Heni et al. (1) published an article in Diabetes demonstrating an increase in whole-body insulin sensitivity (measured as change in glucose infusion rate [GIR] during low-dose hyperinsulinemic-euglycemic clamp) following intranasal insulin application in lean men. This was accompanied by an increase in parasympathetic nervous system activity and hypothalamic blood flow (measured by functional magnetic resonance imaging). Interestingly, obese men did not have an increase in GIR after intranasal insulin. The authors hypothesized that obese men have “brain insulin resistance” and that impaired brain outputs contribute to the pathogenesis of whole-body insulin resistance in obesity. However, the data depicted in Fig. 3 (relation between change in GIR and change in parasympathetic nervous system activity) and Fig. 4 (relation between change in GIR and change in hypothalamic blood flow) show that obese men had similar responses in these two parameters as compared with lean men. Thus, it follows that while the neurons of lean and obese men respond normally to intranasal insulin application, the peripheral insulin-responsive tissues (mainly muscle, liver, and fat) of obese men do not respond to the “brain outputs.” Intranasal insulin suppresses free fatty acid concentrations in healthy subjects but not in those with type 2 diabetes (2). This may account for the increase in insulin sensitivity after intranasal insulin in lean men. Measurement of free fatty acid concentrations of lean and obese men in the study by Heni et al. (1) might have been informative.
Prior studies have shown that intranasal insulin leads to improvements in cerebral perfusion, brain functional connectivity, memory, and mood and leads to decreases in adrenocorticotropic hormone concentrations similarly in lean and obese subjects (3,4). One can hypothesize that intranasal insulin is able to stimulate the neurons of obese subjects, but neuronal outputs do not result in the peripheral effects, such as suppression of lipolysis, hepatocellular fat content, insulin sensitization, and weight loss (2,3). Alternately, it is possible that the neurons of obese subjects are resistant to intranasal insulin in some aspects, but we need data to support that notion. Forthcoming studies in this field will undoubtedly clarify these concepts.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.