A quarter of men with obesity or type 2 diabetes have hypogonadotropic hypogonadism. Animal studies and in vitro data have shown that insulin action and insulin responsiveness in the brain are necessary for the maintenance of the functional integrity of the hypothalamo-hypophyseal-gonadal axis. We conducted a randomized, placebo-controlled trial to evaluate the effect of one dose of intranasal insulin (40 IU of regular insulin) or saline on LH concentrations in 14 men (8 with type 2 diabetes and 6 healthy lean men). Insulin or saline was administered intranasally on two different occasions, at least one week apart. Blood samples were collected to measure LH concentrations every 15 minutes for 5 hours. Study drug was administered intranasally after a 2-hour baseline sampling period. Patients remained fasting throughout the procedure. The primary endpoint of the study was to compare the change in LH concentrations after intranasal insulin as compared to placebo (intranasal saline). Change was defined as the difference between baseline LH concentrations (average of the 9 samples collected in two hours prior to drug administration) and average LH concentrations following drug administration (average of the 12 samples collected in 3 hours). There was no change in LH concentrations following insulin administration as compared to placebo in men with diabetes or in lean men. We conclude that one dose of 40 IU of regular insulin administered intranasally does not change LH concentrations acutely in men.

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 insulinresponsive 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.

Recurrent pleural effusions are associated with significant morbidity and mortality. Drug-related reactions causing pleural effusions are not common, but their identification can potentially improve patient outcome. Minoxidil has been implicated in pleuropericardial effusions in patients with chronic kidney disease. The exact mechanism by which pleural effusion occurs is still unclear. We report a case of isolated exudative pleural effusion associated with minoxidil in a patient without underlying kidney disease that almost completely resolved after the drug was discontinued.