Effect of intranasal insulin on peripheral glucose profile in dexamethasone-induced insulin resistance in Wistar rats

Abstract

This study evaluates the therapeutic potential of intranasal insulin (INI) in dexamethasone-induced insulin resistance in Wistar rats. In the first phase of the study, thirteen, healthy, untreated male Wistar rats were divided into 2 groups and administered either vehicle (0.9% Normal saline, 20 µl) or insulin (2 IU) intranasally to assess intranasal delivery of insulin in brain. In the second phase of experiments, to evaluate the acute effects of intranasal insulin on peripheral blood glucose, intranasal or intraperitoneal insulin was co-administered with or without dexamethasone 10 mg/kg to 26 male Wistar rats and blood glucose monitored. To evaluate effect of intranasal insulin in peripheral metabolic disease model, insulin or vehicle was administered via intranasal or intraperitoneal (IP) route to control or dexamethasone (Dex)-treated (0.5 mg/kg, IP) female Wistar rats for seven consecutive days. Twenty-four hours after last dose, trunk blood was collected via cardiac puncture. Biochemical assay of glucose, lipid and insulin was performed on serum while enzyme activity – glucokinase and glucose-6-phosphatase (G6Pase) or lactate dehydrogenase (LDH) and glucose-6-phosphate dehydrogenase (G6PDH) were assayed from liver and brain homogenates respectively. Acute intranasal but not intraperitoneal insulin elevated brain insulin after 30 min. In animals administered single dose of 10 mg/kg dexamethasone, intranasal and intraperitoneal insulin lowered blood glucose within one hour. However, only the former’s effect was maintained at the 3rd and fourth hour. Dex-induced hyperglycemia was associated with increased hepatic glucose-6-phosphatase activity and decreased high-density lipoprotein (HDL), these effect were attenuated by subchronic (INI) administration. Also INI did not induce oxidative stress in the brain which suggests no brain damage during the period of study. Subchronic administration of INI was able to reduce the effect of Dex-induced hyperglycemia that is associated with increased hepatic glucose-6-phosphatase activity and decreased high-density lipoprotein (HDL) without damage to the brain. We demonstrate the potential of brain targeting with intranasal insulin in a rat model of insulin resistance and peripheral metabolic disease. Keywords: Intranasal insulin, Dexamethasone, Hepatic glucose, Hyperglycemia