Plasma IL-1Ra: linking hyperapoB to risk factors for type 2 diabetes independent of obesity in humans

BACKGROUND/OBJECTIVE: Plasma apoB predicts the incidence of type 2 diabetes (T2D); however, the link between apoB-linpoproteins and risks for T2D remain unclear. Insulin resistance (IR) and compensatory hyperinsulinemia characterize prediabetes, and the involvement of an activated interleukin-1 (IL-1) family, mainly IL-1β and its receptor antagonist (IL-Ra), is well documented. ApoB-lipoproteins were reported to promote IL-1β secretion in immune cells; however, in vivo evidence is lacking. We hypothesized that obese subjects with hyperapoB have an activated IL-1 system that explains hyperinsulinemia and IR in these subjects. SUBJECTS/METHODS: We examined 81 well-characterized normoglycemic men and postmenopausal women (⩾27 kg m(−2), 45–74 years, non-smokers, sedentary, free of chronic disease). Insulin secretion and sensitivity were measured by the gold-standard Botnia clamp, which is a combination of a 1-h intravenous glucose tolerance test (IVGTT) followed by 3-h hyperinsulinemic euglycemic clamp. RESULTS: Plasma IL-1β was near detection limit (0.071–0.216 pg ml(−1)), while IL-1Ra accumulated at 1000-folds higher (77–1068 pg ml(−1)). Plasma apoB (0.34–1.80 g l(−1)) associated significantly with hypersinsulinemia (total(IVGTT): C-peptide r=0.27, insulin r=0.22), IR (M/I=−0.29) and plasma IL-1Ra (r=0.26) but not with IL-1β. Plasma IL-1Ra associated with plasma IL-1β (r=0.40), and more strongly with hyperinsulinemia and IR than apoB, while the association of plasma IL-1β was limited to second phase and total insulin secretion (r=0.23). Adjusting the association of plasma apoB to hyperinsulinemia and IR for IL-1Ra eliminated these associations. Furthermore, despite equivalent body composition, subjects with hyperapoB (⩾80th percentile, 1.14 g l(−1)) had higher C-peptide secretion and lower insulin sensitivity than those with low plasma apoB (⩽20th percentile, 0.78 g l(−1)). Adjustment for plasma IL-1 Ra eliminated all group differences. CONCLUSION: Plasma apoB is associated with hyperinsulinemia and IR in normoglycemic obese subjects, which is eliminated upon adjustment for plasma IL-1Ra. This may implicate the IL-1 family in elevated risks for T2D in obese subjects with hyperapoB.