Intranasal Insulin Enhances Postprandial Thermogenesis and Lowers Postprandial Serum Insulin Levels in Healthy Men

Abstract

OBJECTIVEAnimal studies indicate a prominent role of brain insulin signaling in the regulation of peripheral energy metabolism. We determined the effect of intranasal insulin, which directly targets the brain, on glucose metabolism and energy expenditure in humans.RESEARCH DESIGN AND METHODSIn a double-blind, placebo-controlled, balanced within-subject comparison, 19 healthy normal-weight men (18–26 years old) were intranasally administered 160 IU human insulin after an overnight fast. Energy expenditure assessed via indirect calorimetry and blood concentrations of glucose, insulin, C-peptide, and free fatty acids (FFAs) were measured before and after insulin administration and the subsequent consumption of a high-calorie liquid meal of 900 kcal.RESULTSIntranasal insulin, compared with placebo, increased postprandial energy expenditure, i.e., diet-induced thermogenesis, and decreased postprandial concentrations of circulating insulin and C-peptide, whereas postprandial plasma glucose concentrations did not differ from placebo values. Intranasal insulin also induced a transient decrease in prandial serum FFA levels.CONCLUSIONSEnhancing brain insulin signaling by means of intranasal insulin administration enhances the acute thermoregulatory and glucoregulatory response to food intake, suggesting that central nervous insulin contributes to the control of whole-body energy homeostasis in humans.

Nasal insulin changes peripheral insulin sensitivity simultaneously with altered activity in homeostatic and reward-related human brain regions

“…Starting at 60 min post-spray, insulin sensitivity was even better after intranasal insulin than it was after placebo. Thus, in the long run, central insulin action seems to promote insulin's actions in the periphery, a finding that is consistent with a recent report [21]. In that study, nasal insulin was administered more than 1 h before participants drank a liquid high-energy meal.…”

“…No increase in plasma insulin was accompanied by a decrease in C-peptide. The absorption of small amounts of nasally delivered insulin into the peripheral circulation was not unexpected, having been noted in other studies [11,15,21]. A transient 20 % increase in plasma insulin as observed in our study at 30 min should be biologically active [22,23], regardless of whether it is of endogenous or exogenous origin.…”

Intranasal insulin administration does not modulate incretin secretion, gastric emptying, and appetite in healthy young adults

“…Benedict et al demonstrated that preprandial intranasal INS administration reduced postprandial serum INS and C-peptide levels [19]. In studies with rats, it has been reported that INS infusion into the cerebral ventricle directly inhibited hepatic gluconeogenesis via the brain-liver axis mediated by the vagal nerve [7,8] hepatic INS sensitivity and resulted in marked increases in hepatic glucose production compared with control animals, although they had similar blood INS levels [28].…”

“…INS and PL were administered using a plastic nasal pump spray bottle (AS ONE Co., Osaka, Japan) that fills the nasal cavity with aerosol, enabling the solution to effectively target the olfactory epithelium. The dose of intranasal INS administration used here has been shown effective in stimulating INS receptors in the CNS without affecting peripheral blood INS levels in healthy humans [12,[18][19][20].…”

Maternal insulin sensitivity is associated with oral glucose-induced changes in fetal brain activity

“…Recently it has been suggested that changes in insulin action in the brain not only affect the regulation of appetite and body weight but are also crucial in controlling glucose metabolism [1][2][3]. There is evidence in humans that brain insulin resistance is not the consequence of peripheral metabolic changes but may itself contribute to the development of diabetes and obesity [4][5][6]. By recording brain activity with magnetoencephalography during a euglycaemichyperinsulinaemic stepwise clamp, we showed in adult humans that obesity, peripheral insulin resistance, age and genetic background are all associated with impaired central insulin sensitivity [7,8].…”