Reduced circulating Mig-6 levels are associated with dysglycemia in metabolic dysfunction associated steatotic liver...

Type 2 diabetes mellitus (T2D) accelerates the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) to hepatic fibrosis, and a subset of MASLD subjects has T2D. Identification of molecular mediators linking T2D and MASLD progression remains unmet. Studies revealed patients with steatohepatitis have lower hepatic Mitogen inducible gene-6 (Mig-6) expression, and Mig-6 gene silencing causes hyperglycemia in a preclinical study. However, the relationship between Mig-6 and dysglycemia in MASLD, including its association with pancreatic β-cell dysfunction, is unknown. We assessed serum Mig-6 level in MASLD with or without dysglycemia, and its association with Homeostasis Model Assessment of β-cell function (HOMA-β).

Fibrosis 4 Index (FIB-4) score was calculated in 479 MASLD patients; those scoring 1.3-2.67 underwent liver vibration-controlled transient elastography for fibrosis assessment. F2 and F3 fibrosis subjects (119) were classified as normal glucose tolerance (NGT) (35), impaired glucose tolerance (44), and treatment-naïve T2D (40), as per American Diabetes Association criteria. Serum Mig-6 levels were measured by ELISA. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and HOMA-β were computed using serum C peptide.

Metabolic syndrome was present in 68% and 27% of participants with FIB-4>1.3 and <1.3, respectively. Reduced serum Mig-6 level was observed in the FIB-4 score >1.3 group. Participants with dysglycemia had lower (p<0.05) serum Mig-6 levels compared with NGT. Mig-6 showed a negative correlation with fasting plasma glucose, hemoglobin A1C and HOMA-IR and a positive correlation with HOMA-β. A cut-off value of serum Mig-6 level <97.49 pg/mL predicted dysglycemia in metabolic dysfunction-associated steatohepatitis (sensitivity 77.50%, specificity 73.08%, receiver operating characteristic analysis curve). 74.2% of the treatment-naïve T2D subjects had a low serum Mig-6, compared with 22% of subjects with NGT. HOMA-β was lower in the group having Mig-6 below the cut-off level (97.49 pg/mL). Positive predictive and negative predictive values of Mig-6 in identifying pancreatic β-cell dysfunction were 79.41% and 85.17%, respectively. For patients having HOMA-IR>1.6, corresponding values were 80% and 86.67%, respectively.

Serum Mig-6 levels may identify MASLD patients at an increased risk of dysglycemia and positively correlate with pancreatic β-cell dysfunction.