Intranasal insulin suppresses systemic but not subcutaneous lipolysis in healthy humans

Abstract

Context: Insulin infused into the central nervous system of rats suppresses lipolysis in white adipose tissue, indicating a role of brain insulin in regulating systemic lipid metabolism.

Objective: We investigated whether central nervous insulin delivery suppresses lipolysis in healthy humans.

Design: Placebo-controlled, balanced within-subject comparisons were performed in both a main and an independent corroborative experiment. SETTING/PARTICIPANTS/INTERVENTION: Two groups of healthy volunteers were examined at the German University Clinics of Lübeck and Tübingen, respectively, with molecular analyses taking place at Mt Sinai School of Medicine (New York, New York). The 14 healthy male subjects of the main study and the 22 women and 5 men of the corroborative study each received 160 IU of human insulin intranasally.

Main outcome measures: In the main study, we measured systemic levels of free fatty acids (FFAs), triglycerides, and glycerol and the rate of appearance of deuterated glycerol as an estimate of lipolysis before and after intranasal insulin administration. We also analyzed the expression of key lipolytic enzymes in sc fat biopsies and measured blood glucose and glucoregulatory hormones. In the corroborative study, FFA concentrations were assessed before and after intranasal insulin administration.

Results: In the main experiment, intranasal insulin suppressed circulating FFA concentrations and lipolysis (rate of appearance of deuterated glycerol) in the absence of significant changes in circulating insulin levels. Lipolytic protein expression in sc adipose tissue was not affected. The corroborative study confirmed that intranasal insulin lowers systemic FFA concentrations.

Conclusions: Our findings indicate that brain insulin controls systemic lipolysis in healthy humans by predominantly acting on non-sc adipose tissue.

Figure 1.

Design of the main study and key results. A, At 8:00 am, an infusion of d-[1,1,2,3,3–2H5]glycerol and microdialysis started. Baseline blood sampling took place at 7:45 am, 9:15 am, and 9:45 am for blood glucose, C-peptide, and insulin, and at 9:15 am and 9:45 am for all other blood parameters along with one baseline collection of sc adipose tissue via biopsy at 9:15 am. Intranasal insulin (160 IU) or vehicle was administered from 9:45–10:00 am (t = 0; nose symbol) and posttreatment measurements followed as depicted. Serum concentrations of FFAs (B) and triglycerides (C) (both n=14), Ra glycerol (n=12) (D), free glycerol in serum (n=14) (E), and glycerol in sc adipose tissue as assessed by microdialysis (n=10) (F) measured before (baseline, averaged across pretreatment measurements) and after intranasal administration of insulin (black dots and solid lines) and placebo (white dots and dashed lines), respectively are shown. Mean baseline values of both conditions are averaged to a common baseline. **, P < .01, *, P < .05 for comparisons of AUC_0–60min between conditions (pairwise t tests). Activation state of Hsl as assessed by Western blot analyses using phospho-specific antibodies detecting the activating phosphorylation sites Ser563 (G) and Ser660 (H) in sc adipose tissue biopsied 30 minutes before (baseline) and 180 minutes after intranasal administration of placebo (white bars) and insulin (black bars) is also shown. Data are expressed as fold change compared with baseline values of placebo-treated individuals and are normalized to β-actin. I, Individual treatment effects (expressed as difference between the insulin and the placebo condition) on Ra glycerol (AUC_0–60min) plotted against the respective effects on serum insulin concentrations, indicating statistical independence of both effects (n = 12, r = 0.20, P > .54). J, Corroborative study. Plasma concentrations of FFAs (left) and insulin (right) expressed as AUC_0–60min after intranasal administration of placebo (white bars) and 160 IU insulin (black bars), respectively, adjusted for sex. *, P < .03 for comparison between conditions (pairwise t test). Note that the difference in FFA concentrations was also significant after adjustment for age and BMI (P < .05) and plasma insulin (AUC_{0–60 min}; P < .02).