Intranasal insulin: From nose to brain

BackgroundIntranasal insulin has proven useful to control hyperglycemia in diabetics but its mechanism of action has not been well defined. We attempted to understand several aspects of human insulin metabolism by measurement of and interaction of insulin and its associated moieties in nasal mucus, saliva and blood plasma under various physiological and pathological conditions.MethodsInsulin, insulin receptors, insulin-like growth factor 1 (IGF1) and insulin-like growth receptor 3 (IGFR3) were measured in nasal mucus, saliva and blood plasma in normal subjects, in thin and obese subjects and in diabetics under fasting and fed conditions.ResultsThere are complex relationships among each of these moieties in each biological fluid. Insulin and its associated moieties are present in both nasal mucus and saliva. These moieties in nasal mucus and saliva report on physiological and pathological changes in glucose metabolism as do these moieties in plasma. Indeed, insulin and its associated moieties in nasal mucus may offer specific data on how insulin enters the brain and thereby play essential roles in control of insulin metabolism.InterpretationThese data support the concept that insulin is synthesized not only in parotid glands but also in nasal serous glands. They also support the concept that insulin enters the brain following intranasal administration either 1) by direct entry through the cribriform plate, along the olfactory nerves and into brain parenchyma, 2) by entry through specific receptors in blood-brain barrier and thereby into the brain or 3) some combination of 1) and 2). Conversely, data also show that insulin introduced directly into the brain is secreted out of brain into the peripheral circulation. Data in this study demonstrate for the first time that insulin and its associated moieties are present not only in saliva but also in nasal mucus. How these complex relationships among nasal mucus, saliva and plasma occur are unclear but results demonstrate these relationships play separate yet interrelated roles in physiology and pathology of human insulin metabolism.