Twenty‐five‐year trajectories of insulin resistance and pancreatic β‐cell response and diabetes risk in nonalcoholic fatty liver disease

Background & Aims Insulin resistance is a risk marker for non‐alcoholic fatty liver disease, and a risk factor for liver disease progression. We assessed temporal trajectories of insulin resistance and β‐cell response to serum glucose concentration throughout adulthood and their association with diabetes risk in non‐alcoholic fatty liver disease. Methods Three thousand and sixty participants from Coronary Artery Risk Development in Young Adults, a prospective bi‐racial cohort of adults age 18‐30 years at baseline (1985‐1986; Y0) who completed up to 5 exams over 25 years and had fasting insulin and glucose measurement were included. At Y25 (2010‐2011), non‐alcoholic fatty liver disease was assessed by noncontrast computed tomography after exclusion of other liver fat causes. Latent mixture modelling identified 25‐year trajectories in homeostatic model assessment insulin resistance and β‐cell response homeostatic model assessment‐β. Results Three distinct trajectories were identified, separately, for homeostatic model assessment insulin resistance (low‐stable [47%]; moderate‐increasing [42%]; and high‐increasing [12%]) and homeostatic model assessment‐β (low‐decreasing [16%]; moderate‐decreasing [63%]; and high‐decreasing [21%]). Y25 non‐alcoholic fatty liver disease prevalence was 24.5%. Among non‐alcoholic fatty liver disease, high‐increasing homeostatic model assessment insulin resistance (referent: low‐stable) was associated with greater prevalent (OR 95% CI = 8.0, 2.0‐31.9) and incident (OR = 10.5, 2.6‐32.8) diabetes after multivariable adjustment including Y0 or Y25 homeostatic model assessment insulin resistance. In contrast, non‐alcoholic fatty liver disease participants with low‐decreasing homeostatic model assessment‐β (referent: high‐decreasing) had the highest odds of prevalent (OR = 14.1, 3.9‐50.9) and incident (OR = 10.3, 2.7‐39.3) diabetes. Conclusion Trajectories of insulin resistance and β‐cell response during young and middle adulthood are robustly associated with diabetes risk in non‐alcoholic fatty liver disease. Thus, how persons with non‐alcoholic fatty liver disease develop resistance to insulin provides important information about risk of diabetes in midlife above and beyond degree of insulin resistance at the time of non‐alcoholic fatty liver disease assessment.