Hyperinsulinemia due to altered insulin secretion contributes to insulin resistance in chronic intermittent hypoxia independently of obesity

Clinical studies have demonstrated a link between obstructive sleep apnea (OSA) and insulin resistance (IR), however it is not clear which is the main event that determines IR development. We hypothesize that hyperinsulinemia is a main driver of IR in chronic intermittent hypoxia (CIH), that mimics OSA, independently of obesity, adipose tissue hypoxia and severity of CIH. Male Wistar Rats were submitted to 2 CIH protocols: 1) a mild CIH paradigm obtained by 5/6 hypoxic (5%O2) cycles/h, 10.5 h/day during 35 days; and 2) a severe CIH paradigm obtained by 40 s, 5%O2/80 s, air, equivalent to an apnoea–hypopnoea index of 30, 8h/day for 14 days. CIH animals were compared with controls. Fasting glycemia, insulinemia, C-peptide and insulin sensitivity through KITTand HOMA index were measured. Insulin clearance was calculated. Weight and fat mass were assessed. Adipose tissue dysfunction and inflammation were assessed by evaluation of several proteins involved in insulin signaling pathways and hypoxia and inflammation pathways. Mild CIH increased insulin secretion by 214% (CTLmildCIH =1.01±0.21ug/L) while severe CIH increased by 103% (CTLsevereCIH= 1.1±0.04ug/L) with no alterations in fasting glycemia in both CIH protocols. HOMA index increased by 112% in mild CIH and by 108% in severe CIH animals. None of CIH protocols alter weight gain and fat mass deposition. Mild and severe CIH increased IR in adipose tissue, with no changes in HIF1 and 2α expression. We can conclude that both mild and severe CIH protocols induce insulin resistance, which is associated with an increase insulin secretion by the pancreas being independent of obesity and fat mass.