Hepatic-Adjusted Metabolic Resistance Index (HAMRI): A Novel Fasting Surrogate Decoupling Target-Tissue Insulin Resistance from Hepatic Extraction Defects in MASLD and Type 2 Diabetes

Abstract

Abstract

Objective: Standard peripheral insulin-based surrogates, such as the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), fail to account for first-pass hepatic extraction kinetics. In Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD), impaired hepatic clearance leads to peripheral hyperinsulinemia that HOMA-IR misinterprets as peripheral resistance. This study describes the development and clinical validation of the Hepatic-Adjusted Metabolic Resistance Index (HAMRI)—a novel fasting surrogate designed to decouple pre-hepatic pancreatic secretion from hepatic extraction defects.

Methods: A prospective validation cohort (N = 140; 40 healthy controls, 50 MASLD without diabetes, and 50 type 2 diabetes with concurrent MASLD) was evaluated using fasting plasma glucose (FPG), fasting peripheral serum insulin (FINS), and fasting C-peptide (FCP). A substudy (n = 120) was conducted where participants underwent gold-standard hyperinsulinemic-euglycemic clamps to Measure Lean body Mass–normalized glucose disposal rates (MLBM) alongside 3.0-Tesla Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF) liver fat quantification.

Results: Log-transformed HAMRI exhibited a significantly stronger inverse correlation with clamp-derived MLBM (r = -0.84, P < 0.001) than log-transformed HOMA-IR (r = -0.61, P < 0.001; Steiger's Z = 4.82, P < 0.001). The diagnostic overestimation inherent to HOMA-IR relative to HAMRI expanded in direct proportion to MRI-PDFF liver fat severity (P_trend < 0.001). For identifying severe target-tissue insulin resistance (lowest MLBM quartile), HAMRI demonstrated superior diagnostic accuracy compared with HOMA-IR, with an area under the ROC curve (ROC AUC) of 0.91 vs. 0.76 (DeLong's P < 0.001). 

Conclusion: HAMRI successfully decouples target-tissue insulin resistance from hepatic extraction defects in patients with steatotic liver disease. Requiring only routine fasting blood draws, HAMRI represents a physiologically accurate, scalable, and cost-effective tool for precision metabolic phenotyping, clinical risk stratification, and trial outcome evaluation in MASLD and type 2 diabetes.