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Obesity is associated with an imbalance in the activity of the autonomic nervous system (ANS), specifically in the organs involved in energy metabolism. The pancreatic islets are richly innervated by the ANS, which tunes the insulin release due to changes in energy demand. Therefore, changes in the sympathetic input that reach the pancreas can lead to metabolic dysfunctions. To evaluate the role of the sympathetic ends that innervate the pancreas, 60-day-old male Wistar rats were subjected to sympathectomy (SYM) or were sham-operated (SO). At 120 day-old SYM rats exhibited an increase in body weight, fat pads and metabolic dysfunctions. Decreases in the HOMA-IR and reductions in insulin release were observed both in vivo and in vitro . Furthermore, the SYM rats exhibited altered pancreatic islet function in both muscarinic and adrenergic assays and exhibited high protein expression of the alpha-2 adrenergic receptor (α2AR). Because α2AR has been linked to type 2 diabetes, these findings demonstrate the clinical implications of this study. [ABSTRACT FROM AUTHOR]

The cooperative effect of glucagon-like peptide 1 (GLP-1) and acetylcholine (ACh) was evaluated in a beta cell line model (BRIN BD11). GLP-1 (20 nM) and ACh (100 μM) increased insulin secretion by 24–47%, whereas in combination there was a further 89% enhancement of insulin release. Overnight culture with 100 ng/mL pertussis toxin (PTX) or 10 nM PMA significantly reduced the combined insulinotropic action (P<0.05 and P<0.001, respectively) and the sole stimulatory effects of GLP-1 (PTX treatment; P<0.01) or ACh (PMA treatment; P<0.05). Under control conditions, ACh (50 nM–1 mM) concentration-dependently inhibited by up to 40% (P<0.001) the 10-fold (P<0.001) elevation of cyclic 3′,5′-adenosine monophosphate (cAMP) induced by 20 nM GLP-1. The paradoxical inhibitory action of ACh was abolished by PTX pre-treatment, suggesting involvement of Gi and/or Go G protein alpha subunit. Effects of selective muscarinic receptor antagonists on the concentration-dependent insulinotropic actions of ACh (50 nM–1 mM) on 20 nM GLP-1 induced insulin secretion revealed inhibition by ρ-FHHSiD (M3 antagonist, P<0.05), stimulation with pirenzepine (M1 antagonist, P<0.001) and no significant effects of either methoctramine (M2 antagonist) or MT-3 (M4 antagonist). Antagonism of M2, M3 and M4 muscarinic receptor effects with methoctramine (3–100 nM), ρ-FHHSiD (3–30 nM) or MT-3 (10–300 nM) did not significantly affect the inhibitory action of ACh on GLP-1 stimulated cAMP production. In contrast, M1 receptor antagonism with pirenzepine (3–300 nM) resulted in a concentration-dependent decrease in the inhibitory action of ACh on GLP-1 stimulated cAMP production (P<0.001). These data indicate an important functional cooperation between the cholinergic neurotransmitter ACh and the incretin hormone GLP-1 on insulin secretion mediated through the M3 muscarinic receptor subtype. However, the insulinotropic action of ACh was associated with a paradoxical inhibitory effect on GLP-1 stimulated cAMP production, achieved through a novel PTX- and pirenzepine-sensitive M1 muscarinic receptor activated pathway. An imbalance between these pathways may contribute to dysfunctional insulin secretion. [Copyright &y& Elsevier]