The role of efferent cholinergic transmission for the insulinotropic and glucagonostatic effects of GLP-1

TY - JOUR

T1 - The role of efferent cholinergic transmission for the insulinotropic and glucagonostatic effects of GLP-1

AU - Plamboeck, Astrid

AU - Veedfald, Simon

AU - Deacon, Carolyn F

AU - Hartmann, Bolette

AU - Vilsbøll, Tina

AU - Knop, Filip K

AU - Holst, Jens J

N1 - Copyright © 2015 the American Physiological Society.

PY - 2015/9/3

Y1 - 2015/9/3

N2 - The importance of vagal efferent signaling for the insulinotropic and glucagonostatic effects of glucagon-like peptide-1 (GLP-1) was investigated in a randomized single-blinded study. Healthy male participants (n = 10) received atropine to block vagal cholinergic transmission or saline infusions on separate occasions. At t =15 min, plasma glucose was clamped at 6 mmol/l. GLP-1 was infused at a low dose (0.3 pmol·kg-1·min-1) from t = 45-95 min and at a higher dose (1 pmol·kg-1·min-1) from t = 95-145 min. Atropine blocked muscarinic, cholinergic transmission, as evidenced by an increase in heart rate [peak: 70 ± 2 (saline) vs. 90 ± 2 (atropine) beats/min, P < 0.002] and suppression of pancreatic polypeptide levels [area under the curve during the GLP-1 infusions (AUC45-145): 492 ± 85 (saline) vs. 247 ± 59 (atropine) pmol/l × min, P < 0.0001]. More glucose was needed to maintain the clamp during the high-dose GLP-1 infusion steadystate period on the atropine day [6.4 ± 0.9 (saline) vs. 8.7 ± 0.8 (atropine) mg·kg-1·min-1, P < 0.0023]. GLP-1 dose-dependently increased insulin secretion on both days. The insulinotropic effect of GLP-1 was not impaired by atropine [C-peptide AUCs45-145: 99 ± 8 (saline) vs. 113 ± 13 (atropine) nmol/l × min, P = 0.19]. Atropine suppressed glucagon levels additively with GLP-1 [AUC45-145: 469 ± 70 (saline) vs. 265 ± 50 (atropine) pmol/l × min, P = 0.018], resulting in hypoglycemia when infusions were suspended [3.6 ± 0.2 (saline) vs. 2.7 ± 0.2 (atropine) mmol/l, P < 0.0001]. To ascertain whether atropine could independently suppress glucagon levels, control experiments (n = 5) were carried out without GLP-1 infusions [AUC45-145: 558 ± 103 (saline) vs. 382 ± 76 (atropine) pmol/l × min, P = 0.06]. Our results suggest that efferent muscarinic activity is not required for the insulinotropic effect of exogenous GLP-1 but that blocking efferent muscarinic activity independently suppresses glucagon secretion. In combination, GLP-1 and muscarinic blockade strongly affect glucose turnover.

AB - The importance of vagal efferent signaling for the insulinotropic and glucagonostatic effects of glucagon-like peptide-1 (GLP-1) was investigated in a randomized single-blinded study. Healthy male participants (n = 10) received atropine to block vagal cholinergic transmission or saline infusions on separate occasions. At t =15 min, plasma glucose was clamped at 6 mmol/l. GLP-1 was infused at a low dose (0.3 pmol·kg-1·min-1) from t = 45-95 min and at a higher dose (1 pmol·kg-1·min-1) from t = 95-145 min. Atropine blocked muscarinic, cholinergic transmission, as evidenced by an increase in heart rate [peak: 70 ± 2 (saline) vs. 90 ± 2 (atropine) beats/min, P < 0.002] and suppression of pancreatic polypeptide levels [area under the curve during the GLP-1 infusions (AUC45-145): 492 ± 85 (saline) vs. 247 ± 59 (atropine) pmol/l × min, P < 0.0001]. More glucose was needed to maintain the clamp during the high-dose GLP-1 infusion steadystate period on the atropine day [6.4 ± 0.9 (saline) vs. 8.7 ± 0.8 (atropine) mg·kg-1·min-1, P < 0.0023]. GLP-1 dose-dependently increased insulin secretion on both days. The insulinotropic effect of GLP-1 was not impaired by atropine [C-peptide AUCs45-145: 99 ± 8 (saline) vs. 113 ± 13 (atropine) nmol/l × min, P = 0.19]. Atropine suppressed glucagon levels additively with GLP-1 [AUC45-145: 469 ± 70 (saline) vs. 265 ± 50 (atropine) pmol/l × min, P = 0.018], resulting in hypoglycemia when infusions were suspended [3.6 ± 0.2 (saline) vs. 2.7 ± 0.2 (atropine) mmol/l, P < 0.0001]. To ascertain whether atropine could independently suppress glucagon levels, control experiments (n = 5) were carried out without GLP-1 infusions [AUC45-145: 558 ± 103 (saline) vs. 382 ± 76 (atropine) pmol/l × min, P = 0.06]. Our results suggest that efferent muscarinic activity is not required for the insulinotropic effect of exogenous GLP-1 but that blocking efferent muscarinic activity independently suppresses glucagon secretion. In combination, GLP-1 and muscarinic blockade strongly affect glucose turnover.

U2 - 10.1152/ajpregu.00123.2015

DO - 10.1152/ajpregu.00123.2015

M3 - Journal article

C2 - 26136531

SN - 0363-6119

VL - 309

SP - R544-51

JO - American Journal of Physiology: Regulatory, Integrative and Comparative Physiology

JF - American Journal of Physiology: Regulatory, Integrative and Comparative Physiology

IS - 5

ER -