Lean subjects compared to obese with NAFLD have better beta cell function, similar insulin resistance and less fibrosis.

Abstract Background: Heterogeneous information on Insulin resistance (IR), adiposity and histological severity in Non-alcoholic Fatty Liver Disease (NAFLD) in lean individuals (NAFLD-L) continues to confound the clinical approach and therapy targets for NAFLD-L, despite its’ growing public health significance, unlike NAFLD in overweight/obese individuals (NAFLD-O). Method: NAFLD-L was evaluated against NAFLD-O in a community cohort (CC) and Tertiary cohort (TC), simultaneously. Leanness was defined as normal BMI with absence of abdominal obesity, using cut-offs for Asians. CC (n=6134), selected from a population project (https://www.shds.co.in/about-birpop/), underwent noninvasive evaluation (HOMA2-IR, Transient Elastography and Dual Energy X-ray Absorptiometry). TC (n=305), selected from two tertiary institutes belonging to the referral hierarchy for the said community, underwent additional evaluation for IR/beta-cell function (BCF) by ‘Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT) and histology. Results: NAFLD-L had more android fat than gynoid compared to NAFLD-O [Android to Gynoid Fat mass ratio: median(IQR); 1.38(1.33, 1.39) vs 1.22(1.12, 1.40) in NAFLD-L and NAFLD-O of CC, respectively, p=0.032]. NAFLD-L and NAFLD-O had comparable IR [Median(IQR); 2.47(1.19, 14.80) vs 2.18(1.29, 3.29) mM.mu/l*2 in NAFLD-L and NAFLD-O, respectively, p=0.76] and Non-alcoholic Steatohepatitis (NASH) prevalence. BCF was better in NAFLD-L [Median(IQR); 90.46(59.90, 272) vs 86.63(53.22, 138.15) mu/mM in NAFLD-L and NAFLD-O, respectively, p=0.034]. Cirrhosis was detected only in NAFLD-O. Conclusion: NAFLD-L has IR and NASH prevalence similar to NAFLD-O underscoring uniform pathophysiology and IR as potentially common therapeutic target. Metabolic advantage of having lower prevalence of MS and better BCF is negated by preferential accumulation of more insulin resistant android fat in NAFLD-L.