pancreas. Blood levels of asprosin are elevated in diabetic patients and are being investigated as a potential therapeutic target (3).
Increased blood asprosin levels have been observed in patients with type 2 diabetes, correlating with insulin resistance (4). Asprosin levels are elevated in hyperglycemia and type 2 diabetes. Since asprosin levels are higher in individuals with impaired glucose regulation compared to those with type 2 diabetes, it has been suggested that asprosin could serve as a predictor for the development of diabetes (5). However, another study indicated that type 2 diabetes is independently associated with elevated fasting blood sugar and triglyceride levels, suggesting that asprosin is not an ideal biomarker for predicting type 2 diabetes (6).
Asprosin levels were found to be high in patients with newly diagnosed type 2 diabetes, and these levels normalized with metformin treatment (7).
Asprosin acts as an anti-insulin hormone and increases during fasting. Although asprosin also increases during fasting in patients with type 1 diabetes, this response is impaired in those with insulin resistance (8).
Elevated placental asprosin levels have been observed in pregnant women with gestational diabetes compared to those without diabetes (9).
It is hypothesized that asprosin may also play a role in the development of diabetic nephropathy, with higher asprosin levels found in diabetics with albuminuria compared to those without (10).
Asprosin has also been associated with obesity. While saliva and blood asprosin levels are low in lean individuals, they are higher in overweight and obese individuals, proportional to their weight (11).
Serum asprosin levels are elevated, and adiponectin levels are reduced in patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MAFLD). These two biomarkers have been suggested as potential diagnostic tools for MAFLD (12).
Metabolic dysfunction–associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), is increasingly recognized as a major health issue for individuals with diabetes, particularly those with type 2 diabetes and obesity. MASLD affects approximately two-thirds of people with type 2 diabetes, increasing the risk of steatohepatitis (MASH), cirrhosis, and liver cancer. Additionally, it is linked to extrahepatic cancers, cardiovascular disease, and the progression from prediabetes to diabetes. Despite these risks, many individuals and healthcare providers remain unaware of the condition’s impact. A recent consensus report from the American Diabetes Association calls for routine screening for liver fibrosis in individuals with prediabetes or type 2 diabetes, particularly those with obesity, to prevent long-term liver complications (13).
MASLD is prevalent in approximately 70% of patients with diabetes and is a significant risk factor for diabetes complications (14). Moreover, diabetes accelerates the progression of MASLD. Thiazolidinediones, commonly used in diabetes treatment, have been shown to slow the progression of MASLD, while bariatric surgery has proven beneficial in managing nonalcoholic steatohepatitis (NASH). However, the effectiveness of other diabetes medications in managing MASLD remains uncertain (14).
In this study, we compared 25 patients with diabetes and a diagnosis of MAFLD to 15 healthy controls to investigate the role of asprosin, a hormone involved in diabetes, obesity, and appetite regulation, in the development of MAFLD in diabetic patients. Additionally, we measured blood asprosin levels in diabetic patients with MAFLD at baseline and again at the 6th month following Pioglitazone treatment for comparison.
MATERIAL AND METHODS
Blood samples were collected from 25 patients diagnosed with diabetic fatty liver disease at Kayseri City Hospital Internal Medicine Polyclinic between May 1, 2022, and March 1, 2024. Samples were obtained at the time of diagnosis and again 6 months after pioglitazone treatment. Additionally, blood samples were taken from 15 healthy volunteers as a control group.
Among the diabetic patients presenting for follow-up, those with elevated liver function tests (AST, ALT, GGT, ALP, T.Bil, D.Bil) were included in the study. Alcohol use was excluded as a possible etiology. Hepatitis markers were tested, and hepatobiliary ultrasound (USG) was performed. Patients with negative hepatitis markers and evidence of hepatosteatosis on USG were diagnosed with diabetic fatty liver disease.
These patients were started on pioglitazone, as recommended by current guidelines. Liver function tests and hepatobiliary USG were repeated at the 6-month follow-up, along with diabetes monitoring. As obesity, fatty liver, and insulin resistance are interconnected in type 2 diabetes, the weight, height, and body mass index (BMI) of the patients were recorded at baseline and at follow-up visits.
Body Mass Index (BMI) Calculation
Body mass index (BMI) was calculated by dividing body weight in kilograms by the square of height in meters (kg/m2).
FIB-4 Score Calculation
The FIB-4 score was used to estimate the degree of liver fibrosis. This score was calculated using the following validated formula:
FIB-4=Age (years) × AST (U/L)/Platelet count (109/L) × √ALT (U/L)
Patients who had no other diseases besides diabetes and did not receive treatments other than those for fatty liver disease, with a glomerular filtration rate (GFR) ≥60, were included in the study.
Patients aged over 75 years or under 18 years, those with stage 3-4 heart failure, GFR <60, or advanced liver failure were excluded from the study.
Pioglitazone was introduced to patients with an HbA1c value of 6.5% or higher, or to those using oral antidiabetic drugs and/or insulin. For patients with HbA1c below 6.5%, treatment was switched to pioglitazone after discontinuing metformin and sulfonylureas, or a DPP-4 antagonist, if the patient had not been using these medications.
Blood tests were conducted on patients, and no experimental drugs were administered. Diabetes treatment was provided according to current guidelines, with no additional treatments. Thus, there were no risks to participants.
This study has a case-control design. Ethics committee approval was obtained from the Kayseri City Hospital Clinical Research Ethics Committee on April 7, 2022, with decision number 609.
Informed consent forms were completed by all volunteers before blood sample collection.
The blood samples were sent to the Kayseri City Hospital Medical Biochemistry Laboratory. After centrifugation, the samples were stored at -80¯C. When the target number of patients and healthy volunteers was reached over approximately two years, the samples were analyzed using the ELISA method in the Medical Biochemistry Laboratory. The results were entered into the SPSS software for statistical analysis.
Parametric data were expressed as mean ± standard error, while non-parametric data were presented as median (minimum–maximum). A p-value <0.05 was considered statistically significant.
For comparisons between diabetic patients and healthy controls, a T-test was used for parametric data, and the Mann-Whitney U test was used for non-parametric data. In case-control comparisons, paired T-tests were used for parametric data, and the Wilcoxon Signed Rank test was used for non-parametric data. Spearman’s correlation analysis was performed to assess relationships between variables.
RESULTS
The degree of fatty liver, as determined by ultrasonography, showed that grade 1 steatosis was present in 3 patients (12%), grade 2 steatosis in 17 patients (68%), and grade 3 steatosis in 5 patients (20%). After 6 months of Pioglitazone treatment, although biochemical improvements were observed in fatty liver, no change was detected in ultrasonography grades.
When comparing the diabetes and hepatosteatosis group with the healthy control group, significant differences were found in age, BMI, glucose, HbA1c, AST, ALT, GGT, ALP, triglycerides (TG), and Fib-4 scores, all of which were higher in the diabetic group. No difference in asprosin levels was found between the two groups (Table 1).
Table 1.
Comparison of patients with diabetic fatty liver and healthy control group
| Diabetes and MAFLD. n (25) | Healty control. n (15) | P value | ||
|---|---|---|---|---|
| Age. (min-max) | 51 (20-63) | 33 (26-49) | 0.001 | |
| Gender | Female | 13 (%52) | 10 (%66.7) | 0.512 |
| Male | 12 (%48) | 5 (%33.3) | ||
| BMI kg/m2. (min-max) | 33.9 (26.8-46.3) | 24 (20.1-28) | 0.001 | |
| Hb g/dL. mean±SE | 14.9±1.8 | 14.3±1.8 | 0.252 | |
| Plt 103/μL. mean±SE | 269±67 | 261±58 | 0.704 | |
| FPG mg/dL. (min-max) | 132 (94-325) | 85 (74-97) | 0.001 | |
| HbA1c %. (min-max) | 7.9 (6.2-12.6) | 5.4 (5-5.6) | 0.001 | |
| Creatinine mg/dL. (min-max) | 0.70 (0.53-1.05) | 0.70 (0.54-1.00) | 0.752 | |
| AST U/L. (min-max) | 43 (21-116) | 15 (13-28) | 0.001 | |
| ALT U/L. (min-max) | 54 (34-193) | 13 (8-39) | 0.001 | |
| GGT U/L. (min-max) | 45 (27-140) | 13 (6-51) | 0.001 | |
| ALP U/L. (min-max) | 89 (45-136) | 59 (40-81) | 0.001 | |
| T.Bil mg/dL. (min-max) | 0.4 (0.2-1.2) | 0.5 (0.3-1.1) | 0.094 | |
| D.Bil mg/dL. (min-max) | 0.2 (0.1-0.4) | 0.2 (0.1-0.3) | 0.654 | |
| TC mg/dL | 197±33 | 187±29 | 0.322 | |
| LDL mg/dL. (min-max) | 125 (54-393) | 127 (47-152) | 0.633 | |
| TG mg/dL. (min-max) | 196 (79-935) | 87 (42-238) | 0.001 | |
| Fib 4. mean±SE | 1.03±0.48 | 0.61±0.15 | 0.001 | |
| Asprosin ng/mL. (min-max) | 46.01 (34.76-228.24) | 57.76 (18.87-115.43) | 0.900 | |
P-values < 0.05 were considered statistically significant.
SE: Standard Error, BMI: Body Mass Index, Hb: Hemoglobin, Plt: Platelet, FPG: Fasting Plasma Glucose, HbA1c: Hemoglobin A1c, AST: Aspartate Aminotransferase, ALT: Alanine Aminotransferase, GGT: Gamma-glutamyl transferase, ALP: Alkaline Phosphatase, T.Bil: Total Bilirubin, D.Bil: Direct Bilirubin, TC: Total Cholesterol, LDL: Low-Density Lipoprotein, TG: Triglycerides, Fib 4: Fibrosis-4 Index, Asprosin: Asprosin Protein.
In comparison to baseline values before treatment, a significant regression was observed in glucose, HbA1c, AST, ALT, GGT, ALP, and Fib-4 scores after 6 months of Pioglitazone treatment. However, no significant changes were detected in BMI and asprosin levels (Table 2).
Table 2.
Comparison of patients with diabetic fatty liver before and 6 months after pioglitazone treatment
| Before treatment | 6th month after treatment | P value | |
|---|---|---|---|
| BMI kg/m2, mean±SE | 35.85±6.04 | 35.38±6.10 | 0.121 |
| Glucose mg/dL, (min-max) | 132 (94-325) | 111 (71-247) | 0.016 |
| HbA1c %,(min-max) | 7.9 (6.2-12.6) | 6.8 (5.8-9.2) | 0.002 |
| AST U/L, (min-max) | 43 (21-116) | 26 (12-42) | 0.001 |
| ALT U/L, (min-max) | 54 (34-193) | 29 (15-74) | 0.001 |
| GGT U/L, (min-max) | 45 (27-140) | 33 (12-120) | 0.002 |
| ALP U/L, (min-max) | 89 (45-136) | 78 (52-141) | 0.018 |
| T.Bil mg/dL, (min-max) | 0.4 (0.2-1.2) | 0.5 (0.1-0.8) | 0.545 |
| D.Bil mg/dL, (min-max) | 0.2 (0.1-0.4) | 0.2 (0.1-0.3) | 0.655 |
| TC mg/Dl, mean±SE | 197±33 | 198±56 | 0.595 |
| LDL mg/dL, (min-max) | 125 (54-393) | 115 (60-230) | 0.911 |
| TG mg/dL, (min-max) | 196 (79-935) | 182 (102-436) | 0.135 |
| Fib 4, mean±SE | 1.03±0.48 | 0.90±0.39 | 0.047 |
| Asprosin ng/mL, (min-max) | 46 (35-228) | 44 (37-110) | 0.177 |
P-values < 0.05 were considered statistically significant.
SE: Standard Error, BMI: Body Mass Index, HbA1c: Hemoglobin A1c, AST: Aspartate Aminotransferase, ALT: Alanine Aminotransferase, GGT: Gamma-glutamyl transferase, ALP: Alkaline Phosphatase, T.Bil: Total Bilirubin, D.Bil: Direct Bilirubin, TC: Total Cholesterol, LDL: Low-Density Lipoprotein, TG: Triglycerides, Fib 4: Fibrosis-4 Index, Asprosin: Asprosin Protein.
Correlation analysis revealed no significant relationship between asprosin levels and diabetes-related parameters, liver function tests, or cholesterol levels. However, a significant correlation was found between total protein and albumin levels and asprosin levels (Table 3).
Table 3.
Results of correlation analysis between asprosin levels and other parameters (Persons Diabetes and MAFLD + Healty volunteers included)
| Spearman’s rho Correlations | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Glucose | AST | ALT | GGT | ALP | T.Prot | Albumin | HbA1c | Fib4 | LDL | TG | ||
| Asprosin | Correlation coefficient | 0.059 | -0.006 | 0.073 | 0.117 | 0.120 | 0.544** | 0.554** | -0.005 | -0.024 | -0.146 | -0.11 |
| Sig. (2-tailed) | 0.719 | 0.971 | 0.656 | 0.482 | 0.468 | 0.001 | 0.001 | 0.785 | 0.131 | 0.374 | 0.947 | |
Spearman’s rho Correlation Coefficients were calculated for the relationship between asprosin levels and various biochemical parameters.
Correlation is significant at the 0.05 level (2-tailed).
Correlation is significant at the 0.01 level (2-tailed).
Asprosin: Asprosin Protein, HbA1c: Hemoglobin A1c, AST: Aspartate Aminotransferase, ALT: Alanine Aminotransferase, GGT: Gamma-glutamyl transferase, ALP: Alkaline Phosphatase, T. Prot: Total Protein, Fib 4: Fibrosis-4 Index, LDL: Low-Density Lipoprotein, TG: Triglycerides.
Multivariate analysis identified HbA1c, urine microprotein/creatinine ratio, LDL, and TG levels as potential factors influencing asprosin levels (Table 4).
Table 4.
Results of multivariance analysis with parameters that may affect asprosin levels (Persons Diabetes and MAFLD+ Healty volunteers included)
| Tests of Between-Subjects Effects | ||||||
|---|---|---|---|---|---|---|
| Source | Dependent Variable | Type III Sum of Squares | df | Mean Square | F | Sig. |
| Asprosin | BMI | 576.392 | 13 | 44.338 | 73.286 | 0.091 |
| Hb | 27.536 | 13 | 2.118 | 105.908 | 0.076 | |
| PLT | 36116.833 | 13 | 2778.218 | 7.622 | 0.277 | |
| Glucose | 8799.733 | 13 | 676.903 | 1.171 | 0.628 | |
| Creatine | 0.338 | 13 | 0.026 | 3.613 | 0.392 | |
| AST | 7677.100 | 13 | 590.546 | 0.390 | 0.866 | |
| ALT | 16136.433 | 13 | 1241.264 | 0.136 | 0.982 | |
| GGT | 11977.100 | 13 | 921.315 | 1.346 | 0.596 | |
| ALP | 7171.733 | 13 | 551.672 | 2.280 | 0.481 | |
| T.Protein | 0.952 | 13 | 0.073 | 14.651 | 0.202 | |
| Albumin | 1.212 | 13 | 0.093 | 2.072 | 0.500 | |
| HbA1c | 44.884 | 13 | 3.453 | 690.528 | 0.030 | |
| Urine microprotein/creatine | 171261.663 | 13 | 13173.974 | 7222.376 | 0.009 | |
| TSH | 22.961 | 13 | 1.766 | 5.253 | 0.330 | |
| Free T4 | 62.184 | 13 | 4.783 | 0.663 | 0.759 | |
| Cholesterol | 15841.333 | 13 | 1218.564 | 67.698 | 0.095 | |
| LDL | 11926.933 | 13 | 917.456 | 458.728 | 0.037 | |
| TG | 1139422.833 | 13 | 87647.910 | 2164.146 | 0.017 | |
| Fib-4 score | 1.778 | 13 | 0.137 | 19.411 | 0.176 | |
Asprosin: Asprosin Protein, Hb: Hemoglobin, PLT: Platelet, HbA1c: Hemoglobin A1c, AST: Aspartate Aminotransferase, ALT: Alanine Aminotransferase, GGT: Gamma-glutamyl transferase, ALP: Alkaline Phosphatase, T. Protein: Total Protein, Fib-4: Fibrosis-4 Index, LDL: Low-Density Lipoprotein, TG: Triglycerides.
Urine microprotein/creatine: Urinary microprotein/creatinine ratio.
F: F statistic, Sig.: Significance level.
Note on Statistical Significance:
A p-value < 0.05 indicates statistical significance (bolded results in the table).
DISCUSSION
The significant decrease in glucose, HbA1c, AST, ALT, GGT, ALP, and Fib-4 scores after Pioglitazone treatment suggests that Pioglitazone is effective in managing both diabetes and MAFLD. Previous studies have demonstrated that Pioglitazone can improve hyperglycemia and liver dysfunction, with marked improvements in liver enzyme levels and insulin sensitivity (15). Specifically, pioglitazone has been shown to significantly improve steatosis, inflammation, and ballooning, and also to provide modest but significant improvement in fibrosis compared with placebo (16). These findings align with our results, although we observed a regression in the Fib-4 score with treatment, indicating a potential benefit in terms of liver fibrosis in our patient cohort.
While biochemical improvements were noted with Pioglitazone treatment, no changes were detected in ultrasonography grades. This discrepancy may be attributed to the small sample size and relatively short follow-up period in our study. Longer follow-up durations and larger sample sizes may provide more robust insights into the correlation between biochemical markers and liver imaging findings. The fact that asprosin levels were not significantly different in patients with diabetic fatty liver compared to healthy controls, and that no significant change in asprosin levels was observed after Pioglitazone treatment, suggests that diabetic fatty liver occurs via mechanisms independent of asprosin. Furthermore, the lack of correlation between asprosin levels and liver function tests, including AST, ALT, GGT, and Fib-4 scores, further supports the hypothesis that asprosin may not be a key mediator in the pathogenesis or progression of MAFLD in this context.
Interestingly, multivariate analysis revealed that HbA1c, urine microprotein/creatinine ratio, LDL, and TG levels may influence asprosin levels. This finding is consistent with other studies that have shown relationships between asprosin and TG, LDL, and HbA1c (17). These results suggest that asprosin may be more closely linked to metabolic dysfunction rather than liver-specific pathologies, particularly in the context of diabetes and MAFLD.
Asprosin is thought to play a role in the development of diabetic nephropathy. Elevated blood asprosin levels have been observed in diabetics with albuminuria compared to those without (10). Our finding that the urine microprotein/creatinine ratio affects asprosin levels further supports this association and highlights the potential for asprosin as a marker for early renal dysfunction in diabetes. Moreover, asprosin has been shown to contribute to inflammation and insulin resistance, which are central to both diabetic nephropathy and the progression of MAFLD. Further studies are needed to investigate whether targeting asprosin could provide therapeutic benefits in diabetic complications such as nephropathy and fatty liver disease.
The positive correlation we observed between total protein and asprosin levels may be related to the protein structure of asprosin itself, which could influence its interaction with other proteins in circulation. Serum albumin is responsible for the transport of fatty acids and has also been linked to post-menopausal obesity (18). Our finding of a positive correlation between asprosin and albumin may be due to their shared relationship with obesity. This relationship warrants further exploration, particularly in understanding how asprosin and albumin interact in the context of obesity and metabolic diseases.
In conclusion, in this study, we observed that pioglitazone treatment significantly improved key clinical parameters such as glucose levels, HbA1c, liver enzymes (AST, ALT, GGT, ALP), and Fib-4 scores in patients with diabetes and MAFLD. However, no significant change was detected in asprosin levels, either before or after treatment, suggesting that asprosin may not play a direct role in the pathogenesis or progression of diabetic fatty liver disease. Additionally, the lack of difference in asprosin levels between patients with diabetes and MAFLD and healthy controls indicates that the mechanisms underlying diabetic fatty liver disease are independent of asprosin activity.
These findings suggest that while pioglitazone may be effective in managing both diabetes and MAFLD, its therapeutic action does not appear to involve modulation of asprosin levels. Further research is needed to explore the complex interactions between asprosin, insulin resistance, and fatty liver disease, as well as to investigate potential biomarkers for monitoring the progression and treatment of MAFLD in diabetic patients. Understanding these mechanisms could ultimately lead to more targeted and effective treatment strategies for individuals affected by both conditions.
Conflict of Interest
The authors declare that they have no conflict of interest.
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