Sympathetic inhibition attenuates hypoxia induced insulin resistance in healthy adult humans

Abstract

Acute exposure to hypoxia decreases insulin sensitivity in healthy adult humans; the mechanism is unclear, but increased activation of the sympathetic nervous system may be involved. We have investigated the hypothesis that short-term sympathetic inhibition attenuates hypoxia induced insulin resistance. Insulin sensitivity (via the hyperinsulinaemic euglycaemic clamp) was determined in 10 healthy men (age 23 ± 1 years, body mass index 24.2 ± 0.8 kg m⁻² (means ± SEM)), in a random order, during normoxia (FIO₂ =0.21), hypoxia (FIO₂ =0.11), normoxia and sympathetic inhibition (via 48 h transdermal administration of the centrally acting α2-adrenergic receptor agonist, clonidine), and hypoxia and sympathetic inhibition.Oxyhaemoglobin saturation (pulse oximetry) was decreased (P<0.001) with hypoxia (63 ± 2%) compared with normoxia (96 ± 0%), and was unaffected by sympathetic inhibition (P>0.25). The area under the noradrenaline curve (relative to the normoxia response) was increased with hypoxia (137 ± 13%; P =0.02); clonidine prevented the hypoxia induced increase (94 ± 14%; P =0.43). The glucose infusion rate (adjusted for fat free mass and circulating insulin concentration) required to maintain blood glucose concentration at 5 mmol l⁻¹ during administration of insulin was decreased in hypoxia compared with normoxia (225 ± 23 vs. 128 ± 30 nmol (kg fat free mass)⁻¹ pmol l⁻¹ min⁻¹; P =0.03), and unchanged during normoxia and sympathetic inhibition (219 ± 19; P =0.86) and hypoxia and sympathetic inhibition (169 ± 23; P =0.23). We conclude that short-term sympathetic inhibition attenuates hypoxia induced insulin resistance.

Figure 1. Oxyhaemoglobin saturation (via pulse oximetery) prior to (−15 min) and during (0–180 min) normoxia ( = 0.21) and hypoxia ( = 0.11), with and without sympathetic inhibition (48 h transdermal clonidine), during measurement of insulin sensitivity via the hyperinsulinaemic euglycaemic clamp

Hypoxic gas breathing appreciably decreased oxyhaemoglobin saturation (P < 0.01) compared with normoxia. Oxyhaemoglobin saturation was unaffected by clonidine (P > 0.25). Data are means ± SEM.

Figure 2. Plasma adrenaline (upper panel) and noradrenaline (lower panel) prior to (−15 min) and during (0–180 min) normoxia ( = 0.21) and hypoxia ( = 0.11), with and without sympathetic inhibition (48 h transdermal clonidine), during measurement of insulin sensitivity via the hyperinsulinaemic euglycaemic clamp

The area under the noradrenaline curve (relative to the normoxia response) was increased with hypoxia (137 ± 13%; P = 0.02); clonidine prevented the hypoxia induced increase (94 ± 14%; P = 0.43). The area under the adrenaline curve (relative to the normoxia response) was appreciably increased in hypoxia (371 ± 40%; P < 0.001). Clonidine did not affect the hypoxia induced increase in adrenaline (346 ± 82%; P < 0.001). Data are means ± SEM.

Figure 3. The rate of intravenous glucose administration (adjusted for fat free mass and circulating insulin concentration) required to maintain blood glucose concentration at 5 mmol l⁻¹ during standardized intravenous insulin administration during normoxia ( = 0.21) and hypoxia ( = 0.11), with and without sympathetic inhibition (48 h transdermal clonidine)

Data are means ± SEM. *Difference from normoxia without clonidine (P < 0.05). GIR: glucose infusion rate.

Figure 4. Plasma concentrations of factors known to influence insulin sensitivity that are partially regulated by hypoxia prior to (−15 min) and during (0 and 180 min) normoxia ( = 0.21) and hypoxia ( = 0.11), with and without sympathetic inhibition (48 h transdermal clonidine), during measurement of insulin sensitivity via the hyperinsulinaemic euglycaemic clamp

Data are means ± SEM. P values reflect interaction between time, and clonidine. NEFA: non-esterified fatty acids. PEDF: pigment epithelium derived factor. LDL: low density lipoprotein. TNFα: tumour necrosis factor α.