The role of peripheral beta-amyloid in insulin resistance, insulin secretion, and prediabetes: in vitro and populationbased studies

Background: Previous experimental studies have shown that mice overexpressing amyloid precursor protein, in which b-amyloid (Ab) is overproduced, exhibit peripheral insulin resistance, pancreatic impairment, and hyperglycemia. We aimed to explore the effects of Ab on insulin action and insulin secretion in vitro and the association of plasma Ab with prediabetes in human. Methods: We examined the effects of Ab40 and Ab42 on insulin-inhibited glucose production in HepG2 cells, insulin-promoted glucose uptake in C2C12 myotubes, and insulin secretion in INS-1 cells. Furthermore, we conducted a case-control study (N = 1142) and a nested case-control study (N = 300) within the prospective Tongji-Ezhou cohort. Odds ratios (ORs) and 95% confidence intervals (CIs) for prediabetes were estimated by using conditional logistic regression analyses. Results: In the in vitro studies, Ab40 and Ab42 dose-dependently attenuated insulin-inhibited glucose production in HepG2 cells, insulin-promoted glucose uptake in C2C12 myotubes, and basal and glucose-stimulated insulin secretion in INS-1 cells. In the case-control study, plasma Ab40 (adjusted OR: 2.00; 95% CI: 1.34, 3.01) and Ab42 (adjusted OR: 1.94; 95% CI: 1.33, 2.83) were positively associated with prediabetes risk when comparing the extreme quartiles. In the nested case-control study, compared to the lowest quartile, the highest quartile of plasma Ab40 and Ab42 were associated with 3.51-fold (95% CI: 1.61, 7.62) and 2.75-fold (95% CI: 1.21, 6.22) greater odds of prediabetes, respectively. Conclusion: Elevated plasma Ab40 and Ab42 levels were associated with increased risk of prediabetes in human subjects, which may be through impairing insulin sensitivity in hepatocytes and myotubes and insulin secretion in pancreatic b-cells.