Effect of intranasal insulin on osteocalcin levels and postoperative delirium in elderly patients undergoing joint replacement

Abstract Background Recently, intranasal insulin has shown great promise in preventing perioperative neurocognitive disorders through ameliorating insulin sensitivity and cognitive function. Whether osteocalcin, as a bone-derived hormone that can directly regulate insulin sensitivity and cognitive function, is linked to the mechanism of intranasal insulin remains ill-defined. Aims To explore the effect of intranasal insulin on osteocalcin levels and the incidence and severity of postoperative delirium (POD) in elderly patients undergoing joint replacement. Methods The study is designed as a randomized, double-blind, placebo-controlled clinical study. 212 elderly patients (≥65) were randomly assigned to receive either twice 40 IU insulin (n=106) or placebo (n=106). The incidence and severity of POD were estimated by the Confusion Assessment Method (CAM) and the Delirium Rating Scale (DRS)-98. The levels of total osteocalcin (tOC), uncarboxylated osteocalcin (ucOC), insulin and glucose in venous blood and cerebrospinal fluid were detected by Enzyme-linked immunosorbent assay (ELISA). Insulin sensitivity was assessed by Homeostasis model Assessment of Insulin Resistance (HOMA-IR). The primary objective was to compare the difference of osteocalcin levels and insulin sensitivity between two groups, with the secondary objective to compare the difference of POD incidence and severity. Main Results It showed that 8 patients (8.33%) occurred POD in insulin group within 5 days after surgery, significantly fewer than 23 patients (23.23%) in placebo group (P=0.004). Mean peak DRS in insulin group was significantly lower than that in placebo group (P<0.001). After intranasal insulin intervention of 3 days, levels of tOC and ucOC in cerebrospinal fluid were significantly elevated in insulin group at D 0 (all P<0.001). Levels of tOC in plasma were significantly higher in insulin group than that in placebo group on D 0 , D 1 and D 3 (all P<0.001). Plasma ucOC level in insulin group was higher on D 0 , but lower on D 1 and D 3 than placebo group (all P<0.001). HOMA-IR was significantly lower on D 3 in insulin group than placebo group (P=0.002). Conclusions Intranasal insulin notably reduced the incidence and severity of POD in elderly patients undergoing joint replacement, and alco significantly improved central and peripheral osteocalcin levels and peripheral insulin sensitivity. Though these preliminary results needed further confirmation, it suggested that osteocalcin was promisingly involved in the mechanism of intranasal insulin in improving insulin sensitivity and POD. Trial registry numbers Chinese Clinical Trial Registry (ChiCTR2300068073) Highlights It is the first time of our study to find the remarkable elevated effect of intranasal insulin on peripheral and central osteocalcin. Besides, intranasal insulin showed a significantly reduction in the incidence and severity of postoperative delirium in elderly patients undergoing joint replacement, as well as an amelioration in insulin sensitivity. Considering the positive role of osteocalcin played in insulin secretion and brain function maintenance, our findings may suggest that the improvements of peripheral insulin sensitivity and decrease of postoperative delirium are probably associated with elevated peripheral and central osteocalcin levels. Though further studies are needed to confirm, it suggested that osteocalcin is a promising biomarker that involves in the effect of intranasal insulin both in improving peripheral metabolism and central cognition.